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CPD 62: TYPE 2 DIABETES Biography Biography -- Sinead Sinead Ryan Ryan graduated graduated from from the the University University of of Brighton Brighton in in 2008, 2008, and completed her pre-registration in Chelsea and Westminster Hospital and completed her pre-registration in Chelsea and Westminster Hospital NHS NHS Foundation Foundation Trust, Trust, London. London. She She worked worked in in a a number number of of clinical clinical positions positions in in London before before returning returning to to Ireland Ireland in in 2011. 2011. She She completed completed her her higher higher diploma diploma London in in community community pharmacy pharmacy from from Trinity Trinity College College Dublin Dublin in in 2014. 2014. Sinead Sinead is is currently currently working working as as a a community community pharmacist pharmacist in in Limerick. Limerick.

1. REFLECT REFLECT -- Before Before reading reading this this module, module, 1. consider the the following: following: Will Will this this clinical clinical area area consider be be relevant relevant to to my my practice. practice. 2. 2. IDENTIFY IDENTIFY -- If If the the answer answer is is no, no, II may may still be be interested interested in still in the the area area but but the the article article may not not contribute contribute towards towards my may my continuing continuing professional development development (CPD). (CPD). If If the the answer answer professional is yes, yes, II should should identify identify any any knowledge knowledge gaps gaps in in is the clinical clinical area. area. the 3. PLAN PLAN -- If If II have have identified identified a a knowledge knowledge gap gap 3.

will this this article article satisfy -- will satisfy those those needs needs -- or or will will more reading reading be be required? required? more 4. EVALUATE EVALUATE -- Did 4. Did this this article article meet meet my my learning needs needs -- and and how how has has my my practise practise learning changed as as a a result? result? changed Have II identified identified further further learning learning needs? needs? Have 5. WHAT NEXT At this time you may like like 5. WHAT NEXT - At this time you may to record record your your learning learning for for future future use to use or or assessment. Follow Follow the the 4 4 previous previous steps, steps, assessment. log and and record record your your findings. findings. log

Type 2 diabetes INTRODUCTION Diabetes affects around 382 million people worldwide1, and the numbers are increasing. World Health Organisation (WHO) estimates the global prevalence of diabetes is approximately 9% among adults aged over 18 years2. Diabetes is one of the fastest growing conditions in Ireland. The total number of people living with diabetes in Ireland is estimated to be over 225,000. The International Diabetes Federation estimates that by 2030 there will be approximately 280,000 people living with Type 2 Diabetes in Ireland3. The morbidity from Type 2 diabetes predominantly relates to its microvascular and macrovascular complications. Patients with type 2 diabetes are at higher risk of stroke, cardiovascular disease, renal impairment, retinopathy and peripheral nerve damage. The UK National Diabetes Audit showed that in patients with diabetes, the risk of stroke increased by 60%, angina by 140%, heart attack by 95%, and end-stage renal failure by 270%3. Metformin, Sulphonylureas and insulin remain important drug choices for patients with Type 2 diabetes. Newer drugs such as GLP-1 agonists, DDP4 inhibitors, SGLT2 inhibitors and the newer insulin analogs provide further treatment options for Type 2 Diabetes. This article will discuss the current management options and the National Institute of Clinical Excellence (NICE) guidelines for Diabetes published in December 2015. WHAT IS DIABETES? Diabetes is a chronic disease that occurs either when the pancreas does not produce enough insulin or when the body cannot effectively use the insulin it produces. Insulin is a hormone that regulates blood sugar4. Hyperglycaemia, or raised blood sugar, is a common effect of

uncontrolled diabetes and over time leads to serious damage to many of the body’s systems particularly the nerves and blood vessels. Glucose is the primary source of energy for the body’s cells. The levels of glucose in the body are controlled by the hormone insulin, which is made by the pancreas. Insulin helps glucose enter the cells. TYPE 2 DIABETES Type 2 diabetes, or non-insulin dependent diabetes develops when the insulin producing cells in the body are unable to produce enough insulin, or when the insulin that is produced does not work properly (insulin resistance). Type 2 diabetes accounts for between 85 - 95 % of all patients with Diabetes4, and Type 1 diabetes accounts for 5-15% of patients. Type 2 diabetes usually appears in patients over the age of 40. South Asian people appear to be at a greater risk and may present with Type 2 diabetes from the age of 25. Increased Body Mass Index (BMI) and physical inactivity are the highest risk factors for developing Type 2 Diabetes. Healthy diet, regular physical activity, maintaining a normal body weight and avoiding tobacco use can prevent or delay the onset of Type 2 diabetes5. According to the Healthy Ireland survey, over 850,000 adults over the age of 40 in Ireland are at increased risk of developing (or have) Type 2 diabetes. There are a further 300,000 in the 30 – 39 year age group that are overweight and not participating in the recommended weekly 150 minutes of physical activity; leaving them at an increased risk of developing Type 2 Diabetes. Symptoms of Type 2 diabetes may be similar to those of Type 1 diabetes, but they are often less marked. As a result, the diagnosis may be delayed for several years after onset after complications have already arisen. Until recently, Type 2 diabetes was only diagnosed in adults but it is now also occurring in children6.

