GLP-1

GLP-1 (Glucagon-Like Peptide-1) is a 30 amino acid peptide hormone secreted by L cells in the small intestine in response to food intake. Discovered in the 1980s, this peptide belongs to the incretin family and plays a central role in regulating glucose metabolism and appetite.

Unlike research peptides such as BPC-157 or TB-500, GLP-1 receptor agonists have undergone extensive clinical trials and are now approved medications by global health authorities (FDA, EMA) for the treatment of type 2 diabetes and obesity.

The therapeutic revolution of GLP-1 agonists began with liraglutide (Victoza, Saxenda) and accelerated with semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound). These molecules have demonstrated unprecedented weight loss in clinical trials, exceeding 15-20% of initial body weight, thus redefining the standards of metabolic medicine.

GLP-1 exerts its biological effects by binding to the GLP-1R receptor, a G protein-coupled receptor (GPCR) expressed in the pancreas, brain, gastrointestinal tract, heart, and kidneys. This binding triggers an intracellular signaling cascade involving cAMP and PKA/EPAC pathways.

At the pancreatic level, GLP-1 stimulates insulin secretion in a glucose-dependent manner: the effect is only significant in the presence of elevated blood glucose, thus minimizing the risk of hypoglycemia. It also inhibits glucagon secretion by alpha cells, reducing hepatic glucose production. Studies suggest a trophic effect on beta cells, promoting their proliferation and survival.

At the central level, GLP-1 acts on the hypothalamus and brainstem to reduce appetite and increase satiety. GLP-1R receptors are particularly concentrated in the arcuate nucleus and the nucleus of the solitary tract, key regions for controlling food intake. Activation of these receptors modulates reward circuits, reducing the appeal of high-calorie foods.

At the gastrointestinal level, GLP-1 slows gastric emptying, prolonging postprandial satiety. This slowing also helps attenuate postprandial blood glucose spikes. The effect on gastric motility is responsible for some side effects such as nausea.

Tirzepatide, a dual GIP/GLP-1 agonist, also activates the GIP receptor (Glucose-dependent Insulinotropic Polypeptide), producing synergistic effects on adipose tissue and appetite that neither receptor can generate independently.

GLP-1 receptor agonists are currently approved for several therapeutic indications, with continuous expansion of their scope of use:

Type 2 Diabetes: Main historical indication. Ozempic, Mounjaro, and Victoza are approved as second-line treatments after metformin, demonstrating significant HbA1c reduction (1-2% on average) and cardiovascular protection in high-risk patients.

Obesity and Overweight: Wegovy (semaglutide 2.4mg) and Zepbound (tirzepatide) are approved for adults with BMI ≥30 or BMI ≥27 with comorbidities. These indications have transformed the perception of obesity as a medically treatable disease. Since then, the FDA has also approved an oral semaglutide for obesity (Wegovy pill, December 2025), a higher-strength semaglutide injection (Wegovy HD, March 2026) and orforglipron (Foundayo, April 2026), the first non-peptide oral GLP-1 agonist.

Metabolic Steatohepatitis (MASH): In August 2025, the FDA approved semaglutide for the treatment of MASH (formerly NASH) following positive results from the ESSENCE trial. This new indication opens a considerable market for metabolic liver diseases.

Heart Failure: Completed trials have studied people with obesity and heart failure with preserved ejection fraction (HFpEF): STEP-HFpEF (semaglutide, 2023) improved symptoms, physical limitations and exercise capacity, and SUMMIT (tirzepatide, 2025) reduced the composite of cardiovascular death or worsening heart failure (9.9% vs 15.3% of participants) over a median of two years.

Neurodegenerative Diseases: Preliminary studies are exploring the neuroprotective potential of GLP-1 agonists in Alzheimer's disease and Parkinson's disease, with encouraging results requiring confirmation. However, the phase 3 EVOKE and EVOKE+ trials of oral semaglutide in early Alzheimer's disease (3,808 participants) did not slow disease progression (November 2025).

GLP-1 agonists have a characteristic side effect profile, primarily gastrointestinal, generally transient and dose-dependent:

Gastrointestinal effects (30-50% of patients): Nausea, vomiting, diarrhea, constipation. These effects are more frequent at treatment initiation and decrease over time. Gradual dose escalation is recommended to minimize them. Slowed gastric emptying can cause a prolonged feeling of fullness.

Pancreatitis risk: Cases of acute pancreatitis have been reported, although the causal link is not established with certainty. Patients with a history of pancreatitis should be monitored. Treatment should be discontinued if pancreatitis is suspected.

Thyroid tumors: Animal studies have shown an increased risk of medullary thyroid tumors in rodents. This risk has not been confirmed in humans, but GLP-1 agonists are contraindicated in patients with MEN2 syndrome or family history of medullary thyroid carcinoma.

Muscle mass loss: Recent research (November 2025) revealed that weight loss under GLP-1 includes a significant proportion of lean mass (up to 40% of total loss). Adequate protein intake and resistance exercise are recommended to preserve muscle mass.

Gastroparesis risk: Cases of severe gastroparesis have been reported, sometimes requiring treatment discontinuation. Patients with a history of gastric motility disorders should be carefully evaluated.

Drug interactions: Slowed gastric emptying may affect the absorption of other oral medications. Oral contraceptives, antibiotics, and drugs with narrow therapeutic windows deserve particular attention.

GLP-1-based medicines are supported by large randomized trials, but several common beliefs go further than the data.

Lasting results after stopping. In the STEP 1 extension, people who stopped semaglutide regained about two-thirds of the weight they had lost within one year, and their cardiometabolic improvements largely faded. A similar pattern was seen in SURMOUNT-4 when tirzepatide was replaced by placebo. No GLP-1 medicine has shown durable weight loss after treatment ends.

Comparisons between molecules. Only a few trials compare these drugs directly. SURMOUNT-5 is the main head-to-head obesity trial (tirzepatide -20.2% vs semaglutide -13.7% at 72 weeks). Comparisons with orforglipron, the Wegovy pill or retatrutide rely on separate trials with different populations and analyses, so differences of a few percentage points between them should not be read as proven.

Effects of the newest agents on hard outcomes. Semaglutide has outcome data on heart attacks, strokes and kidney disease (SELECT, FLOW, SOUL). Retatrutide and orforglipron do not yet have completed outcome trials; in TRIUMPH-3, cardiovascular events were too few to draw conclusions. TRIUMPH-1 (NEJM) and TRIUMPH-2 (The Lancet) have been published, but other retatrutide results are so far known only from company announcements.

Heart failure. STEP-HFpEF (semaglutide) and SUMMIT (tirzepatide) showed better symptoms and, in SUMMIT, fewer worsening heart-failure events or cardiovascular deaths in people with obesity and heart failure with preserved ejection fraction. These trials were modest in size, and they do not show benefit in people without obesity.

Body composition and the long term. Part of the weight lost is lean mass, and the long-term consequences for strength and function are not established. Trials last at most a few years, and data in pregnancy, older adults and adolescents remain limited. Brain effects, such as a possible benefit in Alzheimer's disease, have not been confirmed: the phase 3 EVOKE trials of oral semaglutide did not slow Alzheimer's progression.

Rare risks. The EMA concluded in 2025 that NAION, a sudden loss of vision in one eye, is a very rare side effect of semaglutide (up to 1 in 10,000 people). Whether it applies to the whole class is still being studied. Compounded and research-use-only products have no verified content, and trial results cannot be assumed for them.