New medicines for type 2 diabetes

10 minutes to Read
Contributor
Dr Alesha Smith
3 February 2021
Puzzle
Availability of two new classes of medicine for type 2 diabetes has potential to unlock benefits for many New Zealanders

Inequities exist in all aspects of diabetes care. Alesha Smith outlines some examples, proposes some actions, and explains where the new medicines fit in.

The announcement that ethnicity has been added as an eligibility criterion for the newly funded diabetes medicines is a landmark decision and an organisational first for PHARMAC. It is a step towards achieving equitable access to medicines.

There is direct evidence of inequities in access to health care and medicines, and examples relating to diabetes are easy to find.

KEY FACT: To effectively address diabetes inequities we must do more than just talk about equity

Disparities in health status between different groups within a population are found worldwide.1,2 In Aotearoa, the greatest health inequities are experienced by:

  • Māori
  • Pacific peoples
  • People experiencing socioeconomic deprivation
  • People from former refugee backgrounds
  • Residents of rural/isolated locations.

Type 2 diabetes affects both indigenous and non-European populations disproportionately to European populations, and this is a key area for improvement via the health system. For example, Māori are considerably less likely than non-Māori to:

  • Receive diabetes monitoring, and the rate has steadily decreased over time
  • Be tested early for kidney disease
  • Receive treatment escalation for uncontrolled diabetes
  • Have good diabetes control.

Māori and Pacific patients also have consistently higher hospital admission rates than European patients, and are 2.8 times as likely as non-Māori to have renal failure. These differences have persisted for more than 20 years.3

National quality improvement programmes such as the annual diabetes review, that address specific areas of harm to patients, have achieved good results for non-Māori in many cases, but some have increased inequity in some areas for Māori.4 Providing Māori with the same or similar levels of monitoring and screening as non-Māori may not be sufficient to achieve equitable outcomes – we need to do more!

This may be as simple as taking a wider population-health view, as well as an individual approach.

This could involve monitoring inequities within patient populations and regularly reassessing health practitioner behaviours to ensure treatment and management decisions contribute to improving health equity for all individuals and their communities.

WANT TO KNOW MORE about diabetes inequities and where to start the change?

KEY FACT: Understanding the demographics of your diabetes patients can help improve the quality of care for all patients

To be able to effect change you need to understand who your diabetes patients are – this can help to:

  • Identify and address differences in care; for example, screening or medicines use, for specific populations.
  • Distinguish which populations do not achieve optimal outcomes; for example, those who go to hospital with diabetes complications.
  • Assess whether the care being delivered is culturally safe.
  • Develop additional patient-centred services.

Assessing these demographic aspects is important for providing equitable, accessible, and optimal services for every patient with diabetes. These data are useful not only in guiding the ways in which clinical care delivery could be improved but also in determining the service provision which addresses non-clinical aspects of patient care. Examples include staff recruitment, designing the look and feel of your practice, providing accessible multilingual material and deciding on opening hours.
With new classes of medicines being funded, understanding more about your patients with diabetes will also help to determine who is eligible for these medicines.

WANT TO KNOW MORE about who has diabetes in New Zealand?

KEY FACT: Māori adults are about 1.5 times as likely as non-Māori adults to have been diagnosed with diabetes after 25 years of age

Type 2 diabetes is a progressive disorder defined by deficits in insulin secretion and action that lead to abnormal glucose metabolism and related metabolic derangements, resulting in hyperglycaemic states.

Common macrovascular (coronary heart, cerebrovascular and peripheral -vascular disease) and microvascular (retinopathy, nephropathy and neuropathy) complications are often seen. Diagnosing and appropriately treating type 2 diabetes early has proven long-term benefits and reduces complications.

Type 2 diabetes is most often diagnosed following routine screening – now is a good time for general practice staff to look at who has been screened within the past five years. This may help identify people who would benefit from a review.

KEY FACT: Glycaemic targets should be individualised for each patient and measured three monthly until the patient target has been reached, and then six monthly once stable

An ideal range or target HbA1c level will vary from person to person and depends on age, type of diabetes and comorbidities. The following ranges provide a general guide:

Less than or equal to 53mmol/mol is a healthy HbA1c level for most patients.

