Submission to PHARMAC – diabetes

Submission to PHARMAC New approach to management of type 2 diabetes

John Baker Chairman, Diabetes Foundation Aotearoa 7 May 2020

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Contents Executive summary ................................................................................................................................................. 3 Background ............................................................................................................................................................. 3 Diabetes Foundation Aotearoa........................................................................................................................... 3 Diabetes Care Support Service (DCSS) ................................................................................................................ 3 Governance......................................................................................................................................................... 3 Evaluation of the DCSS audit .................................................................................................................................. 4 Role of Professor David Simmons ....................................................................................................................... 4 Population changes over time ............................................................................................................................ 4 Changes over time in people with type 2 diabetes ............................................................................................ 4 Interpretation of the evaluation findings ........................................................................................................... 4 Primary Care perspective: Type 2 diabetes management tools ............................................................................. 5 Current approach................................................................................................................................................ 5 New approach..................................................................................................................................................... 5 Patient perspectives ............................................................................................................................................... 6 Personal observations ........................................................................................................................................ 6 Cost ......................................................................................................................................................................... 7 Benefit .................................................................................................................................................................... 7 Patient acceptability ........................................................................................................................................... 7 Health benefit ..................................................................................................................................................... 7 Recommendation ................................................................................................................................................... 8 References .............................................................................................................................................................. 9

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Executive summary A 25-year audit of diabetes care in Primary Care was conducted in South Auckland between 1994 and 2018.

The audit which encompassed 79,912 patients and 661 GPs examined quality of care and provided feedback to General Practitioners (GPs) as part of a process of continuous quality improvement. Overall standards of diabetes care in Primary Care were good, but GPs struggled to control blood glucose (HbA1c) with current therapies. HbA1c levels remained high with no improvement over the last 10 years of the audit and this is related to poor health outcomes particularly for MÄ ori and Pacific patients.

Based on these findings, the Diabetes Foundation Aotearoa recommends: 1. that PHARMAC fund new drugs for diabetes (metformin XR, SGLT-2 inhibitors, & GLP-1 receptor agonists) on an open-access basis 2. that a whole new approach to treating type 2 diabetes using these drugs is adopted consistent with international guidelines and focussing on prevention of cardiovascular disease (premature death) and end-stage kidney failure (dialysis) 3. that a quality program is implemented throughout New Zealand to provide systemic education and support for Primary Care in the management of type 2 diabetes and to promote the use of the new medicines

Background Diabetes Foundation Aotearoa The Diabetes Foundation Aotearoa previously known as the Diabetes Projects Trust is a charitable trust established in 1992 with offices at 2/100 Alexander Crescent, Otara, South Auckland. The business of Diabetes Foundation Aotearoa is health promotion activities in the community focussing on wellness, living with diabetes, quality of care, and avoiding the long-term complications of diabetes. Projects have been funded by the Ministry of Health, District Health Boards and the Auckland Council. One of these projects was an audit of diabetes management in Primary Care that operated between 1994 and 2018.

Diabetes Care Support Service (DCSS) South Auckland is known to have a high prevalence of type 2 diabetes and harm from its complications for over 30 years. Early epidemiological studies clearly showed that people with diabetes in South Auckland experienced high rates of end stage kidney failure, blindness, amputations and adverse pregnancy outcomes, along with relatively poor management of risk factors for diabetes complications (1). More than 85% of type 2 diabetic patients are managed in Primary Care. The DCSS was established by Dr David Simmons in 1991 to undertake general practice audits in South Auckland to monitor standards of diabetes care (2). Primary Care practices participated at no cost and allowed trained DCSS audit nurses to visit participating general practices and to undertake a structured review of the electronic and paper patient notes of all patients with diabetes and pre-diabetes. Summary reports of audit findings were regularly fed back to primary care together with recommendations for practice improvements. Initially, audits were undertaken annually, but as the number with diabetes within each practice increased, the time between audits sometimes became longer (e.g. undertaking alternate year or every third-year audits). Overall, 661 general practices/practitioners and 79,912 patients with type 1 and type 2 diabetes in South Auckland participated in the audit programme.

Governance The DCSS was funded by annual contract from the Counties Manukau District Health Board (CMDHB) and operated fully between 1994 and 2018. The DCSS audit was administered by the Diabetes Foundation Aotearoa and a group of General Practitioners, diabetes nurse specialists, and Endocrinologists provided oversight of the program (DCSS executive). The DCSS audit program ended in 2018.

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Evaluation of the DCSS audit Role of Professor David Simmons Evaluation of the audit was funded by a grant from the Middlemore Foundation Trust. Dr David Simmons, currently Distinguished Professor of Medicine at West Sydney University, was invited to come back to conduct the evaluation. Professor Simmons is an international expert in diabetes and integrated care. Prior to his current role, Professor Simmons held positions as Professor of Rural Medicine, University of Melbourne, Professor of Medicine, University of Auckland, and Professor of Medicine, Cambridge University UK. Evaluation findings were presented in Auckland at a meeting of Primary Care, Secondary Care, DHB and Ministry of Health stakeholders on 31st July 2019 and several papers have been submitted to peer review medical journals.

