Update Journal – Endocrinology and Diabetology

Patients with type 2 diabetes should expect more after metformin

Once-weekly type 2 diabetes and superior

ENDOCRINOLOGY AND DIABETOLOGY

CLINICAL ARTICLES ON:

More than double the weight

prescribing. in pre-filled pen. Ozempic semaglutide (human glucagontreatment of adults with insufficiently when metformin is considered products for the treatment of and cardiovascular events, and Posology and administration: subcutaneously in the abdomen, be increased to 0.5 mg once increased to 1 mg once weekly insulin, a reduction in dose of Blood glucose self-monitoring is started and insulin is reduced. dose adjustment is required with severe renal impairment is impairment: impairment is limited. Caution

Contraindications: for use:

Not a substitute for insulin. rapid discontinuation or dose NYHA class IV and is therefore with gastrointestinal adverse function as nausea, vomiting, and Acute pancreatitis has been the characteristic symptoms

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mellitus as an adjunct to diet and exercise • as monotherapy when metformin is considered inappropriate due combinations, effects on glycaemic control and cardiovascular events and the populations studied, see sections 4.4, 4.5 SUSTAIN = Semaglutide Unabated across SUSTAIN trials, which included placebo, sitagliptin, dulaglutide, risk (CV death, nonfatal myocardial infarction [MI] or nonfatal stroke) versus placebo in patients with type 2 diabetes When added to standard of care, which included oral antidiabetic treatments, insulin, antihypertensives,

Diabetic foot disease, PCOS, and continuous glucose monitoring technology and service provision at the National Gender Service

of acute pancreatitis. If pancreatitis is suspected, semaglutide should should not be restarted. Caution should be exercised in patients with combination with a sulfonylurea or insulin may have an increased the dose of sulfonylurea or insulin when initiating treatment with treated with insulin and semaglutide, an increased risk of developing observed. Caution should be exercised when using semaglutide in insulin. These patients should be monitored closely and treated according in glucose control has been associated with a temporary worsening cannot be excluded. When semaglutide is used in combination with advised to take precautions to avoid hypoglycaemia while driving Women of childbearing potential are recommended to Should not be used during pregnancy or breast-feeding. Discontinue

Very common (≥1/10); Hypoglycaemia medications, decreased appetite, dizziness, diabetic retinopathy complications, distension, constipation, dyspepsia, gastritis, gastro-oesophageal reflux

Rare:

The Summary of Product Characteristics should be consulted for a 0.5 mg pre-filled filled pen EU/1/17/1251/005. Each pre-filled pen delivers 4 doses and POM. For complete prescribing information, please which is available on www.medicines.ie or by email from infoireland@novonordisk.com and Regulatory Department, Novo Nordisk Limited, 1st Floor, Block Pratley RE Semaglutide versus dulaglutide once-weekly in patients with type 2 diabetes (SUSTAIN al. 2016;375:1834-1844.

This medicinal product is subject to additional monitoring. safety information. Healthcare Professionals are asked to the Health Products Regulatory Authority. Information about www.hpra.ie. Adverse events should also be reported to Novo

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Once weekly Semaglutide vs Canagliflozin safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulf multinational, phase 3a trial. Efficacy and safety placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, medical care in diabetes—2018.

Engl J Med.

Metformin use in pregnancy, and a promising new biomarker for improved diagnosis of GDM and prediction of adverse pregnancy outcomes

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Prescribing Information:

For the treatment of diabetes mellitus in adults, adolescents and children from the age of 6 years1 ®

Toujeo (insulin glargine 300 units/ml)

Please refer to Summary of Product Characteristics (SmPC) before prescribing.

Presentation: Toujeo SoloStar and DoubleStar pre-filled pens. Each ml contains 300 units of insulin glargine. SoloStar pen contains 1.5ml (450 units) of solution for injection. DoubleStar pen contains 3ml (900 units) of solution for injection.

Indication: Treatment of diabetes mellitus in adults, adolescents and children from the age of 6 years. Dosage and

Administration: Toujeo is administered subcutaneously, by injection into the abdominal wall, the deltoid or the thigh, once daily, at any time of the day, preferably at the same time every day. Injection sites must be rotated within a given injection area from one injection to the next in order to reduce the risk of lipodystrophy and cutaneous amyloidosis. The dose regimen (dose and timing) should be adjusted according to individual response. Do not administer intravenously. In type 1 diabetes mellitus, Toujeo must be combined with short-/rapid-acting insulin to cover mealtime insulin requirements. In patients with type 2 diabetes mellitus, recommended daily starting dose is 0.2 units/kg followed by individual dose adjustments. Toujeo can also be given together with other anti-hyperglycaemic medicinal products. Switch between insulin glargine 100 units/ ml and Toujeo: Insulin glargine 100 units/ml and Toujeo are not bioequivalent and are not directly interchangeable. When switching from insulin glargine 100 units/ml to Toujeo, this can be done on a unit to unit basis, but a higher Toujeo dose (approximately 10-18%) may be needed to achieve target ranges for plasma glucose levels. When switching from Toujeo to insulin glargine 100 units/ml, the dose should be reduced (approximately by 20%). Switching from other basal insulins to Toujeo: A change of dose and/or timing of the basal insulin and concomitant anti hyperglycaemic treatment may be required. Dose adjustments may also be required if the patient’s weight or lifestyle changes, the timing of insulin dose is changed or other circumstances arise that increase susceptibility to hypo- or hyperglycaemia. Toujeo must not be mixed or diluted with any other insulin or other medicinal products. Close metabolic monitoring is recommended during a switch and in the initial weeks thereafter. SoloStar 1-80 units per single injection in steps of 1 unit and DoubleStar 2-160 units in steps of 2 units. When changing from Toujeo SoloStar to Toujeo DoubleStar, if the patient’s previous dose was an odd number then the dose must be increased or decreased by 1 unit. Toujeo DoubleStar prefilled pen is recommended for patients requiring at least 20 units per day. Special Populations: Insulin requirements may be diminished in the elderly or patients with renal or hepatic impairment. Paediatric: When switching basal insulin to Toujeo, dose reduction of basal and bolus insulin needs to be considered on an individual basis, in order to minimise the risk of hypoglycaemia. The safety and efficacy of Toujeo in children and adolescents below 6 years of age have not been established. Contraindications: Hypersensitivity to insulin glargine or any excipients. Precautions and Warnings: Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Toujeo is not the insulin of choice for treatment of diabetic ketoacidosis. Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden change in the injection site to an

References: 1. Toujeo® Summary of Product Characteristics

Date of preparation: September 2020 | MAT-IE-2001062 (v1.0)

unaffected area has been reported to result in hypoglycaemia. Blood glucose monitoring is recommended after the change in the injection site, and dose adjustment of antidiabetic medications may be considered. Hypoglycaemia: In case of insufficient glucose control or a tendency to hyper/hypoglycaemic episodes, the patient’s adherence to the prescribed treatment regimen, injection sites and proper injection technique and all other relevant factors must be reviewed before dose adjustment is considered. Particular caution should be exercised, and intensified blood glucose monitoring is advisable for patients in whom hypoglycaemic episodes might be of clinical relevance and in those where dose adjustments may be required. Warning signs of hypoglycaemia may be changed, less pronounced or absent in certain risk groups, potentially resulting in severe hypoglycaemia and loss of consciousness. Risk groups include patients in whom glycaemic control is markedly improved, hypoglycaemia develops gradually, an autonomic neuropathy is present, or who are elderly. The prolonged effect of subcutaneous insulin glargine may delay recovery from hypoglycaemia. Intercurrent illness: Requires intensified metabolic monitoring and often it is necessary to adjust the insulin dose. Insulin antibodies: administration may cause insulin antibodies to form. Use with pioglitazone: Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs. Medication errors: Insulin labels must always be checked before each injection to avoid errors between Toujeo and other insulins. Patients must be instructed to never use a syringe to remove Toujeo from the SoloStar or DoubleStar pre-filled pen, A new sterile needle must be attached before each injection. Needles must not be re-used. Pregnancy and lactation: There is no data from exposed pregnancies in controlled clinical trials. However, there is a large amount of data on use of insulin glargine 100 units/ml in pregnant women indicating no specific adverse effects on pregnancy and no specific malformative nor feto/neonatal toxicity. The use of Toujeo may be considered during pregnancy, if clinically needed. Careful monitoring of glucose control is essential. It is unknown if insulin glargine is excreted in breast milk. Interactions: Substances that affect glucose metabolism may require adjustment of insulin glargine. Adverse Reactions: Very common: Hypoglycaemia. Prolonged or severe hypoglycaemia may be life-threatening. Common: Lipohypertrophy, injection site reactions, including redness, pain, itching, hives, swelling, or inflammation. Legal Category: POM. Marketing Authorisation Number: SoloStar 3 Pen pack: EU/1/00/133/034, DoubleStar EU/1/00/133/038. Marketing Authorisation Holder: Sanofi Aventis Deutschland GmbH, D-65926 Frankfurt am Main, Germany. Further information is available from: Medical Information, Sanofi 18 Riverwalk, Citywest Business Campus, Dublin 24 or contact IEmedinfo@sanofi.com. Date of preparation: July 2020.

Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie; email: medsafety@hpra.ie Adverse events should also be reported to Sanofi Ireland Ltd. Tel: 01 403 5600. Alternatively, send via email to IEPharmacovigilance@sanofi.com

Furthering knowledge in diabetes care

A message from Priscilla Lynch, Editor

Welcome to the latest edition of Update Endocrinology and Diabetology.

As health services continue to grapple with providing care in the ‘new normal’ caused by the Covid-19 pandemic, there remains concern about missed opportunities and early warning signs being ignored in people with chronic diseases such as diabetes.

The effects of the pandemic on type 1 diabetes (T1D) and type 2 diabetes (T2D) were very different, according to a systematic review and meta-analysis of 33 studies looking at how diabetes control changed with the onset of lockdowns in over 4,700 patients from 10 countries.

The findings, presented at the recent Annual Meeting of the European Association for the Study of Diabetes (EASD), suggest that glycaemic control substantially improved in individuals with T1D. In contrast, lockdown contributed to a short-term worsening in blood sugar control and weight gain in many people with T2D.

However, despite the ongoing impact of the pandemic, there has been some positive developments in relation to new practice documents and research findings in the area of diabetes.

A new comprehensive consensus report to manage T1D was recently launched by EASD and the American Diabetes Association (ADA). The wide-ranging document follows their successful collaboration to provide similar guidance for people with T2D back in 2019. People with T1D represent 5-to-10 per cent of all people with diabetes, which amounts to over 25 million people worldwide.

Meanwhile, a new consensus statement from the Endocrine Society, EASD, Diabetes UK and the ADA has concluded that people with T2D should be considered in remission after sustaining normal blood sugar levels for three months or more.

Irish Society for Clinical Nutrition and Metabolism (IrSPEN) spokesperson, and expert group member, Prof Carel le Roux said the report has agreed that: “The term remission be used rather than cure, that this be identified when blood sugar levels return to below the level indicative of diabetes (HbA1c <48mmol/mol), continue for at least three months and without the use of medications.”

He added that testing to determine long-term maintenance of a T2D remission should be done at least yearly, together with the routine testing for potential complications.

IrSPEN spokesperson and UCD Chair of Surgery at St Vincent’s University Hospital Prof Helen Heneghan said a return to normal sugar levels in patients with typical T2D can now be attained by several therapies, which is very positive for patients. “Language around diabetes definition is critical and there is a need for the accuracy which this medical consensus report has provided.

“However, the frequency of sustained improvement, its likely duration, and its effect on subsequent medical outcomes remain unclear for now – but research underway here in Ireland will help answer these questions.” So a very positive development given that T2D currently affects one in every 15 people in Ireland and consumes more than 10 per cent of the entire HSE budget, with incidence continuing to rise.

Rates of gestational diabetes (GDM) also continue to rise and this issue of Update has a special focus on the condition, looking at the use of metformin during pregnancy and the potential of CD59, a novel biomarker for glycaemic assessment, as a new method to

more accurately detect and predict GDM. Diagnosing GDM is important not only for the short-term adverse outcomes related to pregnancy and delivery, but also for the long-term health consequences affecting both the mother and the child.

This edition of Update also contains in-depth clinical articles on diabetic foot disease, continuous glucose monitoring (CGM) technologies, and an update on the new screening pathway for low-risk patients under Diabetic RetinaScreen, as well as an expert outline of the latest diagnosis and management approaches for polycystic ovary syndrome (PCOS).

There is also a comprehensive overview of transgender healthcare and service provision at the National Gender Service, where the referral rate has gone from fewer than 10 cases per year in 2005 to over 10 per week, currently.

In relation to obesity, there is an article explaining the work being carried out by SOPHIA, a large European Union-funded obesity research project, coordinated by University College Dublin (UCD) in Ireland, which aims to change how we view, diagnose, and treat the disease of obesity.

Conference-wise, there is a round-up of the most topical research presented at the recent 2021 EASD meeting, held virtually again this year.

So all in all, a packed edition that should hopefully prove interesting and useful to all our readers.

Thank you to our expert contributors for taking the time to share their knowledge and advice for the betterment of patient care.

We always welcome new contributors and suggestions for future content, as well as any feedback on our content to date. Please contact me at priscilla@mindo.ie if you wish to comment or contribute an article. ■

35

Key issues facing diabetes care in Ireland: Diabetes Ireland pre-Budget submission

37

A pragmatic approach to investigating obesity

40 Transgender healthcare at the National Gender Service

Editor Priscilla Lynch priscilla@mindo.ie

Sub-editor Emer Keogh emer@greenx.ie

Creative Director Laura Kenny laura@greenx.ie

Advertisements Graham Cooke graham@greenx.ie

Administration Daiva Maciunaite daiva@greenx.ie

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EASD 2021 meeting report

Priscilla Lynch presents a round-up of some of the most topical research presented at this year’s Annual Meeting of the European Association for the Study of Diabetes (EASD), which was held online from 27 September – 1 October

Men with young-onset type 2 diabetes at higher risk of retinopathy, study finds

New research presented at the 2021 Annual Meeting of the European Association for the Study of Diabetes (EASD), held online this year, found that men who are diagnosed with type 2 diabetes (T2D) at a young age are more likely to develop retinopathy than those diagnosed aged 50-plus.

Men diagnosed with T2D before the age of 40 years were 72 per cent more likely to have retinopathy than males who had T2D for the same amount of time but were diagnosed at the more typical age of 50 or over.

Dr Katrina Tibballs and colleagues at the University of Oslo, Norway, analysed data from the GP records of 10,242 people with T2D to find out the prevalence of young-onset diabetes in Norway and to explore the relationship between age at diagnosis and complications.

The dataset was representative for Norway and the average age of diagnosis with T2D among all the participants was 56.

A total of 980 (10.2 per cent) had youngonset diabetes (diagnosis under the age of 40) and their average age of diagnosis was 33.3 years old. This group had T2D for 11.4 years, on average, at the time of the study, 55.6 per cent were male, and 15.5 per cent had retinopathy.

Their risk of retinopathy and coronary heart disease, another complication of

T2D, was compared with a group of 6,627 people who were diagnosed with T2D aged 50-plus (normal onset T2D).

The average age of diagnosis in this group was 62.7 years. This group had T2D for 7.8 years, on average, at the time of the study, 53.4 per cent were male, and 5.9 per cent had retinopathy.

Those diagnosed before the age of 40 had, on average, a higher HbA1c at diagnosis than those diagnosed after 50 (7.6 per cent versus 6.9 per cent).

In those with young-onset T2D, HbA1c levels were higher already from the point of diabetes diagnosis, but also increased more rapidly with time.

Risk of coronary heart disease was more strongly linked to age in both groups than to diabetes duration. Risk of retinopathy, however, increased with diabetes duration, with the risk increasing particularly sharply in those with young-onset T2D.

When other relevant factors including diabetes duration, HbA1c, current age, BMI and blood pressure were considered and adjusted for, men with young-onset diabetes were 72 per cent more likely to have retinopathy than those with normal-onset T2D.

In contrast to men with young-onset T2D, women with young-onset T2D weren’t at significantly higher risk of

retinopathy than those with normalonset T2D, after taking all the aforementioned factors into account.

The analysis also showed that retinopathy developed sooner after diagnosis in men, but not women, with young-onset T2D than in normal-onset T2D.

The study authors say that diagnosis may be more likely to be delayed in males, who tend to visit their GP less often than females. This would mean their T2D was uncontrolled for longer, raising their risk of complications.

In addition, young-onset T2D may be a more aggressive form of the condition.

The researchers say that the higher average blood sugar levels found in those with young-onset T2D could be a sign of more rapid deterioration of the insulin-producing cells and therefore a more severe form of the condition.

Dr Tibballs, a GP and PhD student, concluded: “It is important that youngonset type 2 diabetes is detected early enough and treated adequately to reduce the likelihood of retinopathy and other complications.

“The current guidelines on diabetes prevention and treatment should be updated to reflect the higher risk of complications in those with young-onset diabetes, particularly the elevated risk of retinopathy in men.”

Bigger waistlines raise the risk of serious liver damage in people with type 2 diabetes, study suggests

New research presented at the Annual Meeting of EASD found a link between larger waistlines and the progression of non-alcoholic fatty liver disease (NAFLD) in people with type 2 diabetes (T2D).

Each 1cm increase in waist circumference was associated with a 5 per cent higher likelihood of developing advanced fibrosis.

It is already known that that up to 15-to-20 per cent of those with T2D have advanced fibrosis. But little is known about what effect, if any, it has on the complications of diabetes.

Dr Tiphaine Vidal-Trécan, of Lariboisiere Hospital, Paris, France, and colleagues studied the relationship in 684 T2D patients.

The participants had an average age of 61 years, a BMI of 28.7, a waist circumference of 104cm, and 59 per cent were male.

Vibration-controlled transient elastography scans showed that 74.5 per cent had NAFLD. In 12.4 per cent of the participants it had progressed to advanced fibrosis.

A quarter (24.8 per cent) of the participants had macrovascular complications of T2D, such as heart disease, while 20.5 per cent had retinopathy; 39.4 per cent had neuropathy; and 38.3 per cent had nephropathy.

Analysis revealed nephropathy to be significantly more common in those with advanced fibrosis than the other T2D patients. Just over half (52.1 per cent) of those with advanced fibrosis had nephropathy, compared to 36.3 per cent of the other T2D patients. The study authors say that more research is needed to confirm this link.

Rates of the other complications (macrovascular, retinopathy and neuropathy)

did not differ between those with advanced fibrosis and the other T2D patients. Again, more research is needed to confirm this.

The study also found that every 1cm increase in waistline was associated with a 5 per cent increase in the likelihood of the participants developing advanced fibrosis.

Higher levels of AST, a marker of liver damage, were also associated with higher odds of advanced fibrosis.

Dr Vidal-Trécan concluded: “Doctors treating people with type 2 diabetes should be aware of these links and check for advanced fibrosis when their waist circumference or level of AST is high.

“A large waist circumference is linked to metabolic syndrome and fat accumulation in the abdomen, which can lead to NAFLD.”

Prescription of antidepressant and antipsychotic drugs common ahead of type 2 diabetes diagnosis

Almost three-in-10 people with type 2 diabetes (T2D) in Scotland were prescribed antidepressants before they were diagnosed with diabetes, according to new research presented at the 2021 Annual Meeting of EASD.

The study, from Ms Charlotte Greene, Prof Sarah Wild and colleagues at the University of Edinburgh, UK, also found that just over one-in-10 people were prescribed antipsychotics prior to diagnosis of T2D.

The aim of the study was to provide information about patterns of antidepressant and antipsychotic drug prescribing prior to the diagnosis of diabetes. This is part of a broader piece of research, which aims to look at whether prescribing patterns of these drugs in people with diabetes have changed over time

and whether these drugs affect the risk of complications in people with diabetes.

The study used the Scottish Care Information-Diabetes Collaboration (SCI-Diabetes) dataset, which contains information on almost all patients diagnosed with diabetes in Scotland, to provide information on the prevalence and patterns of antidepressant and antipsychotic drug prescribing in the four years prior to diagnosis of T2D in 266,186 adults.

Analysis revealed that 22.5 per cent were prescribed antidepressants, 5.3 per cent were prescribed antipsychotics, and 6.6 per cent were prescribed both antidepressants and antipsychotics. (Comparable figures are not available for the general population.)

Of those prescribed antidepressants, 32.9 per cent were prescribed a selective serotonin reuptake inhibitor (SSRI), 30.5 per cent a tricyclic antidepressant, and 9.9 per cent another type of antidepressant. The remaining 28.6 per cent were prescribed more than one type of antidepressant.

Of those prescribed antipsychotics, 80.4 per cent were prescribed a first-generation drug, 14.2 per cent a second-generation drug, and 5.5 per cent antipsychotics of more than one type.

Those prescribed antidepressants and or antipsychotics were more likely to be women than those not given the drugs. They were also more likely to live in more socioeconomically deprived areas, be current smokers, obese and have high blood pressure and high cholesterol.

Hospital admissions for psychiatric disorders were also more common in those prescribed antidepressants or antipsychotics.

The study’s authors say that while it isn’t known why the prescription of these drugs is common ahead of T2D diagnosis, mental illness is thought to increase the risk of T2D for several reasons.

For example, people with mental illness are more likely to have a poor diet, be physically inactive, smoke, and misuse alcohol, than people without mental illness. They are also more likely to live in socioeconomically deprived areas – all of which are associated with a higher risk of T2D.

Ms Greene adds: “Additionally, some antidepressants and antipsychotics are

thought to increase risk factors related to the development of type 2 diabetes, including weight gain, independently of mental illness.

“More research is needed to investigate prescription patterns after diabetes diagnosis and to determine whether use of these drugs affects the risk of complications of diabetes including heart disease, stroke, and retinopathy.”

Breastfeeding protects against type 1 diabetes, but cow’s milk raises risk, research suggests

New research presented at the Annual Meeting of EASD shows that breastfeeding is associated with a lower risk of developing type 1 diabetes (T1D). Drinking more than two or three glasses of cow’s milk a day in childhood, however, is linked with higher odds of developing T1D.

Incidence of T1D, the most common form of diabetes in children, is increasing worldwide. The number of diagnoses in young people is rising by an estimated 3.4 per cent annually in Europe and 1.9 per cent in the US.

Numerous foodstuffs have been linked to islet autoimmunity and T1D, but none of the associations have been firmly established and the existence of a link remains controversial.

In the first study of its kind, Ms Anna-Maria Lampousi and colleagues from the Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, carried out a systematic review and meta-analysis of the existing research to identify which foods have been consistently linked to T1D.

The Medline, Embase, and Cochrane Library databases were searched from formation until October 2020, for studies on diet, T1D and islet autoimmunity.

Of the 5,935 studies identified, 152 were eligible for inclusion. The analysis produced estimates for how much 27

dietary components increased or reduced the risk of developing T1D. This included foods eaten by the mother in pregnancy and foods consumed in infancy and childhood, as well as being breastfed.

Babies that were breastfed for longer and those that were breastfed exclusively were less likely to develop T1D.

Those breastfed for at least six-to-12 months were less than half as likely (61 per cent less likely) to develop T1D than those breastfed for less time. Those given only breast milk for the first two-to-three months were 31 per cent less likely to develop the condition than those who weren’t exclusively breastfed.

The researchers say that breastfeeding promotes the maturation of babies’ immune system and enhances their gut microbiota.

Higher consumption of cow’s milk and dairy products such as butter, cheese, yoghurt, and ice-cream during childhood (under 15 years old) was associated with a higher risk of islet autoimmunity and T1D.

For example, those who drank at least two to three glasses of cow’s milk a day were 78 per cent more likely to be develop T1D than those who consumed less than this amount of milk.

It isn’t known what is behind the association, but some research has suggested that amino acids (the building blocks of proteins) in cow’s milk can trigger the immune system’s attack on the insulin-producing cells of the pancreas.

Early introduction of cow’s milk to the diet was also associated with a higher risk of T1D. Those who started drinking cow’s milk at two or three months old were 31 per cent less likely to develop T1D than those who started consuming it earlier.

Later introduction of gluten to the diet more than halved the odds of developing T1D. Infants who started eating glutencontaining foods, such as cereal, bread, pastries, biscuits and pasta, at three-to-six months old were 54 per cent less likely to develop T1D than those introduced to the foods earlier.

Waiting until a child was four-tosix months old to introduce fruit to their diet was associated with a 53 per cent reduction in their likelihood of developing T1D.

The study authors say it isn’t clear if delaying introduction to these foods directly protects against T1D or if the infants are benefiting from being breastfed for longer.

Age at introduction to formula milk, meat and vegetables was not linked to risk of T1D. Nor were there any associations between a mother’s intake of gluten and vitamin D in pregnancy and her child’s odds of the condition.

Ms Lampousi commented: “Diet in infancy and childhood may influence the risk of type 1 diabetes. The strongest findings were for the beneficial effects of breastfeeding and the harmful effects of early introduction to cow’s

milk, gluten and fruit.

“However, most of the evidence to-date is of limited quality and further high-quality research is necessary before any specific dietary recommendations can be made.”

Covid-19 lockdowns have major impact on diabetes control, international study finds

The effects of the Covid-19 pandemic on type 1 diabetes (T1D) and type 2 diabetes (T2D) were very different, according to a systematic review and meta-analysis of 33 studies looking at how diabetes control changed with the onset of lockdowns in over 4,700 patients from 10 countries.

The findings, presented at the Annual Meeting of EASD, suggest that glycaemic control substantially improved in individuals with T1D. In contrast, lockdown contributed to a shortterm worsening in blood sugar control and weight gain in many with T2D.