Published Published by by IPN. IPN. Copies Copies can can be be downloaded downloaded from from www.irishpharmacytraining.ie www.irishpharmacytraining.ie Disclaimer: All All material material published published in in CPD CPD and and the the Disclaimer: Pharmacy is is copyright copyright and and no no part part of of this this can can Pharmacy be used used within within any any other other publication publication without without the the be permission of of the the publishers publishers and and author. author. permission

60 Second Summary Type 2 diabetes is a major cause of morbidity and mortality in Ireland and worldwide, with an an increasing increasing prevalence. prevalence. It is by It is characterized characterized by a relative a relative deficiency of insulin or a deficiency or a of resistance resistance of to insulin the effects Insulin. Itto the effects of for Insulin. It accounts between accounts between 85 and for 95% of 85 and 95% of diabetes. all peopleThe withDiabetes diabetes. all people with The Diabetes of Ireland Federation of Federation Ireland estimates there is a estimates prevalence of upyear to prevalencethere of upistoa 6% in the 20-79 6% the 20-79 year age group. age in group. Type 2 diabetes is commonly associated with obesity, physical inactivity, raised blood pressure, disturbed blood lipid levels and a tendency to develop thrombosis, and therefore is recognised to have an increased cardiovascular risk. It is associated with long-term long‑term microvascular and macrovascular complications, together with reduced quality of life and life expectancy. Metformin, Sulphonylureas and insulin remain important drug choices for patients with Type 2 diabetes. Newer drugs such as GLP-1 agonists, DDP4 inhibitors, SGLT2 inhibitors and the newer insulin analogs provide further treatment options for Type 2 Diabetes. Pharmacists have a crucial role in educating patients on diabetes and helping patients manage the long-term consequences of Type 2 diabetes.

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CPD 62: TYPE 2 DIABETES

 fasting venous plasma glucose (FPG) ≥7.0 mmol/l; or  venous plasma glucose ≥11.1 mmol/l at two hours after a 75 g oral glucose load (oral glucose tolerance test (OGTT)). In 2011, WHO recommended that glycated haemoglobin (HbA1c) could be used as an alternative to standard glucose measures to diagnosis Type 2 diabetes. HbA1c forms when red cells are exposed to glucose in the plasma. The HbA1c test reflects average plasma glucose over the previous 8–12 weeks. Unlike the oral glucose tolerance test, an HbA1c test can be performed at any time of the day and does not require any special preparation, such as fasting. HbA1c is a continuous risk factor for type 2 diabetes. This means there is no fixed point when people are (or are not) at risk. The World Health Organization recommends a level of 48 mmol/mol (6.5%) for HbA1c as the cut-off point for diagnosing type 2 diabetes. NICE guidance state, the range 42–47 mmol/mol (6.0–6.4%) is considered to be 'high risk'. SIGNS AND SYMPTOMS OF TYPE 2 DIABETES  Increased fatigue  Irritability  Extreme thirst  Frequent urination  Erectile Dysfunction  Unexplained weight loss  Frequent Infections  Slow healing of wounds  Blurred vision  Regular thrush  Numbness or tingling of hands or feet RISK FACTORS FOR TYPE 2 DIABETES Age – Risk of diabetes increases in patients over 40 years old or patients over 25 years old in patients of African or Asian decent. Family history and ethnicity – Having diabetes in first-degree family relatives increases the risk of developing diabetes. Patients from South Asian or Afro-Caribbean decent are at least five times more likely to develop diabetes. Weight – Over 80 % of patients diagnosed with Type 2 diabetes are overweight for their height. Increased BMI is directly correlated with increased risk of developing Type 2 diabetes. High blood pressure and high cholesterol increase the incidence of developing Type 2 diabetes. Activity – The more inactive the patient is the higher their risk of developing Type 2 Diabetes. The minimum recommended daily exercise is 30 minutes per day. Waist size – In women if the waist measures

