Type 2 diabetes: Two medications offer fresh management paradigm

Current international guidelines for type 2 diabetes management include the use of two new classes of medication: sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, in people with established kidney disease, heart disease or heart failure, or with high cardiovascular risk¹. These new agents can reduce mortality and cardiovascular events, including heart failure, and reduce progression of renal failure. As of 1 February 2021, the SGLT2 inhibitor empagliflozin is funded for type 2 diabetes in New Zealand under Special Authority. The GLP-1 receptor agonist dulaglutide will also be funded once approved by Medsafe.

More than 250,000 people have diabetes in New Zealand, with 90 per cent of these estimated to have type 2 diabetes. The prevalence of type 2 diabetes increases with age and parallels the increased population prevalence of obesity with known risk factors such as a calorific diet, low physical activity, family history and genetics. People who are of Pacific, Indian and Māori ethnicities are affected at an earlier age compared with those of European ethnicity. At the age of 55, the proportion of people with diabetes is approximately 35 per cent in people of Pacific and Indian ethnicity, 20 per cent in Māori and 8 per cent in New Zealand Europeans (Figure 1). Although socioeconomic deprivation is associated with an increase in diabetes prevalence, there still appears to be a higher prevalence among people of non-European ethnicity, particularly Pacific peoples, Māori and people of Indian ethnicities (Figure 2).

Sustained hyperglycaemia leads to microvascular and macrovascular complications, which are amplified by other cardiovascular risk factors such as elevated blood pressure and lipid levels, smoking, renal disease and increased age. Almost universal screening for diabetes as part of annual cardiovascular risk assessments means that more new cases of type 2 diabetes are screen-detected, rather than symptomatically diagnosed many years after diabetes onset. Unfortunately, the proportion of people with poor diabetes control still appears to be rising and an increasing number of people with diabetes require dialysis and experience cardiovascular events and premature death. Māori and Pacific peoples are over-represented in the proportion of patients with type 2 diabetes and poor glucose control, and in those who experience complications of diabetes.

An elevated HbA1c test or elevated fasting glucose with or without symptoms of diabetes such as polyuria and polydipsia, blurred vision, weight loss and fatigue indicate diabetes. In asymptomatic cases, two HbA1c readings above 50mmol/mol (or fasting glucose above 7mmol/L) are required to diagnose diabetes; whereas when symptoms are present, one laboratory test is diagnostic. Careful enquiry will often reveal a history of osmotic symptoms. After diagnosis of diabetes, correct classification is critical for ensuring people receive appropriate treatment and management.

Type 1 diabetes is caused by the autoimmune destruction of pancreatic beta cells and results in severe insulin deficiency. Insulin replacement (usually with multiple daily injections or through an insulin pump) is required. The presentation of type 1 diabetes may be latent – an absence of a clear family history of type 2 diabetes and poor response to oral therapy may indicate latent autoimmune diabetes in adults (LADA) especially in the slimmer patient. The presence of glutamic acid decarboxylase antibodies will confirm diagnosis and the patient should be referred for specialist investigation.

Patients with type 2 diabetes continue to produce substantial amounts of their own insulin and therefore respond to non-insulin therapy and have more stable glycaemia. In type 2 diabetes, hyperglycaemia occurs due to a combination of metabolic factors that culminate in insulin resistance and eventual insulin deficiency as the pancreatic beta cells no longer produce sufficient insulin to compensate. Excessive insulin production in response to obesity related insulin resistance can result in visceral deposition of fat, contributing to fatty liver disease. People with type 2 diabetes often have a reduced incretin response to food. Incretin hormones, such as GLP-1, are usually secreted by the intestinal mucosa and enhance insulin secretion, slow gastric emptying, increase satiety, and inhibit the action of glucagon (glucagon stimulates glycogenolysis and increases blood glucose levels).²

As insulin production declines, progressively more treatments are required. Weight loss through lifestyle changes, as well as glucose-lowering therapies and other medications targeting cardiovascular risk, can lower morbidity and mortality in people with type 2 diabetes.

Recent cardiovascular and renal outcome trials show that SGLT2 inhibitor and GLP-1 receptor agonist medications provide multifactorial benefits in patients with diabetes. These agents can reduce CVD, renal disease, heart failure and mortality when used alongside existing therapies and international guidelines¹ now recommend these disease-modifying treatments be prescribed for appropriate patients. It is important to consider these new medications in all people with type 2 diabetes, alongside existing medications, lifestyle modification, low energy diets and bariatric surgery.

General practice teams need to become confident in introducing these medications to their patients who have cardiovascular disease (CVD), renal disease or risk factors for these.

Metformin and lifestyle change remain the standard management approach in patients with a new-onset diabetes diagnosis, however, updated management guidelines recommend the use of SGLT2 inhibitor and GLP-1 receptor agonist medications to produce significant cardiovascular and renal benefits, in addition to their glucose-lowering ability. These beneficial effects appear to be independent of the magnitude of glucose lowering and are additional to other desirable effects of these medications in promoting weight loss and a low risk of hypoglycaemia (Panel 1). The main change in the international guidelines1 is the removal of a need for glycaemic control to add a medication with cardio-renal benefit; however, there is an HbA1c requirement for funded use of these medications in New Zealand for rationing purposes (Panel 2).