“As the pandemic unfolded, there were concerns that an increase in remote consultations and the scale back of face-to-face appointments alongside changes in daily life and exercise, and increased feelings of stress and anxiety would have a negative impact diabetes control,” noted lead author Prof Claudia Eberle from the University of Applied Sciences in Fulda, Germany.

“Our analysis has revealed that lockdown improved the way people with type 1 diabetes managed their condition. However, people with type 2 diabetes paid a heavy price, with many experiencing deteriorating glycaemic control and weight gain – which are associated with many of the common types of cancer, blindness, amputations as well as heart attacks and strokes.”

In 2019, over 9 per cent of adults aged 20to-79 years worldwide – over 463 million adults – were living with diabetes. T1D is the second most common chronic disease in children, accounting for 85 per cent of diabetes in the under 20s (1.1 million cases

in 2019), and it is on the rise.

In this study, researchers searched for all studies published in English or German, which reported the impact of Covid-19 lockdowns on glycaemic control in patients with either T1D or T2D. In total, 33 peer-reviewed studies up to March 2021 were included in the analyses.

The researchers found that in 25 studies including 2,881 individuals with T1D, 18 studies (72 per cent) showed clear improvements in glycaemic control, four (16 per cent) showed no changes, while three studies (12 per cent) reported a deterioration – possibly due to an interruption in healthcare services, as seen in India where insulin was in short supply.

The changes in HbA1c and time spent in the target blood sugar range (TIR, between 70 and 180mg/dL) from pooled studies were also favourable. Compared to before lockdown, HbA1c values went down significantly in 11/25 studies, with HbA1c levels declining by an average of 0.05 per cent. The TIR also improved significantly (by an average 3.75 per cent) in 18/25 studies.

“Lockdown measures may have given people with type 1 diabetes more time to look after themselves, allowing them to eat more healthily and keep a close eye on their blood sugar levels. A more ordered routine, especially with respect to meal timing, may also have had health benefits,” explained Prof Eberle. “On top of that, the availability of digital management like telemedicine may have improved contact with healthcare providers, while almost all of the patients in our study had access to digital treatments – such as continuous and flash

glucose monitoring that track sugar levels in real time and insulin pumps that provide a steady stream on insulin into the body. These factors may have counteracted lockdown consequences, such as less physical activity and the harmful effects on mental health.”

Worsening blood sugar control and weight gain in type 2 diabetes

In contrast, the analysis found that in eight studies including 1,823 individuals with T2D, half the publications noted short-term worsening in blood sugar control during lockdown, while a quarter (two studies) showed some improvement. Overall, HbA1c levels increased by an average of 0.14 per cent through the lockdowns. Moreover, three studies reported increases in BMI of between 0.3 kg and 0.95 kg, while one reported a substantial improvement in BMI.

According to Prof Eberle: “During lockdown, people with type 2 diabetes may have developed unhealthy habits, such as eating more snacks, more screen time, and less physical activity. At the same time, lack of sleep, increased stress, anxiety, and restricted access to hospitals and pharmacies, may have heightened the difficulty of achieving good blood sugar control. Larger studies in different locations will be needed to identify the actual impact of lockdown in people with diabetes on a broader scale.”

The authors note several limitations in the methodology and reporting of studies in the analysis, including that many were based on patients from Europe, particularly Italy and Spain, where lockdowns tended to be very strict, so the findings may not be generalisable to all countries.

Common osteoporosis drug may reduce risk of type 2 diabetes development

The widely used osteoporosis drug alendronate reduces the risk of type 2 diabetes, new research presented at the 2021 Annual Meeting of EASD suggests.

It has been known for decades that patients with diabetes have a higher risk of fractures – suggesting a link between blood sugar regulation and bone quality. More recently, animal studies have suggested that the modification of bone cells by osteoporosis drugs affects glucose regulation.

“Thus, we speculated that the treatment of osteoporosis might impact on the risk of type 2 diabetes,” says Dr Rikke Viggers, of Aalborg University Hospital, Aalborg, Denmark.

To find out more, Dr Viggers and colleagues compared diabetes rates among those prescribed the bisphosphonate alendronate with those not given the treatment.

Hospital records were used to identify all individuals with type 2 diabetes in Denmark between 2008 and 2018. Each diabetes patient was matched by age and sex with three healthy people from the population.

Prescription records were used to determine whether the participants had ever been prescribed alendronate.

The 163,588 patients with type 2 diabetes and 490,764 participants without diabetes had an average age of 67 years and 55 per cent were male.

than half (53 per cent) compared to those who have never used alendronate. Further analysis suggested a dose-dependent effect.

The study authors say that it isn’t clear how alendronate reduces the risk of developing type 2 diabetes. One theory is that the drug reduces low-grade inflammation and oxidative stress, two processes thought to be central to the development of insulin resistance. It is not known if other osteoporosis medicines have the same effect.

Dr Viggers adds: “Type 2 diabetes is a serious lifelong condition that can lead to other serious health issues such as stroke, heart disease, blindness and limb amputation, and anything that prevents, or even delays it, will also reduce a person’s risk of all these other conditions.

Analysis revealed that those who had taken alendronate were 34 per cent less likely to have been diagnosed with type 2 diabetes than those who had never taken the drug. Factors such as smoking, alcohol use, obesity, income, and marital status were included in the analysis.

Taking alendronate for at least eight years could potentially reduce the risk by more

“Excitingly, our research suggests that alendronate, an inexpensive medicine widely used to treat osteoporosis, may also protect against type 2 diabetes.

“We believe that doctors should consider this when prescribing osteoporosis drugs to those with pre-diabetes or at high risk of type 2 diabetes.”

EASD outlines diabetes remission diagnosis criteria

People with type 2 diabetes (T2D) should be considered in remission after sustaining normal blood sugar levels for three months or more, according to a new consensus statement from the Endocrine Society, EASD, Diabetes UK and the American Diabetes Association, and co-published in the Journal of Clinical Endocrinology & Metabolism, Diabetologia, Diabetic Medicine, and Diabetes Care

The statement was highlighted during

the 2021 Annual Meeting of EASD.

“Our international group of experts suggest an HbA1c (average blood sugar) level of less than 6.5 per cent at least three months after stopping diabetes medication as the usual diagnostic criterion for diabetes remission,” said statement author and Endocrine Society member Dr Matthew Riddle of Oregon Health and Science University in Portland, US. Dr Riddle is chair of the Diabetes

Remission Consensus writing group that developed the statement. “We also made suggestions for clinicians observing patients experiencing remission and discussed further questions and unmet needs regarding predictors and outcomes.”

The authors developed the following criteria to help clinicians and researchers evaluate and study diabetes remission using more consistent terminology and methods:

Analysis revealed that those who had taken alendronate were 34 per cent less likely to have been diagnosed with type 2 diabetes than those who had never taken the drug

1. Remission should be defined as a return of HbA1c to less than 6.5 per cent that occurs spontaneously or following an intervention and that persists for at least three months in the absence of usual glucose-lowering pharmacotherapy.

2. When HbA1c is determined to be an unreliable marker of long-term glycaemic control, fasting plasma glucose of less than 126mg/dL (<7.0mmol/L) or estimated HbA1c less than 6.5 per cent calculated from CGM values can be used as alternate criteria.

3. Testing of HbA1c to document a remission should be performed just prior to an intervention and no sooner than three months after initiation of the intervention or withdrawal of any glucose-lowering pharmacotherapy.

4. Subsequent testing to determine longterm maintenance of a remission should be done at least yearly, together with the testing routinely recommended for potential complications of diabetes.

“Diabetes remission may be occurring more often due to advances in treatment,” said Prof Amy Rothberg of the University of Michigan, US. Prof Rothberg represents the Endocrine Society as a member of the Diabetes Remission Consensus writing group. “More research is needed to determine the frequency, duration and

effects on short- and long-term medical outcomes of remission of type 2 diabetes using available interventions.”

Meanwhile, separate research presented at the meeting found that contrary to the perceived wisdom, people of normal weight with T2D can reverse the condition through substantial weight loss.

The latest results are from the Reversal of Type 2 Diabetes upon Normalisation of Energy Intake in the Non-obese (ReTUNE) trial, which is looking at whether weight loss can also reverse the condition in people of normal weight.

Eight of the 12 participants achieved remission after losing 10-to-15 per cent of their body weight, despite having a BMI that fell in the normal weight, which was a similar proportion to previous studies involving overweight and obese participants. Remission was defined as HbA1c of less than 48mmol/mol and off all medication.

Levels of fat in the liver and pancreas fell substantially and the activity of the insulin-producing cells in the pancreas was restored.

The finding clearly demonstrates weight loss can be beneficial in T2D, even in those who are of normal weight, says Prof Roy

Taylor, of Newcastle University, Newcastle, UK, the principal investigator on the trial.

It also supports the idea that every person has a ‘personal fat threshold’ and if we go above it, we will develop T2D, even if we are still of normal weight.

Prof Taylor explains: “Our previous research has shown that weight loss of 10-to-15 per cent can achieve remission in people with type 2 diabetes who are overweight or obese.

“Doctors tend to assume, however, that type 2 diabetes has a different cause in those who aren’t overweight. This means that, unlike those who are overweight, those who are of normal weight aren’t usually advised to lose weight before being given diabetes drugs and insulin.

“Instead, there’s a tendency to start them on insulin and other medication at a much earlier stage.

“What we’ve shown is that if those of normal weight lose 10-to-15 per cent of their weight, they have a very good chance of getting rid of their diabetes.

“This should be a wake-up call to doctors and, with one-in-10 of the 4.5 million people with type 2 diabetes in the UK of normal weight at diagnosis, there is no time to be lost in getting the message across.”

Risk of stroke in people with T2D increases with insulin resistance, study suggests

A study of more than 100,000 people with type 2 diabetes (T2D) has found that that insulin resistance is associated with stroke.

The higher the insulin resistance, the greater the risk of stroke, the research presented at this year’s Annual Meeting of EASD found.

Dr Alexander Zabala and colleagues at the Karolinska Institute and researchers at Gothenburg University and the National

Diabetes Registry in Sweden, used estimated glucose disposal rate (eGDR) as a measure of insulin resistance.

eGDR has previously been shown to be a good proxy for insulin resistance and is calculated using a formula that factors in a patient’s waist circumference, HbA1c and whether they have high blood pressure.

Health records were used to calculate the

eGDR of 104,697 T2D patients in Sweden. The participants had an average age of 63 years and 44.5 per cent were female.

They were followed up for an average of 5.6 years, during which 4,201 (4 per cent) had a stroke.

Analysis revealed that the higher a person’s insulin resistance, the greater their chance of having a stroke. Those

with the lowest insulin resistance (the highest eGDR) were 40 per cent less likely to have a stroke than those with the highest insulin resistance.

Age, cholesterol levels, smoking, heart conditions and other traditional risk factors for stroke were all adjusted for.

The study also found that higher insulin resistance was linked to a higher risk of death after a stroke. Those with the lowest

resistance were 28 per less likely to die during the follow-up period than those with the most severe insulin resistance.

Further analysis showed high blood pressure to be more strongly linked to stroke than waist circumference or HbA1c.

The study’s authors concluded: “We found that in individuals with type 2 diabetes, a low eGDR, a simple measure of insulin resistance, was associated with an

increased risk of stroke and mortality.”

Dr Zabala adds: “eGDR could be used to help T2D patients better understand and manage their risk of stroke and death.

“It could also be of importance in research. In this era of personalised medicine, better stratification of type 2 diabetes patients will help optimise clinical trials and further vital research into treatment, diagnosis, care and prevention.”

Men are at much greater risk of dying following bariatric surgery than women

Men who undergo bariatric surgery are five times as likely to die within 30 days of the procedure compared to women, and their long-term mortality is almost three times higher, according to an observational analysis of national data from Austria spanning 10 years.

The findings, presented at the 2021 Annual Meeting of EASD, indicate that men tend to be older and have higher rates of comorbidities such as cardiovascular disease and type 2 diabetes (T2D) at the time of surgery, highlighting a pressing need to educate men about the importance of treating obesity earlier, before they develop potentially life-threatening comorbidities.

Lead author Dr Hannes Beiglböck from the Medical University of Vienna in Austria, said: “Although the absolute risk of dying after bariatric surgery is low, the findings of our large nationwide study highlight a substantially increased mortality risk among men compared to women. Women seem more willing to look at surgical weight loss earlier in life, whereas men tend to wait until they have more comorbidities.”

Despite similar rates of obesity among men and women, over 70 per cent of patients undergoing bariatric surgery are women

To find out more, researchers retrospectively analysed medical health claim data from the Austrian state insurance (the Österreichische Gesundheitskasse) that covers around 98 per cent of the population (around nine million Austrians in 2018). In total, 19,901

associated with obesity (ie, type 2 diabetes, cardiovascular diseases, psychiatric disorders, and cancers) in patients who died.

Between January 2010 and April 2020, less than 2 per cent (367/19,901; 176 men and 191 women) of bariatric surgery patients died. Nevertheless, overall postoperative mortality rates (per year of observation) were almost three times higher among men than women (0.64 per cent vs 0.24 per cent) – although deaths were rare in absolute terms; whilst 30-day mortality was five-fold higher in men compared to women (25 deaths, 0.5 per cent vs 12 deaths, 0.1 per cent).

patients (14,681 women, average age 41 years; 5,220 men, average age 42 years) who had undergone bariatric surgery (ie, sleeve gastrectomy, gastric bypass, biliopancreatic diversion, or gastric banding) between January 2010 and December 2018 were included in the analyses and followed for an average of five years (107,806 patient years of observation). Researchers analysed sex-specific differences in comorbidities

Among those who died, cardiovascular diseases (84 per cent of men, 80 per cent of women) and psychiatric disorders (51 per cent of men, 58 per cent of women) were the most common comorbidities. T2D was more common in men than women who died (43 per cent vs 33 per cent), and cancers were more common in women than men (41 per cent vs 30 per cent).

“The challenge now is to understand potential barriers for men to undergo bariatric surgery and further research should be performed to explore if earlier surgical intervention in men could improve mortality outcomes,” said Dr Beiglböck.

Among those who died, cardiovascular diseases (84 per cent of men, 80 per cent of women) and psychiatric disorders (51 per cent of men, 58 per cent of women) were the most common comorbidities

THE POWER TO ACCOMPLISH MORE

Multiple benefits * Proven protection

JARDIANCE is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise 1 - as monotherapy when metformin is considered inappropriate due to intolerance

- in addition to other medicinal products for the treatment of diabetes

1. JARDIANCE (empagliflozin) Summary of Product Characteristics 2019. Available at: http://www.medicines.ie/medicine/16081/SPC/Jardiance+10+mg+and+25+mg+Film-Coated+Tablets

2. Zinman B, Wanner C, Lachin JM et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-2128. (& Supplementary Appendix)

3. Data on File. Boehringer Ingelheim

Prescribing Information (Ireland) JARDIANCE® (empagliflozin)

Film-coated tablets containing 10 mg or 25 mg empagliflozin. Indication: Jardiance is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise: as monotherapy when metformin is considered inappropriate due to intolerance; in addition to other medicinal products for the treatment of diabetes. For study results with respect to combinations, effects on glycaemic control and cardiovascular events, and the populations studied, refer to the Summary of Product Characteristics. Dose and Administration: The recommended starting dose is 10 mg once daily. In patients tolerating empagliflozin 10 mg once daily who have eGFR ≥ 60 ml/min/1.73 m2 and need tighter glycaemic control, the dose can be increased to 25 mg once daily. The maximum daily dose is 25 mg. When used with sulphonylurea or insulin a lower dose of these may be considered to reduce the risk of hypoglycaemia. Renal impairment: The glycaemic efficacy is dependent on renal function. No dose adjustment is required for patients with an eGFR ≥60 ml/ min/1.73 m2 or CrCl ≥60 ml/min. Do not initiate in patients with an eGFR <60 ml/min/1.73 m2 or CrCl <60 ml/min. In patients tolerating empagliflozin whose eGFR falls persistently below 60 ml/min/1.73 m2 or CrCl below 60 ml/min, the dose of empagliflozin should be adjusted to or maintained at 10 mg once daily. Discontinue when eGFR is persistently below 45 ml/ min/1.73 m2 or CrCl persistently below 45 ml/min. Not for use in patients with end stage renal disease (ESRD) or on dialysis. Hepatic impairment: No dose adjustment is required for patients with hepatic impairment. Not recommended in severe hepatic impairment. Elderly patients: No dose adjustment is recommended based on age. In patients 75 years and older, an increased risk for volume depletion should be taken into account. Not recommended in patients 85 years or older. Paediatric population: No data are available. Method of administration: The tablets can be taken with or without food, swallowed whole with water. If a dose is missed, it should be taken as soon as the patient remembers; however, a double dose should not be taken on the same day. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Warnings and Precautions: Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been reported in patients treated with SGLT2 inhibitors, including empagliflozin. Consider the risk of DKA in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness and assess patients for ketoacidosis immediately, regardless of blood glucose level. In patients where DKA is suspected or diagnosed, treatment should be discontinued immediately. Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. Monitoring of ketones is recommended in these patients. Measurement of blood ketone levels is preferred to urine. Treatment with empagliflozin may be restarted when the ketone values are normal and the patient’s condition has stabilised. Before initiating

empagliflozin, consider factors in the patient history that may predispose to ketoacidosis. Use with caution in patients who may be at higher risk of DKA. Jardiance should not be used for treatment of patients with type 1 diabetes. Renal impairment: See under Dose and Administration; Monitor renal function prior to initiation and at least annually. Cases of hepatic injury have been reported with empagliflozin in clinical trials. A causal relationship between empagliflozin and hepatic injury has not been established. Haematocrit increase was observed with empagliflozin treatment. Osmotic diuresis accompanying therapeutic glucosuria may lead to a modest decrease in blood pressure. Therefore, caution should be exercised in patients with known cardiovascular disease, patients on anti-hypertensive therapy with a history of hypotension or patients aged 75  years and older. In case of conditions that may lead to fluid loss (e.g. gastrointestinal illness), careful monitoring of volume status and electrolytes is recommended. Temporary interruption of treatment with empagliflozin should be considered until the fluid loss is corrected. Elderly: See under Dose and Administration; special attention should be given to volume intake of elderly patients in case of co-administered medicinal products which may lead to volume depletion (e.g. diuretics, ACE-inhibitors). Temporary interruption of empagliflozin should be considered in patients with complicated urinary tract infections. Cases of necrotising fasciitis of the perineum (Fournier’s gangrene), have been reported in patients taking SGLT2 inhibitors. This is a rare but serious and potentially lifethreatening event that requires urgent surgical intervention and antibiotic treatment. Patients should be advised to seek medical attention if they experience a combination of symptoms of pain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be aware that either uro-genital infection or perineal abscess may precede necrotising fasciitis. If Fournier’s gangrene is suspected, Jardiance should be discontinued and prompt treatment should be instituted. An increase in cases of lower limb amputation (primarily of the toe) has been observed in long-term clinical studies with another SGLT2 inhibitor, counsel patients on routine preventative footcare. Experience in New York Heart Association (NYHA) class I-II is limited, and there is no experience in clinical studies with empagliflozin in NYHA class III-IV. Due to its mechanism of action, patients taking Jardiance will test positive for glucose in their urine. The tablets contain lactose and should not be used in patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Interactions: Use with diuretics may increase the risk of dehydration and hypotension. Insulin and insulin secretagogues may increase the risk of hypoglycaemia therefore, a lower dose of insulin or an insulin secretagogue may be required. The effect of UGT induction (e.g. induction by rifampicin or phenytoin) on empagliflozin has not been studied. Co-treatment with known inducers of UGT enzymes is not recommended due to a potential risk of decreased efficacy. If an inducer of these UGT enzymes must be co-administered, monitoring of glycaemic control

to assess response to Jardiance is appropriate. Interaction studies suggest that the pharmacokinetics of empagliflozin were not influenced by coadministration with metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin, torasemide and hydrochlorothiazide. Interaction studies conducted in healthy volunteers suggest that empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, simvastatin, warfarin, ramipril, digoxin, diuretics and oral contraceptives. Fertility, pregnancy and lactation: There are no data from the use of empagliflozin in pregnant women. As a precautionary measure, it is preferable to avoid the use of Jardiance during pregnancy. No data in humans are available on excretion of empagliflozin into milk. Jardiance should not be used during breast-feeding. No studies on the effect on human fertility have been conducted for Jardiance. Undesirable effects: Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), not known (cannot be estimated from the available data). Very common: hypoglycaemia (when used with sulphonylurea or insulin). Common: vaginal moniliasis, vulvovaginitis, balanitis and other genital infections, urinary tract infection (including pyelonephritis and urosepsis), thirst, pruritus (generalised), rash, increased urination, serum lipids increased. Uncommon: urticaria, volume depletion, dysuria, blood creatinine increased/glomerular filtration rate decreased, haematocrit increased. Rare: DKA. Not known: necrotising fasciitis of the perineum (Fournier’s gangrene), angioedema. Prescribers should consult the Summary of Product Characteristics for further information on side effects. Pack sizes: 10 mg; 28 tablets, 25 mg: 28 tablets. Legal category: POM. MA numbers: 10 mg/28 tablets EU/1/14/930/013; 25 mg/28 tablets EU/1/14/930/004.

Marketing Authorisation Holder: Boehringer Ingelheim International GmbH, D-55216 Ingelheim am Rhein, Germany. Prescribers should consult the Summary of Product Characteristics for full prescribing information. Additional information is available on request from Boehringer Ingelheim Ireland Ltd, The Crescent Building, Northwood, Santry, Dublin 9. Prepared in October 2020

Adverse events should be reported. Reporting forms and information can be found at https://www.hpra.ie/homepage/about-us/report-an-issue. Adverse events should also be reported to Boehringer-Ingelheim Drug Safety on 01 2913960, Fax: +44 1344 742661, or by e-mail: PV_local_UK_Ireland@ boehringer-ingelheim.com

doctor CPD.ie

TRUE/FALSE QUESTIONS

Q1 CGM devices measure capillary blood glucose

True or false?

Q2 CGM glucose readings lag behind fingerprick glucose readings by approximately five minutes

True or false?

Q3 CGM devices have not been shown to have a significant effect on hypoglycaemia frequency in patients with T1DM

True or false?

Q4 The FreeStyle Libre ‘Flash’ CGM device requires confirmatory fingerprick glucose testing if the patient is experiencing symptoms of hypoglycaemia

True or false?

Q5 CGM devices have not been shown to have a significant impact on HbA1c levels

True or false?

Q6 The time in range (TIR) target in a young, non-pregnant adult with T1DM using CGM is >70 per cent

True or false?

Q7 Impaired hypoglycaemia awareness, frequent nocturnal hypoglycaemia, and frequent severe hypoglycaemia are examples of patient characteristics that may benefit from CGM

True or false?

Q8 Paracetamol can cause falsely low interstitial glucose readings by interfering with the sensor’s mechanism of action

True or false?

Q9 The default hypoglycaemia alert for any CGM device with an alert function is recommended to be <3.9mmol/L

True or false?

Q10 Government funding for CGM and FGM is available to all patients in Ireland with T1DM

True or false?

To complete this module and earn free CPD points, go to www.doctorCPD.ie and answer the 10 true or false questions and complete the five MCQs based on this case study.

Diabetes continuous glucose monitoring

AUTHORS: Dr Michael Lockhart, Endocrinology SpR; and Prof Diarmuid Smith, Consultant Diabetologist and Endocrinologist, Academic Department of Diabetes and Endocrinology, Beaumont Hospital, Dublin, and RCSI Medical School

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune condition characterised by autoimmune destruction of the pancreatic beta cell. It is associated with macrovascular and microvascular complications. Tight glycaemic control has been shown to ameliorate the longterm complications of T1DM. Monitoring glucose levels frequently helps patients to achieve more intensive glycaemic control. Fingerprick blood glucose monitoring has traditionally been the most commonly used method. More recently, continuous

glucose monitoring (CGM) systems have shown improvements in glycaemic control, reduced frequency of hypoglycaemia, improved recognition of hypoglycaemia and an improvement in quality-of-life. This article will summarise the evidence for CGM and its current role in the management of patients with T1DM.

The field of glucose monitoring in diabetes mellitus has changed dramatically in the last 100 years, from Stanley Rossiter Benedict’s methods for measuring urinary

ARROW WHAT THE ARROWS MEAN

Intersitial glucose rising by more that 0.11mmol/L per minute or by 3-to-5mmol/l over the next 30 minutes

glucose in the early 1900s (using Benedict’s solution), laboratory plasma glucose measurements in the 1950s, self-monitoring of blood glucose with glucose test strips in the late 1970s and early 1980s and finally the availability of the first CGM device in 1999. CGM devices have rapidly improved in the years since and there are now several options available. CGM devices provide interstitial glucose readings from sites in the abdomen or arm and make use of alarms and alerts to improve glycaemic control and reduce frequency of hypoglycaemia. Their use in patients on multiple daily insulin injections or in conjunction with insulin pump therapy has the potential to revolutionise the care of patients with T1DM.