more than 31.5in (80cm) the risk of Type 2 Diabetes increases. In men if the waist measures more than 37in (94cm) the risk of Type 2 Diabetes increases. Gestational Diabetes – Pregnant women can develop a temporary type of diabetes called gestational diabetes because the mother’s body is not able to produce enough insulin during pregnancy. Having gestational diabetes throughout pregnancy or giving birth to a large baby (baby over 10 pounds/4.5kg), can increase the risk of a woman going on to develop Type 2 diabetes in the future. Gestational diabetes is diagnosed through prenatal screening, rather than reported symptoms. PREVENTION OF TYPE 2 DIABETES Simple lifestyle measures have been shown to be effective in preventing or delaying the onset of Type 2 diabetes. To help prevent Type 2 diabetes and its complications, people should:  Achieve and maintain a healthy Body Mass Index (BMI)  Be physically active – at least 30 minutes of regular, moderate-intensity activity daily.  Eat a healthy diet including between 3 and 5 servings of fruit and vegetables a day and reduce sugar and fat intake.  Avoid tobacco use – smoking increases the risk of cardiovascular disesases. DIAGNOSIS AND BLOOD GLUCOSE MANAGEMENT The clinical diagnosis of diabetes is often indicated by the presence of symptoms such as polyuria, polydipsia, and unexplained weight loss, and is confirmed by measurement of abnormal hyperglycaemia. The World Health Organization (WHO) advises that the range of blood glucose indicative of diabetes mellitus is as follows:

NICE guidelines recommend that in adults with type 2 diabetes, HbA1c levels should be measured at:  3–6-monthly intervals (tailored to individual needs), until the HbA1c is stable on unchanging therapy  6-monthly intervals once the HbA1c level and blood glucose lowering therapy are stable. It is recommend that if HbA1c levels that are not adequately controlled by a single diabetic drug and rise to 58 mmol/mol (7.5%) or higher:  Reinforce advice about diet, lifestyle and adherence to drug treatment  Support the person to aim for an HbA1c level of 53 mmol/mol (7.0%)  Intensify drug treatment. CURRENT TYPE 2 DIABETES MANAGEMENT The current management strategy for Type 2 diabetes is based on evidence from the UK Prospective Diabetes Study (UKPDS), a large clinical study in patients newly diagnosed with type 2 diabetes over a thirty year period7. The results of this study established that improving glycaemic control reduced the rates of diabetic complications, including retinopathy, neuropathy, nephropathy and diabetes related deaths. Analysis of the study showed that for every 1% reduction in glycated haemoglobin (HbA1C), there was a 35% reduction in microvascular complications and a 25% reduction in diabetes-related deaths8. Importantly, the reduction in diabetes-related risk shows a “legacy effect”; the improved outcomes for those with better controlled blood sugar persisted for many years after the study had finished, even though the difference in glycaemic control ceased after the trail ended9. Early diagnosis and more aggressive treatment of blood glucose levels are therefore associated with improved clinical outcomes.

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CPD 62: TYPE 2 DIABETES

Meformin is unequivocally the first-line treatment in patients with Type 2 Diabetes. It belongs to the biguanide class of medicines and acts by increasing hepatic insulin sensitivity. It also increases the uptake of glucose into peripheral cells, reduces hepatic glucose production and aids weight loss. Metformin can induce gastrointestinal side effects such as abdominal bloating, cramps, nausea, vomiting and diarrhea, which can be reduced by starting metformin at a low dose. NICE guidelines recommend gradually increasing the dose of standard-release metformin over several weeks to minimize the risk of gastrointestinal side effects. If the patient experiences gastrointestinal side effects with standard release metformin one should consider a trial of modified-release metformin. Metformin is excreted by the kidneys, and for this reaction caution is advised when used in patients with impaired renal function or other conditions that may increase the risk of lactic acidosis, such as acute heart failure or shock. The 2015 NICE guidelines recommend that if metformin is contraindicated or not tolerated, consider drug treatment with a DPP-4 Inhibitor or Pioglitazone or a Sulfonylurea. Sulfonylureas (e.g. Gliclazide (Diamicron ), Glimepiride (Amaryl®), Meglitinides, Glipizide, Tolbutamide, Glimperidine) are commonly used as second-line agents in patients with type 2 diabetes, but can also be used as an alternative first-line treatment instead of metformin if the patient is underweight, or is unable to tolerate metformin. It is also suitable if a rapid therapeutic response is required. Sulfonylureas can also be added to metformin if glycaemic control is inadequate. ®

