GLP-1 receptor agonist (revision 42)

A GLP-1 receptor agonist (GLP-1 RA) is a drug that activates the GLP-1 receptor, reproducing and prolonging the actions of the endogenous incretin hormone Glucagon-like peptide-1. The class was developed for type 2 diabetes and has since been approved, for several of its members, for the treatment of obesity and for reduction of cardiovascular risk.^[1]

Native GLP-1 is unusable as a medicine because Dipeptidyl peptidase-4 inactivates it within one to two minutes of secretion. Every clinically successful agonist therefore solves the same engineering problem in one of a small number of ways: substitution of the residue attacked by the protease, fatty-acid acylation that ties the molecule to serum albumin, fusion to an immunoglobulin fragment, or use of a naturally protease-resistant scaffold such as exendin-4.^[2]

Efficacy within the class is not uniform. Placebo-adjusted weight loss over 68 weeks ranges from roughly 4% for the earliest daily peptides to about 15% for weekly semaglutide at 2.4 mg, and glycaemic effect broadly tracks it.^[3] Members of the class supplied through research-chemical channels are not approved for human use, and material obtained that way carries none of the identity, purity or fill assurances that accompany a licensed product; see Research use only.

The GLP-1 receptor is a class B G-protein-coupled receptor expressed on pancreatic beta cells, on gastric smooth muscle and enteric neurons, on cardiomyocytes, and at several sites in the central nervous system including the arcuate nucleus of the hypothalamus and the area postrema. Agonist binding couples principally to G_s, raising intracellular cAMP.^[1]

At the beta cell, the rise in cAMP amplifies glucose-stimulated insulin secretion without initiating it. Because the amplification requires a permissive glucose signal, agonism does not provoke insulin release at low glucose, and monotherapy carries a low intrinsic risk of hypoglycaemia — a property that distinguishes the class sharply from sulfonylureas.^[4]

Three further actions contribute to the clinical effect. Glucagon secretion from alpha cells is suppressed in a similarly glucose-dependent manner, reducing hepatic glucose output. Gastric emptying is delayed, blunting the postprandial glucose excursion and contributing to early satiety. Central agonism reduces food intake, and this — rather than any effect on energy expenditure — accounts for the great majority of weight loss observed in trials.^[1]

Native GLP-1 has a circulating half-life of one to two minutes. The agonists in clinical use extend that by between three and four orders of magnitude, and the strategies fall into four families.

Albumin binding is the dominant approach because it is reversible: the bound fraction acts as a circulating depot from which free drug is released continuously, flattening the peak-to-trough ratio as well as extending exposure. The C-18 diacid used in semaglutide binds albumin more tightly than the C-16 monoacid used in liraglutide, which is the principal reason for the difference in dosing interval.^[2]

Small-molecule agonists such as orforglipron achieve oral bioavailability by abandoning the peptide backbone entirely. They are not subject to proteolysis and do not require an absorption enhancer, but they engage a different portion of the receptor and their efficacy relative to injected peptides remains under evaluation.^[5]

Across the STEP, SUSTAIN and SURPASS programmes the class has been assessed against placebo and against active comparators in both diabetic and non-diabetic populations. In people with obesity and without diabetes, weekly semaglutide 2.4 mg produced a mean weight change of −14.9% against −2.4% for placebo at 68 weeks.^[3] In type 2 diabetes the same class produces glycated-haemoglobin reductions of roughly 1.0–1.8 percentage points, with the larger figures at the higher doses of the more recent agents.^[4]

Cardiovascular outcome trials have shown benefit for several members. The SELECT trial reported a reduction in major adverse cardiovascular events in people with established cardiovascular disease and overweight or obesity but without diabetes, and the FLOW trial reported slowing of kidney-disease progression.^[6] These are outcome findings for specific molecules at specific doses and are not properties of the class as a whole; extrapolation between members is not supported by the trial evidence.

Effect sizes reported in trials are means. Individual response is broadly distributed, and a substantial minority of participants in every published programme lose less than 5% of body weight. The determinants of that variation are not established.^[3]

Gastrointestinal events dominate. Nausea, vomiting, diarrhoea and constipation are reported by between 20% and 45% of participants depending on agent and dose, are most frequent during escalation, and diminish with time at a stable dose. They are the commonest reason for discontinuation.^[1] A fuller treatment is given at Adverse effects of GLP-1 receptor agonists.

Less common but clinically significant concerns include gallbladder disease, acute pancreatitis, and — on the basis of rodent carcinogenicity data — a labelled contraindication in people with a personal or family history of medullary thyroid carcinoma. Delayed gastric emptying has prompted revised guidance on preoperative fasting.^[4]

Loss of lean mass accompanies the loss of fat mass, in a proportion broadly comparable with that seen in other forms of substantial caloric restriction. Whether this proportion is materially different from that of diet-induced weight loss is disputed, and the trials were not designed to settle it.^[3]

Peptides of this class are synthesised and sold as research chemicals by a large number of organisations, and the resulting material is not a medicine: it is not manufactured under a marketing authorisation, is not released against a pharmacopoeial specification, and carries no regulatory assurance of identity, purity, sterility or fill mass.^[7]

Documentation supplied with such material varies from a full lot-specific certificate of analysis with named methods to a single unattributed purity figure. A purity figure alone is not sufficient to characterise a peptide: without a peptide content determination and a water figure, the mass of active substance in a vial cannot be calculated, and a nominal 5 mg vial may contain substantially less. Underfilling is documented in independently tested material.^[8]

This wiki records what submitted documents say and does not represent any such material as suitable for human use.

• Glucagon-like peptide-1
• GLP-1 receptor
• Dual incretin agonist
• Semaglutide
• Liraglutide
• Adverse effects of GLP-1 receptor agonists
• Comparison of GLP-1 receptor agonists

• Müller TD, Finan B, Bloom SR, et al. "Glucagon-like peptide 1 (GLP-1)." Molecular Metabolism 30:72–130 (2019).

• SELECT — NCT03574597 — Registry record for the cardiovascular outcome trial cited above.