Intersitial glucose rising by between 0.06 and 0.11mmol/L per minute or by 1-to-3mmol/l over the next 30 minutes

Intersitial glucose stable Intersitial glucose falling by between 0.06 and 0.11mmol/l per minute or by 1-to-2mmol/l over the next 30 minutes

Intersitial glucose falling by more than 0.11mmol/L per minute or by 3-to-5mmol/l over the next 30 minutes –when glucose is falling fast, blood glucose will be lower than intersitial value

The DCCT trial, published in 1993, provides the most definitive evidence that tighter glucose control is associated with better long-term outcomes in patients with diabetes. In the trial, a total of 1,441 patients with T1DM were randomly assigned to either intensive insulin therapy (insulin pump therapy or three or more daily injections of insulin) or conventional insulin therapy (at the time of the study, one-to-two injections of insulin per day). The trial showed that intensive insulin therapy (which resulted in an average HbA1c of 53mmol/mol compared to 75mmol/mol in the conventionally-treated group) reduced the risk of development of proliferative retinopathy or severe nonproliferative retinopathy by 47 per cent, development of microalbuminuria by 34 per cent, and development of neuropathy by 69 per cent. The trial also showed that even in patients who do not achieve the optimal HbA1c, any improvement in glucose control is clinically significant with a HbA1c reduction of 1 per cent associated with a 40 per cent relative risk reduction in progression of microvascular complications. The downside of intensive

FIGURE 1: The meaning of the trend arrows for the FreeStyle Libre device

therapy was a higher risk of severe hypoglycaemia. Therefore, devices or technologies which may be associated with an improvement in diabetes control, whilst at the same time reducing the risk of severe hypoglycaemia, would have a significant impact in the care of patients with T1DM.

Different technologies

There are two categories of CGM –professional CGM (used by physicians in the short-term to help detect fluctuations in glucose levels) and real-time CGM (long-term patient use – RT-CGM). Intermittently-scanned CGM (isCGM) devices (also known as flash glucose monitoring [FGM] devices), such as the FreeStyle Libre device, are included under the umbrella of CGM, but are different to RT-CGM in that they require patients to self-scan to acquire data – a patient with an FGM device who does not self-scan will not have any glucose data to interpret.

There are some important points regarding interstitial glucose readings, as opposed to blood glucose readings, that must be noted. Interstitial readings lag behind blood readings by approximately five-to-10 minutes. The lag time is increased if there are rapid fluctuations in the blood glucose levels. This is particularly pronounced and important at lower levels, where without calibration and/or confirmatory testing, hypoglycaemia can be missed.

Patients using the FreeStyle Libre device must be aware that, because of the discrepancy between interstitial and blood glucose readings, which is particularly pronounced at lower levels, confirmatory fingerpick testing must be carried out if the Libre device shows their blood sugar level is less than 4.0mmol/L, if they are experiencing symptoms of hypoglycaemia, but the Libre device is showing a normal reading or if the Libre trend arrows are showing rapid changes in glucose. The current Libre device does not have an alarm function.

Two of the key features of CGM are alarm systems and trend arrows. Alarm systems,

recommended to trigger at interstitial glucose levels <4mmol/L, alert patients to the development of hypoglycaemia and allow them to correct promptly to avoid severe hypoglycaemia. Trend arrows show direction of glucose changes (ie, increasing or decreasing) as well as the rate of change. Guidelines exist for how patients should adjust insulin doses or correct developing hypoglycaemia for different CGM devices. Figure 1 is a table explaining the meaning of the trend arrows for the FreeStyle Libre device, as an example.

should be <4 per cent. A TIR of 70 per cent correlates well with a HbA1c of 7 per cent.

Trial data

Perhaps the two largest RCTs in patients with T1DM using RT-CGM are the GOLD and the DIAMOND trials, both published in 2017.

The DIAMOND trial randomly assigned 105 patients with T1DM using multiple daily injections to a CGM device (the DEXCOM G4 Platinum CGM system), and 53 to fingerprick blood glucose monitoring at least four times per day. The study ran for 24 weeks. In the CGM group, HbA1c was shown to have reduced by 0.6 per cent. Time in hypoglycaemic range was 43 minutes per day in the CGM group vs 80 minutes per day in the fingerprick group. There was no significant difference in risk of severe hypoglycaemia in the study period between the two groups.

Benefits

There is a growing body of evidence for the benefits of CGM in T1DM. Early research showed significant improvements in HbA1c by 0.4-to-0.6 per cent and a reduction in time spent in hypoglycaemic range by 20-to-40 per cent with the use of CGM. Accurate interpretation of CGM data requires >70 per cent use over the 14 days prior to time of review. To streamline data interpretation, time in range (TIR) has been identified as the metric of glycaemic control that provides the most actionable information in those using CGM.

Specifically, TIR, time below range (TBR), and time above range (TAR) are the three metrics to be considered when reviewing CGM data, as a complement to HbA1c monitoring. The primary goal is to increase the TIR while reducing the TBR. In a nonpregnant adult with T1DM, the TAR target should be <25 per cent, the TIR target should be >70 per cent and the TBR target

The GOLD trial randomly assigned 161 patients over the age of 18 years with T1DM using multiple daily injections to either a CGM device (the DEXCOM G4 Platinum, the same device used in the DIAMOND trial) or to fingerprick blood glucose monitoring in a 1:1 ratio. The trial ran for 26 weeks. HbA1c was 0.43 per cent lower in the CGM arm at the end of the trial period. Those using CGM spent 2.79 per cent of the time in the hypoglycaemic range, while those using self-monitoring with fingerprick blood glucose measurements spent 4.79 per cent of the trial period in the hypoglycaemic range.

In relation to isCGM or FGM, such as the FreeStyle Libre device, most of the clinical data comes from audit of clinical practice. One of the few randomised controlled trials using Freestyle Libre was published in The Lancet in 2016. In this trial, 120 patients with well controlled T1DM (HbA1c ≤58mmol/mol or ≤7.5 per cent) were assigned to use the FreeStyle Libre device and 121 patients to self-monitoring of blood glucose for five months. There was a 38 per cent reduction in time in hypoglycaemia in the FGM group, without significant change in HbA1c.

CGM devices provide interstitial glucose readings from sites in the abdomen or arm and make use of alarms and alerts to improve glycaemic control and reduce frequency of hypoglycaemia

The ABCD audit published in 2020 using data from 102 NHS hospitals assessed glycaemic control, hypoglycaemia awareness, and hospitalisation among 10,370 FreeStyle Libre users for a 12-month period following commencement of FGM. Mean HbA1c was 0.4 per cent lower with FGM use compared to baseline HbA1c pre-FGM. Mean GOLD score (a seven-point questionnaire for identifying impaired awareness of hypoglycaemia) was reduced from 2.7 to 2.4 with FGM use, indicating improved awareness of hypoglycaemia. Over 50 per cent of patients with baseline impaired awareness of hypoglycaemia (GOLD score >4) regained hypoglycaemia awareness. Hospitalisations for hyperglycaemia/DKA were reduced from 269 to 86 after commencement

with built-in CGM as discussed later).

National guidelines on T1DM published in 2018 did not recommend the routine use of CGM in all patients with T1DM, however, as time goes on and with more data coming through on the benefits of CGM it does appear clear that in patients with T1DM, who are willing to commit to using the CGM device at least 70 per cent of the time, CGM devices can improve diabetes control, reduce the risk and fear of hypoglycaemia, improve hypoglycaemia awareness, reduce diabetes distress, and improve quality-of-life, and are associated with less hospital admissions. CGM has further utility when used in combination with insulin pump therapy. The Medtronic 640G pump, for example,

which analyses CGM data in real-time and adjusts insulin doses accordingly. The Medtronic 670G, currently not available in Ireland, is a hybrid closed-loop system with automated basal (but not bolus) adjustments. The Medtronic 780G insulin pump is now available in Ireland and is another hybrid closed-loop system using the Guardian 3 sensor CGM. The system monitors glucose every five minutes and adjusts basal insulin to keep levels within a tighter range. As with the 670G, the user still needs to manually enter the amount of carbohydrates taken with a meal and administer bolus insulin. The device can also manage correction boluses automatically. Development of fully automated closed-loop systems is ongoing.

Conclusion

of FGM, while hospitalisations for hypoglycaemia decreased from 120 to 45. Diabetes-related distress also improved with an improvement in quality-of-life in those using FGM.

In Ireland there is very little data as yet on the benefits of FGM in patients with T1DM. An audit of over 80 patients from three different centres showed similar results to the ABCD audit, with an improvement in diabetes control of 0.4 per cent, improvement in hypoglycaemia awareness, and reduced diabetes distress. On the back of these and other trials, CGM has become a useful tool in the treatment of T1DM.

Ireland

There are currently three CGM devices available in the Republic of Ireland. These are DEXCOM G6, the FreeStyle Libre Flash Glucose Monitor, and the Medtronic Guardian Connect (standalone CGM devices – also available are insulin pumps

can be combined with CGM (specifically the Guardian Connect device) and, when used in combination, the system can predict low blood glucose levels. Using a predictive threshold suspend feature, the pump can then stop the delivery of insulin via the pump before the patient becomes hypoglycaemic, with an alarm to alert the patient that they are hypoglycaemic and it then will automatically redeliver the insulin once the blood glucose levels rise to a safe level.

The Medtronic 640G sensor augmented pump has been shown to reduce both nocturnal hypoglycaemia by 38 per cent and time in hypoglycaemia compared to patients on standard insulin pump therapy. As the technology evolves, there is ongoing research involving CGM as part of the development of closed-loop technology, or the ‘artificial pancreas’. These closed-loop systems involve CGM, an insulin pump, and a digital controller,

CGM devices now play a significant role in the management of patients with T1DM. They have multiple benefits including an improvement in diabetes control, less hypoglycaemia, improved awareness of hypoglycaemia, reduced fear of hypoglycaemia, reduced diabetes distress, and improved quality-of-life. They have also been shown to reduce hospital admission with reduced DKA and hypoglycaemic admissions and increasing data would show CGM devices to be cost-effective through their multiple benefits and by reducing the need for blood glucose testing. Countries around Europe including Northern Ireland now make CGM devices available free of charge to patients with T1DM. In Ireland, the Government only routinely funds CGM devices for patients with T1DM under the age of 21 years. Other patients have to self-fund these devices. It is hoped this decision will be reversed and that the Government will see sense and make CGM devices available to all adult patients with T1DM who are willing to use them and have received a diabetes structured programme. ■

References on request

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Alarm systems, recommended to trigger at interstitial glucose levels <4mmol/L, alert patients to the development of hypoglycaemia and allow them to correct promptly to avoid severe hypoglycaemia

Metformin for pregnancy and beyond; healthy mother, healthy baby?

AUTHORS: Dr Christine Newman 1 (CA) and Prof Fidelma P Dunne, 1 1College of Medicine, Nursing and Health Science, National University of Ireland, Galway

SUMMARY

 Metformin is currently the most commonly used drug for the treatment of type 2 diabetes in Ireland; it has been used in many countries to treat gestational diabetes since the 1970s.

 Metformin has many proven benefits for the mother including reduced weight gain during pregnancy and in some studies a reduced risk of delivery by Caesarean section. It is also highly acceptable to patients.

 However in some studies a number of infants exposed to metformin were born small for

Metformin has been used since the 1960s to treat hyperglycaemia and it is currently the most popular oral hypoglycaemic agent in Ireland and the US. Its mechanism of action is incompletely understood, however it acts to reduce hepatic gluconeogenesis and a number of its other benefits, including its ability to halt tumorigenesis, are under investigation.1

Metformin has been used in pregnancy since the 1970s. It was first used in South Africa where its low cost and ease of administration made it a highly acceptable treatment intervention. In addition to lowering glucose, metformin reduces gestational weight gain (GWG) and reduces the rate of large for gestational age (LGA) infants.

Despite these advantages some clinicians have concerns over its use. Unlike insulin, the most commonly used alternative to metformin in pregnancy, metformin crosses the placenta. The levels of metformin in the foetal circulation can be as high as those in

gestation age (SGA) and some followup studies have suggested that infants exposed to metformin are heavier and have higher body mass indexes (BMI) in childhood.

 Despite these concerns, metformin’s low cost, acceptability and efficacy make it a very attractive treatment intervention in a population affected by rising rates of obesity, gestational diabetes mellitus (GDM) and type 2 diabetes (T2DM).

 Here we consider the pros and cons of metformin before, during and after pregnancy.

the maternal circulation and while there is no evidence to suggest that metformin exposure in early pregnancy is teratogenic, some studies have suggested that foetuses exposed to metformin in the second and third trimesters grow up to be heavier in childhood.

Although many of the studies of metformin in pregnancy conducted in recent years plan to follow metformin-exposed infants into their teenage and adult years, there is currently no long-term data on the health of adults who were exposed to metformin in utero and this has led to concern in regarding the long-term safety of metformin use for the offspring.

Insulin, on the other hand, is effectiveand has no long-term sequalae. It does, however, carry its own risks and these should be balanced against its benefits (see Table 1).

The aim of this review is to discuss the evidence for metformin use before, during and after pregnancy.

Pre-pregnancy

Metformin has a modest effect on weight loss 2 and may be prescribed to obese women with impaired glucose tolerance or polycystic ovarian syndrome (PCOS).

For women with PCOS, metformin may increase the rate of ovulatory menses, 3 however, it is probably only moderately effective in increasing live birth rates when compared to other treatments. The use of metformin remains important in this cohort, however, as patients may unintentionally be exposed to metformin in early pregnancy. It is important to reassure patients that although there is a higher rate of congenital anomalies seen in women with diabetes, this is associated with hyperglycaemia and is not associated with metformin use.4

Pregnancy Obesity

There are three key studies which evaluated the effect of metformin therapy in pregnancies complicated by obesity. The GROW, 5 EMPOWaR,6 and MOP7 randomised controlled trials (RCTS) all evaluated metformin in addition to dietary and lifestyle interventions from the second trimester onwards in women with BMIs of >25, 30 and 35kg/m 2 respectively. All three studies identified that metformin was safe in pregnancy, however, only the MOP RCT identified a statistically significant decrease in GWG and pre-eclampsia. Importantly, rates of GDM did not reduce in women exposed to metformin and compliance in each RCT was rated between 60-to-80 per cent due to gastrointestinal side-effects.

There is no long-term data on the infants exposed to metformin during these studies.

PCOS

There is some observational data to suggest that metformin reduces rates of GDM, miscarriage and pre-term delivery in women with PCOS, however, this has not been supported by RCT data. The PREGMET and PREGMET 2 RCTs, which contained nearly 500 patients, did not identify any change in GDM rates, foetal size or pre-term delivery. 8,9 In both trials, however, women in the metformin arm gained less weight.

At follow-up, infants exposed to metformin were more likely to be overweight or obese at four and 10 years.10 Of note, in the original studies there was no difference in foetal size at birth.

GDM

GDM is a complex disease with an increasing prevalence. It is associated with adverse foetal and maternal outcomes. In some countries metformin has been used to treat GDM for decades and there is a large body of observational data which supports its efficacy and safety. A number of small RCTs suggested that metformin reduces GWG and infant size11,12 and two large RCTs containing a combined 850 overweight/obese patients have found that metformin (with or without insulin) reduces GWG, Caesarean section and the need for/dose of insulin.13,14 In the larger study, rates of neonatal hypoglycaemia (<1.6mmol/L) were also lower in the metformin arm.13 Importantly neither study identified any difference in foetal size. The

upcoming EMERGE trial (NCT02980276) will evaluate the use of metformin in women of all BMI categories diagnosed by the International Association of Diabetes in Pregnancy Study Group (IADPSG) criteria against placebo. Its primary outcome is a composite of insulin initiation and fasting glucose levels >5.3mmol/L at gestational weeks 32 or 38 and will provide a further insight into the utility of metformin for women across all BMI categories.

The best long-term follow-up data comes from the GDM cohort where data from two and seven-to-nine years has been published.15,16 Infants of the women in the metformin arm had larger upper-arm circumferences, subscapular and bicep skinfold thickness;

TABLE 1: Advantages and disadvantages of insulin and metformin in pregnancy *subject to controversy, discussed in main text

importantly this same group were slightly smaller at birth, though this did not reach statistical significance.

This same group published their outcomes from seven-to-nine years. These results were especially interesting as they found that in a subset of the group, at seven years, the infants of mothers with poor glycaemic control and born LGA were not obese in childhood; while the infants of women exposed to metformin who had good glycaemic control and gained less weight in pregnancy had higher weights, upper arm and waist circumferences. This suggests a complex interplay between maternal BMI and in-utero nutritional exposure and long-term health, which has been named the ‘thrifty phenotype hypothesis’17 (see Figure 1).18 The thrifty phenotype hypothesis suggests that infants who did not receive adequate nutrition inutero display an accelerated growth pattern in

early childhood that is associated with obesity and cardiometabolic disease in adulthood.

Type 2 diabetes mellitus

In Ireland, T2DM accounts for one-third of cases of pre-gestational diabetes.19 This group is particularly vulnerable to congenital anomalies, stillbirth and pre-eclampsia and strict glycaemic control is a cornerstone of therapy. To evaluate the use of metformin in addition to insulin, the Metformin in women with Type 2 diabetes in pregnancy (MiTy) RCT examined 500 women with T2DM on insulin +/- metformin up to a dose of 2g per day.20 This landmark trial identified a number of key findings in the metformin arm, namely:

1. Fewer injections of insulin per day.

2. Less GWG (1.8kg).

3. A 10 per cent decrease in Caesarean section delivery.

4. A lower mean birthweight (3,156g vs 3,375g).

5. A reduced rate of macrosomia and LGA.

6. Higher rates of SGA (13 per cent vs 7 per cent, p<0.05).

Although some small RCTs in women with GDM had identified a reduction in foetal size in those exposed to metformin, 21 this RCT brought the risk of SGA births to the forefront of the discussion around metformin use in pregnancy.

Currently there is very little follow-on data available from RCTs of women with T2DM exposed to metformin, however, data from the MiTy Kids (NCT01832181) and subsequent MiTy Tykes RCTs is eagerly awaited.

Post-partum

It is well-established that women with a previous history of GDM face an increased risk of T2DM later in life. Screening for dysglycaemia and appropriate treatment

FIGURE 1: The Thrifty Phenotype Hypothesis17,18 (No changes have been made to this image. Licence at https://creativecommons.org/licenses/by/3.0/)

are essential in this cohort. The Diabetes Prevention Programme22 compared the outcomes of women with impaired glucose tolerance and previous GDM on metformin versus placebo. Metformin reduced the risk of T2DM by 50 per cent and the number need to treat to prevent T2DM was six. At 10 years, metformin reduced the risk of T2DM by 40 per cent.

In summary, metformin is a safe and effective way to prevent T2DM after GDM, however, it is roughly on par with lifestyle interventions and patients should be involved in decision making.

In conclusion

There is a broad range of factors and data to be considered before commencing a patient on metformin. We have summarised our key discussion points with patients as follows:

References

1. Vancura A, et al. Metformin as an anti-cancer agent. Trends Pharmacol Sci, 2018. 39(10): p. 867-878

2. Pu R, et al. Effects of metformin in obesity treatment in different populations: A metaanalysis. Ther Adv Endocrinol Metabl, 2020

3. Fleming R, et al. Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomised double blind placebo-controlled trial. J Clin Endocrinol Metab, 2002. 87(2): p. 569-74

4. Given, JE, et al. Metformin exposure in first trimester of pregnancy and risk of all or specific congenital anomalies: Exploratory case-control study. BMJ, 2018. 361: p. k2477

5. Dodd JM, et al. Metformin for women who are overweight or obese during pregnancy for improving maternal and infant outcomes. Cochrane Database of Systematic Reviews, 2018(7)

6. Chiswick C, et al. Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): A randomised, doubleblind, placebo-controlled trial. Lancet Diabetes Endocrinol, 2015. 3(10): p. 778-86

7. Syngelaki A, et al. Metformin versus placebo in obese pregnant women without diabetes mellitus. New Engl J Med, 2016. 374(5): p. 434-443

8. Vanky E, et al. Metformin versus placebo from first trimester to delivery in polycystic

1. Any decision needs to fully involve the patient.

2. Consider starting metformin in pregnant women with a BMI of >35kg/m 2 to minimise GWG. Patients should be fully aware their risk of GDM will not be reduced.

3. In women with PCOS it is reasonable to continue metformin in those with a BMI of >30kg/m 2 .

4. In women with GDM consider starting metformin in very obese women as there is good evidence it reduces GWG and the dose of insulin needed (which may reduced the burden of insulin injection significantly)

5. In women with T2DM consider initiating metformin in very obese women already on insulin or those on large doses of insulin as it may reduce the dose of insulin needed.

6. We do not advise treating T2DM in pregnancy with metformin alone.

7. In all patients consider stopping metformin

if the infant is SGA on ultrasound, in anyone with a suspicion of type 1 diabetes (ie, slim patients diagnosed with GDM and marked hyperglycaemic on diet alone), or in those with a previous history of SGA infants.

8. All patients should be made aware of the lack of long-term data in some areas and a personalised approach should be taken.

9. For those with dysglycaemia after GDM ensure that the patient is offered both metformin therapy and information on dietary and lifestyle interventions. ■

Conflicts of interest: Prof Fidelma Dunne and Dr Christine Newman are the principal investigator (PI) and sub-PI for the Effectiveness of Metformin in addition to usual care in the Reduction of Gestational Diabetes Mellitus effects (EMERGE) randomised controlled trial.

Contact: Christine.newman@nuigalway.ie

ovary syndrome: A randomised, controlled multicenter study. J Clin Endocrinol Metab, 2010. 95(12): p. E448-55

9. Løvvik TS, et al. Use of metformin to treat pregnant women with polycystic ovary syndrome (PregMet2): A randomised, double-blind, placebocontrolled trial. Lancet Diabetes Endocrinol, 2019. 7(4): p. 256-266

10. Hanem LGE, et al. Intrauterine metformin exposure and offspring cardiometabolic risk factors (PedMet study): A 5-10 year follow-up of the PregMet randomised controlled trial. Lancet Child Adolesc Health, 2019. 3(3): p. 166-174

11. Ainuddin J, et al. Metformin versus insulin treatment in gestational diabetes in pregnancy in a developing country: A randomised control trial. Diabetes Res Clin Pract, 2015. 107(2): p. 290-9

12. Mesdaghinia E, et al. Comparison of newborn outcomes in women with gestational diabetes mellitus treated with metformin or insulin: A randomised blinded trial. International Journal of Preventive Medicine, 2013. 4(3): p. 327-333

13. Rowan JA, et al. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med, 2008. 358(19): p. 2003-15

14. Picón-César MJ, et al. MeDiGes Study. Metformin versus insulin in gestational diabetes: Glycemic control, and obstetrical and perinatal outcomes. Randomised prospective trial. Am J Obstet Gynecol, 2021

15. Rowan JA, et al. Metformin in Gestational

Diabetes: The offspring follow-up (MiG TOFU). Diabetes Care, 2011. 34(10): p. 2279

16. Rowan JA, et al. Metformin in gestational diabetes: The offspring follow-up (MiG TOFU): body composition and metabolic outcomes at 7-9 years of age. BMJ open diabetes research and care, 2018. 6(1): p. e000456-e000456

17. Hales CN, Barker DJ. The thrifty phenotype hypothesis. Br Med Bull, 2001. 60: p. 5-20

18. Eberle C, Ament C. Diabetic and metabolic programming: mechanisms altering the intrauterine milieu. ISRN pediatrics, 2012. 2012: p. 975685-975685

19. Newman C, et al. Diabetes care and pregnancy outcomes for women with pregestational diabetes in Ireland. Diabetes Res Clin Pract, 2021. 173: p. 108685

20. Feig DS, et al. Metformin in women with type 2 diabetes in pregnancy (MiTy): A multicentre, international, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol, 2020. 8(10): p. 834-844

21. Tarry-Adkins JL, Aiken CE, Ozanne SE. Neonatal, infant, and childhood growth following metformin versus insulin treatment for gestational diabetes: A systematic review and meta-analysis. PLoS medicine, 2019. 16(8): p. e1002848-e1002848

22. Ratner RE, et al. Prevention of diabetes in women with a history of gestational diabetes: Effects of metformin and lifestyle interventions. J Clin Endocrinol Metab, 2008. 93(12): p. 4774-4779

Thanks to you...

Aspirin Atorvastatin Ramipril

6 Available Formulations

1st polypill licensed for secondary prevention of cardiovascular events in Ireland

The

Reduce pill burden by 730 pills per year*

Capsules shown are not actual size. Capsules are Size 0. Please refer to SmPC before prescribing.

*The calculation of a reduction of 730 pills per year is based on a patient taking the three individual components of Trinomia (aspirin, atorvastatin, ramipril) on a daily basis for 365 days compared to a patient taking a Trinomia capsule once daily for 365 days.