Sulfonylureas act by binding to a specific receptor on pancreatic beta cells, leading to increased secretion of endogenous insulin. The main side effects of sulfonylureas are weight gain and hypoglycaemia. The sulfonylureas are excreted through the liver and the side effects are increased in patients with mild to moderate renal impairment and severe hepatic impairment. As sulphonylureas release insulin, they can cause hypoglycaemia therefore blood glucose monitoring is advisable. There are also reports of weight gain, therefore a diet and exercise regimen must be adhered to whilst on treatment. Thiazolindinediones (e.g. Pioglitazone (Actos ), Rosiglitazone) are an alternative second-line or a third-line therapy. The NICE guidelines recommends that they should be considered as second-line therapies, in addition to metformin as the risk of hypoglycaemia with sulfonylureas would be unacceptable, for example if the patient lives alone in vulnerable circumstances or if sulphonylureas are not tolerated. NICE suggests that in these cases the risks and benefits should be discussed with each patient10. ®

Thiazolindinediones act via the peroxisome proliferator-activated receptor (PPARϒ), that decreases insulin resistance and have been shown to lead to a significant reduction in HbA1C, both as a monotherapy and when

used in combination with other oral agents such as metformin and/or sulphonylureas. Thiazolidinediones are associated with an increased fracture risk and in certain patients may lead to heart failure therefore they are not suitable for patients with established heart failure. In 2010, the European Medicines Agency (EMA) suspended marketing authorization for rosiglitazone as new evidence suggested that its cardiovascular risks outweighed its benefits. There are also reports of possible increased risk of bladder cancer with the use of pioglitazone. NICE guidelines advise not to offer or continue pioglitazone if the patient has any of the following: heart failure, hepatic impairment, diabetic ketoacidosis, current or a history of bladder cancer. DDP-4 Inhibitors (e.g. Sitagliptin (Januvia ), Linagliptin (Trajenta®), Saxagliptin (Onglyza®), Vildagliptin(Galvus®) are recommended by NICE as an alterative second-line or third-line therapy. It can be used in addition to a Sulphonylurea if metformin is not suitable. Due to their mechanism of action, DDP4- inhibitors have a low risk of hypoglycaemia and do not lead to weight gain. ®

GLP-1 Receptor Agonists (e.g. Exenatide (Bydureon®), Liraglutide (Victoza®), Lixisenatide (Lyxumia®), Dulaglutide (Trulicity®). Collectively, GLP-1 receptor agonists increase insulin release, decrease glucagon release and slow gastric emptying. In contrast to other diabetes treatments, GLP-1 receptor agonists aid weight loss, and liraglutide was recently licensed for non-diabetic individuals as a weight loss treatment. A common side effect of GLP-1 receptor agonists is nausea, which is usually temporary and disappears around two weeks after treatment initiation. In addition, GLP-1 receptors also increase satiety and augment weight loss. At present, GLP-1 receptor agonists are only available in an injectable form. SGLT2 Inhibitors Sodium glucose co transporter 2 Inhibitors (e.g. Dapagliflozin (Forxiga®), Canagliflozin (Invokana®), Empagliflozin (Jardiance®). They control blood glucose by controlling blood sugar levels via the kidneys. Under normal conditions, glucose is filtered out of the blood by the kidneys via a transporter protein (SGLT-2). Blocking the action of these transporters, allows more glucose to be excreted in the urine. There is a risk of hypoglycaemia with these drugs. The increased excretion of glucose can lead to osmotic effects that can cause hypotension and dehydration, in particular with patients on diuretics. The main side effect of SGLT2 inhibitors are an increase in fungal genital infections and urinary tract infections. These infections are more prevalent in women then in men. Secretagogue (e.g. Repaglinide (Novonorm®) is a short acting oral secretagogue. It lowers the blood glucose levels by stimulating the release of insulin from the pancreas, an effect dependent upon functioning β cells in the pancreatic islets. It is indicated in combination with metformin in adults with Type 2 diabetes

