GLP-1 receptor agonists: mechanism and clinical trials

GLP-1, a gut hormone

Glucagon-like peptide-1 (GLP-1) is secreted by intestinal L cells when nutrients arrive. It contributes to the “incretin effect”: at the same blood glucose level, oral glucose triggers a stronger insulin response than an intravenous infusion.

According to reference reviews, activating the GLP-1 receptor (GLP-1R) has several effects:

• Pancreas: glucose-dependent stimulation of insulin secretion and restraint of glucagon secretion.
• Stomach: slower gastric emptying.
• Brain: a satiety signal in the hypothalamus and brainstem.

Native GLP-1 is broken down within minutes by the enzyme DPP-4. The molecules studied clinically are therefore analogues engineered to resist this degradation and circulate for longer.

Single, dual and triple agonism

Agonists differ by the receptors they activate:

• GLP-1R only: semaglutide is the most studied example.
• GLP-1R + GIPR: tirzepatide adds the receptor for GIP, the other major incretin.
• GLP-1R + GIPR + GCGR: retatrutide adds the glucagon receptor, linked to energy expenditure in preclinical models.

Semaglutide and tirzepatide are prescription medicines authorised in several jurisdictions, including the European Union. Retatrutide remains experimental: its profile summarises the status published by the manufacturer.

What the published trials show

Three placebo-controlled randomised trials published in the New England Journal of Medicine serve as reference points in adults with obesity or overweight:

• STEP 1 (semaglutide): mean weight loss of about 15% at 68 weeks, versus about 2% on placebo.
• SURMOUNT-1 (tirzepatide): up to about 21% at 72 weeks in the highest arm, versus about 3% on placebo.
• Retatrutide phase 2: up to about 24% at 48 weeks in the highest arm, versus about 2% on placebo.

These figures are not directly comparable: durations, populations and trial phases differ, and none of these trials compares the molecules head to head. The most frequently reported adverse events are gastrointestinal (nausea, diarrhoea, vomiting).

What this means for a laboratory

For basic research, these three profiles make it possible to compare incretin and glucagon signalling within the same experimental system. A clinical result does not qualify a reagent, however: the identity and purity of a batch are checked in its own records, as explained in how to read a certificate of analysis.

This article is not medical advice. Velia Labs reagents are intended for laboratory research only and excluded from any human or veterinary use.

Sources

• Holst, Physiol Rev 2007: the physiology of GLP-1
• Drucker, Cell Metab 2018: mechanisms of action of GLP-1
• Wilding et al., NEJM 2021: the STEP 1 trial
• Jastreboff et al., NEJM 2022: the SURMOUNT-1 trial
• Jastreboff et al., NEJM 2023: retatrutide phase 2