HbA1c <48mmol/mol is appropriate when the risk of hypoglycaemia is low (ie, the patient is not on insulin and/or sulfonylureas) and in patients who are either:

- Young
- Considering pregnancy or are pregnant
- Exhibiting diabetic microvascular complications (particularly retinopathy and nephropathy).

Between 54mmol/mol and 70mmol/mol is sometimes a reasonable target HbA1c level when the risks of hypoglycaemia likely outweigh the benefits of tight glycaemic control such as:

- When life expectancy is limited by non-diabetes-related comorbidities
- When previous episodes of severe hypoglycaemia have occurred
- When there is significant hypoglycaemic unawareness
- In the frail elderly and/or those with cognitive impairment
- In people who are functionally dependent on others for some or all activities of daily living.

Agreeing on and setting an explicit HbA1c target and review plan with the patient is useful for limiting treatment inertia – and can ensure treatment is reviewed and modified if targets are not being reached. This is especially important as the new medicines become available. He Ako Hiringa will be providing tools to help general practice identify patients who have not had regular diabetes check-ups.

WANT TO KNOW MORE about glycaemic targets?

KEY FACT: PHARMAC has announced that Māori and Pacific peoples are priority populations for receiving the new diabetes medicines when clinically indicated

From 1 February 2021, the SGLT2 inhibitor empagliflozin (alone or as a combination product with metformin) will be funded for the treatment of type 2 diabetes. The GLP-1 agonist dulaglutide will be funded as soon as practicable following Medsafe approval.

With the listing of these medicines, PHARMAC has included an ethnicity-based Special Authority criterion, for the first time ever in New Zealand. Patients eligible for funding of these medicines include those with type 2 diabetes who have not met their HbA1c target (despite using treatment for at least three months), AND who are Māori or Pacific peoples, or have diabetic kidney disease, or have established cardiovascular disease (CVD) or a five-year CVD risk of ≥15 per cent, or have a high lifetime CVD risk due to being diagnosed with type 2 diabetes during childhood or as a young adult.

SEE MORE about the Special Authority criteria at tinyurl.com/PHARMACfund

SGLT2 INHIBITORS

What is an SGLT2 inhibitor?
Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a relatively new class of diabetes medicines – known as the “gliflozins”.

How do they work?
By inhibiting SGLT2, gliflozins prevent the kidneys’ reuptake of glucose from the glomerular filtrate and subsequently lower blood glucose and promote excretion of glucose in the urine.

What formulations are available in New Zealand?
Empagliflozin (10mg and 25mg) marketed as Jardiance, and empagliflozin with metformin (various dosage forms) marketed as Jardiamet.
These are taken as an oral tablet usually once a day in combination with other blood-glucose-lowering agents.

Are they funded?
Funded from 1 February 2021 under Special Authority.

Can cause:

  • Genitourinary infection
  • Reversible increase in serum creatinine
  • Diabetic ketoacidosis (uncommon)
  • Volume depletion (rare).

Avoid in patients:

  • Periprocedurally
  • Who are fasting
  • Who are on very-low-carbohydrate diets
  • Who have eGFR <30mL/min.

WHAT YOU NEED TO KNOW ABOUT SGLT2 INHIBITORS

Reduce hyperglycaemia
SGLT2 inhibitors inhibit reabsorption of approximately 30–50 per cent of the glucose filtered by the kidneys and thereby increase urinary glucose excretion, reducing hyperglycaemia anywhere from 1–5 per cent from baseline. As they act independently of insulin there is very low risk of hypoglycaemia, so they can be used as monotherapy or in combination with other agents.

Dramatic beneficial cardiovascular outcomes5
Studies into SGLT2 inhibitors report a lower risk of stroke, heart attack, heart failure hospitalisation, and death from CVD in people with type 2 diabetes.

The actual mechanism(s) responsible for these beneficial effects is not completely clear; many mechanisms have been proposed, including lowering blood pressure, inhibiting the sympathetic nervous system and reducing inflammation.

Promote weight loss and minimise weight gain
SGLT2 inhibitors can induce weight loss of 2–3kg, with a fast decline of 1–2kg in the first weeks which may be the result of acute osmotic diuresis by blockade of the SGLT2 receptor.

Thereafter, body weight declines more gradually over 20 weeks, which can be related to reductions
in fat mass, and then reaches a plateau phase. Clinical data up to four years show that bodyweight reduction with SGLT2 inhibitors is maintained.