who are not satisfactorily controlled with metformin alone. The use of Repaglinide may be associated with an increased incidence of acute coronary syndrome. NEW LONGER ACTING INSULINS Longer acting insulins have been developed to provide a more stable basal insulin profile over a 24 hour period. The action of insulin can be delayed by increasing its size and delaying its absorption. Degludec (Tresiba®) in clinical trails, of patients with Type 2 diabetes, indicated that it was non inferior to glargine and had lower levels of hypoglycaemic episodes, particularly at night (nocturnal hypoglycaemia). The benefit of the longer half-life of Degludec (Tresiba®) compared with traditional, long-acting insulins means that patients can be much more flexible about the timing of their basal insulin doses, without compromising their glycaemic control. This may be particularly useful for patients with erratic lifestyles. Glargine U300 (Toujeo®) is a more concentrated form of insulin glargine available as 300 units/ml in a pre-filled pen. It has a longer half-life compared with glargine. It is associated with fewer nocturnal hypoglyacemic events than glargine, with no change in the overall glycaemic control11. The traditional long-acting glargine (Lantus®) is administered subcutaneously once daily. It can be administered at any time, but it should be given at the same time each day. Insulin glargine is used as an additional therapy to oral hypoglycaemic agents in Type 2 diabetes where oral hypoglycaemic agents do not provide adequate glucose control on their own. COMBINATION THERAPIES First Intensification of drug treatment The 2015 NICE guidelines recommend that in adults with Type 2 diabetes, when initial drug treatment with metformin has not continued to control HbA1c to below the patients individually agreed threshold for intensification, dual therapy should be considered with:  metformin and a DPP-4 inhibitor or  metformin and pioglitazone or  metformin and a sulfonylurea. Second Intensification of drug treatment In adults with Type 2 diabetes, when dual therapy with metformin and another oral drug has not continued to control HbA1c to below the person's individually agreed threshold for intensification, consider:  triple therapy with: metformin, a DPP-4 inhibitor and a sulfonylurea or  metformin, pioglitazone and a sulfonylurea or  starting insulin-based treatment. COMPLICATIONS OF DIABETES The complications of Type 2 diabetes fall into two main groups. The microvascular and the macrovascular.

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CPD 62: TYPE 2 DIABETES  Microvascular complications are retinopathy, nephropathy and neuropathy. Plasma glucose levels, high blood pressure and smoking are the key modifiable risk factors.

macrovascular complications. Tight controls of blood pressure, cholesterol levels and reducing BMI are important to reduce macrovascular complications.

 Macrovascular complications are stroke, ischaemic heart disease and peripheral vascular disease. Blood pressure, smoking, proteinuria and cholesterol concentrations are more important risk factors than plasma glucose levels.

Hypertension Management

Two major clinical trials (DCCT and UKPDS) demonstrated that tight control of plasma glucose can reduce the severity and slow the development of these complications. MICROVASCULAR COMPLICATIONS Diabetic Retinopathy Damage to the retina, caused by damage to the retinal blood vessels, directly impairs vision. This is the most common cause of impaired sight in the 30 to 69 years of age group and it is most commonly caused by diabetes mellitus. Cataracts and glaucoma also occur more commonly in diabetic patients. Tight control of plasma glucose levels after diagnosis can slow down the progression and prevent retinopathy. Type 2 diabetic patients need to have an eye examination on initial diagnosis and an annual dilated retinal screening thereafter. Diabetic Neuropathy Damage to nerves follows hyperglycaemia and most commonly results in an asymptomatic but progressive condition that mainly affects sensory nerves. The feet are frequently affected and 40-50% of diabetics are at high risk of developing foot ulcers. Vascular factors (e.g. ischaemia) may also contribute to the formation of an ulcer. Recurrence of ulcers is common and amputation may be the result of poor care. Foot care is a priority for Type 2 diabetic patients. Inquiring about foot care, and regularly asking about development of any problems with the feet should be a routine part of the continuing care that pharmacists offer patients. Reporting any sores or feet problems such as corns or cuts to the diabetic team is important. Regular appointments with the podiatrist/chiropodist are essential and referral to the patient’s GP or hospital team should be considered if the ulcer(s) are recurrent. Diabetic Nephropathy Nephropathy particularly microalbuminuria and proteinuria are predictive of renal impairment and decreased survival rates in Type 2 diabetic patients. Proteinuria is indicative of a significant risk of end stage renal disease. This could lead to the patient requiring either renal dialysis or a renal transplant. Control of plasma glucose levels and hypertension are essential. ACE inhibitors are considered to be the drugs of choice for patients with microalbuminuria or proteinuria.

