Glucagon-like Peptide-1 Analogues

Glucagon-like peptide-1 (GLP-1) analogues are one of the newer medicine classes for the management of type 2 diabetes. This group includes the following agents:

• Dulaglutide;
• Exenatide;
• Liraglutide; and
• Semaglutide.

Glucagon-like peptide-1 is one of the main incretins and plays an important role in blood glucose regulation. This peptide functions to increase insulin secretion, inhibit glucagon release, reduce gastrointestinal motility, and enhance satiety. GLP-1 is secreted from the L-cells in the ileum and colon in response to nutrient ingestion.

While GLP-1 is effective at improving glucose-dependent insulin secretion, its short plasma half-life (around 2 minutes) limits its use as a therapeutic agent. This short half-life is due to rapid metabolism by dipeptidyl peptidase 4 (DPP4 – the enzyme targeted by the gliptin class of medicines). The GLP-1 analogues used therapeutically have been modified to prolong their half-life by increasing resistance to DPP4, slowing their absorption, and reducing their renal clearance.

A comparison of the GLP-1 analogues used in the management of type 2 diabetes is shown in Table 1.

Table 1. GLP-1 analogues available for the management of type 2 diabetes

*The modified-release formulation of exenatide (Bydureon®) has recently been discontinued, but is still listed on the PBS under ‘Supply Only’ arrangements.

Clinical benefits

Although there are no blinded direct comparative trials published for GLP-1 analogues, they have all demonstrated efficacy in reducing HbA_1c (around 5-20mmol/mol reduction expected). The short and intermediate-acting GLP-1 analogues have the greatest effect on postprandial glucose levels, while the long-acting agents have a more significant effect on fasting glucose levels.

Other clinical benefits of GLP-1 analogues may include:

• Modest weight loss (around 2-5kg over 30 weeks);
• Reduction in systolic blood pressure (1-5mmHg);
• Improved lipid levels (reduced LDL and total cholesterol);
• Prevention of cardiovascular events (evidence for liraglutide, semaglutide and dulaglutide); and
• Renal benefits (evidence for liraglutide, dulaglutide and semaglutide).

Adverse effects:

Hypoglycaemia is unlikely to occur with GLP-1 analogues, unless they are used in combination with a sulfonylurea or insulin. The most common adverse effects are gastrointestinal, with up to 50% of patients experiencing nausea and vomiting. However, these effects tend to improve with continued treatment. Initial dose titration is recommended for liraglutide, semaglutide and exenatide to improve gastrointestinal tolerability.

Other common adverse effects include:

• Dyspepsia;
• Abdominal pain;
• Diarrhoea;
• Constipation; and
• Injection site reactions.

Pancreatitis has been associated with GLP-1 analogues. However, studies suggest that any increased risk is likely to be very low. These agents should not be used in patients with a history of pancreatitis and should be ceased if pancreatitis occurs.

Drug interactions:

Owing to their ability to delay gastric emptying, it is theorised that GLP-1 analogues could affect the absorption of orally administered medicines. However, most studies demonstrate that this is not clinically relevant for dulaglutide, liraglutide, or semaglutide.

In the case of exenatide, consideration is recommended when co-administered with:

• Medicines that require rapid gastrointestinal absorption (e.g. some antibiotics);
• Medicines that are sensitive to degradation in the stomach (e.g. proton pump inhibitors); and
• Medicines associated with local gastrointestinal irritation (e.g. bisphosphonates, tetracyclines).

These interactions may be avoided by taking these other medicines at least one hour before or four hours after injecting exenatide. There have also been reports of raised INR when exenatide is administered with warfarin; monitoring is recommended.

As GLP-1 analogues stimulate insulin release, co-administration with insulin or a sulfonylurea significantly increases the risk of hypoglycaemia. A dose reduction of the insulin or sulfonylurea may be required.

Place in therapy

Lifestyle modification is central to the management of type 2 diabetes. The choice of antihyperglycaemic drug is dependent upon a range of patient and drug-related factors. Metformin is the usual first-line option, unless contraindicated or not tolerated; GLP-1 analogues are considered a second-line option.

All GLP-1 analogues approved in Australia must be administered by subcutaneous injection, which may limit their acceptability. Use of long-acting agents that only require weekly administration may improve adherence for some patients. An oral formulation of semaglutide has been approved in several countries. This product is formulated with an absorption enhancer (sodium N-(8-[2-hydroxylbenzoyl] amino) caprylate) that increases the local pH to protect semaglutide against degradation and aid its absorption. Although this formulation is not yet approved for use in Australia, oral GLP-1 analogues may be an option in the future.