Trinomia 100 mg/20 mg/10 mg, 100 mg/20 mg/5 mg, 100 mg/20 mg/2.5 mg hard capsules (acetylsalicylic acid, atorvastatin (as atorvastatin calcium trihydrate) and ramipril) and Trinomia 100 mg/40 mg/10 mg, 100 mg/40 mg/5 mg, 100 mg/40 mg/2.5 mg hard capsules (acetylsalicylic acid, atorvastatin (as atorvastatin calcium trihydrate) and ramipril) Abbreviated Prescribing Information Please consult the Summary of Product Characteristics (SmPC) for full prescribing information. Presentation: Hard capsules containing: two 50 mg acetylsalicylic film-coated tablets, two 10 mg atorvastatin film-coated tablets and one 10 mg ramipril film-coated tablet; or two 50 mg acetylsalicylic filmcoated tablet, two 10 mg atorvastatin film-coated tablets and one 5 mg ramipril film-coated tablet; or two 50 mg acetylsalicylic film-coated tablet, two 10 mg atorvastatin film-coated tablets and one 2.5 mg ramipril film-coated tablet; or two 50 mg acetylsalicylic film-coated tablets, two 20 mg atorvastatin film-coated tablets and one 10 mg ramipril film-coated tablet; or two 50 mg acetylsalicylic film-coated tablet, two 20 mg atorvastatin film-coated tablets and one 5 mg ramipril film-coated tablet; or two 50 mg acetylsalicylic film-coated tablet, two 20 mg atorvastatin film-coated tablets and one 2.5 mg ramipril film-coated tablet. Uses: Secondary prevention of cardiovascular accidents as substitution therapy in adult patients adequately controlled with the monocomponents given concomitantly at equivalent therapeutic doses Dosage: Oral administration. 1 capsule per day, preferably after a meal. Swallow with liquid. Do not chew or crush. Avoid grapefruit juice. Patients currently controlled with equivalent therapeutic doses of acetylsalicylic acid, atorvastatin and ramipril can be directly switched. Treatment initiation should take place under medical supervision. Cardiovascular prevention, target maintenance dose of Ramipril is 10 mg once daily. Daily dose in renal impairment based on creatinine clearance - ≥ 60 ml/min, maximum daily dose is 10 mg ramipril; 30-60 ml/min, maximum daily dose is 5 mg ramipril. Contraindicated in hemodialysis and/or with severe renal impairment (creatinine clearance <30 ml/min). Administer with caution with hepatic impairment. Perform liver function tests before initiation of treatment and periodically thereafter. Maximum daily dose is 2.5 mg ramipril and initiate treatment under close medical supervision. Contraindicated in severe or active hepatic impairment. Start treatment in very old and frail patients with caution. In patients taking elbasvir/grazoprevir concomitantly with atorvastatin, the dose of atorvastatin should not exceed 20 mg/day. Contraindications: Hypersensitivity to any component, to other salicylates, to NSAIDs, to any other ACE inhibitors, tartrazine, soya or peanut. History of previous asthma attacks or other allergic reactions to salicylic acid or other NSAIDs. Active, or history of recurrent peptic ulcer and/or gastric/intestinal haemorrhage, other kinds of bleeding. Haemophilia and other bleeding disorders. Severe kidney and liver impairment. Hemodialysis. Severe heart failure. Concomitant treatment with methotrexate at a dosage of 15 mg or more per week. Concomitant use with aliskiren-containing products with diabetes mellitus or renal impairment. Nasal polyps associated with ashma induced or exacerbated by acetylsalicylic acid. Active liver disease or unexplained persistent elevations of serum transaminases. Pregnancy, lactation and in women of child-bearing potential not using appropriate contraceptive measures. Concomitant treatment with tipranavir, ritonavir, ciclosporin, glecaprevir/pibrentasvir,sacubitril/valsartan therapy. Trinomia must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan. History of angioedema. Extracorporeal treatments leading to contact of blood with negatively charged surfaces. Significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney. Hypotensive or haemodynamically unstable states. Children and adolescents below 18 years of age. Warnings and Precautions: Only for use as a substitution therapy in patients adequately controlled with the monocomponents given concomitantly at equivalent therapeutic doses. Special populations requiring particularly careful medical supervision: Hypersensitivity to other analgesics/antiinflammatory/antipyretic/antirheumatics or other allergens. Other known allergies, bronchial asthma, hay fever, swollen nasal mucous membranes and other chronic respiratory diseases. History of gastric or enteric ulcers, or of gastrointestinal bleeding. Reduced liver and/or renal function. Particular risk of hypotension: strongly activated renin-angiotensin-aldosterone system, transient or persistent heart failure post MI, risk of cardiac or cerebral ischemia, in case of acute hypotension medical supervision including blood pressure monitoring is necessary. Deterioration of cardiovascular circulation. Glucose 6 phosphate dehydrogenase deficiency. Risk of elevated levels of uric acid. Consumption of substantial quantities of alcohol and/or have a history of liver disease. Diagnosed pregnancy, stop treatment immediately, and, if appropriate, start alternative therapy. ACE inhibitors cause higher rate of angioedema in black patients than in non-black patients. The blood pressure lowering effect of ACE inhibitors is somewhat less in black patients than non-black patients. Monitoring during treatment is required for: Concomitant treatment with NSAIDs, corticosteroids, SSRIs, antiplatelet drugs, anticoagulants, ibuprofen. Signs or symptoms suggestive of liver injury. Stop treatment temporarily prior to elective major surgery and when any major medical or surgical condition occurs. Particularly careful monitoring is required in patients with renal impairment, risk of impairment of renal function, particularly with congestive heart failure or after a renal transplant. Serum potassium: ACE inhibitors can cause hyperkalemia in patients with impaired renal function and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim or co-trimoxazole and especially aldosterone antagonists or angiotensin-receptor blockers, hyperkalemia can occur. Potassium-sparing diuretics and angiotensin-receptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored. Other situations that may increase the risk of hyperkalaemia are: age >70 years, uncontrolled diabetes mellitus, dehydration, acute cardiac decompensation or metabolic acidosis.Specific side-effects: Perform liver function tests before use and monitor periodically and with liver injury or increased transaminase levels. Use with caution with substantial alcohol use or history of liver disease. Potential risk of hemorrhagic stroke. May affect the skeletal muscle and cause myalgia, myositis, and myopathy that may progress to rhabdomyolysis, ask patients to promptly report skeletal muscle effects (muscle pains, cramps or weakness) especially if accompanied by malasie or fever and measure CK levels, stop treatment if significantly elevated or if severe muscular symptoms occur. Prescribe with caution in patients with pre-disposing factors for rhabdomyolysis. Benefit/risk of treatment should be considered and clinical monitoring recommended. Do not measure CK following strenuous exercise or in presence of plausible alternative cause of CK increase. If CK levels significantly elevated at baseline, re-measure levels 5 to 7 days later to confirm the results. Risk of rhabdomyolsis with use of potent CYP3A4 inhibitors, transport proteins or HIV protease inhibitors. Consider alternative treatments if risk of myopathy. Consider lower starting or maximum dose and appropriate clinical monitoring with potent CYP3A4 inhibitors and medicinal products that increase the plasma concentration of atorvastatin respectively. The risk of myopathy may also be increased with the concomitant use of gemfibrozil and other fibric acid derivates, antivirals for the treatment of hepatitis C (HCV) (boceprevir, telaprevir, elvasvir/grazoprevir), erythromycin, niacin or ezetimibe. Do not co-administer with systemic fusidic acid or within 7 days of stopping fusidic acid. Where use of systemic fusidic acid considered essential, discontinue statin treatment during fusidic acid treatment. Reports of rhabdomyolysis in patients receiving fusidic acid and statins in combination. Where prolonged systemic fusidic acid needed, consider need for co-administration of Trinomia and fusidic acid on case by case basis with close medical supervision. Discontinue statin treatment if interstitial lung disease occurs. Monitor patients at risk of diabetes mellitus. Discontinue treatment if angioedema occurs and initiate emergency treatment promptly. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated. due to the increased risk of angioedema. Treatment with sacubitril/valsartan must not be initiated earlier than 36 hours after the last dose of Trimomia. Caution should be used when starting racecadotril, mTOR inhibitors and vildagliptin in a patient already taking an ACE inhibitor as there is an increased risk of angioedema. Concomitant use of ACE-inhibitors and angiotensin II receptor blockers or aliskiren is not recommended and should not be used in patients with diabetic nephropathy. Anaphylactic reactions during desensitization, consider temporary discontinuation of Trinomia during desensitization. Monitor white blood cells for neutropenia/agranulocytosis and more regularly in the initial phase of treatment, impaired renal function, concomitant collagen disease and other medicines that can change the blood picture. Cough. Contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Interactions: Acetylsalicylic acid: other platelet aggregation inhibitors, other NSAIDs, and antirheumatics, systemic glucocorticoids, diuretics, alcohol, SSRIs, uricosuric agents, metamizole, anticoagulant and thrombolytic therapy, digoxin, antidiabetic agents including insulin, methotrexate, valproic acid, antacids, ACE inhibitors, ciclosporin, vancomycin, interferon , lithium, barbiturates, zidovudine, phenytoin, laboratory tests. Atorvastatin: CYP3A4 inhibitors, CYP3A4 inducers, transport protein inhibitors, gemfibrozil/fibric acid derivatives, ezetimibe, colestipol, fusidic acid, colchicine, digoxin, oral contraceptives, warfarin. Ramipril: potassium salts, heparin, potassium-retaining diuretics and other plasma potassium increasing active substances, antihypertensive agents and other substances that may decrease blood pressure, vasopressor sympathomimetics and other substances, allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood cell count, lithium salts, antidiabetic agents including insulin. Monitor as appropriate. Consider lower maximum dose of atorvastatin with potent CYP3A4 inhibitors. Pregnancy and Lactation: Contraindicated in pregnancy and breast-feeding. Women of child-bearing potential should use effective contraception during treatment. Side Effects: Ramipril: Common (≥1/100, <1/10): dyspepsia, nausea, diarrhoea, vomiting, digestive disturbances, abdominal discomfort, gastrointestinal inflammation, non-productive tickling cough, bronchitis, sinusitis, dyspnoea, headache, dizziness, rash in particular maculo-papular, blood potassium increased, myalgia, muscle spasms, chest pain, fatigue, hypotension, orthostatic blood pressure decreased, syncope. Atorvastatin: Common: dyspepsia, nausea, diarrhoea, constipation, flatulence, pharyngolaryngeal pain, epistaxis, nasopharyngitis, headache, allergic reactions, hyperglycaemia, myalgia, muscle spasms, pain in extremity, joint swelling, back pain, arthralgia, liver function test abnormal, blood creatine kinase increased. ASA: Very Common (≥ 1/10): Gastrointestinal complaints such as heartburn, nausea, vomiting, stomach ache and diarrhea, minor blood loss from the gastrointestinal tract (micro-bleeding). Common: Paroxysmal bronchospasm, serious dyspnoea, rhinitis, nasal congestion. For less frequent side effects see SmPC. Pack Sizes: Blister containing 28 hard capsules. Legal Category: POM. Product Authorisation Numbers: PA 1744/002/001-006 Product Authorisation

Diabetic foot disease in focus

AUTHOR: Theresa Lowry-Lehnen, CNS, GPN, RNP, PhD, and Associate Lecturer at IT Carlow

Diabetic foot ulceration (DFU) is a vascular complication of diabetes mellitus and associated with extensive periods of hospitalisation and a high degree of morbidity and mortality. The pathogenicity of diabetic foot ulcers are multifactorial. Diabetic foot syndrome (DFS) is associated with neurologic abnormalities and peripheral arterial disease (PAD) of the lower limbs of varied severity. DFS involves infection, ulceration, or destruction of deep tissues of the foot (including bones) in a patient with diabetes mellitus and is defined by the World Health Organisation (WHO) as an “ulceration of the foot (distally from the ankle and including the ankle) associated with neuropathy and different grades of ischaemia and infection”.1,3

Diabetes mellitus is a disorder of glucose haemostasis, which causes hyperglycaemia. When high blood glucose levels persist, complications occur causing damage in the wall of blood vessels throughout the body systems. A combination of damage in both small and large blood vessels leads to the presence of DFS manifesting in DFU. Neuropathy and vascular abnormalities are involved in the development of DFS. The underlying cause of DFS is the complex interaction between large vessel disease causing PAD and small vessel disease leading to peripheral diabetic sensory neuropathy. 2

Motor neuropathy results in atrophy of foot muscles, disturbing the flexor-extensor balance and leading to contractures. Sensory neuropathy including abnormal sensation of pain, temperature, and touch exposes the patient to repeated uncontrolled injuries, increasing the risk of ulcerations. Autonomic neuropathy results in the formation of arteriovenous fistulae and trophic changes and atherosclerosis of the lower extremities results in foot

ischaemia. All these changes are associated with the development of local osteoporosis and may also lead to osteomyelitis, avascular necrosis, fractures, dislocations, and Charcot foot arthropathy. 3

DFS affects nearly 6 per cent of individuals with diabetes, and around 0.5-to-1.5 per cent of patients with DFS require amputation. Most amputations start with ulcerations and can be prevented with good foot care and screening to assess the risk of foot complications. DFS is associated with neurologic abnormalities and PAD of the lower limbs of varied severity. 3

All patients with diabetes should have an annual screen to identify their foot ulcer risk status. Those with any risk factors require specific foot care education as well as regular contact with a healthcare professional, usually a podiatrist. Most important in the identification of the high-risk neuropathic foot is good clinical observation and removal of the shoes and socks, with careful inspection of the feet as part of the routine follow up of all patients with diabetes. 6

Risk factors for developing diabetic foot ulcers

All people with diabetes are at risk of developing foot ulcers. The trilogy of peripheral neuropathy, PAD and susceptibility to infection are the main predisposing factors for lesions on the foot. Other factors that increase the risk include poorly fitting or poor quality shoes, not washing regularly or thoroughly or not drying the feet well after washing, improper trimming of toenails, plantar calluses, elevated foot pressures, foot deformity, visual disturbance as a consequence of retinopathy, cardiac disease, renal disease, oedema, obesity, alcohol and tobacco

use, ethnic and poor social backgrounds. DFU is most common in older men. It is the interaction and combination of risk factors working together that leads to skin breakdown. 4,6 Of all the risk factors for DFU the most important is a past history of ulceration and/or amputation.

It is estimated that 19-to-34 per cent of patients with diabetes are likely to be affected by DFU in their lifetime, and the International Diabetes Federation reports that 9.1-to-26.1 million people will develop DFU annually. A UK populationbased cohort study demonstrated that the development of DFU is associated with a 5 per cent mortality in the first 12 months and a 42 per cent mortality within five years. Patients with DFU were also found to have a 2.5-fold increased risk of death compared with their diabetic counterparts without foot wounds. 5

Effective glycaemic control reduces the incidence of DFU and decreases the risk of amputation. In assessing glycaemic control the HbA1c test should be performed routinely in all patients with diabetes. HbA1c is an indirect measure of average glycaemia and has a strong predictive value for diabetes complications. A target of 53mmol/l (7 per cent) or below is recommended as the optimal target for diabetes patients. 8 Self-monitoring of blood glucose (SMBG) allows real time measurement of blood glucose levels for individuals. It is important for patients who are self-monitoring to have a good understanding of glucose levels, what their targets are, how well they are achieving this, and to play an active role in managing and tailoring their levels and preventing complications. 2

Routine diabetes foot screening should ensure that all patients with diabetes are offered annual screening and regular

ON DIAGNOSIS OF DIABETES AND AT ANNUAL REVIEW THEREAFTER:

Trained practice nurse will examine patient’s feet and lower limbs for risk factors, this should include:

 Testing vibration and 10g monofilament sensation

 Palpation of dorsalis pedis and posterior tibial pulses in both feet

 Inspection of any foot deformity

 Inspection of footwear

LOW RISK

CLINICAL FINDINGS

Normal sensation

 Intact pressure and vibration sensation

No peripheral arterial disease (PAD)

 All pedal pulses present

 No signs or symptoms of PAD, ie, claudication pallor, dependent rubor, poor tissue vitality

No previous ulcer or lower limb amputation

 No foot deformity

 Normal vision

MODERATE RISK

CLINICAL FINDINGS

Any one of the following:

 Loss of sensation/peripheral neuropathy

 PAD:

 Absent pulses

 Signs or symptoms of PAD

 Previous vascular surgery

 Structural foot deformity

 Significant visual impairment

 Physical disability (eg, stroke or gross obesity)

AT RISK

ACTIVE FOOT DISEASE

HIGH RISK

CLINICAL FINDINGS

PAD and sensory loss and/ or previous diabetes-related foot ulcer or lower limb amputation and/or previous Charcot neuroarthropathy

CLINICAL FINDINGS

Active foot ulceration and/or active Charcot neuroarthropathy

MANAGEMENT PLAN

Referral with rapid access (within 24 hours/next working day) to multidisciplinary foot care service in tertiary centre

MANAGEMENT PLAN

 Access to vascular, orthopaedics, orthotics

MANAGEMENT PLAN

MANAGEMENT PLAN

 Annual foot screening in primary care

 Practice nurse/primary care nurse to screen

 Clinical nurse specialist and/or podiatrist to provide education to practice nurse/ public health nurse to provide screening

 Patient education/ smoking cessation

 Annual foot examination by foot protection team and ongoing review by podiatrist member of the foot protection team based in either the hospital or the community

 Education in foot protection

 Vascular assessment, biomechanical, orthopaedic assessment and orthotics if indicated

 Referral to community podiatry for non-diabetic foot pathology

 Called for formal review by foot protection team and routine ongoing review by GP/ practice nurse/hospital diabetes clinic

 Examination for deformity, neurological and vascular status, and footwear and orthotics as indicated

 Education in foot protection

 If ulceration present then refer within 24 hours to multidisciplinary foot care service (Model 4 hospital)

 Access to vascular laboratory, radiology, microbiology, infectious disease

HEALED ULCER

 Once ulcer healed refer patient back to the foot care team in the referral Model 3 hospital

 If the healed ulcer belongs to a patient who originated from Model 4 hospital, they remain under the care of the specialist diabetes foot service in the Model 4 hospital

Figure 1: Foot assessment and classification protocol. (Source : HSE Model of Care for the Diabetic Foot)

foot examinations from early diagnosis. Foot review and screening is carried out by appropriately trained staff and foot care education is provided to individuals according to their clinical and personal needs. Patients are regularly assessed for their risk of DFU and classified as low, at risk (moderate or high risk), or with active foot disease.7

Foot care management in diabetes is based on three categories of risk 7

1. Patients at low risk of diabetic foot disease are managed preventatively through annual screening and regular foot examinations by primary care nurses. A low risk patient has normal foot pulses, normal vibration and sensation to 10g monofilament, no history of foot ulceration, no significant foot deformity, or no visual impairment.7

2. Patients at risk of diabetic foot disease may be classed as either moderate or high risk. All patients will be under regular surveillance by primary care nurses/GPs. Moderate risk patients will be referred to the podiatrist, either in the community or in the hospital, for an annual review and these patients will remain under the clinical governance of the GP and podiatrist. The moderate risk patient has either impaired peripheral sensation or impaired circulation or significant visual impairment or a structural foot deformity. High risk patients will be reviewed at least annually by the diabetes foot protection team in one of the 16 designated centres and will be under the governance of the foot protection team for their foot care. The high risk patient has an abnormality that predisposes them to foot ulceration. This can be impaired sensation and impaired circulation, or a previous foot ulcer, previous lower limb amputation or previous Charcot foot.7

3. Patients with active diabetic foot disease have an active foot ulcer (full thickness skin break) or a Charcot foot and will be actively managed by a multidisciplinary specialist foot care service, in conjunction with vascular surgery, orthopaedics,

and orthotics input as required. This is available in the eight Model 4 indicative hospitals.7 The HSE National Model of Care states that patients with active DFU should be referred to the multidisciplinary diabetic foot team (MDFT) in the Model 4 hospital within one working day.

Diabetic foot care involves a multidisciplinary team approach including a wide range of professionals as well as patients and their carers. Central to diabetes foot care are patients, carers, podiatrists, general practice nurses and other primary care nurses, GPs, diabetes specialist nurses, diabetes consultants, orthoptists, vascular surgeons, and orthopaedic surgeons. Other groups with an important input into diabetes foot care are tissue viability nurses, physiotherapists, infectious disease service, radiology consultants, ward nurses, and emergency department (ED) staff.7

 Footwear.

 Daily self-examination of the feet.

 Not walking in bare feet.

 Checking footwear and hosiery before putting them on.

 Breaking shoes in should never be attempted.

 No hot water bottles.

 Checking bath and shower temperature.

 Avoidance of home remedies, eg, corn plasters.

 What to do and the appropriate person to contact if foot problems develop.

 A low risk foot information sheet should be provided.

A patient with low risk of diabetic foot disease does not routinely need to see a podiatrist for diabetes-related purposes.

Moderate risk foot: A patient at moderate risk of foot complications has either a reduction in vibration or 10g monofilament sensation or has absent foot pulses in either or both feet. There must be no history of ulceration and no significant foot deformity.7 Foot examination frequency requires ongoing review by GP/general practice nurse or primary care nurse or hospital diabetes clinic as part of routine follow-up. Annual podiatry review by the specialist podiatrist is based either in the community or in the hospital.7

Patients previously classified as moderate risk should have the following foot examination:

Screening and assessment

Low risk foot: Patients previously classified as low risk or patients newly diagnosed with diabetes mellitus should receive annual foot screening as part of their general diabetes care and have the following foot examination:7

 Inspection of skin, nails and for structural foot deformity.

 Vibration perception testing (128Hz tuning fork) and cutaneous pressure perception testing using the 10g monofilament.

 Palpation of foot pulses.

 Examination of footwear.

Foot care education involves:7

 Nail care.

 Emollient use.

 Inspection for structural foot deformity.

 Skin and nail examination.

 Vibration perception testing (128Hz tuning fork) and cutaneous pressure perception testing using the 10g monofilament.

 Palpation of foot pulses.

 A comprehensive vascular assessment where indicated, including Doppler waveform analysis, ankle brachial index, and toe brachial pressure index calculation.

 Examination of footwear.

Management

If there is loss of vibration and 10g monofilament sensation the patient should be educated on how to protect their feet. If there is intact sensation and absence of foot

Diabetic foot care involves a multidisciplinary team approach including a wide range of professionals as well as patients and their carers

pulses in either or both feet, the patient may require further vascular assessment, particularly if there are symptoms of vascular insufficiency. Foot deformity may not need any action, but if it is severe the patient should be referred for specialist assessment. Podiatry advice, biomechanical assessment and discussion of all treatment options including accommodative footwear and orthoses should be provided where required. In some cases orthopaedic surgery may be required. If there is other foot pathology such as nail conditions, corns, callus or verrucae, these can be dealt with during the examination by the podiatrist and a referral to a community podiatrist should be made.7 Foot care education as previously described should be provided for the patient.7

High risk foot: A patient with high risk of foot complications has both a reduction in vibration and monofilament sensation and PAD – absence of foot pulses. If there is a previous history of ulceration, lower limb amputation or Charcot neuroarthropathy then the foot is classified as high risk automatically and remains in the high risk category. Foot examination frequency requires ongoing review by GP/ primary care nurse/hospital diabetes team. Patients will be called for formal annual review or more frequently as required by the members of the foot protection team or service where appropriate.7

Patients classified as high risk should have the following foot examination:7

 Inspection for structural foot deformity.

 A comprehensive neurological assessment.

 A comprehensive vascular assessment where indicated, including Doppler waveform analysis, ankle brachial and toe brachial pressure index calculation.

 Examination of footwear.

Management 7

 The diabetes foot protection clinic should take place on a monthly basis at minimum, within the Model 3 or Model 4 hospital and should have input from a diabetes specialist, podiatrist, and diabetes nurse with input where necessary from vascular,

orthopaedics, and orthotics.

 Podiatrists within the foot protection team or foot care service should review the high risk foot at least once every 12 months.

 If ulceration is present the patient should be referred within 24 hours or the next working day to the multidisciplinary foot care service (Model 4 hospital).

 The educational needs of the patient should be reviewed.

 If there is a problem with footwear, the patient should be referred to a podiatrist/ orthotist for footwear assessment and orthoses provision.

 The patient should be referred to vascular services.

 If there is other foot pathology such as nail conditions, corns, callus or verrucae, referral to a community podiatrist should be made.

 The hospital podiatrist will work closely with the community podiatrist in the joint care of high risk foot patients.

 Foot care education as previously described should be provided for the patient.

Active foot disease: All diabetes patients with an active foot ulcer or active Charcot foot should be referred to the diabetes foot clinic urgently and patients should be seen within 24 hours or on the next working day by the diabetes multidisciplinary foot care service, and involve the appropriate specialties. Patients will be seen weekly by a member of the multidisciplinary foot care service until healing of the ulcer occurs and will be seen regularly in the specialist multidisciplinary foot care clinic until ulcer healing or the Charcot foot becomes stable and inactive.

Patients with active foot disease should have the following foot examination:

 Inspection for structural foot deformity.

 A comprehensive neurological assessment.

 A comprehensive vascular assessment where indicated, including Doppler waveform analysis, ankle brachial, toe brachial pressure index calculation and/or radiological imaging of the lower limb vasculature.

 Radiology investigations where indicated including foot x-ray or MRI of the foot.

Isotope bone scan may also be used in certain circumstances.

 Examination of footwear.

Management 7

 The diabetes foot care clinic should take place on a monthly basis at minimum within the Model 4 hospital and should have input from a diabetes consultant, senior podiatrist and diabetes nurse, with input where necessary from vascular, orthopaedics, orthotics, tissue viability, physiotherapy, plastic surgery, and infectious disease.

 Podiatrist within the foot care service should review the active foot disease patient at least weekly until healing occurs.

 Review the educational needs of the patient.

 Referral to a podiatrist/orthotist for footwear assessment and orthoses provision if required.

 Refer to vascular and/or orthopaedics where necessary.

 If there is other foot pathology such as nail conditions, corns, callus or verrucae, referral to a community podiatrist should be made.

 If there are clinical signs of infection, antibiotics should be commenced immediately.

 If there are clinical signs of severe/ limb-threatening infection then the patient should be admitted urgently for intravenous antibiotic therapy.

 If there is evidence or suspicion of osteomyelitis the patient should be referred for radiological and orthopaedic review.

 Control vascular risk factors.

 Once the foot ulcer has healed and appropriate footwear organised for the patient, they can be moved back to the ‘high risk group’ in the ‘at risk’ category. However, if there is the likelihood of re-ulceration the patient should continue to attend the multidisciplinary foot care service in a Model 4 hospital.

