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Glucagon-like peptide-1 (GLP-1) agonists bind to and activate GLP-1 receptors to stimulate insulin secretion and inhibit glucagon in a glucose dependent manner.
GLP-1 agonists mimic the action of the hormone incretin and also delay gastric emptying, promote satiety and reduce hunger.
GLP-1 is released after the ingestion of carbohydrates or fats. The GLP-1 response in those with type 2 diabetes is diminished, so this class of drug is an effective treatment option for these patients, achieving HbA1c reductions and weight loss.
Some GLP-1 receptor agonists such as dulaglutide, liraglutide and semaglutide have been demonstrated to have cardiovascular benefits, making this drug class more appealing.1
There are a number of GLP-1 agonists approved in the UK for the management of type 2 diabetes. See Table 1 (below) for administration and dosing details.
The current type 2 diabetes guideline from the National Institute for Health and Care Excellence (NICE) recommends that GLP-1 agonist therapy should be considered in those patients with a body mass index (BMI) ≥ 35kg/m2 (or those with a BMI < 35kg/m2 and for whom insulin therapy is not suitable or weight loss is deemed beneficial).
If triple therapy with metformin and two other oral drugs is ineffective, not tolerated or contraindicated, one oral drug can be switched to a GLP-1 receptor agonist.
It is important to note that GLP-1 receptor agonists can only be continued if a patient with type 2 diabetes has had a beneficial metabolic response (i.e. HbA1c reduction ≥ 11 mmol/mol and weight reduction of at least 3 per cent or more in the first six months).3
The Scottish Intercollegiate Guidelines Network (SIGN) recommends GLP-1 receptor agonists to be considered in patients with a BMI ≥ 30kg/m2 in combination with oral glucose-lowering drugs and/or basal insulin as third- or fourth-line treatment, when HbA1c is not at target.4
Safety should be considered before prescribing a GLP-1 agonist. Table 2 depicts the clinical situations where a GLP-1 agonist can be initiated safely, when caution needs to be exercised, or when it should be avoided.1
| Table 1: Administration and dosing of GLP-1 receptor agonists available in the UK1,2 | |||
| Administration | GLP-1 RA | Dosing | |
| Twice daily subcutaneous injection | Exenatide (Byetta) |
5mcg twice daily within one hour before the morning and evening meals (> 6 hours apart); can increase to 10mcg twice daily to further improve glycaemic control after one month |
Pen device requires attachable needle |
|
Once daily |
Lixisenatide (Lyxumia) |
10mcg daily within one hour before any meal of the day for 14 days; increase to 20mcg daily on day 15 |
Pen device requires attachable needle |
|
Liraglutide (Victoza) |
0.6mg daily at any time of the day; after at least one week increase to 1.2mg; after at least another week may increase to 1.8mg to further improve glycaemic control |
Pen device requires attachable needle |
|
|
Once weekly |
Dulaglutide (Trulicity) |
0.75mg once weekly as monotherapy; 1.5mg once weekly as add-on therapy administered at any time of day; the 1.5mg dose may be increased after at least four weeks to 3mg once weekly; and after at least another four weeks increased to 4.5mg once weekly for additional glycaemic control |
Single-use |
|
Exenatide (Bydureon) |
2mg once weekly administered at any time of day on the same day each week |
Single-use |
|
|
Semaglutide (Ozempic) |
0.25mg once weekly administered at any time of the day; after four weeks increase to 0.5mg once weekly; after at least another four weeks may increase to 1.0mg once weekly to improve glycaemic control |
Pen device requires attachable needle (included with pen) |
|
|
Once daily oral formulation |
Oral semaglutide (Rybelsus) |
3mg daily administered with 120ml of water any time of the day on a fasted (ideally >6 hours) stomach for one month and increase to a maintenance dose of 7mg; after at least one month the dose can be increased to 14mg to further improve glycaemic control. Wait |
|
How to use GLP-1 agonists safely
Although GLP-1 receptor agonists do not cause hypoglycaemia, there is an increased risk of this happening if taken in combination with insulin and/or a sulfonylurea. The dose of insulin and/or sulfonylurea may need to be reduced to minimise this risk of hypoglycaemia.1
In 2019 the MHRA confirmed that diabetic ketoacidosis (DKA) had been reported in patients with type 2 diabetes on a combination of a GLP-1 receptor agonist and insulin, who had doses of concomitant insulin rapidly reduced or discontinued.
