Incretin agonist

Exenatide is the original GLP-1 receptor agonist, and it came out of a lizard. Exendin-4 was isolated from the venom of the Gila monster, Heloderma suspectum, and turned out to be a full agonist at the human GLP-1 receptor that resists the enzyme which destroys the human hormone. It reached the market in 2005 as twice-daily Byetta and later as weekly Bydureon, and everything that followed - liraglutide, semaglutide, tirzepatide - descends from the idea it proved. By modern standards it is weak: roughly 1% of body weight lost, and its cardiovascular outcome trial, EXSCEL, missed superiority at a hazard ratio of 0.91 with a confidence interval touching 1.00. Its most interesting current life is outside diabetes, and that story ended badly too: a promising phase 2 result in Parkinson's disease was followed by a clean negative phase 3.

Mazdutide is a glucagon/GLP-1 dual agonist built on oxyntomodulin, a natural gut peptide that hits both receptors. It was licensed from Eli Lilly to Innovent Biologics and developed almost entirely in China, which makes its trial program unusual: every efficacy result comes from Chinese participants, who start from a lower mean body weight than the Western obesity trials. GLORY-1 gave 14.01% weight loss at 6 mg over 48 weeks against a 0.30% gain on placebo, and GLORY-2, at 9 mg over 60 weeks, gave 16.65% against a 1.50% loss. Those are tirzepatide-class numbers. The caveat is the population: whether they transfer to a heavier, more metabolically damaged Western cohort has not been tested, and a head-to-head against semaglutide is only now running.

Orforglipron is the first GLP-1 receptor agonist that is not a peptide. That matters for a practical reason: a small molecule can be made by ordinary chemical synthesis rather than fermentation, and swallowed as a normal tablet with no food or water restrictions - unlike oral semaglutide, which needs an absorption enhancer and an empty stomach. In ATTAIN-1, 72 weeks of 36 mg daily gave a mean 11.2% weight loss against 2.1% on placebo; in ATTAIN-2, in people with obesity and type 2 diabetes, 9.6% against 2.5%. That places it below injected semaglutide and well below tirzepatide on weight, and roughly where oral semaglutide sits - while being far easier to take and, in principle, far easier to manufacture at scale.

Retatrutide is an experimental once-weekly injected peptide from Eli Lilly that activates three hormone receptors: GIP, GLP-1 and glucagon. In a 48-week phase 2 trial in adults with obesity, the 12 mg dose lowered body weight by 24.2%, against 2.1% on placebo. The first phase 3 trial, in type 2 diabetes, confirmed large falls in HbA1c and weight. It is not approved; in the cited literature its phase 3 obesity trials are still under way.

Semaglutide is the GLP-1 receptor agonist that turned obesity into a treatable condition in mainstream medicine. In STEP 1, 68 weeks of 2.4 mg weekly produced a mean 14.9% weight loss against 2.4% on placebo, with half of participants losing 15% or more. In SELECT, 17,604 people with obesity and established cardiovascular disease but no diabetes had a 20% reduction in major cardiovascular events over the trial - the result that moved it from a weight drug to a cardiovascular one. The costs are real and well documented: gastrointestinal effects in most people, about 4.5% discontinuing for them in STEP 1, and weight regain when it stops. A year after withdrawal in the STEP 1 extension, participants had regained two-thirds of what they lost.

Survodutide activates the glucagon receptor as well as the GLP-1 receptor. Adding glucagon agonism to an incretin is counterintuitive - glucagon raises blood sugar - but it also raises energy expenditure and acts directly on the liver, and in a weight-losing context the GLP-1 arm covers the glycemic downside. The phase 2 obesity trial gave 14.9% weight loss at 4.8 mg over 46 weeks against 2.8% on placebo. The more striking result is hepatic: in a phase 2 trial in MASH, 48 weeks improved histological steatohepatitis without worsening fibrosis in 47-62% of participants against 14% on placebo, and a phase 3 trial in MASLD found 84.2% achieved a 30% or greater reduction in liver fat against 24.3%. The tolerability cost is high: vomiting in 41% against 4% on placebo in the MASH trial.

Tirzepatide is a once-weekly injected peptide that activates two gut-hormone receptors, GIP and GLP-1. It is approved for type 2 diabetes and, as Zepbound, for chronic weight management. In a 72-week trial in adults with obesity, the top dose lowered body weight by 20.9%, against 3.1% on placebo. In a head-to-head trial it caused more weight loss than semaglutide (20.2% vs 13.7%). Most side effects are gastrointestinal, and the weight comes back when treatment stops.