Population changes over time Overall, there were 58,352 audits undertaken between 1994 and 2018 for people with type 2 diabetes. The proportion of European descent dropped from 44% to 32%, and proportion of Māori, Pacific and Asian peoples did not change significantly at 17%, 27% and 12% respectively. The proportion living in a low NZ Deprivation Index (NZDEP 2006) area, increased from 82% to 92%. Proportion of obese people remained at 54% over time, with obesity more common among Māori and Pacific patients. There were no ethnic differences in care processes and, there is no evidence that Māori and Pacific patients received less care.

Changes over time in people with type 2 diabetes •

• •

• •

• •

Glucose control (as measured by HbA1c) improved 1994-2008 and then plateaued to 2018 with less than 50% of patients achieving the target (HbA1c <53 mmol/mol). Māori and Pacific patients had the poorest glucose control, which remains worse than populations reported from other OECD countries.

Only about 40% of Māori and 30% of Pacific patients achieved the target needed to minimise the risk of diabetes complications.

Despite the widespread poor glucose control, insulin usage decreased and was comparable between ethnic groups in 2018 at approximately 20% of patients.

Blood pressure improved such that the proportion in target 1994-2018 improved from just under 50% to about 75% achieving target blood pressure (BP <130/80). The improvement was slightly better among Māori and Pacific patients.

Total cholesterol improved between 1994-2018 but under 50% of patients achieving the target (total cholesterol <4). There are few ethnic group differences Microalbuminuria (early kidney damage) remained at high levels throughout the DCSS effecting 20% of NZ Europeans and approximately 35% of Māori and Pacific patients. This is a precursor to end stage kidney disease and dialysis in many of the patients.

Mortality rates in 2015 remained high compared with the general population at 2-fold among NZ Europeans, 4-fold among Māori and over 3-fold among Pacific patients.

Hospitalisation rates primarily due to end-stage kidney diseases increased over the time of the audit with rates of 7-9% among European and Pacific patients and over 11% among Māori patients.

Interpretation of the evaluation findings From these data, Professor Simmons concludes that Primary care and the wider health system coped well with blood pressure control and cholesterol control. However, blood glucose remained severely under-managed and likely the cause of the high levels of premature death and end-stage kidney diseases. Insulin use declined, reflecting the unpopularity/complexity of insulin as a therapeutic agent. The inability of Primary or Secondary Care to effectively manage blood glucose suggests a capability gap likely due to not having all of the modern tools (no access to potent glucose lowering medications SGLT-2 inhibitors and GLP-1 receptor agonists, the only drugs shown to reduce death), insufficient expertise (indicating the need for up skilling and a systematic primary care education programme) and insufficient support from secondary care services.

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Primary Care perspective: Type 2 diabetes management tools Current approach Type 2 diabetes is a complex disorder with two metabolic abnormalities: insulin resistance or lack of responsiveness to insulin; and insulin deficiency or inability of the body to overcome insulin resistance by secreting enough insulin. Type 2 diabetes tends to get worse as patients get older and this is irrespective of body weight. Success of our current approach to treatment requires lifestyle change, multiple doses of medicine each day and regular dose adjustments to achieve good blood glucose control (HbA1c <53 mmol/mol). Diabetes control remains poor if regular dose adjustments are not made (this is termed clinical inertia). Outcomes rely not just on the success or failure of primary care efforts, but also on the combined input from patient and whanau, secondary care, and social services. Most patients with persistent uncontrolled glucoses have repeated contact with multiple services over a long period of time. Insulin becomes the mainstay of management for many patients with long-standing diabetes because of the high incidence of secondary failure of sulphonylurea therapy. Fear of needles, fear of hypoglycaemia (low blood glucose level) and weight gain often limits the utilisation and effectiveness of insulin therapy. The last new diabetes medication funded by PHARMAC during the 25-year course of the audit was pioglitazone in 2003.

Vildagliptin, a DPP-4 inhibitor class of medicine, was funded in October 2018 after the audit completed.