Slow the progression of kidney disease6
CKD occurs in approximately 40 per cent of people with type 2 diabetes. Diabetes is the leading cause of CKD globally, accounting for nearly half of all cases of kidney failure requiring replacement therapy.

SGLT2 inhibitors improve glomerular haemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD.

The kidney benefits of SGLT2 inhibitors appear to be largely independent of glycaemic control, ie, they are beneficial for those with or without well--controlled glycaemia.

GLP-1 RECEPTOR AGONISTS

What is a GLP-1 receptor agonist?
Glucagon-like peptide-1 receptor agonists/analogues are a relatively new class of diabetes medicines – known as the “glutides”.

How do they work?
GLP-1 receptor agonists are incretin mimetics. They stimulate the insulin response to glucose and prevent glucagon release after meals. They also increase satiety and slow gastric emptying.

What formulations are available in New Zealand?
Dulaglutide injection (1.5mg per 0.5mL) is to be listed, marketed as Trulicity.
This prefilled injection pen is usually administered subcutaneously once a week.

Are they funded?
Not currently – but will be funded under Special Authority as soon as practicable following Medsafe approval.

Disadvantages:

  • Requires injection
  • Frequent gastrointestinal side effects.

Avoid in patients with acute pancreatitis or history of pancreatitis.

WHAT YOU NEED TO KNOW ABOUT GLP-1 RECEPTOR AGONISTS

Aid in glycaemic control 7
GLP-1 receptor agonists decrease HbA1c by stimulating glucose-dependent insulin secretion. Most people see an approximate reduction in HbA1c of up to 1.5 per cent from baseline.

There is a low risk of hypoglycaemia, and this is only usually seen when used in combination with a sulfonylurea or insulin.

Cardioprotective and reduce cardiovascular risk 7
The latest studies show that when GLP‐1 receptor agonists are used in type 2 diabetes they reduce major cardiovascular events (including cardiovascular death, myocardial infarction and stroke) by 13 per cent, reduce hospitalisation for heart failure by 9 per cent, and all‐cause mortality by 11 per cent.

They also have a beneficial effect on lipid profile and blood pressure.

Promote weight loss 7
GLP-1 receptor agonists are known to have good efficacy for weight loss and are often called weight--negative agents. They inhibit glucagon secretion and reduce gastric emptying, gastrointestinal motility and pancreatic secretions. They also promote satiety. Weight loss can vary depending on the dose, but, on average, people lose about 1.5 to 2.5kg.

Renoprotective, with some hepatic health benefits8
Protecting the kidneys is a critical target in type 2 diabetes. GLP-1 receptor agonists reduce the risk of composite kidney outcomes (a decline in glomerular filtration rate [GFR], end-stage kidney disease or renal death) significantly by as much as 17 per cent, which was shown to be driven mainly by a 24 per cent reduction in macroalbuminuria.

KEY FACT: SGLT2 inhibitors and GLP-1 receptor agonists are recommended for patients at high risk of heart and kidney complications from type 2 diabetes

Why is this important? About 80 per cent of adults with type 2 diabetes have concurrent dyslipidaemia or hypertension, 70 per cent are overweight or obese, and around 15 per cent are current smokers. On average, adults with type 2 diabetes are up to twice as likely to die of stroke or myocardial infarction compared with those without diabetes. However, data indicate that adults with type 2 diabetes who optimally manage glucose, blood pressure and lipid levels, and smoking and weight have a risk of major cardiovascular events that is not significantly above the risk of age and sex-matched, non-diabetic peers.

Therefore, care of adults with type 2 diabetes must include management of all major cardiovascular risk factors to individualised targets. In addition to glucose control, this includes smoking cessation, blood pressure control, lipid control, antiplatelet use for patients with known coronary heart disease, and use of ACE inhibitors or angiotensin-II receptor antagonists for patients with CKD or -proteinuria. Furthermore, use of antihyperglycaemic agents that reduce cardiovascular or overall mortality or cardiovascular events may be especially beneficial in those who have type 2 diabetes and established CVD or are at risk of CVD.

Minimising cardiovascular risks

Assessment of cardiovascular risk using a validated cardiovascular risk calculator is important for all patients with diabetes because:

  • Most patients with diabetes die from macrovascular disease – they are 40 times more likely to die of macrovascular than microvascular complications of diabetes.
  • It aids decision making on antiplatelet, blood pressure and lipid-lowering therapies.