Any reduction of insulin should therefore be done in a stepwise manner with careful glucose self-monitoring, as abrupt discontinuation or reduction in insulin doses can lead to poor glycaemic control and a risk of diabetic ketoacidosis.5
| Table 2: Prescribing GLP-1 receptor agonist therapy in type 2 diabetes2 | ||
| Patients to consider | Use with caution in... | Do not initiate in... |
|
Those with type 2 diabetes and high BMI, adjusted for ethnicity Patients with type 2 diabetes and Patients with type 2 diabetes and Patients with type 2 diabetes and chronic kidney disease (CKD) or heart failure, unsuitable for SGLT2 inhibitors |
Patients in whom weight loss would cause concern (e.g. frailty) Patients with a history of gallstones Women of child-bearing age (ensure adequate contraception) Patients with irritable bowel syndrome (IBS) or gastro-oesophageal reflux disease (GORD) Patients with renal or hepatic impairment Active proliferative or pre-proliferative retinopathy (semaglutide) |
Patients with type 1 diabetes (although used unlicensed under specialist initiation) Children (although liraglutide is licensed for use in adolescents and children aged 10 years and over) Pregnant women Patients with a history of, or risk factors for, pancreatitis Patients with a history of medullary thyroid cancer or multiple endocrine neoplasia type 2 |
What to advise individuals on GLP-1s
Gastrointestinal adverse events are usually mild or moderate, dose-dependent and transient. To mitigate symptoms, suggest reducing meal sizes, eating more often and reducing fat content (which slows gastric emptying). Short-term antiemetics can be offered if symptoms are persistent.2
This may occur due to the delay in gastric emptying. Dyspepsia agents can be considered.2
Constipation may occur due to delay in gastric emptying. Consider osmotic laxatives. Encourage fluids if as a result of reduced oral intake.2
GLP-1 receptor agonists are linked to acute pancreatitis, so this should be considered if a patient is having severe abdominal pain which radiates to the back. Medical advice should be sought if pancreatitis is suspected.1
If a patient is unable to eat or drink, or has persistent vomiting or diarrhoea, then the SADMAN drugs (SGLT2is, ACE inhibitors, diuretics, metformin, angiotensin-2 receptor blockers and NSAIDs) should be temporarily stopped and restarted 24-48 hours after recovery from illness. Advise the patient to keep hydrated (two to three litres of fluid should be drunk per day) and to eat little and often. If they are not able to eat normally, meals should be replaced with high carbohydrate snacks or drinks.
Patients should be advised to keep using insulin and other diabetes medicines (apart from metformin, SGLT2is and GLP-1 receptor agonists) even if not eating, as blood glucose levels are likely to rise during illness. Check blood glucose levels every four hours and the doses of insulin and/or sulfonylurea should be guided by the blood glucose profile.1,6
The injection site should be rotated after each injection. Needles (if using) should be disposed of safely after each injection and not reused.2
References
1. Fernando K, Bain SC, Holmes P et al. Glucagon-Like Peptide 1 Receptor Agonist Usage in Type 2 Diabetes in Primary Care for the UK and Beyond: A Narrative Review. Diabetes Ther 12, 2267-2288 (2021). doi.org/10.1007/s13300-021-01116-9
2. Milne N (2023). How to use GLP-1 receptor agonist therapy safely and effectively. Diabetes & Primary Care 25: 11-3
3. Overview: Type 2 diabetes in adults: Management: Guidance (2022).
4. Scottish Intercollegiate Guidelines Network. Management of diabetes 116. A national clinical guideline. Health Improvement Scotland.(2017)
5. GLP-1 receptor agonists: Reports of diabetic ketoacidosis when concomitant insulin was rapidly reduced or discontinued. gov.uk (2019)
6. Wilding J, Fernando K, Milne N et al. SGLT2 Inhibitors in Type 2 Diabetes Management: Key Evidence and Implications for Clinical Practice. Diabetes Ther 9, 1757-1773 (2018) doi.org/10.1007/s13300-018-0471-8
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