Current approach Metformin • First used 1957 • Max dose 2 tabs three time daily • Requires multiple dose titration • High rate of side effects (15-30%) Sulphonylurea e.g. Glipizide • First used 1956 • Max dose 2 tabs three time daily • Requires multiple dose titration • Causes hypoglycaemia/ weight gain • Requires BG monitoring • High secondary failure rate (>4 years) Insulin (basal – premixed – basal/bolus) • First used 1922 • One to five injections daily • Requires multiple dose titration • Causes hypoglycaemia/weight gain • Requires BG monitoring

New approach Metformin XR • First used 2004 • 1 tab twice daily • No dose titration • Moderate side effect rate (13%) SGLT-2 inhibitor e.g. Empagliflozin • First used 2013 • 1-tab daily • No dose titration • Causes weight loss • Improves renal & CVD outcomes GLP- agonist e.g. Liraglutide • First used 2005 • I injection daily • Single dose titration • Causes weight loss • Improves CVD outcomes

New approach A joint American (ADA) and European (EASD) Consensus Guideline (3) advocating a new approach to the management of type 2 diabetes was presented at the EASD annual meeting in Berlin September 2018.

Following that meeting, most nations in the Western world have adopted the new approach to management.

Metformin remains the mainstay of management largely because it does not cause hypoglycaemia and it is weight neutral (it does not cause weight gain). The extended release form of metformin (metformin XR) is preferred because of a lower rate of side effects (nausea, vomiting, diarrhoea). Second-line therapy is a new class of medicines, SGLT-2 inhibitors. For added patient convenience, metformin XR and SGLT-2 inhibitors are available as a combined tablet medication. Third-line therapy is another new class of medicines (GLP-1 receptor agonists) that are administered by injection. GLP-1 receptor agonists are available as twice daily injection, daily injection, and weekly injection formulations. Daily or weekly injection formulations are preferred because of patient convenience and improved adherence.

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Patient perspectives Personal observations This relates to comments by patients attending a hospital diabetes clinic What patients say

Current Therapy

“Too many pills”

Maximal oral therapy (metformin & glipizide) is 12 tablets per day with extra tablets for BP and cholesterol

“I forget my pills (insulin)”

Research shows that needing to take more than one dose per day is associated with lower adherence (e.g. adherence is <50% for 3 times /day treatment)

Adherence with a single dose per day therapy is >80%

“I feel bad when I take my medicine”

A high proportion of patients suffer nausea/vomiting/diarrhoea with metformin IR (drug side-effect).

Symptoms go away if patients stop their treatment which only serves to encourage non-adherence

Metformin XR (extended release) has a far lower rate of side effects.

SGLT-2 inhibitors and GLP- agonist are well tolerated with low rate of major side effects (<5%)

“My medicine isn’t working”

This is a common reason for referral to secondary care clinics. It is often caused by medication nonadherence

Adherence with a single dose per day therapy is >80%

“I hate needles”

Insulin is the default therapy when tablet treatment fails. Many patients dislike needles and adherence is poor (i.e. <70%)

Insulin is no longer the default therapy

“I’m afraid of hypoglycaemia”

Hypoglycaemia is a common sideeffect of insulin therapy. Symptoms are usually mild, but hypoglycaemia may cause confusion, coma, convulsions and death. This is an issue for patients who are occupational drivers and patients operating heavy machinery. This is also a reason for nonadherence.

Insulin is no longer the default therapy.

Metformin, SGLT-2 inhibitors, & GLP-1 agonist do not cause hypoglycaemia

“Insulin makes me gain weight”

Weight gain of 3-4 kg is common after starting insulin. This is a reason for nonadherence

Insulin is no longer the default therapy.

SGLT-2 inhibitors, & GLP-1 agonist cause weight loss rather than weight gain

“Blood glucose testing gives me sore fingers”

Frequent blood glucose monitoring is needed for medication dose titration and to detect hypoglycaemia

There is no risk of hypoglycaemia and no need for dose-titration, so blood glucose monitoring is not required.

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What the new therapy approach offers for patients Metformin XR and SGLT-2 inhibitor therapy may be combined on the same tablet (i.e.

2 tablets per day)

Cost It is difficult to generate accurate pharmaceutical costs for this new approach to management because of the non-availability of drug-cost information. There are multiple drugs in class for SGLT-2 inhibitors (dapagliflozin, canagliflozin, empagliflozin, ertugliflozin) and GLP-1 receptor agonists (exenatide, exenatide LA, liraglutide, semaglutide, dulaglutide), but most of these drugs are not available in New Zealand. We have selected a representative drug in class (empagliflozin & liraglutide) and used Australian online retail pharmacy costs. We have calculated numbers of patients to be treated based on DCSS audit data and the assumption that there are 260,000 diabetic patients in New Zealand and 90% (234,000) have type 2 diabetes. The cost of the new approach is approximately $58.8 million after subtracting cost of existing therapies that are no longer needed.