There is evidence to suggest that lowering blood pressure significantly reduces diabetes related deaths, strokes, heart failure and microvascular complications12. Angiotensinconverting enzyme inhibitors, such as ramipril, are preferred as first-line drugs because they limit the progression of renal damage. Patients with Type 2 Diabetes should have their blood pressure taken at least once a year. NICE guidelines recommend adding medication if lifestyle measures do not reduce blood pressure to below 140/80 mmHg (or below 130/80 mmHg) if there is kidney, eye or cerebrovascular damage. Blood pressure should be monitored every 1-2 months and the medication therapy intensified until target ranges are achieved. Cholesterol Management Hyperlipidaemia is common in patients with Type 2 diabetes. Full lipid profiles should be monitored on diagnosis and then at least once every year. Cholesterol levels should be kept below a target level of 5mmol/litre. For patients with increased risk of cardiovascular events, initiation of cholesterol medication may be appropriate even if levels are within range. Anti-platelet therapy Anti-platelet therapy can be used to prevent thrombus formation in various patient groups. The updated NICE guidelines advise that antiplatelet therapy (e.g. aspirin or clopidogrel) should not be administered to adults with Type 2 diabetes without cardiovascular disease. Pharmacists Role in Type 2 diabetes  Monitoring and promoting medication compliance  Medication counseling  Support with blood glucose monitoring and encourage self-care  Providing patient education and advice  Monitoring blood pressure, lipid profiles and BMI  Dietary and lifestyle advice  Smoking cessation advice  Weight loss management and monitoring  Advising patients on the importance of regular eye and feet examinations. REFERENCES

Macrovascular Complications

1 - Diabetes Facts and Stats: 2014 – Diabetes UK, published 2014.Available at http://www. diabetes.org.uk/About_us/What-we-say/ Statistics/.

Ischaemic heart disease, including angina, and thrombotic conditions such as stroke and myocardial infarction are the most common

2 - Global status report on noncomunicable diseases 2014.Geneva, World Health Organization, 2012.

3 - International Diabetes Federation Diabetes Atlas (2013). www.idf.org/sites/default/files/EN6E_Atlas_Full_0.pdf. 4 - Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus. Geneva, World Health Organization, 1999 (WHO/NCD/NCS/99.2). 5 - Global status report on noncommunicable diseases 2010. Geneva, World Health Organization, 2011. 6 - World Health Organisation 2012, Fact Sheet (312). Type 2 Diabetes. 7 - King P, Peacock I & Donnelly R. The UK Prospective Diabetes Study (UKPDS): clinical and therapeutic implications for type 2 diabetes. Br J Clin Pharmacol 1999; 48(5):643648.doi;10.1046/j. 1365-2125,1999.00092.x. 8 - American Diabetes Association. Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care 2000; 23(1):S27-31. PMID: 12017673. 9 - Campbell IW. The UK Prospective Diabetes Study (UKPDS): Its legacy for type 2 diabetes management. Prim Care Cardiovasc J 2009;2(1):48-49. Doi:10.3132/pccj.2009.012. 10 - National Institute of Health and Clinical Excellence. Type 2 diabetes : newer agents; NICE 2015. 11 - Woo VC. New Insulins and New Aspects in Insulin Delivery. Can J Diabetes 2015; 39(4):335-343. Doi:10.1016/j.jcjd.2015.04.006. 12 - UK Prospective Diabetes Study (UKPDS) Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317:703.doi:10.1136/bmj.317.7160.703. 13 - Nauck MA. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Design, Development and Therapy 2014:8; 1335-1380. Doi:10.2147/DDDT. S50773. 14 - Health and Social Care Information Centre, National Diabetes Audit 2012-2013. Report 2: Complications and Mortality. Available at: http:// www.hscic.gov.uk/catalogue/PUB 16496/natidiab-audi-12-13-rep2.pdf. 15 - Nathan DM, Buse JB, et al. Management of hyperglycaemia in Type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetologia 2006; 49:1711-1721. 16 - Packer M, Crasto W et al. Type 2 diabetes: Pharmacological Management Strategies. Pharmaceutical Journal November 2015. 17 - BRITISH NATIONAL FORMALARY. No 69. March 2015. BNF online www.bnf.org.uk.

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Cpd 62 type 2 diabetes  
Cpd 62 type 2 diabetes  
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