 The high risk foot information sheet should be given to the patient.

A comprehensive assessment of the patient’s general health, glycaemic control, extent of peripheral neuropathy and detailed dermatologic and musculoskeletal

examination are included in the evaluation. Clinical evaluation of the foot wound should include a detailed description of the site, size, and depth of wound. Neuropathic ulcers typically occur in the warm but insensate foot, often under pressure-bearing areas, and are surrounded by callus. Ischaemic wounds tend to occur in the cool, poorly perfused foot and are often at lateral fifth metatarsal head regions or the medial first metatarsal head regions. Correct identification of the degree of ischaemia is of great importance when evaluating a wound. 6

Classification

Ulcers are graded using the University of Texas Classification System (Figure 2), which is a validated tool specifically for diabetic foot ulcers. The Meggitt-Wagner grading system was regarded as the gold standard for many years. One problem with the Meggitt-Wagner grading system is that the ischaemic status of the wound is not included and therefore a number of new classification systems for diabetic foot wounds have been proposed and validated over the last 20 years. The University of Texas Classification System incorporates the Meggitt-Wagner grades, but also enables the practitioner to stage the wound with respect to the presence or absence of infection and/or ischaemia.6,9

Treatment and management

Depending on the primary underlying cause of ulceration, the wound will be assessed and a management plan will be developed. The management of DFU is multifaceted and combines revascularisation, infection management, debridement of dead tissue and offloading of pressure in addition to hyperglycaemic treatment and wound care. 2 Treatment of hyperglycaemia, ketoacidosis, renal insufficiency and other comorbidities that may coincide in the ulcerated patient should be treated simultaneously with the foot lesion. Debridement is important as it reduces devitalised tissue, promotes proliferation, granulation, and epithelialisation, eliminates potential

pathogens, allows exudate drainage, reveals the true extent of ulceration and reduces pressure on subcutaneous tissue.9

DFU should heal if there is an adequate arterial inflow, infection is aggressively managed, and pressure is removed from the wound and its margins. Pressure reduction is essential for a patient who has just been treated for a diabetic foot and off-loading or reducing the pressure plays a significant role in managing the healing process. There are various off-loading

enhance patient understanding of the need for offloading. 6,9

Identification of infection in wounds can be challenging and particularly so in DFU. In the presence of neuropathy and ischaemia, signs of infection can be diminished as the normal inflammatory response is impaired. The correct diagnosis of infection in the diabetic foot wound is critical as it is often the combination of untreated infection and PAD that lead to amputation in the diabetic foot. If osteomyelitis is suspected plain x-rays can assist diagnosis, however, initially reports may prove normal and evidence of osteomyelitis may not be apparent for 14 days. Antibiotic usage should be guided by clinical signs of infection and microbiologic analysis of deep tissue specimens.6,9

modalities such as the total-contact casts (TCC), removable cast walkers (RCW) and half shoes, and studies have been conducted to compare their effectiveness to heal neuropathic foot ulcerations in diabetic individuals. Although less commonly used, results reveal that TCC is better and heals a comparatively higher number of wounds in a shorter duration of time. In the management of plantar neuropathic ulcers, offloading is critical and all efforts must be made to

Most adjunctive therapies have little evidence to support their use, although recent trials suggest efficacy for a number of topical therapies including LeucoPatch and sucrose octasulfate. Negative pressure wound therapy has also been shown to be helpful in certain cases. There is currently no indication for hyperbaric oxygen usage, whereas recent studies suggest that topical oxygen therapies may help wound healing. 6,10

Wound dressings are important to keep the ulcer clean, but the placement of a large dressing on a wound may mislead

Figure 2: The University of Texas Wound Classification System

Antibiotic usage should be guided by clinical signs of infection and microbiologic analysis of deep tissue specimens

the patient into believing that the dressing of an ulcer is curative. Although there has been much progress in the understanding and management of diabetic foot disorders over the last three decades, much of what we use in clinical practice today still lacks an evidence-base. This is particularly true for dressings and there is little evidence from randomised controlled trials (RCTs) that any dressing is superior to another.6

Prevention and recurrence

Prevention of diabetic foot disease can only be successful with the early identification of patients who have risk factors for foot ulceration. All patients with diabetes should, at whatever stage, be screened for evidence of complications at least annually. The principle aim of the annual review is to identify those with early signs of complications and provide appropriate management to prevent progression. The most important aspect of the annual foot review is the removal of shoes and socks with very careful inspection of both feet including between toes. Many neuropathic feet can be identified by this simple clinical observation, looking for features such as small muscle wasting, clawing of the toes, prominence of the metatarsal heads, distended dorsal foot pains, dry skin, and callus formation. For evidence of neuropathy, the perception of pressure using the 10g monofilament should be used at four sites in each foot. An additional test, which might include a vibrating 128Hz tuning fork, should also be used to confirm any abnormality. For the vascular assessment, foot pulse palpation is most important. The ankle brachial index may be falsely elevated in many patients with diabetic neuropathy and therefore listening to the Doppler signal may be more helpful.

Other simple devices developed for clinical screening that have been validated in clinical studies include the ‘Ipswich Touch Test’, which assesses the ability of the patient to perceive the touch of a finger on the toes and the ‘Vibratip’, a battery-operated disposable vibrating

stylus used to assess vibration sensation. A number of studies are currently looking at ‘smart technology’ in the prevention of recurrent DFU. These include the use of sensors in socks or shoes to detect pressure change and also various devices to measure differentials in skin temperature. These technologies aim to alert patients in the pre-ulcerative phase with the hope of preventing the actual ulcer from developing. 6

Recurrence is common after the healing of neuropathic or neuro-ischaemic foot ulcers, and the patient is termed in remission rather than healed following an episode of DFU. While the symptoms may have resolved the underlying disease process remains and the symptoms of the disease will likely re-occur. Rates of DFU recurrence are up to 40 per cent one

References

1. Tuttolomondo A, Maida C, Pinto A. (2015). Diabetic foot syndrome: Immune-inflammatory features as possible cardiovascular markers in diabetes. World J Orthop. 2015 Jan 18; 6(1): 62–76.doi: 10.5312/wjo.v6.i1.62

2. Wilson P, Fu W, Doyle J. (2021). Joining the dots… Diabetes mellitus and foot disease. Irish Pharmacy News, Volume 13, Issue 7, pp 68-69. Available at: www.pharmacynewsireland.com/ digital-magazines/

3. Rodríguez-Gutiérrez R, Quintanilla-Flores DL, Soto-Garcia AJ, Gonzalez-Gonzalez JG, Sieradzki J, Płaczkiewicz-Jankowska E. Diabetic foot syndrome. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. https://empendium.com/mcmtextbook/chapter/ B31.II.13.4.4

4. Healthline (2021). Diabetic ulcers: Causes and treatment. Available at: www. healthline.com/health/type-2-diabetes/ hyperglycemic-hyperosmolar-syndrome

5. Everett E, Mathioudakis N. Update on management of diabetic foot ulcers. Ann N Y Acad Sci. 2018 Jan; 1411(1): 153–165. doi: 10.1111/nyas.13569

year following DFU. It is important that patients and their families are educated about the persistence of DFS even in the absence of DFU. 2

All individuals with diabetes should receive regular screening and structured education to empower them to maintain their own foot health. Early identification of problems and rapid referral to the specialist multidisciplinary team can reduce the risk of DFU and unnecessary amputations.9 Foot care programmes accentuating preventive management can reduce the incidence of foot ulceration through modification of self-care practices, appropriate evaluation of risk factors and formulation of treatment protocols directed at patient education/re-education, early intervention, limb preservation, and prevention of new lesions. ■

6. Boulton A, Whitehouse W. (2020). The diabetic foot. NCBI. Available at: www.ncbi.nlm. nih.gov/books/NBK409609/

7. HSE (2011). Model of care for the diabetic foot. HSE. Available at: www.hse.ie/ eng/services/list/2/primarycare/east-coastdiabetes-service/management-of-type-2diabetes/foot-care/model-of-care-diabetic-foot. pdf

8. Diabetes Ireland (2021). Know your numbers and targets. Diabetes Ireland. Available at: www.diabetes.ie/are-you-at-riskfree-diabetes-test/a-numbers-game/

9. NUI Galway (nd). Foot screening and education of the patient with diabetes. Discipline of Podiatry School of Health Sciences NUI Galway. Available at: www.hse.ie/eng/ services/publications/clinical-strategy-andprogrammes/foot-screening-and-education-ofthe-patient-with-diabetes.pdf

10. Niederauer M, Michalek J, Liu Q, et al. (2018). Continuous diffusion of oxygen improves diabetic foot ulcer healing when compared with a placebo control: A randomised, double-blind, multicenter study.  J Wound Care. 2018; 27 suppl 9:S30–S45

Changes to the Diabetic RetinaScreen screening pathway for eligible participants

AUTHOR: Priscilla Lynch

Diabetic retinopathy is the most common cause of blindness in working-age individuals’ in Ireland, at the present time. People with both type 1 and type 2 diabetes are at risk of developing diabetic retinopathy. It is estimated that there are approximately 190,000 people in Ireland with diabetes and 10 per cent of them are at risk of sight-threatening retinopathy. Screening and prompt treatment together can reduce visual disability by 90 per cent.

The national diabetic retinopathy screening programme, Diabetic RetinaScreen, has been providing free retinal screening to all diabetes patients in Ireland over the age of 12 years since 2013.

Digital retinal photography with mydriasis is the gold standard screening test to detect diabetic retinopathy, which is used by the programme. As a part of screening, two retinal photographs are taken of each eye and visual acuity is measured at each visit.

The photographs are then graded R1, R2, or R3 for severity of retinopathy based on signs present in each eye. R1 is the low risk stage of retinopathy, R2 grade is considered to be of moderate risk, and R3 grade has high risk of visual deterioration.

Since the programme’s launch, prevalent, undiagnosed, and untreated diabetic retinopathy and maculopathy have been successfully identified and referred for evidencebased treatments at the programme’s seven treatment centres before any significant visual symptoms occur.

In the first screening cycle of the programme, 4.5 per cent of the patients screened were referred for having vision-threatening retinopathy (pre-proliferative and proliferative). This proportion of visionthreatening retinopathy in the community being recognised in the last full cycle of the

programme pre-Covid-19 had reduced to 1.5 per cent of approximately 105,000 clients screened.

Screening frequency change

Until this year, the programme had invited programme participants for screening once a year. However, in February Diabetic RetinaScreen extended the interval to two years for people with diabetes who are at low risk of retinopathy.

If a person has received a result of ‘no retinopathy’ from their previous two screenings, their next screening invitation will be two years from the time of their last screen. The new pathway aims to reduce the number of screening appointments and reduce unnecessary clinic visits and examinations, and is also timely given the impact the Covid-19 pandemic had on delaying screening appointments in the last 18 months. Other countries that offer twoyearly screening intervals include Canada, Denmark, Finland, Iceland, and Scotland.

The change was made on foot of a recommendation by the National Screening Advisory Committee (NSAC), which is an independent advisory committee that advises the Minister for Health on all new proposals for population-based screening programmes and revisions to existing programmes, in line with international best practice.

Prof Niall O’Higgins, Chair of the NSAC, acknowledged the implementation of the new pathway. “The NSAC considered and approved a formal application from the Diabetic RetinaScreen Programme to extend the interval between screens from one-totwo-years for people with diabetes who are at low risk of developing sightthreatening diabetic retinopathy, and recommended to the Minister that he approve the modification to the Programme.

“I would like to acknowledge the valuable support given to the NSAC by HIQA in reviewing and analysing the evidence and assisting us in reaching the decision to recommend the change.

“In making this recommendation, the NSAC also highlighted the importance of communicating and reassuring eligible participants of the changes, and I am pleased to see the early implementation by the Diabetic RetinaScreen Programme of the new pathway.”

Prof David Keegan, Clinical Director of Diabetic RetinaScreen said: “International evidence shows that if a person has two consecutive results of ‘no retinopathy’, it is safe for them to attend their screening appointment every two years. People who have had two consecutive results of ‘no retinopathy’ have been found to be at very low risk of progressing to retinopathy between screens.”

If a person is suitable to avail of a two-yearly screening, Diabetic RetinaScreen will let them know. They will then be invited for screening every two years. Then, if their next screening results detect retinopathy, they will be returned to annual screening or referred for treatment.

Prof Keegan added that it is important that people who have diabetes continue to attend for their screening test when they are invited. “And if a person has sight loss, they should not wait to receive an invitation from DRS [Diabetic RetinaScreen]. They should contact their GP, eye doctor or optician immediately for advice. When the condition is caught early, treatment is effective at reducing or preventing damage to sight.” ■

Adding patients to the register to be screened is easy and can be done by a patient’s GP or allied health professional using the free phone number: 1800-454-555 or email info@ diabeticretinascreen.ie Full screening information is available at www.diabeticretinascreen.ie.

For patients with wet AMD1

THEIR VISION IS A WORK OF ART

For patients

NOW AVAILABLE

THEIR WORK

In two head-to-head trials vs aflibercept, Beovu®1:

• Demonstrated robust vision gains and non-inferiority vs. aflibercept in mean BCVA change from baseline to week 482*

• Outperformed aflibercept with superior fluid resolution at Weeks 16 and 482†

• Maintained a majority of patients on a q12w interval immediately after loading through Week 481

• Exhibited an overall welltolerated safety profile3

STUDY DESIGN: The safety and efficacy of Beovu was assessed in 2 randomized, multicenter, double-masked, active-controlled Phase III studies (HAWK and HARRIER) in patients with wet AMD. A total of 1817 patients were treated for 2 years (Beovu [N=1088]; aflibercept [N=729]). Patients were randomized to either Beovu (6.0 mg [n=360; n=372], q12w/q8w in HAWK and HARRIER, respectively; 3.0 mg [n=358], q12w/q8w in HAWK only) or aflibercept (2.0 mg, q8w). For patients on Beovu, after 3 initial monthly doses (Weeks 0, 4, and 8), disease activity assessments (DAAs) were conducted at Weeks 16 and 20. Patients selected for q12w received first treatment at Week 20 and continued on q12w unless disease activity (DA) was identified at any subsequent DAA visit (Weeks 20, 32, 44, 56, 68, 80, and 92). Patients identified with a q8w need at Week 16 and Week 20 were switched to q8w for the remainder of the study. Additional assessments and potential dosing interval adjustments occurred at Weeks 28, 40, 52, 64, 76, and 88 in HARRIER only. Aflibercept was administered every 8 weeks after 3 initial monthly doses. There was no hypothesis testing after Week 48.1,3,4 AMD=age-related macular degeneration; BCVA=best corrected visual acuity; ETDRS=Early Treatment Diabetic Retinopathy Study; q12w/q8w=treatment every 12/8 weeks.

ABBREVIATED PRESCRIBING INFORMATION

Beovu▼ (brolucizumab) 120 mg/ml solution for injection in pre-filled syringe. Please refer to the Summary of Product Characteristics (SmPC) before prescribing. Presentation: Each pre-filled syringe contains 19.8 mg of brolucizumab in 0.165 mL solution. This provides a usable amount to deliver a single dose of 0.05 ml solution containing 6 mg of brolucizumab. Indication: Beovu is indicated for the treatment of neovascular (wet) age-related macular degeneration (AMD). Administration and Dosage: Single-use pre-filled syringe for intravitreal use only. Each pre-filled syringe should only be used for the treatment of a single eye. Beovu must be administered by a qualified ophthalmologist experienced in intravitreal injections. Adults: Posology: The recommended dose is 6 mg brolucizumab (0.05 ml solution) administered by intravitreal injection every 4 weeks (monthly) for the first 3 doses. Thereafter, the physician may individualise treatment intervals based on disease activity as assessed by visual acuity and/or anatomical parameters. A disease activity assessment is suggested 16 weeks (4 months) after treatment start. In patients without disease activity, treatment every 12 weeks (3 months) should be considered. In patients with disease activity, treatment every 8 weeks (2 months) should be considered. The physician may further individualise treatment intervals based on disease activity. If visual and anatomical outcomes indicate that the patient is not benefiting from continued treatment, Beovu should be discontinued. Special populations: Renal and Hepatic impairment: No dose adjustment is required. Elderly: No dose adjustment is required in patients aged 65 years or above. Pediatric patients: Safety and efficacy have not been established. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Patients with active or suspected ocular or periocular infections. Patients with active intraocular inflammation. Warnings and precautions: Traceability: the name and the batch number of the administered product should be clearly recorded. Intravitreal injection-related reactions: Intravitreal injections, including those with Beovu, have been associated with endophthalmitis, intraocular inflammation, traumatic cataract retinal detachment, retinal vasculitis, and/or retinal vascular occlusion (see section 4.8 of the SPC). Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been reported with the use of Beovu (see sections 4.3 and 4.8). In patients developing these events, treatment with Beovu should be discontinued and the events should be promptly managed. Proper aseptic injection techniques must always be used when administering Beovu. Patients should be instructed to report any symptoms suggestive of the above-mentioned events without delay. Transient increases in intraocular pressure have been seen within 30 minutes of injection, similar to those observed with intravitreal administration of other VEGF inhibitors. Special precaution is needed in patients with poorly controlled glaucoma (do not inject Beovu while the intraocular pressure is ≥30 mmHg). Both intraocular pressure and perfusion of the optic nerve head must be monitored and managed appropriately. The safety and efficacy of brolucizumab administered in both eyes concurrently have not been studied. As this is a therapeutic protein, there is a potential for immunogenicity with brolucizumab (see section 4.8). Patients should be instructed to inform their physician if they develop symptoms such as eye pain or increased discomfort, worsening eye redness, blurred or decreased vision, an increased number of small particles in their vision, or increased sensitivity to light (see section 4.8). There are no data available on the concomitant use of Beovu with other anti-VEGF medicinal products in the same eye. Brolucizumab should not be administered concurrently with other anti-VEGF medicinal products (systemic or ocular). In intravitreal anti-VEGF treatments, the dose should be withheld and treatment should not be resumed earlier than the next scheduled treatment in the event of a decrease in best-corrected visual acuity (BCVA) of ≥30 letters compared with the last assessment of visual acuity; a retinal break; a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage

wet AMD. A total and HARRIER, respectively; assessments (DAAs) at any subsequent Additional assessments monthly doses. There AMD=age-related

ABBREVIATED PRESCRIBING INFORMATION (brolucizumab) 120 mg/ml solution for Characteristics (SmPC) before prescribing. Presentation: in 0.165 mL solution. This provides a usable amount Beovu is indicated for Single-use should only be used for the treatment of a single Posology: administered by intravitreal injection every 4 weeks individualise treatment intervals based on disease A disease activity assessment is suggested 16 activity, treatment every 12 weeks (3 months) should 8 weeks (2 months) should be considered. The physician activity. If visual and anatomical outcomes indicate

is ≥50% of the total lesion area; performed or planned intraocular surgery within the previous or next 28 days. Risk factors associated with the development of a retinal pigment epithelial tear after anti-VEGF therapy for wet AMD include a large and/or high pigment epithelial retinal detachment. When initiating brolucizumab therapy, caution should be used in patients with these risk factors for retinal pigment epithelial tears. Treatment should be discontinued in subjects with rhegmatogenous retinal detachment or stage 3 or 4 macular holes. Systemic adverse events, including non-ocular haemorrhages and arterial thromboembolic events, have been reported following intravitreal injection of VEGF inhibitors and there is a theoretical risk that these may relate to VEGF inhibition. There are limited data on safety in the treatment of patients with AMD with a history of stroke, transient ischaemic attacks or myocardial infarction within the last 3 months. Caution should be exercised when treating such patients. Interactions: No formal interaction studies have been performed. Pregnancy, Lactation, and Fertility: ♦Women of child-bearing potential: should use of effective contraception during treatment with brolucizumab and for at least one month after last dose when stopping treatment. ♦Pregnancy: brolucizumab should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus. ♦Breast-feeding: Brolucizumab is not recommended during breast-feeding. Breast-feeding should not be started for at least one month after the last dose when stopping treatment with brolucizumab. ♦Fertility: Based on the mechanism of VEGF inhibitors, there is a potential risk for female reproduction and to embryofoetal development. Adverse Reactions: Common (1 to 10%): Hypersensitivity (including urticaria, rash, pruritus, erythema) Visual acuity reduced, retinal haemorrhage, uveitis, iritis, vitreous detachment, retinal tear, cataract, conjunctival haemorrhage, vitreous floaters, eye pain, intraocular pressure increase, conjunctivitis, retinal pigment epithelial tear, vision blurred, corneal abrasion, punctate keratitis. Uncommon (<1%): Endophthalmitis, blindness, retinal artery occlusion, retinal detachment, conjunctival hyperaemia, lacrimation increased, abnormal sensation in eye, detachment of retinal pigment epithelium, vitritis, anterior chamber inflammation, irirodyclitis, anterior chamber flare, corneal oedema, vitreous haemorrhage. There is a potential for an immune response in patients treated with Beovu. There is a theoretical risk of arterial thromboembolic events, including stroke and myocardial infarction, following intravitreal use of VEGF inhibitors. Not known: Retinal vascular occlusion and Retinal vasculitis. Please refer to SmPC for full listing of all undesirable effects. Pack Size: Beovu is supplied in packs containing one pre-filled syringe. Legal category: POM. Marketing authorisation number: EU/1/19/1417/001. Marketing authorisation holder: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland. Full prescribing information is available upon request from: Novartis Ireland Limited, Vista Building, Elm Park Business Park, Elm Park, Dublin 4. Tel: 01-2601255 or at www.medicines.ie. Detailed information on this product is also available on the website of the European Medicines Agency http://www.ema.europa.eu. Prescribing Information last revised: September 2020.

▼ This medicinal product is subject to additional monitoring. Reporting suspected adverse reactions of the medicinal product is important to Novartis and the HPRA. It allows continued monitoring of the benefit/risk profile of the medicinal product. All suspected adverse reactions should be reported via HPRA Pharmacovigilance, website www.hpra.ie. Adverse events could also be reported to Novartis preferably via www.report.novartis.com or by email: drugsafety.dublin@novartis.com or by calling 01 2080 612.

Special populations: Renal No dose adjustment is required in patients aged Hypersensitivity with active or suspected ocular or periocular infections. the name and the batch Intravitreal endophthalmitis, intraocular inflammation, traumatic (see section 4.8 of the SPC). presence of intraocular inflammation, have been developing these events, treatment with Beovu Proper aseptic injection techniques must always to report any symptoms suggestive of the above-mentioned pressure have been seen within 30 minutes of of other VEGF inhibitors. Special precaution is Beovu while the intraocular pressure is ≥30 mmHg). must be monitored and managed appropriately. concurrently have not been studied. As this is brolucizumab (see section 4.8). Patients should as eye pain or increased discomfort, worsening particles in their vision, or increased sensitivity to use of Beovu with other anti-VEGF medicinal concurrently with other anti-VEGF medicinal the dose should be withheld and treatment should event of a decrease in best-corrected visual acuity acuity; a retinal break; a subretinal haemorrhage

Beovu Summary of Product Characteristics.

masked trials of brolucizumab for neovascular

*The primary efficacy endpoint for the studies was the primary objective to demonstrate noninferiority

*The primary efficacy endpoint for

CD59, a novel biomarker for glycaemic assessment – a review with a focus on diabetes in pregnancy

AUTHORS: Dr Delia Bogdanet1 and Prof Fidelma Dunne,1 1College of Medicine, Nursing and Health Sciences, National University of Ireland Galway

Gestational diabetes (GDM) is the most common metabolic complication of pregnancy. Diagnosing GDM is important not only for the short-term adverse outcomes related to pregnancy and delivery, but also for the long-term consequences affecting both the mother and the child such as development of type 2 diabetes (T2DM), obesity, and metabolic, cardiovascular, neurological and psychiatric problems.1 The purpose of GDM screening is the identification of women with GDM, thus facilitating early lifestyle interventions and treatment and ultimately leading to a reduction in adverse outcomes.

GDM is diagnosed by performing an oral glucose tolerance test (OGTT). The OGTT has been used in clinical medicine for over 100 years.2 Ever since, however, the validity of the OGTT has been contested. The reproducibility of the OGTT has been shown to range between 65.5 and 78 per cent.3-5

More so, a recent article 6 highlighted the numerous variables that affect the reproducibility and accuracy of the OGTT in terms of the total testing process – pre-analytical, analytical and post-analytical phases: (1) pre-analytical : physiological (hydration, exercise, gastric emptying, stress, temperature) and pretesting factors (sample type, collection tube, preparatory diet, glucose load, time of fasting, storage and transport); (2) analytical (traceability, imprecision, bias); and (3) post-analytical (reporting of results, identification of critical results, interpretation of results) ( Figure 1).

Despite scientists raising concerns about

the reproducibility of the OGTT for over 50 years, it remains the only available test and the current ‘gold standard’ for diagnosing T2DM and GDM.