The beneficial effects of these drugs do not appear to be mediated through glucose lowering and are seen irrespective of patients’ HbA1c level at baseline. In fact, there is emerging evidence that benefits in chronic kidney disease (CKD) and CVD occur even in patients without diabetes. The main advantage of these drugs and reasons for using them is their beneficial effects on heart failure, kidney disease and cardiovascular death, with the positive side benefit on blood glucose.

Panel 1 | SGLT2 inhibitor or GLP-1 receptor agonist: Which to choose?

• There is a clear benefit for SGLT2 inhibitors in reduction of heart failure compared with GLP-1 receptor agonists, which produce no direct benefits on heart failure.
• Clear renal benefits are seen with SGLT2 inhibitors, and results from several GLP-1 receptor agonists studies have shown reduced macroalbuminuria and slower eGFR decline.
• Patients with moderate to severe CKD will benefit from glucose-lowering and slowing of eGFR decline with GLP-1 receptor agonists.
• In moderate to severe CKD, SGLT2 inhibitors will slow renal decline but not lower glucose.
• Patients wishing to lose weight would benefit from GLP-1 receptor agonists over SGLT2 inhibitors.
• Dulaglutide is available as a once-weekly preparation. Teaching injection technique should not be a deterrent as this is very simple with automated pens, tiny needles and simple dosing.

Panel 2 | Special Authority criteria for subsidy of empagliflozin, empagliflozin with metformin, or dulaglutide

Initial application from any relevant practitioner (including GPs, nurse practitioners and pharmacist prescribers). Approvals valid without further renewal unless notified for applications meeting the following criteria⁸:

All of the following:
1. Patient has type 2 diabetes; and

2. Any of the following:

• Patient is Māori or any Pacific ethnicity; or
• Patient has pre-existing cardiovascular disease or risk equivalent*; or
• Patient has an absolute 5-year cardiovascular disease risk of 15% or greater according to a validated cardiovascular risk assessment calculator; or
• Patient has a high lifetime cardiovascular disease risk due to being diagnosed with type 2 diabetes during childhood or as a young adult; or
• Patient has diabetic kidney disease**; and

3. Target HbA1c (of 53mmol/mol or less) has not been achieved despite the regular use of at least one blood-glucose lowering agent (eg, metformin, vildagliptin, or insulin) for at least 3 months; and

4. SGLT2 therapy will not be funded if patient is taking a funded GLP-1, and vice versa.

The points under criterion 2 describe patients at high risk of cardiovascular or renal complications of diabetes.

* Defined as: prior cardiovascular disease event (ie, angina, myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, transient ischaemic attack, ischaemic stroke, peripheral vascular disease), congestive heart failure or familial hypercholesterolaemia.

** Defined as: persistent albuminuria (albumin:creatinine ratio greater than or equal to 3mg/mmol, in at least two out of three samples over a 3–6 month period) and/or eGFR less than 60mL/min/1.73m² in the presence of diabetes, without alternative cause.

SGLT2 inhibitors decrease renal absorption of glucose, leading to increased excretion of glucose, weight loss of 2–4kg and modest blood pressure lowering. There is no hypoglycaemic risk unless they are used with other medications that could cause hypoglycaemia. SGLT2 inhibitors appear to have a class effect on reducing glucose, heart failure and renal function decline, and empagliflozin has demonstrated cardiovascular benefits. This class of medications also lowers serum uric acid and reduces the incidence of gout by 40 per cent in observational studies. It is not yet fully understood how these medications produce the unexpected benefits on the heart and kidneys although it is thought to be related to natriuresis (sodium excretion via the kidneys). It is critical that healthcare providers consider SGLT2 inhibitors as organ-protective agents rather than merely glucose-lowering drugs.

Care is needed to avoid volume depletion, and there is an increased risk of genital fungal infections (approximately 4 per cent incidence) and a rare risk of ketoacidosis with normal blood glucose concentrations (approximately 0.1 per cent incidence). These medications should therefore be stopped if the patient is fasting or severely unwell. Patients need to be reminded to seek medical attention and must have their ketones checked if they present feeling unwell with nausea, vomiting or abdominal pain.

Dose adjustment of background diabetes medications

When adding an SGLT2 inhibitor, there is no need for dose adjustment of background treatment with metformin or dipeptidyl peptidase-4 (DPP-4) inhibitors as the SGLT2 inhibitor will not cause hypoglycaemia itself. For patients already taking a sulfonylurea, the sulfonylurea dose may need to be reduced or stopped (if they develop hypoglycaemia). A patient already on insulin may require a 10–20 per cent reduction in insulin dose depending on HbA1c and fasting glucose levels.

Use in renal disease

Cardiovascular benefits, including those related to heart failure, extend to patients with type 2 diabetes and estimated glomerular filtration rate (eGFR) reduced to 30mL/min/1.73m². However, the glucose-lowering effects are seen largely in those with higher eGFR^3–5.