Drug Metformin XR Empagliflozin Liraglutide Subtotal

Insulin glargine Solostar 40 units per day (0.5u/kg) Glipizide 5mg tid CareSens N strips i tid Metformin IR 1000mg bid Subtotal NET COST

Usage

Number treated

80% 50% 15%

187,200 117,000 35,100

Cost (online pharmacy) $13.50 per month $40 per month $234 per month

Minus cost of treatments no longer needed 20% 46,800 $40.00 for 5 pens per month 50% 117,000 $15.50 per month 70% 163,800 $36 for 100 strips each month 80% 187,200 $5 per month

Annual cost (million) $30.3 $56.2 $98.6 $185.1

$22.5 $21.8 $70.8 $11.2 $126.3 $58.8

Benefit Patient acceptability The new approach to management is simpler and more convenient for patients. It addresses most of the patient concerns detailed above and adherence is likely to improve. There is no need for dose titration and no risk of hypoglycaemia, so blood glucose monitoring is not required. This means there is a reduced requirement for GP office visits for medication review. In addition, both SGLT-2 inhibitor and GLP-1 receptor agonist classes of drugs cause weight loss which also serves to increase medication effectiveness over time because of reduced insulin resistance.

Health benefit The main argument in favour of the new approach to treatment of type 2 diabetes is that SGLT-2 inhibitors and GLP-1 receptor agonists have been shown in clinical trials to reduce diabetes-related deaths, progression to end-stage kidney disease, death and hospitalisation from heart failure, and risk of CVD event (heart attack & stroke) compared with conventional management at equivalent glucose control (and with contemporary kidney and cardiovascular risk modifying therapies). We have confined our analysis of benefit to premature death and progression to end stage kidney disease which were the main adverse findings of the DCSS audit.

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Cost per year

Premature death

Renal replacement therapy (dialysis) BENEFIT 1.

2.

3.

4.

5.

6.

7.

$33,306 1

$55,000 5

New events per year related to diabetes 1,301 2

291 6

Relative Risk Reduction (RRR)

Preventable events

Potential annual saving (million)

• 38% SGLT-2 inhibitors 3 • 22% GLP-1 agonists 4  34% SGLT-2 inhibitors 7

491

$16.4

286

$9.5

99

$5.4 $31.3

The value of a human life ($33,306 per quality adjusted life year) is from the Treasury’s CBAx tool 2020 Diabetes related deaths per year is from a Ministry of Health briefing paper 2016 (personal communication) RRR for death from diabetes for SGLT-2 inhibitors is from EMPA-REG trial (4) RRR for death from diabetes for GLP-1 receptor agonist is from LEADER trial (5) Cost of renal replacement therapy (dialysis treatment) per year is from Decision Support, CMDHB Number of new renal replacement therapy patients per year is from the Annual Report, Australia and New Zealand Dialysis & Transplant Registry 2019 RRR for dialysis for SGLT-2 inhibitors is from the CREDENCE trial (6)

Potential annual savings ($31.3 million) is likely an under-estimate because savings here refer to a single year whereas benefits are likely to be cumulative. For example, SGLT-2 treatment in patients with chronic kidney disease is likely to delay need for dialysis for more than 1 year. Moreover, we have not included other known adverse outcome costs such as avoidable hospitalisation from heart failure.

Recommendation Based on the findings of the DCSS audit, the Diabetes Foundation Aotearoa recommends: 1.

2.

3.

that PHARMAC fund Metformin XR, an SGLT-2 inhibitor, and a GLP-1 receptor agonist for the treatment of type 2 diabetes on an open access basis that a new approach to treating type 2 diabetes using these drugs is adopted focussing on prevention of cardiovascular disease (premature death) and end-stage kidney failure (dialysis) that a quality program for Primary Care is implemented throughout New Zealand to provide systemic education and support in the management of type 2 diabetes and to promote the use of the new medicines

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References 1.

Atlantis E, Joshy G, Williams M, Simmons D. Diabetes among Maori and other ethnic groups in NZ. In: “Diabetes Mellitus in Developing Countries and Underserved Communities”, Dagogo-Jack, Sam (Ed.) 2017, Springer International Publishing. Pp 165-190

2.

Simmons D, Fleming C, Cutfield R, Patel A, Innes J, Wellingham J (1997) The Diabetes Care Support Service for general practitioners in Auckland, The New Zealand medical journal 110:48-50

3.

Davies M, A’Alessio D, Fradkin J, Kernan WN, Mathieu C, Mingrone G, Rossing P, Tsapas A, Wexler D, Buse J. (2018) Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).

Diabetologia https://doi.org/10.1007/s00125-018-4729-5

4.

Zinman B, Wanner C, Lachin J et al for EMPA-REG OUTCOME investigators (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes, New England Journal of Medicine 373:211728

5.

Marso S, Daniels G, Brown-Frandsen K et al for LEADER Steering Committee (2016) Liraglutide and cardiovascular outcomes in type 2 diabetes, New England Journal of Medicine 375:311-22

6.

Perkovic V, Jardine M, Neal B et al for CREDENCE Trial Investigators (2019) Canagliflozin and renal outcomes in type 2 diabetes and nephropathy, New England Journal of Medicine 380:2295-2306

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