It is time to identify new tests that can accurately and robustly diagnose GDM; tests that require less preparatory and sampling time and that are less affected, if at all, by all the aforementioned factors.

plot of sensitivity versus specificity is called receiver operating characteristic (ROC) curve and the area under the curve (AUC), as an effective measure of accuracy, has been considered with a meaningful interpretations.7 This curve plays a central role in evaluating diagnostic ability of tests to discriminate the true state of subjects, finding the optimal cut-off values, and comparing two alternative diagnostic tasks when each task is performed on the same subject. 8 When test results are available, the positive predicted values (PPV) and negative predicted values (NPV) are two more indices that are important in clinical practice. The PPV is the chance of disease in the case of positive test results, whereas the NPV is the probability of being healthy in the case of negative test results. Although these two metrics are valuable in clinical decision-making, they are influenced by the population’s prior disease prevalence. When there is a higher prevalence of disease, the PPV increases, whereas the NPV diminishes.9

Diagnostic test evaluation is a topic of concern in modern medicine, not only for confirming the existence of disease, but also for ruling out pathology in healthy people. The traditional approach to diagnostic test evaluation uses sensitivity and specificity as indicators of test accuracy in relation to gold standard status in diagnostic tests with dichotomous outcomes (positive/negative test findings). The sensitivity and specificity vary across the different thresholds and the sensitivity is inversely related with specificity. The

CD59

CD59 is a 18-20 kDa glycoprotein which is also known as membrane attack complex (MAC) inhibitory protein (MAC-IP)10,11 and has as a main role to restrict the MAC formation in the cell membrane thus preventing cell lysis and cell death. Glycation of CD59 would lead to the loss of its protective proprieties. While CD59 is a protein bound to the cell membrane, soluble forms are present in the blood, urine and saliva.12-14 Glycation is considered a major pathophysiological mechanism causing cell and tissue damage in diabetic

Despite scientists raising concerns about the reproducibility of the OGTT for over 50 years, it remains the only available test and the current ‘gold standard’ for diagnosing T2DM and GDM

subjects. The link between diabetes complications and increased MAC deposits has been well documented.15-20 The first paper linking the increased MAC deposits in diabetes with CD59 inactivation was by Acosta et al 21 who showed that in vitro CD59 exposure to glucose reduced its protection role.

Building on this work, Qin et al 20 measured CD59 levels in the red blood cells (RBC) of subjects with and without diabetes and found that there is significantly lower levels of CD59 in diabetic RBC compared to non-diabetic subjects with associated increased MAC-mediated lysis in diabetic subjects, indicating that glycation inactivates CD59 in diabetic subjects and provided a probable molecular explanation for the reported findings of increased MAC deposition in diabetic kidneys, nerves, and retinas. Animal models have shown that CD59-deficient mice displayed accelerated atherosclerosis with increased MAC deposits in response to high glucose

levels compared to controls 22 and that humans are particularly susceptible to diabetes complications through CD59 glycation-inactivation at a lysine/histidine residue level only present in our species. 21,23.

CD59 and diabetes in pregnancy

In 2013, Ghosh et al 24 hypothesised that glycated CD59 (gCD59) levels might mirror glucose control in human subjects and developed a sandwich ELISA assay to identify plasma gCD59, which they tested initially in 24 participants with and without T2DM (T2DM n=14, HbA1c >48mmol/mol, controls n=10, HbA1c<42mmol/mol) and then validated it in 190 subjects (T2DM n=100). The gCD59 levels were significantly higher in the 14 individuals with T2DM from the initial testing set compared to controls and was strongly associated with HbA1c levels. The results showed that gCD59 was able to identify T2DM with a sensitivity of 93 per cent, specificity of 100 per cent and AUC of 0.98. In the followup testing set, gCD59 levels were indeed higher in the T2DM group and positively

associated with HbA1c levels, now the test generating an AUC of 0.88.

Continuing this work, Ghosh et al 25 explored the link between gCD59 and glycaemic variables such as HbA1c (in 400 subjects (T2DM n=226)) and glucose levels during the OGTT in individuals with no history of diabetes, but considered high risk for T2Dm development (n=109). The results supported previous findings, with gCD59 levels higher in diabetic vs non-diabetic subjects and independently associated with HbA1c (even in individuals without a diagnosis of diabetes) and with the twohour glucose level on the OGTT (even in individuals with a normal two-hour glucose level). More so, the team also showed an acute response of gCD59 levels to insulin therapy in 21 poorly controlled subjects, with changes in levels in two weeks of treatment while HbA1c and fructosamine took six-to-eight weeks to respond.

This rapid turnover of values would have a particular importance in pregnancy and GDM

FIGURE 1: Variables that influence the oral glucose tolerance test (OGTT)

where time is limited and in utero exposure to hyperglycaemia not without consequences.

In 2017, Ghosh et al 26 explored the association between gCD59 and the results of the glucose challenge test (GCT), the results of the OGTT and the prevalence of large for gestational age (LGA) babies in 1,000 pregnant women at 26 weeks of gestation (500 women passed the GCT and were controls and 500 women failed the GCT and underwent a threehour OGTT). They found that gCD59 was 8.5 times higher in women who failed the GCT compared to those who passed it and 10 times higher in women who were diagnosed with GDM (n=127) on the three-hour OGTT (Carpenter and Coustan criteria). Overall, gCD59 predicted GCT failure with a sensitivity of 90 per cent, specificity of 88 per cent and adjusted AUC of 0.92 (95% CI 0.88-0.93) and predicted the development of GDM compared to controls with a sensitivity of 85 per cent, specificity of 92 per cent and adjusted AUC of 0.92 (95% CI 0.77-0.91), independent of age, BMI, ethnicity of history of diabetes. More so, the team also identified significantly higher gCD59 levels in women who gave birth to an LGA baby. There were some limitations to this study including its observational nature, the use of GCT (which might not be done in the morning), the three-hour OGTT, and use of the Carpenter and Coustan criteria for GDM, diagnosis arguably missing milder cases of GDM and the lack of trimester one and late trimester three samples for a better understanding of the dynamics of this test in pregnancy.

Ma et al 27 studied gCD59’s capacity to predict GDM earlier in pregnancy (sample collected and OGTT performed <20 weeks’ gestation) and the association with adverse pregnancy outcomes using 770 frozen samples collected as part of the Vitamin D and Lifestyle Intervention (DALI) study. 28 All the participants in the DALI study had a BMI ≥29 kg/m 2 and underwent three OGTTs (<20 weeks GDM n=207, 24-28 weeks GDM n=77, and 35 weeks of gestation) and were diagnosed

according to the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria. They found that the gCD59 levels were higher in GDM women diagnosed <20 weeks of gestation independent of age, BMI or ethnicity and predicted the OGTT results <20 weeks with an adjusted AUC of 0.86 (95% CI, 0.83-0.90). When restricting the OGTT between 14-20 weeks of gestation, the AUC was calculated at 0.90 (95% CI 0.86-0.93). Early gCD59 (<14 weeks) predicted GDM at 24-28 weeks with an AUC of 0.68 (95% CI 0.64-0.73). The team also found that higher gCD59 levels were associated with the risk of delivering an LGA baby. Some limitations of the study include the retrospective nature of the study, the inclusion of only high-risk women with a BMI ≥29kg/m 2 , and the low ethnical diversity.

of gestation and neonatal hypoglycaemia was associated with gCD59 at all three time points (AUROC 0.61 in the first trimester, 0.72 at 24 weeks). The study suggested that gCD59 could potentially play a role in prediction of neonatal complications, particularly NICU admission and neonatal hypoglycaemia.

Guo et al31 explored urinary biomarkers for the prediction of GDM. As urine samples compared to blood samples are non-invasive and the protein composition is simple, stable and easy to analyse, the team used urine samples of pregnant women to develop a proteomic analysis between healthy and GDM subjects. The study included 889 women (15-20 weeks of gestation) who underwent a 75g two-hour OGTT at 24-28 weeks of gestation and were diagnosed according to the IADPSG criteria (GDM n=69). Of these, 32 random samples (GDM n=16) were analysed. The expression of CD59 in the GDM group was significantly lower compared to the controlled group (p<0.001) and urinary CD59 identified GDM cases with an AUC of 0.72. Despite the small sample size, the findings suggest that urinary CD59 might have the potential to identify women at risk of developing GDM.

Conclusion

In 2021, Meek et al 29 assessed the predictive performance of CD59 in identifying women with T1DM at risk of adverse pregnancy outcomes. There were 157 study participants recruited from the CGM in pregnant women with type 1 diabetes trial (CONCEPTT). 30 Samples were taken at three time points: At approximately 10-12 weeks, 24-25-weeks and 34-35-weeks’ gestation. The team found significant associations between gCD59 levels at 24 weeks of gestation and the development of preeclampsia, preterm birth and admission to the neonatal intensive care unit (NICU) (AUROC 0.73). LGA was strongly associated with gCD59 taken at 34 weeks

GD59 is a promising biomarker that is showing potential in the diagnosis, early diagnosis of GDM, and prediction of adverse pregnancy outcomes in both GDM and T1DM pregnant women. However, there are still unanswered questions such as: what are the trimester specific cut-off values? Are there any discrepancies in cut-off values amongst different ethnicities? Can CD59 predict the response to GDM treatment? Can CD59 predict adverse pregnancy outcomes? Could CD59 be used for the follow-up of glucose intolerance postpartum and in the long-term? Could early pregnancy CD59 predict the 24-28 OGTT results in a BMI diverse population? Larger prospective studies are required to answer these questions and one such study is currently underway. 32 ■

GD59 is a promising biomarker that is showing potential in the diagnosis, early diagnosis of GDM and prediction of adverse pregnancy outcomes in both GDM and T1DM pregnant women

References

1. Metzger BE. Long-term outcomes in mothers diagnosed with gestational diabetes mellitus and their offspring. Clin Obstet Gynecol. 2007;50(4):972-9

2. Jacobsen A. Untersuchungen über den Einfluss verschiedener Nahrungsmittel auf den Blutzucker bei normalen, zuckerkranken und graviden Personen. Biochem Z. 1913;56:471-494

3. Harlass FE, Brady K, Read JA. Reproducibility of the oral glucose tolerance test in pregnancy. Am J Obstet Gynecol. 1991;164(2):564-8

4. Catalano PM, Avallone DA, Drago NM, Amini SB. Reproducibility of the oral glucose tolerance test in pregnant women. Am J Obstet Gynecol. 1993;169(4):874-81

5. Ko GT, Chan JC, Woo J, Lau E, Yeung VT, Chow CC, et al. The reproducibility and usefulness of the oral glucose tolerance test in screening for diabetes and other cardiovascular risk factors. Ann Clin Biochem 1998;35 ( Pt 1):62-7

6. Bogdanet D, O’Shea P, Lyons C, Shafat A, Dunne F. The oral glucose tolerance test – Is it time for a change? – A literature review with an emphasis on pregnancy. Journal of Clinical Medicine. 2020;9(11):3451

7. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 1982;143(1):29-36

8. Kumar R, Indrayan A. Receiver operating characteristic (ROC) curve for medical researchers. Indian Pediatr. 2011;48(4):277-87

9. Parikh R, Mathai A, Parikh S, Chandra Sekhar G, Thomas R. Understanding and using sensitivity, specificity and predictive values. Indian J Ophthalmol. 2008;56(1):45-50

10. Morgan BP. Complement regulatory molecules: application to therapy and transplantation. Immunol Today. 1995;16(6):257-9

11. Maio M, Brasoveanu LI, Coral S, Sigalotti L, Lamaj E, Gasparollo A, et al. Structure, distribution, and functional role of protectin (CD59) in complement-susceptibility and in immunotherapy of human malignancies (Review). Int J Oncol. 1998;13(2):305-18

12. Väkevä A, Lehto T, Takala A, Meri S. Detection of a soluble form of the complement membrane attack complex inhibitor CD59 in plasma after acute myocardial infarction. Scand J Immunol 2000;52(4):411-4

13. Lehto T, Honkanen E, Teppo AM, Meri

S. Urinary excretion of protectin (CD59), complement SC5b-9 and cytokines in membranous glomerulonephritis. Kidney Int 1995;47(5):1403-11

14. Meri S, Lehto T, Sutton CW, Tyynelä J, Baumann M. Structural composition and functional characterisation of soluble CD59: heterogeneity of the oligosaccharide and glycophosphoinositol (GPI) anchor revealed by laser-desorption mass spectrometric analysis. Biochem J. 1996;316 ( Pt 3):923-35

15. Gehrs KM, Jackson JR, Brown EN, Allikmets R, Hageman GS. Complement, age-related macular degeneration and a vision of the future. Arch Ophthalmol. 2010;128(3):349-58

16. Gerl VB, Bohl J, Pitz S, Stoffelns B, Pfeiffer N, Bhakdi S. Extensive deposits of complement C3d and C5b-9 in the choriocapillaris of eyes of patients with diabetic retinopathy. Invest Ophthalmol Vis Sci 2002;43(4):1104-8.

17. Nevo Y, Ben-Zeev B, Tabib A, Straussberg R, Anikster Y, Shorer Z, et al. CD59 deficiency is associated with chronic hemolysis and childhood relapsing immune-mediated polyneuropathy. Blood. 2013;121(1):129-35

18. Rosoklija GB, Dwork AJ, Younger DS, Karlikaya G, Latov N, Hays AP. Local activation of the complement system in endoneurial microvessels of diabetic neuropathy. Acta Neuropathol. 2000;99(1):55-62

19. Falk RJ, Scheinman JI, Mauer SM, Michael AF. Polyantigenic expansion of basement membrane constituents in diabetic nephropathy. Diabetes. 1983;32 Suppl 2:34-9

20. Qin X, Goldfine A, Krumrei N, Grubissich L, Acosta J, Chorev M, et al. Glycation inactivation of the complement regulatory protein CD59: A possible role in the pathogenesis of the vascular complications of human diabetes. Diabetes 2004;53(10):2653-61

21. Acosta J, Hettinga J, Flückiger R, Krumrei N, Goldfine A, Angarita L, et al. Molecular basis for a link between complement and the vascular complications of diabetes. Proc Natl Acad Sci USA. 2000;97(10):5450-5

22. Liu F, Sahoo R, Ge X, Wu L, Ghosh P, Qin X, et al. Deficiency of the complement regulatory protein CD59 accelerates the development of diabetes-induced atherosclerosis in mice. J Diabetes Complications. 2017;31(2):311-7

23. Sahoo R, Ghosh P, Chorev M, Halperin JA. A distinctive histidine residue is essential for in vivo glycation-inactivation of human

CD59 transgenically expressed in mice erythrocytes: Implications for human diabetes complications. Am J Hematol. 2017;92(11):1198203

24. Ghosh P, Sahoo R, Vaidya A, Cantel S, Kavishwar A, Goldfine A, et al. A specific and sensitive assay for blood levels of glycated CD59: a novel biomarker for diabetes. Am J Hematol. 2013;88(8):670-6

25. Ghosh P, Vaidya A, Sahoo R, Goldfine A, Herring N, Bry L, et al. Glycation of the complement regulatory protein CD59 is a novel biomarker for glucose handling in humans. J Clin Endocrinol Metab 2014;99(6):E999-E1006

26. Ghosh P, Luque-Fernandez MA, Vaidya A, Ma D, Sahoo R, Chorev M, et al. Plasma glycated CD59, a novel biomarker for detection of pregnancy-induced glucose intolerance. Diabetes Care. 2017;40(7):981-4

27. Ma D, Luque-Fernandez MA, Bogdanet D, Desoye G, Dunne F, Halperin JA. Plasma glycated CD59 predicts early gestational diabetes and large for gestational age newborns. J Clin Endocrinol Metab 2020;105(4)

28. Simmons D, Devlieger R, van Assche A, Jans G, Galjaard S, Corcoy R, et al. Effect of physical activity and/or healthy eating on GDM risk: The DALI Lifestyle Study. J Clin Endocrinol Metab. 2017;102(3):903-13

29. Meek CL, Tundidor D, Feig DS, Yamamoto JM, Scott EM, Ma DD, et al. Novel biochemical markers of glycemia to predict pregnancy outcomes in women with type 1 diabetes. Diabetes Care. 2021;44(3):681-9

30. Feig DS, Donovan LE, Corcoy R, Murphy KE, Amiel SA, Hunt KF, et al. Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): A multicentre international randomised controlled trial. Lancet. 2017;390(10110):2347-59

31. Guo Y, Han Z, Guo L, Liu Y, Li G, Li H, et al. Identification of urinary biomarkers for the prediction of gestational diabetes mellitus in early second trimester of young gravidae based on iTRAQ quantitative proteomics. Endocr J. 2018;65(7):727-35

32. Bogdanet D, O’Shea PM, Halperin J, Dunne F. Plasma glycated CD59 (gCD59), a novel biomarker for the diagnosis, management and follow up of women with gestational diabetes (GDM) – protocol for prospective cohort study. BMC Pregnancy Childbirth. 2020;20(1):412

Most patients with type 1 diabetes not meeting the recommended exercise goals

AUTHOR: Priscilla Lynch

A new Irish study, published in the Irish Journal of Medical Science, has found that the majority of patients with type 1 diabetes are not meeting recommended exercise goals.

Physical activity (PA) is known to reduce cardiovascular disease risk (CVD) among patients with type 1 diabetes. Guidelines recommend that adults with type 1 diabetes should engage in at least 150 minutes of moderate-to-vigorous-intensity PA per week. Accurate information on activity levels is limited, however, with possibly inaccurate self-reporting measures being employed rather than objective data collection via electronic devices.

Researchers from Trinity College Dublin at Tallaght University Hospital studied how well patients with type 1 diabetes in Ireland comply with PA guidelines and what the barriers to compliance are.

The study examined PA among a broad range of participants with type 1 diabetes and looked at the association between PA and CVD risk factors. Physical activity was measured objectively over seven days in 72 participants using an Actigraph accelerometer, and subjectively using the International Physical Activity Questionnaire (IPAQ). Perceived barriers to activity were assessed using the Barriers to Physical Activity in Diabetes scale. Researchers also determined the influence of physical activity on HbA1c (a common measure of diabetes control) as well as risk factors for cardiovascular disease.

The findings suggest that patients overestimate their activity levels using self-reported measures, with only one-third of patients actually meeting the PA guidelines when activity levels were measured using an accelerometer.

The fear of developing exercise-induced hypoglycaemia was the strongest barrier to exercise for patients with type 1 diabetes.

Key findings

 The majority of participants with type 1 diabetes failed to meet PA recommendations.

 Exercise was positively correlated with body mass index (BMI), waist circumference, body fat and HbA1c, highlighting the importance of PA among this group.

 Overestimation in PA is a serious concern, as it almost certainly results in individuals not getting sufficient exercise and therefore not realising the associated improvements in CVD risk factors.

 Diabetes-specific barriers do exist, specifically fear of hypoglycaemia, which result in poor uptake of exercise among this group.

This is the first study to show an inverse association between glycaemic control (HbA1c) and accelerometer-measured PA data among adults with type 1 diabetes, which remained significant when controlled for several factors. This inverse association could have important clinical significance with those not meeting PA recommendations having a HbA1c well above clinical targets (8.4 per cent vs 7.3 per cent).

In contrast to these findings, the only other available study that used accelerometermeasured PA data to assess CVD risk benefits did not see a difference in diabetes control with PA. Compensation with diet and insulin adjustments in order to avoid exercise-induced hypoglycaemia could explain the absence of effect on glucose control. However, consistent with their findings, this study also detected an inverse association between PA and several CVD risk factors (weight, BMI, waist circumference, and fat mass).

Mary Finn, Senior Dietitian, Department of Endocrinology, Tallaght University Hospital, and senior author said: “Physical activity is a crucial cornerstone of health for those with type 1 diabetes, and this study highlighted that most patients are not meeting the recommended exercise goals. Safely correcting this deficit will require a concerted effort.”

“Healthcare professionals must offer more support and education to help these individuals increase their exercise levels without increasing the risk of exercise-induced hypoglycaemia.

“Our study results highlight practical gaps that need to be addressed through appropriate education on the impact of exercise on glucose variability and implementation of strategies to avoid exercise-induced hypoglycaemia.

“One educational strategy is the development of targeted online resources and factsheets. Patients could also be directed to the growing number of platforms for accurate information and advice (some examples: www.EXTOD.org, www. Runsweet.org and www.JDRF.org.uk).”

Technology

Technology is also likely to offer a solution and individuals with diabetes should be encouraged to use wearable fitness tracking devices to monitor and validate their level of activity, the study noted.

Medical devices including continuous glucose monitors and closed-loop systems should also be encouraged to increase ‘time in range’. These appliances are also valuable in preventing potentially dangerous exerciseinduced hypoglycaemia and can therefore increase patient safety whilst providing considerable reassurance while exercising.

“As part of my Master’s study we developed a type 1 diabetes app to provide support and education regarding exercising with type 1 diabetes, and we plan to launch this app in due course,” Ms Finn said. ■

Reference

Finn M, Sherlock M, Feehan S, Guinan EM, Moore KB. Adherence to physical activity recommendations and barriers to physical activity participation among adults with type 1 diabetes. Ir J Med Sci (2021). doi: 10.1007/s11845-021-02741-w

Know the issues facing diabetes care in Ireland. Diabetes Ireland pre-Budget submission

AUTHOR: Dr Kate Gajewska, Clinical Manager for Advocacy and Research, Diabetes Ireland

More than 5 per cent of people in Ireland are living with diabetes and the incidence is continuously increasing. In the Euro Diabetes Index 2014 report comparing diabetes care across European countries, Ireland was assessed as 20th out of 30 countries. Ireland has some very strong points in relation to diabetes care: Full reimbursement of medicines as part of the Long-Term Illness (LTI) Scheme, the Diabetic RetinaScreen programme, some excellent researchers and specialist diabetes teams. The quality of care for people with diabetes, although continuously improving, is diverse and has its weak points; for example, waiting times to access education, poor availability of insulin pump therapy for people with type 1 diabetes, high numbers of diabetes complications, and the lack of a national diabetes registry.

Therefore, in our 2022 Pre-budget submission Diabetes Ireland has proposed eight immediate actions for implementation to improve the quality of care in Ireland. These actions require investment now to help to improve the quality-of life for over 225,000 people living with diabetes and reduce the long-term costs of preventable diabetes complications.

The submission is focused on a range of deliverable actions that are personcentred, cost-effective and builds on existing HSE commitments to tackle chronic conditions including diabetes. As follows are the key issues highlighted in the pre-budget submission.

1. Lack of a National Diabetes Registry

Ireland does not have a National Diabetes Registry and it is a major deficiency in our health service. We don’t really know how many people have diabetes, how many suffer from complications, and what their clinical outcomes and needs are. The establishment of a national registry would help with tracking the prevalence of the condition, measuring outcomes and cost of care and planning for future services. A National Diabetes Registry also has the potential to provide an architecture and approach for the subsequent development of a national chronic disease registry.

to other populations. Some specific diabetes-related issues, such as diabetes distress and burnout, lead not only to significant deterioration in mental health, but also to poorer diabetes management and outcomes. It is a vicious cycle, as poorer diabetes control, in turn, can lead to reduced motivation and capacity to deal with the responsibilities associated with diabetes. Therefore good mental health and wellbeing are the core of all aspects of life and are crucial in successful diabetes management.

2. Lack of access to psychology services for people with diabetes

Diabetes is a very demanding chronic condition, requiring continuous selfmanagement and the necessity to make multiple medical decisions daily. This burden is reflected in the significantly higher incidence of depression, anxiety, and other mental health disorders, including eating disorders, in the diabetes population when compared

Although recognised by the HSE, psychosocial support in diabetes care is not formally embedded as part of diabetes management and not in line with diabetes-related health-services delivery in Ireland. Presently, there is a 95 per cent deficit of diabetes psychologists in adult diabetes services in acute hospitals and there is no access to dedicated diabetes psychology services in primary care. For children with diabetes, there is limited access to three paediatric psychologists within national HSE paediatric diabetes services, however, they are all based in Dublin with no access elsewhere in the country.

3. Diabetes education and insulin pump therapy

Of the weakest points in the Euro Diabetes Index, long waiting lists to access education and poor usage of insulin pumps were listed as Irelandspecific issues. Insulin pumps give continuous access to insulin, and the

Ireland does not have a National Diabetes Registry and it is a major deficiency in our health service

opportunity to deliver insulin just by clicking buttons – it improves diabetes management, flexibility and qualityof-life. Although it is reimbursed, the uptake of insulin pumps is very low in Ireland (7 per cent in adults and 35 per cent in children with diabetes in 2016) when compared to other countries. One of the reasons why it is so difficult for some people with diabetes to get an insulin pump is the lack of trained staff (in particular, a pump nurse) and the lack of access to diabetes education. In some clinics, the main criteria to get an

professionals prescribe the Libre based on clinical need, patients are frequently declined access to FGM. The battle to include Libre on the LTI Scheme list is ongoing since 2016, with community-led petitions (almost 20,000 signatures in 2018), healthcare professionals, clinical leads, diabetes advocates and people living with diabetes writing letters; the evidence of this can be seen in the hundreds of parliamentary questions submitted by TDs from 2016 to the present day, and still nothing has changed.

attend their GPs, community nurses, dietitians and podiatrists twice a year at no cost, but patients have to have medical or GP visit cards, which are means-tested.

This means that nearly one-third of people with type 2 diabetes aged ≥50 years who appear to fit the HSE criteria for uncomplicated diabetes care are not eligible for the Cycle of Care: About 3540,000 people of working age and those who are retired and under 70 years are locked out of this scheme.

The roll-out of the Cycle of Care to all people with type 2 diabetes would remove the financial barriers that currently exist to managing uncomplicated diabetes in the community, reduce pressure on hospitals by reducing the numbers attending, and potentially reduce the number of complications arising from lack of regular care due to financial constraints.

insulin pump prescribed is completion of the DAFNE (Dose Adjustment for Normal Eating) structured education programme, where the waiting lists are very long (even a couple of years), and just over half of people living with type 1 diabetes in Ireland have access to this course, as it is delivered only in 12 diabetes centres.

As education is the key to healthy living with diabetes, and improves clinical outcomes, we believe that structured education, available soon after diagnosis, should be a must for any person living with diabetes in Ireland and their families.