GLP-1 is an incretin hormone synthesised and secreted by the gut in response to nutrient intake. It stimulates insulin secretion by pancreatic beta cells in response to rising blood glucose levels, promotes satiety and results in body weight loss, as well as a lowering of blood pressure and lipid levels.

How GLP-1 receptor agonists reduce cardiovascular events is unclear as benefits are seen even in patients who don’t have changes in body weight or lowering of blood pressure or lipid levels. They likely act to decrease inflammation to stabilise atherosclerotic plaque and prevent development and progression of atherosclerotic disease as well as preserving renal function. Some, including dulaglutide and liraglutide, have proven cardiovascular benefits.

The main side effects are transient nausea, vomiting and diarrhoea, occurring in 10–20 per cent of patients, which usually subsides within one to two months. Injection-site reactions have been described. Experience is limited in the use of GLP-1 receptor agonists in patients with gastroparesis, so they are not recommended in these patients.

Dose adjustment of background diabetes medications

When adding a GLP-1 receptor agonist, there is no need for dose adjustment of background treatment with metformin as the GLP-1 receptor agonist will not cause hypoglycaemia itself. For patients taking a DPP-4 inhibitor, for example, vildagliptin, the DPP-4 inhibitor should be stopped and replaced by the GLP-1 receptor agonist. If a patient is already on a sulfonylurea and a GLP-1 receptor agonist is added, the sulfonylurea dose may need reducing or stopping to prevent hypoglycaemia. A patient already on insulin may require a significant reduction in insulin dose when a GLP-1 receptor agonist is added, depending on HbA1c and fasting glucose levels.

Use in renal disease

Dulaglutide can be used without dose adjustments in patients with mild or moderate renal impairment (eGFR >30mL/min/1.73m²).

If a patient has type 2 diabetes and either CVD risk or CKD risk, including persistent microalbuminuria, they may benefit from an SGLT2 inhibitor or a GLP-1 receptor agonist

SGLT2 inhibitors and GLP-1 receptor agonists will add to the variety of diabetes medicines already in the healthcare providers’ toolbox, some of which are described here.

DPP-4 inhibitors

DPP-4 inhibitors work by inhibiting the breakdown of endogenous incretin hormones. DPP-4 inhibitors increase GLP-1 twofold to threefold, whereas injectable GLP-1 receptor agonists increase GLP-1 eightfold to tenfold. DPP-4 inhibitors such as vildagliptin are increasingly replacing sulfonylureas as second line agents as they do not cause hypoglycaemia on their own and are weight neutral. However, generally DPP-4 inhibitors are less effective than sulfonylureas in lowering HbA1c.

Whilst cardiovascular safety studies of vildagliptin have proven its safety, it is generally considered to have a neutral effect on CVD.⁶ Hence, in anyone with significant CVD, heart failure or renal risk, DPP-4 inhibitors should be considered a third-line treatment after SGLT2 inhibitors.

In patients without cardiovascular risk factors, heart failure or CKD, early combination therapy of vildagliptin with metformin should be considered. The VERIFY study7 indicated that patients who commenced dual therapy when HbA1c was between 48 and 58mmol/mol had a longer period of time with a HbA1c <53 mmol/mol than those who received sequential therapy with vildagliptin after failing metformin monotherapy.

Sulfonylureas and thiazolidinediones

Sulfonylureas and thiazolidinediones (TZDs) are the last choice of drugs in the new EU and US guidelines for type 2 diabetes.¹ These therapies are used for glucose-lowering in situations where cost is a major issue and/or there is a reluctance to use insulin to control glycaemia. They have been widely used in New Zealand.

Sulfonylureas close potassium channels at the surface of the pancreatic beta cell and lead to insulin release. The major side effect of sulfonylureas is hypoglycaemia as insulin is released irrespective of blood glucose levels. For this reason, patients are required to pay closer attention to managing the balance between carbohydrate intake and activity and will need to monitor their blood glucose levels.

Pioglitazone is the only drug within the TZD class that is still available. It binds to the nuclear peroxisome-proliferator-activated receptor and modulates gene expression which improves insulin sensitivity. Pioglitazone does not cause hypoglycaemia and is preferred over sulfonylureas if there is a compelling need to minimise hypoglycaemia. Pioglitazone leads to triglycerides reduction and improved fatty liver disease and possibly lowers CVD events. However, pioglitazone therapy is frequently associated with weight gain (approximately 2–3kg) and is not suitable for patients with heart failure or macular oedema, or in patients who are at increased risk of fracture.

Insulin

Insulin should be considered for patients who do not achieve target HbA1c levels on other combination glucose-lowering therapies, but GLP-1 receptor agonists are preferred over insulin when possible. Due to the progressive beta cell failure in type 2 diabetes, many patients will eventually need insulin therapy to achieve target glycaemic levels. Diabetes management guidelines including insulin initiation are available on Regional HealthPathways and an updated New Zealand Type 2 Diabetes Management Guidance is available at t2dm.nzssd.org.nz.

Original article written by Rinki Murphy, endocrinologist and diabetologist at Auckland DHB
Edited for nursing readership by Lisa Sparks, diabetes clinical nurse specialist at Waitemata DHB