The PREDICT CVD risk calculator includes New Zealand specific data and it has easy-to-understand patient risk information.

NB: cardiovascular risk calculators typically underestimate risk in younger patients and/or those with a strong family history of CVD.

SEE MORE on the NZ PREDICT website chd.bestsciencemedicine.com/calc2.html

KEY FACT: Approximately 53,000 people with diabetes will be eligible for funded treatment with SGLT2 -inhibitors or GLP-1 receptor agonists

General nutrition and healthy lifestyle -knowledge (including an individualised nutrition and exercise plan) can improve glycaemic control and quality of life. Cardiovascular risk reduction (blood pressure and lipid control, non-smoking and consideration of antiplatelet therapy) should continue in addition to treatment for all patients moved onto the new medicines.

Following best practice principles, if an SGLT2 inhibitor or a GLP-1 receptor agonist is to be prescribed, choice of agent(s) should be individualised for each person.

Empagliflozin (SGLT2 inhibitor) is typically the choice for patients in whom heart failure or CKD (albuminuria [urine albumin excretion >300mg/day] and estimated GFR <60 but ≥30mL/min/1.73m2) predominates.

Dulaglutide (GLP-1 receptor agonist) is typically the choice for patients in whom CVD or cardiovascular risk predominates, particularly in the setting of higher HbA1c or motivation to lose weight.

KEY FACT: Having well-informed patients who are included in the decision-making process helps improve medicines access equity

With heavy promotion of empagliflozin and dulaglutide likely, patients may request information about them. However, these enquiries may be from patients who have better health literacy levels than others and are already included in treatment decision making.

Identifying who may benefit from these new agents will help to reduce health literacy bias and may lead to more equitable use of medicines.

WANT PATIENT INFORMATION on diabetes and the new medicines?

Conclusion

With the list of funded glucose-lowering therapies growing in New Zealand, personalising medicine use beyond traditional use of metformin, sulfonylureas and basal insulin will become increasingly common. Metformin (from the biguanide class) is first-line therapy unless contraindicated, but any of the other classes of glucose-lowering agents may be considered as second-line therapy when there are specific reasons to do so. The rationale for the choice of therapy should be discussed with the patient, especially in the case of the newest agents. Primary care practitioners must work to ensure those with the greatest need for these new medicines are being offered them.

Dr Alesha Smith is associate professor at the University of Otago School of Pharmacy and a director of Airmed, leading the data team supporting He Ako Hiringa.

WANT TO KNOW MORE? Read the new 2021 NZ Society for the Study of Diabetes guidance at nzssd.org.nz


References

1. Reid P, Robson B. Understanding health inequities. In Robson B, Harris R (Eds), Hauora: Māori Standards of Health IV. A study of the years 2000-2005 (pp.3-8). Wellington: Te Rōpū Rangahau Hauora a Eru Pōmare. 2007. Available at www.otago.ac.nz/wellington/otago067740.pdf

2. PHARMAC. Achieving medicine access equity in Aotearoa New Zealand: Towards a theory of change. New Zealand Government; 2019. Available at https://tinyurl.com/yxe7cd9d

3. Beaton A, Manuel C, Tapsell J et al. He Pikinga Waiora: supporting Māori health organisations to respond to pre-diabetes. Int J Equity Health 2019:18(3). Doi: 10.1186/s12939-018-0904-z

4. Health Quality & Safety Commission. A window on the quality of Aotearoa New Zealand’s health care 2019. Wellington, New Zealand: Health Quality & Safety Commission; 2019. Available at https://tinyurl.com/yxq4tytb

5. Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: A state-of-the-art review. J Am Coll Cardiol Basic Trans Science 2020;5(6):632–44. Doi: 10.1016/j.acbts.2020.02.004

6. Tuttle KR, Brosius FC, Cavendar MA, et al. SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: Report of a scientific workshop sponsored by the National Kidney Foundation. Diabetes 2021;70(1):1–16. Doi: 10.1053/j.ajkd.2020.08.003

7. Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: A systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019;7(10):77–85. Doi: 10.1016/S2213-8587(19)30249-9

8. Greco EV, Russo G, Giandalia A, et al. GLP-1 receptor agonists and kidney protection. Medicina (Kaunas) 2019;55(6):233. Doi: 10.3390/medicina55060233

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