4. No reimbursement of flash glucose monitoring for adults

Flash glucose monitoring (FGM, eg, FreeStyle Libre) is only reimbursed for children and young adults under 21 in Ireland. Although healthcare

The national data from other countries (ie, UK) suggests a great improvement in diabetes-related outcomes in the population of people living with diabetes thanks to the wider implementation and uptake of FGM. As a consequence, it reduces the risk of developing diabetes complications; and the treatment of complications is the most expensive part of any diabetes-related budget in any country. Why can’t we invest now in better diabetes outcomes, instead of waiting for complications to occur and only then treat?

5. Type 2 Diabetes Cycle of Care available for all people with diabetes

The HSE’s Type 2 Diabetes Cycle of Care is an integrated diabetes care scheme that aims to provide care to people with uncomplicated type 2 diabetes in the community. To avail of this structured approach patients can

Other issues we consistently highlight are the need to ensure equal access to specialist community diabetes teams, as part of the Enhanced Community Care Programme, and re-inclusion of women with gestational diabetes in the LTI Scheme, so pregnant women with diabetes do not have to pay for their test strips, medicines and insulin, which costs a lot.

Last, but not least, we would like to ensure that people with diabetes are equally treated in accessing mortgage protection and life cover. We are advocating that every person with diabetes be given the personal choice as to whether they wish to accept or decline an offer of mortgage protection rather than the current system where the insurance company make the choice for them, which is usually 300-400 per cent higher than for a person without diabetes. ■

For more information about Diabetes Ireland’s pre-Budget submission 2022, visit our website www.diabetes.ie.

As education is the key to healthy living with diabetes, and improves clinical outcomes, we believe that structured education, available soon after diagnosis, should be a must for any person living with diabetes in Ireland and their families

A pragmatic approach to investigating obesity

AUTHORS: Dr Werd Al-Najim, Diabetes Complications Research Centre, University College Dublin (UCD); and Prof Carel le Roux, Diabetes Complications Research Centre, UCD

According to the World Health Organisation (WHO), every one-intwo people are currently living with overweight or obesity as defined by the organisation’s new definition of obesity, ie, abnormal or excessive fat accumulation that may impair health. Modernisation and a sedentary lifestyle are often blamed for the rise in global obesity rates. However, obesity is not a new phenomenon. The 35,000-year-old human figurine, Venus of Willendorf, depicts the earliest signs of excessive fat accumulation, suggesting that the hunters-gatherers’ diet and lifestyle was also not sufficient to prevent the development of obesity.

For the past four decades research has focused on how to stop overeating, because it was thought that overeating causes obesity. Intensive modification of diet and lifestyle approaches are effective in lowering body weight by 5 per cent in one-in-two people and by 10 per cent in two-in-10 people. That being said, a state of weight loss is not the same as a state where the disease of obesity is effectively treated. More recent scientific evidence now explain that overeating doesn’t cause obesity. Instead, the disease of obesity causes people to overeat. Medical solutions to treat the disease paved the way to better success with the consequence being weight loss. When the disease is effectively treated with current anti-obesity medications, five out of 10 people feel less hungry, more satisfied, consume fewer calories and, as a consequence, lose 15 per cent in body weight. Bariatric surgery continues to be a very effective treatment for the disease and leads to 30 per cent weight loss in eight out of 10 people. What remains an issue is the percentage of people who are

not responding to these treatments. Can we identify them as early as possible? Can we predict who will respond to each treatment and personalise their treatments accordingly? Can we predict which patients will be at a higher risk for developing health impairment, as per the WHO definition of obesity? These questions and more are the objectives of a large European Union (EU) funded obesity research project, coordinated by University College Dublin (UCD).

SOPHIA’s truism is that obesity is not simply a behavioural or lifestyle issue. It is a a set of chronic, complex diseases worthy of the same consideration as any other life-threatening condition. While obesity is often viewed as a single risk factor for other diseases, there are in fact many distinguishable subpopulations of people with different types of obesity, including those defined by risks of complications and others by optimal treatment response. SOPHIA will explore each of these subpopulations and determine their distinguishable features in an aim to optimise the future treatment of obesity. We understand why this has been challenging: too often, clinicians, payers and patients do not consider obesity a disease. We propose that obesity is in fact a set of complex and chronic diseases that should be taken just as seriously as any other chronic disease, such as diabetes or cancer.

SOPHIA

SOPHIA (Stratification of Obesity

Phenotypes to Optimise Future Obesity Therapy) is a €16 million EU-supported international research consortium www. imisophia.eu that aims to improve risk assessment of complications of obesity and predict treatment response. The five-year project from the Innovative Medicines Initiative (IMI) is a joint undertaking of the European Commission and the European Federation of Pharmaceutical Industries and Associations (EFPIA); JDRF (formerly the Juvenile Diabetes Research Foundation); the Obesity Action Coalition; and T1D Exchange.

If we can diagnose patients with specific concomitant obesity diseases, treatment can then focus on reducing the risks associated with those diseases, and delivering the optimum response. This goes far beyond current ‘one size fits all’ approaches, that have not proven to be effective. By diagnosing and treating small, well-defined subpopulations of obesity, SOPHIA offers new hope. Imagine two patients of the same age and living with a similar body mass index (BMI), one has no complications while the other is living with uncontrolled type 2 diabetes, sleep apnoea, heart disease, depression, and subfertility. The causes of obesity in these two patients may well be different, equally so, the treatment

Intensive modification of diet and lifestyle approaches are effective in lowering body weight by 5 per cent in onein-two people and by 10 per cent in two-in-10 people

targets to improve health will also be different. The response rate to lifestyle modification, medication, or bariatric surgery is unlikely to be the same because their disease of obesity was caused by different factors. This is an over-simplified example that makes it hard to imagine an individual with a genetic cause of obesity having been prescribed a calorie deficit diet only. This is like treating a patient with type 1 diabetes by reducing their carbohydrate intake without exogenic insulin substitution therapy or treating a major depressive disorder with physical exercise. It is ineffective and detrimental to a patient’s health.

To achieve the objectives of the project, SOPHIA is broken down into eight work streams or ‘work packages’, each with a distinctive aim.

Work Package 1 is responsible for the overall project management, reporting, and communications.

Work Package 2 will collect data from previous premier EU cohorts and combine them to create a system known as ‘a federated database’. The federated database brings together previous research studies that were carried out in the field over the last 30 years and thereby increases the power of studies through maximisation of sample size, allowing for additional refined statistical analyses, that ultimately lead to answering research questions that could not be addressed while using a single study.

Using these federated databases, the researchers in Work Packages 3-5 seek to identify subpopulations of patients who are at risk of specific complications (eg, type 1 diabetes, type 2 diabetes, cardiovascular disease, cancers and osteoarthritis). Maybe they will discover different types of obesity, similar to how we differentiate between type 1 and type 2 diabetes. Equally so, these federated databased will be used to identify subpopulations who respond

to specific treatment modalities (diet, exercise, medication, surgery).

Once the variables to predict the risk of complications and those of predicting treatment response have been identified, the group of people in Work Package 6 will then validate the predictive value of these variables before creating clinically useful algorithms to decide ‘when-to-treat’ and ‘how-to-treat’. The first goal will be to combine the operational variables to identify the risks most relevant to an individual patient, and to summarise these as a single risk or decision-to-treat

reimbursement agencies are slow to pay for treatment, and industry try to develop ‘one size fits all’ interventions. This is deeply counterproductive, given the ongoing cost (to the patient’s quality-oflife, in clinical time and resources) of obesity and its complications.

Work Package 7 collaborates with people living with obesity to listen to their stories, hear their views on the current issues, and discuss their preferred treatment approaches. Throughout the project, patients are actively involved where the work of SOPHIA impacts on the patient

score (a more sophisticated replacement for BMI). The second goal will be to support the clinician in selecting the optimum treatment (a ‘how-to-treat score’) for the individual patient. Ultimately, these will be used in clinical practice to personalise and increase the effectiveness of obesity management.

New scientific knowledge generated by SOPHIA will only be of value when it changes perceptions and behaviours of people living with obesity, clinicians, regulatory bodies, payment agencies and industry alike. There is a common illinformed perception that obesity is solely a behavioural condition, rather than a chronic and complex set of diseases. This leads to the error of judgment that it is the responsibility of people living with obesity to address their own condition through willpower alone. Such perception is often held by patients themselves, clinicians, payment agencies, industry and leads to inappropriate choices: Patients do not seek medical help, clinicians fail to apply chronic disease models to treat the disease,

– including data collection and analysis; clinical tests, measurements or questions; new lifestyle programmes, medication or surgical options; the generation of educational material; and the definition of new vocabulary and narratives around obesity. After all, we won’t have a successful outcome unless the patient perspective and priorities are taken into account. Patients will be more likely to engage with and adhere to obesity treatment if they are confident that it will be effective.

Work Package 8 will use this novel information to create a shared value among all stakeholders including patients, clinicians, industry, and payers. Shared value, the idea of doing well by doing good, can be achieved by demonstrating to and educating all stakeholders that obesity is a set of complex and chronic diseases, and that complications and clinical outcomes can be predicted. SOPHIA will thus have the potential to establish a new narrative, understanding and vocabulary that allow us to change how we view, diagnose, and treat the disease of obesity. ■

New scientific knowledge generated by SOPHIA will only be of value when it changes perceptions and behaviours of people living with obesity, clinicians, regulatory bodies, payment agencies and industry alike

Latest module

Diabetes continuous glucose monitoring

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune condition characterised by autoimmune destruction of the pancreatic beta cell. This module will summarise the evidence for CGM and its current role in the management of patients with T1DM.

Authors: Dr Michael Lockhart, Endocrinology

SpR, and Prof Diarmuid Smith, Consultant Diabetologist and Endocrinologist, Academic Department of Diabetes and Endocrinology, Beaumont Hospital and RCSI Medical School

Successful completion of this module will earn you 2 CPD credits

Visit www.medilearning.ie/doctorcpd.ie

Transgender healthcare at the National Gender Service

AUTHORS: Dr Karl Neff, Consultant Endocrinologist, National Gender Service, Ireland East Hospital Group, and Dr Paul Moran, Consultant Psychiatrist, National Gender Service, Ireland East Hospital Group and St John of God Community Services

Gender healthcare has attracted much attention and controversy in recent years. The number of people seeking medical transition (medical care for gender dysphoria) has dramatically increased globally. In addition to an increasing number of referrals, people being referred are increasingly presenting with complex clinical needs that require specialist multidisciplinary input prior to and during medical transition. This creates challenges for both people seeking services and clinicians.

There has been widespread debate about gender healthcare from the legal, political and social rights perspectives, which are not always informed by core clinical principles such as duty of care. While there are guidelines on gender healthcare, these are focused on gender dysphoria and do not take into account all of the varying clinical needs of transgender and gender diverse people attending gender services.1-3 In fairness, this is because these guidelines are reliant on an evidence base that is not as good as we would like it to be and which in the past has focused on diagnosis of gender dysphoria and medical interventions.

At the National Gender Service (NGS), based in St Columcille’s Hospital (SCH), Loughlinstown, Dublin, we employ a multidisciplinary model of care that aims to address all of a person’s needs, and not just focus on their gender or gender dysphoria. This paper is intended to provide a basic understanding of the clinical care provided at the NGS, and give some guidance to clinicians who are not specialist trained in this area. As well as an outline of the NGS, we discuss some of the key clinical domains that

often require attention prior to and during medical transition.

Gender and sex

The concept of ‘gender’ as distinct from ‘biological sex’ has evolved over the past 70 years, with various competing understandings of what ‘gender’ actually is. Put simply; sex refers to the body, whereas gender refers to the person. Sex is easier to understand. It can be defined by chromosomes or anatomy and is binary: Male or female.

Gender is not the same as sex and so is not as clearly defined. Gender is reflected in both subjective terms (gender identity) as well as objective terms (gender expression), which are not always congruent and may change over time. The question of whether a person also has an ‘innate’ gender (as distinct from gender identity and expression) is of relevance to clinical care. ‘Gender theory’ proposes that gender is an entirely social construct (a learned identity), however much research supports the idea that while some aspects of gender identity and expression are socially determined, a person’s fundamental gender is generally innate and immutable.

There is also the question about how gender should be described. Conventionally, gender is understood as a bipolar (rather than binary) attribute and that a person’s gender can be understood as where they sit on a spectrum between masculine and feminine. There are opinions that people may have genders that lie outside the masculine-feminine paradigm, or that gender is not a fixed entity. While these concepts may appear esoteric, it is useful for clinicians to be aware that some patients may present with concepts

regarding their ‘gender’ that fall outside a conventional understanding of what gender means to the clinician.

Gender diversity: Terminology

The language and terminology used to describe gender continues to change, both in everyday life and in clinical practice, and there is not universal agreement about terminology. Many clinicians report a fear of ‘getting the language wrong’ which can make clinical engagement more challenging. This fear can be addressed by understanding that ‘getting the language wrong’ does happen, and that apologising for mistakes made, and then moving on with a commitment to do better, is an acceptable response.

Gender diversity/gender non-conforming are terms that describe the variation in gender identity or expression from the cultural norm. This includes transgender people, gender questioning people, and people with and without gender dysphoria. Terms that may be used to describe various aspects of gender diversity include:

 Gender assigned at birth: Is based on a baby’s biological sex, and the assumption that their gender is congruent with their sex. The abbreviations AMAB (assigned male at birth) and AFAB (female) are often used. Sometimes gender assigned at birth is referred to as birth gender or natal gender.

 Gender identity: An individual’s innate sense of feeling male, female, neither, or some combination of both.

 Gender expression: How an individual is seen by the external world. Gender expression is understood in a cultural context, and in Irish society is usually

understood through dress, hairstyle and the use of make-up. Gender expression does not necessarily correlate with gender assigned at birth or gender identity.

 Cisgender: This is a term used to describe individuals whose gender identity is congruent with the gender that they were assigned at birth (eg, a cisgender man is someone who identifies as male and who was AMAB). This term originates from a play on words, adopting terminology used in organic chemistry to describe mirror molecules (‘trans’ and ‘cis’ chiral enantiomers) and the word cis was adopted by trans people to describe non-trans people. Some ‘cisgender’ people do not accept this term.

 Transgender: This term (commonly shortened to trans) previously described people who identified as the gender other than their natal sex, however, it is currently understood as an umbrella term used to describe those whose gender identity is different in any way from their gender assigned at birth (ie, they do not identify with their birth gender). Including:

● Transgender man/trans man/ transmasculine individual/binarytrans man: Someone with a masculine gender identity who was AFAB.

● Transgender woman/trans woman/ transfeminine individual/binary-trans woman: Someone with a feminine gender identity who was AMAB.

 Nonbinary gender identity: Someone who has a gender identity that is neither masculine nor feminine, or is some combination of the two (somewhere in the middle of the bipolar gender spectrum).

 Other ‘gender’ identities: Some people identify with concepts that lie outside a conventional understanding of gender. These include: Gender fluid, agendered, third gender, and bi-gendered.

 Gender dysphoria: Distress or discomfort that occur if gender identity and gender assigned at birth are not congruent.

 Medical transition: The use of hormones and surgery to alter physiology and anatomy in such a way as to help the person align their physical selves with their gender identity.

It is very likely that these terms will continue to change in meaning. The best thing to do when unclear on what language to use is to respectfully ask someone how they would describe their gender and what pronouns and gender markers they would like to use.

consistent with a diagnosis of DSD.

The gender diverse population and the population with DSD are two distinct clinical populations with differing needs. There is minimal overlap between populations in clinical practice. People with a DSD are usually seen within general endocrine clinics and while they may have additional needs requiring multidisciplinary team (MDT) involvement, these needs are usually not gender related. Gender diverse people are usually seen in a specialist gender service, as when they do have additional needs they often either relate to their gender or interact with their gender in such a way that specialist MDT input is required.

Gender diversity: Prevalence

A note on disorders and differences of sexual development (previously termed intersex condition)

It should be noted that disorders and differences of sexual development (abbreviated to DSD: Previously termed intersex conditions) and gender diversity are two completely separate clinical concepts. In non-clinical dialogues these terms are confused and sometimes used interchangeably or are understood to be intrinsically related. While they can co-exist (ie, a person with a DSD might also be gender diverse or a transgender person may have a DSD), most gender diverse people do not have a DSD and most people with a DSD are comfortable with their gender assigned at birth. Many people who currently identify as intersex do not have any chromosomal or endocrine abnormality (ie, they do not meet diagnostic criteria for DSD), but may have gender dysphoria or body dysmorphic disorder (BDD). Diagnostic screening or testing for a DSD is only needed if there are clinical findings

Given the changing language, and lack or consistent definitions of gender diversity over time, precise prevalence data are not available. There is an increase in the prevalence of people identifying as gender diverse in Ireland as indicated by a significant increase in referral rates to specialist services. The Irish experience is not unique and is in keeping with international trends.

In 1997, the World Health Organisation’s (WHO’s) official prevalence rate was one person in 60,000 (AMAB=1:30,000 AFAB=1:100,000).1 In 2013, DSM V quoted a prevalence rate of one person in 20,000 (AMAB=1:10,000 AFAB=1:30.000). However, some recent estimates suggest a much higher prevalence rate in the order of 1:1000, and has seen an equalisation in the ratio of people AMAB and AFAB. 4,5

In parallel with this apparent increase in prevalence, referral rates to specialist services have increased significantly over the last 20 years. At the NGS in SCH, the referral rate has gone from fewer than 10 referrals per year in 2005 to over 10 per week currently. 5 While these numbers are appearing to plateau from the exponential increase in referral rates seen between 2012 and 2017, the numbers referred continue to increase year on year.

At the NGS in SCH, the referral rate has gone from fewer than 10 referrals per year in 2005 to over 10 per week currently

Gender diversity: Associated clinical needs

With the increase in referral rates over the last five years or more, there has been an obvious change in clinical demographics. As compared to the clinical cohort attending 10 years ago, people currently attending the service are younger by about two decades (most are in their late teens or early 20s), have a greater requirement for social care and active management of social health, and are more likely to have significant functional impairments.

This change in clinical demographics changes the clinical risk profile facing people seeking medical transition. In previous decades, mental illnesses were the most commonly encountered comorbid clinical need, and deterioration in mental health was the most commonly encountered complication. While many people currently attending the NGS have a significant burden of mental health symptoms or an active psychiatric diagnosis, the more common needs we now encounter in daily practice are related to social and occupational function. Sometimes this occurs in the context of neurodiversity or a diagnosis of autism. There is a relatively high prevalence of people with autistic spectrum disorder (ASD) attending the NGS. Approximately 10 per cent of people attending us have a diagnosis of ASD prior to referral, and an additional 25 per cent present with clinical features (including functional impairment) consistent with ASD, but do not have a formal diagnosis.

Mental health

More than 80 per cent of people currently attending the NGS have a history of significant mental health symptoms or have a diagnosis of psychiatric illness. Reported rates of mental health symptoms or psychiatric illness have varied widely over time. However, there is international consensus that people attending gender services have a greatly increased burden of mental health problems, which include affective disorders, addiction, adjustment disorders, deliberate self-harm, and

suicide. These conditions can usually be satisfactorily addressed and stabilised once an appropriate mental health assessment is completed prior to medical transition.

A key pitfall to avoid when managing the mental health of gender diverse people is the assumption that all mental health symptoms are related to their gender dysphoria and that medical transition will result in improvement of these symptoms. In many people attending us, the mental health symptoms are independent of gender dysphoria. While their gender dysphoria will likely interact with, or exacerbate, their mental health symptoms, it is not always the primary cause of their symptoms. Therefore, mental health will need to be addressed in parallel with any intervention aimed at alleviating dysphoria. Relying on medical transition alone to alleviate mental health symptoms may result in a critical, and potentially fatal, decline in mental health following the onset of medical transition.

diagnoses may be missed, or symptoms that are related to the person’s ASD may be incorrectly ascribed to psychiatric illness. Therefore, specialist psychiatric assessment is an essential part of the assessment process prior to medical transition.

Social adversity

Complex social adversity is a common problem for many people attending the NGS. Over 50 per cent of people attending us for initial assessment have a history of complex social adversity. This can include precarious housing (and risk of homelessness), potential for family breakdown (including marriage breakdown and loss of access to children), and social isolation. Assessment of social health and support is therefore a central part of the pre-intervention assessment at the NGS.

The social health complications that we are trying to prevent include homelessness, loss of key personal

Compounding these mental health problems are the effects of social exclusion (including educational and employment), which often places transgender people at risk, especially during medical transition. This is one of the reasons why a focus on social health is essential during the assessment process prior to medical transition.

The growing prevalence of ASD in people referred to the NGS adds complexity to the mental health assessment. There can be significant interplay between co-morbid mental health problems and neurodevelopmental disorders. In the absence of appropriate specialist assessment, important psychiatric

relationships, loss of education or employment, and social isolation. Most people currently presenting to the NGS are in their late teens or early 20s, and are dependent on others (usually parents) for fundamental needs such as housing. Progressing through medical transition without adequate emotional and financial support can result in homelessness, social isolation, and deterioration in mental health. When severe, this can result in acute psychiatric illness or suicide.

Therefore, it is essential to ensure that the person has somewhere safe to live while going through their medical

... there is international consensus that people attending gender services have a greatly increased burden of mental health problems which include affective disorders, addiction, adjustment disorders, deliberate self-harm, and suicide

transition, has adequate income and has a social support network that they can rely on when needed. In many cases, we need to intervene directly with family therapy or social work support to ensure that all aspects of a person’s social health are addressed as they move forward. In some cases, this means securing their own accommodation and income prior to starting medical transition.

Functional impairment

Unprepared medical transition can result in functional decline (leaving full-time education without qualifications, unemployment, and increased dependence on others with respect to activities of daily living and provision of fundamental needs). If functional decline occurs in people who have functional impairment prior to medical transition and who have not been adequately prepared or supported prior to and during transition, then they can become chronically disabled.

Functional impairment is common in people currently attending the NGS. On our most recent audit, at least 25 per cent of people attending the NGS for initial assessment have significant functional impairment. This is often in the context of neurodiversity or a diagnosis of ASD or social anxiety disorder. As mentioned above, approximately one-in-three people currently attending the NGS for initial assessment ether have a pre-existing diagnosis of ASD or have clinical features consistent with ASD.

For many people, the hope is that medical transition will improve occupational function. In the absence of specialist support around the time of medical transition, this is usually not the case. In fact, people with functional impairment can struggle with the changes and stresses inherent to medical transition, and occupational function can decline following the onset of transition. Therefore, it is important to optimise a person’s overall wellbeing and function prior to medical transition, and to ensure

that there are adequate supports in place to address any potential functional decline as medical transition progresses. In the absence of such a clinical strategy, serious functional decline can develop, leading to chronic disability. This can result in social isolation, increased social vulnerability, and a critical deterioration in mental health.

The clinician’s responsibility is to ensure the person is suitable and ready before commencing life-changing medical treatments, and that all possible preparation has been done to ensure a good outcome. It is more important to transition well than quickly.

The NGS: Model of Care and current practice

The NGS is based at SCH in Loughlinstown, where there has been some form of gender service for the last 20 years. Over that time, the way the service has been delivered has changed significantly.

Initially, the gender service in SCH was offered as an ad hoc service, delivered within general endocrinology and liaison psychiatry services. Small numbers of people living with gender dysphoria were referred to Prof Donal O’Shea and Dr Paul Moran because of their previous training and experience in the area.

Given the increased complexity of care as outlined above, the NGS has moved from a service delivered solely by psychiatry and endocrinology to an integrated multidisciplinary model. A Model of Care for the service was developed by the HSE Mental Health Division in 2016, and approved by the Ireland East Hospital Group Steering Group for the Development of an NGS in 2018. This model is based on a comprehensive multidisciplinary psychosocial assessment prior to medical transition, with ongoing MDT review and support as the person moves forward through their medical transition.

A comprehensive multidisciplinary

psychosocial assessment is the first step in our clinical pathway. This assessment is completed prior to any medical transition. The purpose of this assessment is to clarify the needs and goals of every individual and to ensure that they are offered appropriate support and intervention.

This assessment is usually entails two initial visits with two members of the NGS MDT. In addition to understanding the patient’s gender identity in terms of clarity and stability, the assessment explores social health, occupational function, and mental health. The purpose is to identify clinical needs that require intervention or support. As the mental health complications of medical transition include acute psychiatric illness and suicide, one of the two assessment visits will be with a psychiatrist. While every assessment aims to cover the same clinical domains, every assessment is individualised so that the needs of the specific person are explored and understood. An outline of the assessment process can be found on our website: www. nationalgenderserviceireland.com.

Contrary to popular understanding, the assessment is not solely focused on assessing gender dysphoria. While understanding a person’s gender is important, the assessment needs to be much broader than that. An assessment for medical transition should be a psychosocial assessment of need that covers all of the fundamental aspects of a person’s life that will potentially be affected by medical transition, and that ensures that the person is ready for all of the ups and downs that come with medical transition. This also includes exploring intimate relationships and sexual function.

Following assessment, presuming the person’s gender is clear and stable and that any outstanding clinical needs have been addressed, we proceed to medical transition.

Transition: Gender affirming medical and surgical interventions

Gender affirmation is a broad term that encompasses many aspects of a person’s experience of their gender. This includes their own understanding of their gender, their expression of that gender in their social environment, and clinical interventions that help them to become more comfortable with their gender identity by aligning their physical selves with their gender identity (and/or physically differentiating themselves from the gender they were assigned at birth).

