Glucagon-like Peptide-1 Receptor Agonists

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were initially considered well down the line of treatment options for the management of type 2 diabetes. However, updated Australian guidelines now recommend that prescribers consider them earlier to help patients lower their blood glucose levels. They are not regarded as first-line treatment in diabetes, but they can be a valuable part of the overall management plan. They can be prescribed with insulin.

Glucagon-like peptide-1 (GLP1) is a gut-derived hormone (also known as an incretin). It is released from the small intestine in response to food ingested. It has a short half-life of 1-2 minutes and is quickly broken down by the enzyme dipeptidyl peptidase 4 (DPP-4). Physiological actions of GLP1 are:

• Glucose-dependent insulin release from the pancreas
• Slowing of gastric motility, slowing down gastric emptying
• Promote satiety
• Inhibit glucagon release in a glucose-dependent manner

GLP1-RAs are based on human GLP1. However, they have been modified not to be degraded by DPP-4. They are administered subcutaneously. Physiological actions of GLP1-RAs are:

• Increase glucose-dependent insulin secretion and suppress inappropriate glucagon secretion
• Delay gastric emptying, which slows glucose absorption and decreases appetite (results in reduced calorie intake)

GLP1-RAs have a lower risk of causing hypoglycaemia but are only PBS listed for patients that have an HbA1c > 7 and have trialled other glucose-lowering medications with no success.

Apart from insulin, the glucose-lowering effects of GLP1-RAs are greater than other glucose-lowering agents. GLP1-RAs reduce HbA1c levels between 0.3% – 1.3%, with once-weekly GLP1-RAs being more effective than once or twice-daily GLP1-RAs.

• Liraglutide was slightly more effective at reducing HbA_1cthan exenatide
• Dulaglutide appears to be as effective as liraglutide or exenatide
• Semaglutide appears slightly more effective at reducing HbA_1cthan liraglutide or dulaglutide

In trials comparing the addition of an injectable GLP1-RA or insulin in patients needing further glucose lowering, glycaemic efficacy of GLP1-RA was similar or greater than that of basal insulin. GLP1-RAs have an advantage over insulin for their weight loss ability and simplicity. They can be administered within 2-3 days if a dose is missed. They can be confused with insulin because of similar presentation and administration.

The combination of insulin and GLP1-RA has been shown to reduce HbA1c, weight, insulin doses and number of injections per day. In combination with SGLT2 inhibitors, there is a beneficial effect in glucose lowering and weight loss. However, the combination of GLP1-RA and SGLT2 inhibitors together is not PBS listed.

It is not recommended to use a GLP1-RA and a dipeptidyl peptidase-4 (DPP-4) inhibitor together as there are no additional glycaemic or other benefits, and both are incretin mimetics. If a patient is already taking a DPP-4 inhibitor and a GLP1-RA is to be started, guidelines advise ceasing the DPP-4 inhibitor.

GLP1-RAs have shown improvements in major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) but not in heart failure. They have also proved to be beneficial in reducing the risk of renal failure, though they are likely inferior to SGLT2 inhibitors.

GLP1-RAs provide greater weight loss compared to other glucose-lowering medications. Although weight loss is advantageous in people living with type 2 diabetes, pharmacists need to be aware that using GLP1-RAs can lead to excessive weight loss, especially in people who experience nausea and vomiting. Referral to a dietician may be necessary to ensure adequate nutrition.

• Semaglutide has greater HbA1c and weight improvement compared to other GLP1-RAs
• Exenatide (recently discontinued in Australia) is short-acting and needs to be administered twice a day just before meals for maximum efficacy
• Liraglutide is administered once daily
• Semaglutide and dulaglutide are longer-acting and administered once weekly, independent of food intake

Once weekly injections were more consistent and effective in lowering HbA1c. Twice daily GLP1-RAs were more effective in slowing down gastric emptying (hence increased nausea and vomiting) and lowering glucose levels postprandial. Once weekly GLP1-RAs are also marketed and approved for weight loss.

Dulaglutide uses a simpler self-injection auto device compared to semaglutide and exenatide, which require additional steps for administration (e.g. attachment of a needle). This may be advantageous for people who are fearful of needles or who require a simple administration device. Dulaglutide has a simple dose regime too. Semaglutide and exenatide require dose titration. Semaglutide has the added complexity of requiring prescriptions of different pens to achieve the target dose.

Precautions:

• Monitor and use with caution in people with gastroparesis or severe gastro-oesophageal reflux disease as they delay gastric emptying
• There is limited evidence in the safety for use in terminal renal failure and severe hepatic dysfunction.
• Semaglutide should be used with caution in patients with pre-existing retinopathy
• Use with caution in patients with a previous history of pancreatitis or risk factors for pancreatitis (e.g. excessive alcohol intake, hypertriglyceridemia)
• Use with caution if there is a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome.

Adverse effects:

• Up to 50% of patients experience nausea and/or This usually improves with continued treatment. More frequent in exenatide.
• Diarrhoea – more common with once-weekly GLP1-RA
• Constipation
• Dyspepsia
• Gastro-oesophageal reflux disease (GORD)
• Abdominal pain
• Fatigue – reduces with continuous treatment
• Injection site reactions
• Hypoglycaemia – if used in combination with sulfonylureas and/or insulin
• Increased heart rate

Gradual dose titration can help patients to achieve tolerance to the adverse effects.

Healthcare professionals can help manage the gastrointestinal side effects by advising patients to:

• Eat smaller portions
• Eat lower fat foods
• Avoid food and smells that worsen feelings of nausea
• Drink plenty of fluids to manage constipation or prevent dehydration in diarrhoea

Recommended dosages for type 2 diabetes:

• Exenatide – 5mcg twice a day within 60 minutes before morning and evening meals. If tolerated, increase to 10mcg twice a day after 1 month.
• Dulaglutide – 1.5mg weekly
• Semaglutide – 0.25mg weekly for 4 weeks, then5mg weekly for at least 4 weeks. May increase to 1mg weekly thereafter (usually 4-6 weeks after 0.5mg)
• Liraglutide – 0.6 mg once daily. Can increase to 8 mg daily in increments of 0.6 mg with at least one-week intervals to improve gastrointestinal tolerability.

Overall potential benefits of GLP-1 RAs outweigh many of the older second-line therapy options. This medication class can be considered a useful option in the treatment of type 2 diabetes for patients with HbA1c levels that are not at target, or for patients with established cardiovascular disease (CVD) or a high risk of CVD. The convenience of a once-weekly therapy may also appeal to many patients over the additional burden imposed by adding an extra tablet.