Transition is a word used to describe the process of change, which affects all aspects of a person’s life. Each person’s transition is unique and there is no ‘onesize-fits-all’ programme.

Transition can be seen as having three key domains, which together, enable the person to transition in an integrated, safe and healthy way: Personal; social; medical. These domains of transitioning are mutually supportive, and generally proceed in that order. If an aspect of transitioning is neglected or not progressed, it can lead to serious problems. The most common and risky example of this is inadequate social transitioning in people who commence medical treatment.

Personal transition

This terms refers to the process of understanding our own gender. For transgender and gender diverse people, they begin to understand that their gender identity does not match that assigned at birth at different times. For most, this realisation begins in adolescence, but for others it can begin in either childhood or in adulthood.

For some people, the personal transition process can be confusing or distressing and psychological support will be needed. In this scenario, referring people to local counselling services is a good first step. Information on local counselling

services can be found on the HSE website. Linking in with local support groups is also recommended. Some support groups and organisations can offer safe spaces for people to explore their gender and to develop their personal transition in a non-clinical space.

Social transition

Social transition refers to the individual’s gender transition and expression in their social environment. This varies from person to person, but often starts with a name change or changes in pronouns. Social transition also includes changes in dress, hairstyle or make up that helps a person express their gender in a way that is more congruent with their gender identity.

For many people, social transition is challenging. This can be due to misunderstanding or adversity within the family or broader social environment. If there is significant social adversity, then the use of safe spaces is advised as a first step. Safe spaces are places where a person can express their gender identity without fear of adversity. Support organisations often run support groups or will have information on events or safe spaces that people can use to begin their social transition.

However, as people we exist in the world and so social transition in the wider world will be needed for most people at some point. Sometimes people plan to start their hormonal transition prior to any social transition. This is a high risk approach, as many people will usually find that navigating their social environment becomes more complicated rather than less complicated if they are on hormones while not having socially transitioned. Proceeding to a hormonal transition without prior social transition can cause significant distress and result in serious harm.

For those who struggle with their social transition, we can support them in exploring safe spaces and then

the wider world. In cases where the home environment or broader social environment is adverse, we may be able to offer interventions that can reduce adversity. Within a MDT framework, multiple team members can be involved in supporting someone in their social transition with an individualised care plan.

Legal transition is a part of social transition for some people. This refers to the legal process of changing name and gender. This can be done by Deed Poll and by Gender Recognition Certificate (GRC). Neither of these requires clinical input to proceed, but some people will need support in completing the process. Information on applying for a Deed Poll and GRC can be found on our website.

Medical transition

Over time, the concept of gender diversity has broadened and become more inclusive. This means that contrary to previous clinical experience, and current understandings of gender diversity, many gender diverse people do not want or require medical transition (hormones and surgery) or any clinical intervention for gender affirmation. However, for those that do, there are a number of options that include:

 Gender-affirming hormone therapy

● This usually refers to the use of sex steroids (testosterone or oestrogen) to produce physiological and physical effects that help people affirm their gender.

● Sometimes people will use medical therapy to disrupt or suppress the generation of endogenous sex steroids: These agents are usually referred to as blockers. In the NGS the most commonly used blockersare gonadotrophin releasing hormone analogues.

 Gender-affirming surgery

● Gender affirming chest surgery: mastectomy or mammoplasty.

● Gender affirming hysterectomy.

● Gender affirming genital surgery, such as orchidectomy,

vaginoplasty or phalloplasty.

 Gender affirming voice therapy

While we can offer gender affirming hormone and voice therapy, at the time of writing, only gender affirming hysterectomy and orchidectomy are offered in the public system in Ireland. There is some limited private sector access to chest surgery in Ireland, but most people travel abroad for chest surgery with funding support via the EU Cross Border Healthcare Directive. Apart from orchidectomy, gender-affirming genital surgery is not offered in Ireland (in either the public or private sector) and so people will travel abroad for these interventions, usually with funding support from the Treatment Abroad Scheme.

Long-term care

While some people discontinue hormone therapy at some point, many will remain on hormones for life. This can be in the form of continuous therapy or intermittent use. Once a person’s medical transition is well established, and there is no further need for specialist support or monitoring, they are discharged to their GP for ongoing care. On discharge, an individualised care plan is sent to the person’s GP. Some general points on long-term care include the following:

 If on hormonal therapy then monitor bloodwork on an annual basis including:

● Full blood count.

● Liver function tests.

● Renal function.

● Prolactin (only for people using oestrogen).

● Oestrogen and testosterone concentrations.

● FSH and LH.

● Lipid profiles.

 Monitor blood pressure annually.

 In people with a prostate, continue age-appropriate cancer screening.

 In people with a cervix, continue ageappropriate cancer screening.

 Advise women or people on oestrogen on age-appropriate breast care and on breast cancer surveillance in the same way that you would advise a cisgender woman.

 For transgender men or people AFAB who have not had a mastectomy, advise them on age-appropriate breast care and on breast cancer surveillance.

 For people on oestrogen, consider dose reduction or withdrawal of oestrogen after the age of 65, depending on individualised cardiovascular and cancer risk.

 Advise on bone care and on the need for osteoporosis prevention.

 DEXA monitoring is not needed unless:

● The person has had gender affirming genital surgery and has stopped taking their hormones or only takes their hormones intermittently.

● The person is using gonadotrophin releasing hormone analogues but is not using sex steroids.

● There are any other risk factors for osteoporosis that would indicate DEXA screening.

 Long-term post-operative care as needed for people who have had gender affirming surgery: Specific advice should be available from the surgical team.

References

1. CR118 (2013). Good practice guidelines for the assessment and treatment of adults with gender dysphoria. Royal College of Psychiatrists

2. Endocrine Society Guidelines (2017). Endocrine treatment of gender-dysphoric / gender-incongruent persons

3. WPATH (2012). (World Professional Association for Transgender Health). Standards of care for the health of

The NGS remains available to clinicians for advice and guidance following discharge. Any queries about people discharged from the NGS can be directed to us by post, phone or email. Contact details can be found on our website: www.nationalgenderserviceireland.com.

Summary

Transgender healthcare is becoming more challenging as the complexity of clinical needs in people referred to services continues to increase. The challenge becomes even more acute given the dearth of a good evidence base to guide decision making. In the absence of a good evidence base, we must rely on good clinical judgment and a comprehensive assessment of need prior to medical transition.

Addressing any social adversity, functional impairment and mental health symptoms prior to transition is essential. Medical transition alone is likely to be insufficient to alleviate social adversity, loss of occupational function, and mental health symptoms. A holistic person-centred approach delivered by an integrated MDT that considers all of a person’s needs, and not just their gender dysphoria, offers the greatest opportunity to identify and address needs to optimise outcomes and minimise risk of harm. ■

transsexual, transgender, and gender-nonconforming people. Version 7

4. Winter S, Diamond M, Green J, Karasic D, Reed T, Whittle S, Wylie K. Transgender people: Health at the margins of society. Lancet. 2016 Jul;388(10042):390-400

5. Judge C, O’Donovan C, Callaghan G, Gaoatswe G, O’Shea D. Gender dysphoria: Prevalence and c-morbidities in an Irish adult population. Front Endocrino l (Lausanne). 2014 Jun 13;5:87. doi: 10.3389/fendo.2014.00087. PMID: 24982651

Polycystic ovary syndrome (PCOS): An overview

AUTHOR: Theresa Lowry-Lehnen, CNS, GPN, RNP, PhD, and Associate Lecturer at IT Carlow

Polycystic ovary syndrome (PCOS), a heterogeneous disorder characterised by hyperandrogenism and chronic anovulation, is a common endocrine, metabolic, and menstrual disorder in women. Depending on diagnostic criteria, PCOS affects 6-to-10 per cent of women of reproductive age.

While the aetiology is not completely understood, PCOS is believed to be multifactorial in nature with a complex interaction of genetic and environmental factors. PCOS is exacerbated by obesity and has significant metabolic, reproductive, and psychological features, including an increased risk of type 2 diabetes mellitus with an earlier age of onset, subfertility, and an increased risk of depression and anxiety symptoms.

A family history confers a higher risk of developing PCOS and other contributing factors include low birth weight, premature pubarche, obesity, diabetes mellitus, and antiepileptic drug use.

Pathophysiology

The abnormal findings in PCOS are a result of ovarian hyperandrogenism and insulin resistance. Evidence suggests that the ovarian hyperandrogenism in PCOS is a result of primary ovarian dysfunction and is secondary to disordered gonadotropin activity. While not included in diagnostic criteria for PCOS, the elevated level of serum luteinising hormone (LH) in affected patients due to inappropriate secretion has long been recognised. In addition, PCOS pathophysiology appears to have a polygenic predisposition that is exacerbated by environmental factors, especially obesity.3,7

Diagnosis

The diagnosis of PCOS has lifelong

implications, with increased risk for infertility, metabolic syndrome, type 2 diabetes mellitus, and possibly cardiovascular disease and endometrial carcinoma.

Typical clinical features include hirsutism, irregular menses, chronic anovulation, acne, obesity, insulin resistance, and infertility. Patients typically present with acne and menstrual irregularities.1,2,5 PCOS should be considered in any adolescent girl with hirsutism, treatment-resistant acne, menstrual irregularity, or acanthosis nigricans, and evidence of these signs and symptoms should be especially sought in patients being evaluated for obesity.4

Three sets of diagnostic criteria; Androgen Excess and PCOS Society (AES), Rotterdam (Figure 2), and National Institutes of Health (NIH), are commonly used for PCOS and all require the exclusion of other known disorders. 3 Among the different diagnostic criteria used to define PCOS, the Rotterdam criteria are the most widely used and recommended, and like the more liberal AES criteria they allow for different phenotypes of the disorder.

Based on the Rotterdam criteria, a diagnosis of PCOS requires two out of

SUGGESTED PCOS SCREENING TESTS

 Luteinising hormone

 Follicle-stimulating hormone

 Total testosterone, sex hormone binding globulin

 Lipid profile

 Fasting glucose with or without oral glucose tolerance test, glycated haemoglobin

three of the following; hyperandrogenism, menstrual irregularities and polycystic ovaries on ultrasonography. 5

Diagnosis of PCOS requires the exclusion of other conditions, such as pregnancy, thyroid dysfunction, hyperprolactinaemia, Cushing’s syndrome, non-classical congenital adrenal hyperplasia, and androgen-secreting tumours. In women with signs or symptoms of androgen excess, serum total testosterone should be checked and the patient referred to a specialist for evaluation if the level is greater than two times the upper limit of normal.

According to clinical findings, further tests may be necessary including betaHCG, thyroid function, prolactin, 1mg overnight dexamethasone suppression and early morning serum 17-OHP (17-hydroxyprogesterone) tests. Mild elevations in serum prolactin are common in PCOS, but after excluding macroprolactin, levels that are greater than twice the upper limit of normal warrants further investigation. High levels of antiMüllerian hormone, a hormone produced by ovarian follicle granulosa cells, are also seen in PCOS and may be useful in the diagnosis of the condition. 5

 Serum prolactin

 Thyroid function

 Serum ferritin

 25-hydroxy vitamin D

IF CLINICALLY INDICATED

 17 hydroxyprogesterone

 1mg overnight dexamethasone suppression or 24 hour urine-free cortisol

 Sleep study

As PCOS is associated with insulin resistance, all women with PCOS should be screened for diabetes or pre-diabetes, especially if they are planning to conceive, as poorly controlled diabetes is associated with adverse pregnancy outcomes. 5

Screening for coronary artery disease and obstructive sleep apnoea (OSA) should be considered in women who are at high risk.

Obesity increases the risk of endometrial cancer three-fold in women with PCOS. While routine screening for endometrial cancer using ultrasonography is not currently recommended, it is important to have a high level of suspicion for patients with prolonged oligomenorrhoea for more than three months between menses. 5

Iron deficiency is common in PCOS, and may contribute to fatigue and androgenic alopecia. Screening and

treatment with iron if necessary is suggested, targeting serum ferritin in the upper quartile of the reference range. Vitamin D deficiency is also common in patients with PCOS and may have an additive adverse effect on fertility, insulin resistance, and glucose intolerance, therefore screening levels sand replacing any deficiency may be helpful.

Psychological wellbeing due to the effects of PCOS on physical appearance, such as weight gain, acne, and hirsutism, is an important consideration as is being alert for mental health issues, such as depression, anxiety, and self-harm. 5

Treatment

Treatment for PCOS is multi-targeted and individualised to suit each patient’s phenotype, symptoms, goals, and expectations, such as wanting to become pregnant.

First-line therapy for women with PCOS and obesity is lifestyle modification in the form of diet and exercise. This is particularly important in women who are preparing for pregnancy, in order to reduce the risk of complications, such as gestational diabetes, pre-eclampsia, pre-term delivery, macrosomia, birth defects, and stillbirth. Antiandrogens, such as spironolactone, should be stopped for three months before conception, and patients should be counselled about recurrence of androgen excess symptoms while preparing for fertility. Metformin may help, although it is unclear if this is independent of the weight loss benefit it confers. Ovulation induction with clomiphene citrate or letrozole is effective for fertility treatment. 5

Obesity is prevalent in 50-to-80 per cent of women with PCOS. 3 Even modest lifestyle changes can have a significant impact and reducing body weight by 2-to-5 per

Figure 1: Assessment and management of PCOS: Summary of an evidence-based guideline (Teede H, et al, 2011)8

cent has been shown to restore ovulation and increase insulin sensitivity in obese anovulatory women. Weight reduction has additional benefits – reducing the risk of diabetes, hypertension, cardiovascular disease, and certain malignancies.5,6

To induce periods for those with menstrual irregularities, cyclical progesterone can be used every two months to ensure regular shedding of the endometrium. The oral contraceptive pill (OCP) is also effective in controlling menses, with the added benefit of providing contraception and improving androgenic symptoms. However, given many women with PCOS are obese this, together with the OCP, causes an increased risk of thrombosis, so patient selection is important. It is advisable to avoid OCPs with higher oestrogen doses or those containing 19-norprogesterone derivatives, as androgenic progestin may adversely affect the patient’s cardiovascular risk. Starting with low-dose ethinylestradiol combined with a third- or fourth-generation progestin is recommended, as these have the least intrinsic androgenic activity. Metformin can also help to restore menstrual cyclicity.4,5

Hyperandrogenism in PCOS is caused by insulin resistance, hypersecretion of luteinising hormone and ovarian androgens. Medications commonly

used to treat androgen excess target these pathways. Spironolactone is an anti-androgen that blocks the effect of testosterone at the level of the androgen receptor. OCPs suppress LH secretion and reduce ovarian androgen production and metformin improves insulin resistance. If hirsutism is severe, all three medications may be used. The OCP remains the firstline treatment for hirsutism because of its effect on androgen production. OCP use offers the additional benefit of reducing acne if present, and provides protection against endometrial cancer and menstrual cycle irregularity. 3,5

Patients need to be informed that the symptoms of androgen excess, particularly hirsutism, take at least six months to improve. Eflornithine can be applied topically for rapid control of facial hirsutism, although fastidious use is required for the treatment to be effective. Permanent laser hair removal can be an effective treatment and may be considered if the symptoms are causing severe distress. Metformin is beneficial for improving insulin sensitivity and can aid in weight loss, but it is ineffective in controlling hirsutism in the majority of women. Antibiotics and retinoic acid derivatives can also be used for acne treatment.4,5

If first-line measures for cycle control

or androgen excess are ineffective in controlling symptoms, then referral to an endocrinologist, gynaecologist or reproductive medicine specialist should be considered. ■

References

1. Witchel S, Oberfield S, Pena A (2019). Polycystic ovary syndrome: Pathophysiology, presentation, and treatment with emphasis on adolescent girls. Journal of the Endocrine Society, Volume 3, Issue 8, August 2019. doi:10.1210/ js.2019-00078. Available at: https://academic.oup.com/jes/ article/3/8/1545/5518341

2. Pfieffer M. (2019). Polycystic ovary syndrome. Nursing. August 2019. doi: 10.1097/01. NURSE.0000569748.65796.d1. Available at: www.com/ nursing/Fulltext/2019/08000/Polycystic_ovary_syndrome__ An_update.9.aspx

3. Havelock J. (2018). Polycystic ovarian syndrome. BCMJ, Volume 60, Issue 4, May 2018. Available at: https://bcmj. org/articles/polycystic-ovary-syndrome

4. Rosenfield R, Ehrmann D. (2016). The pathogenesis of polycystic ovary syndrome (PCOS): The hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev 2016; 37:467

5. Yin Lua A, How C, King T. (2018). Managing polycystic ovary syndrome in primary care. Singapore Medical Journal 59(11): 567–571.doi: 10.11622/smedj.2018135

6. NHS (2019). Polycystic ovary syndrome. NHS. Available at: www.nhs.uk/conditions/polycystic-ovary-syndrome-pcos/ diagnosis/

7. Hiam D, Moreno-Asso A, Teede H, Laven J, Stepto N, Moran L, Gibson-Helm M. (2019). The genetics of polycystic ovary syndrome: An overview of candidate gene systematic reviews and genome-wide association studies. Journal of Clinical Medicine. Available at: file:///C:/Users/Admin/Downloads/ The_Genetics_of_Polycystic_Ovary_Syndrome_An_Overv.pdf

8. Teede H, Misso M, Deeks A, Moran L, Stuckey B, Wong J, Norman R, Costello M. Assessment and management of polycystic ovary syndrome: Summary of an evidence-based guideline. Med J Aust. 2011, 195, S65–S112

Figure 2: Rotterdam criteria for the diagnosis of PCOS

Patients with type 2 diabetes expect more after metformin

Once-weekly type 2 diabetes treatment with CV benefits† and superior efficacy1-9*

Patients should

SUPERIOR GLYCAEMIC CONTROL

• Ozempic® -1.8% vs dulaglutide‡ -1.4%1,2,§

• Up to 79% achieved ADA target of HbA1c <7% (53 mmol/mol) vs other diabetes treatments1-10

SUPERIOR AND SUSTAINED WEIGHT

• More than double the weight loss vs dulaglutide (-6.5 kg vs -3.0 kg)1,2,§

• Weight loss sustained over 2 years1,3

PROVEN CV BENEFITS1,3†‡

• 26% CV risk reduction in patients with type 2 diabetes and high CV risk, compared to placebo in addition to standard treatment1,3,4,†

an adjunct to diet and exercise • as monotherapy when metformin is considered inappropriate due to intolerance or contraindications • in addition to effects on glycaemic control and cardiovascular events and the populations studied, see sections 4.4, 4.5 and 5.1. of the summary of product characteristics.1 CV=cardiovascular. SUSTAIN = Semaglutide Unabated Sustainability in treatment of Type 2 Diabetes.

is indicated for the treatment of adults with insufficiently controlled type 2 diabetes other medicinal products for the treatment of diabetes. For study results with respect to combinations, reduced

*Results apply to Ozempic® across SUSTAIN trials, which included placebo, sitagliptin, dulaglutide, canagliflozin, exenatide PR and glargine U100.1-9 death, nonfatal myocardial infarction [MI] or nonfatal stroke) versus placebo in patients with type 2 diabetes at high CV risk treated with standard of care.1,3 ‡When added to standard of care, which included oral antidiabetic treatments, insulin, antihypertensives, diuretics and lipid-lowering therapies. §SUSTAIN 7, Ozempic® 1.0 mg vs. dulaglutide 1.5 mg.

prescribing. Ozempic® 0.25 pre-filled pen. Ozempic® 1 (human glucagonadults with insufficiently metformin is considered for the treatment of cardiovascular events, and and administration: subcutaneously in the abdomen, increased to 0.5 mg once 1 mg once weekly reduction in dose of glucose self-monitoring is and insulin is reduced. No dose adjustment adjustment is required renal impairment is No dose adjustment is limited. Caution

Hypersensitivity to the Should not be used substitute for insulin. discontinuation or dose IV and is therefore gastrointestinal adverse nausea, vomiting, and pancreatitis has been characteristic symptoms

of acute pancreatitis. If pancreatitis is suspected, semaglutide should be discontinued; if confirmed, semaglutide should not be restarted. Caution should be exercised in patients with a history of pancreatitis. Use of semaglutide in combination with a sulfonylurea or insulin may have an increased risk of hypoglycaemia, therefore consider reducing the dose of sulfonylurea or insulin when initiating treatment with Ozempic®. In patients with diabetic retinopathy treated with insulin and semaglutide, an increased risk of developing diabetic retinopathy complications has been observed. Caution should be exercised when using semaglutide in patients with diabetic retinopathy treated with insulin. These patients should be monitored closely and treated according to clinical guidelines. Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy, but other mechanisms cannot be excluded. When semaglutide is used in combination with a sulfonylurea or insulin, patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines. Fertility, pregnancy and lactation: Women of childbearing potential are recommended to use contraception when treated with semaglutide. Should not be used during pregnancy or breast-feeding. Discontinue at least 2 months before a planned pregnancy. Effect on fertility unknown. Undesirable effects: Very common (≥1/10); Hypoglycaemia when used with insulin or sulfonylurea, nausea, diarrhoea. Common:(≥1/100 to <1/10); Hypoglycaemia when used with other oral antidiabetic medications, decreased appetite, dizziness, diabetic retinopathy complications, vomiting, abdominal pain, abdominal distension, constipation, dyspepsia, gastritis, gastro-oesophageal reflux disease, eructation, flatulence, cholelithiasis, fatigue, increased lipase, increased amylase, weight decreased. Uncommon: (≥1/1,000 to <1/100); Dysgeusia, increased heart rate, acute pancreatitis, injection site reactions. Rare:(≥1/10,000 to <1/1,000) Anaphylactic reaction.

The Summary of Product Characteristics should be consulted for a full list of side effects. MA Numbers: Ozempic® 0.25 mg pre-filled pen EU/1/17/1251/002. Ozempic® 0.5 mg pre-filled pen EU/1/17/1251/003. Ozempic® 1 mg prefilled pen EU/1/17/1251/005. Each pre-filled pen delivers 4 doses and includes 4 disposable NovoFine® Plus needles. Legal Category: POM. For complete prescribing information, please refer to the Summary of Product Characteristics which is available on www.medicines.ie or by email from infoireland@novonordisk.com or from the Clinical, Medical and Regulatory Department, Novo Nordisk Limited, 1st Floor, Block A, The Crescent Building, Northwood Business Park, Santry, Dublin 9 Ireland. Date last revised: March 2020

t This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare Professionals are asked to report any suspected adverse reactions to the Health Products Regulatory Authority. Information about adverse event reporting is available at www.hpra.ie. Adverse events should also be reported to Novo Nordisk Medical Department Tel; 1850 665 665.

et al. Semaglutide versus dulaglutide once-weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834-1844. 4. Marso SP, Bain SC, Consoli A, 2016;375(suppl1):S1-S108. 5. Lingvay I, et al. Once weekly Semaglutide vs Canagliflozin in type 2 diabetes: results of the SUSTAIN 8 trial. once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 3a trial. Lancet Diabetes Endocrinol. 2017;5: 355–66. 8. Sorli C et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol 2017; 5: 251–60. 9. Ahrén B et al. Efficacy and thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial. Lancet Diabetes diabetes—2018. Diabetes Care. 2018;41(suppl1):S1-S159.

Please refer to the Summary of Product Characteristics (SmPC) before 0.5 mg solution for injection mg solution for injection in pre-filled pen. One ml of solution contains 1.34 mg of semaglutide is indicated for the treatment controlled type 2 diabetes mellitus as an adjunct to diet and exercise • as monotherapy inappropriate due to intolerance or contraindications • in addition to other medicinal diabetes. For study results with respect to combinations, effects on glycaemic control Posology Administered once weekly at any time of the day, with or without meals. Injected subcutaneously thigh or upper arm. Starting dose: 0.25 mg once weekly. After 4 weeks the dose should weekly. After at least 4 weeks with a dose of 0.5 mg once weekly, the dose can be is added to a sulfonylurea or sulfonylurea or insulin should be considered to reduce the risk of hypoglycaemia. Blood is No data available. No for patients with mild, moderate or severe renal impairment. Experience in patients with Hepatic impairment: is required for patients with hepatic impairment. Experience with severe hepatic Contraindications: Special warnings and precautions in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Diabetic ketoacidosis has been reported in insulin-dependent patients whom had reduction of insulin. There is no experience in patients with congestive heart failure not recommended in these patients. Use of GLP-1 receptor agonists may be associated reactions. This should be considered when treating patients with impaired renal function diarrhoea may cause dehydration which could cause a deterioration of renal function. observed with the use of GLP-1 receptor agonists. Patients should be informed of Pratley et N Engl Efficacy and Efficacy and safety of once-weekly diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, American Diabetes Association. Standards of medical

Building, Northwood Business Park

Fax: 01 8629 725, Lo call: 1 850 665665

trademarks owned by Novo Nordisk A/S

Novo Nordisk Limited, First Floor, Block A, The Crescent Building, Northwood Business Park Santry, Dublin 9, D09 X8W3, Ireland. Tel: 01 8629 700, Fax: 01 8629 725, Lo call: 1 850 665665 infoireland@novonordisk.com www.novonordisk.ie Ozempic®, NovoFine® and the Apis bull logo are registered trademarks owned by Novo Nordisk A/S Date of preparation: September 2020. IE20OZM00029

Novo Nordisk Limited, First Floor, Block A, The Crescent Santry, Dublin 9, D09 X8W3, Ireland. Tel: 01 8629 infoireland@novonordisk.com www.novonordisk.ie Ozempic®, NovoFine® and the Apis bull logo are registered Date of preparation: September 2020. IE20OZM00029