Peptides for weight loss: which ones have real evidence

Which peptides for weight loss have phase 3 trials

When someone searches for “peptides for weight loss,” two groups of molecules usually get mixed together: drugs tested in randomized trials of thousands of people, and catalog products with little or no human data. The gap between them is huge. In obesity, phase 3 evidence belongs to one family: analogs of gut hormones called incretins, mainly GLP-1, sometimes combined with GIP or amylin¹²⁴.

Semaglutide 2.4 mg weekly was tested in 1,961 adults without diabetes for 68 weeks: body weight changed by −14.9% versus −2.4% with placebo, and 50.5% lost at least 15%¹. Liraglutide 3.0 mg daily, an earlier GLP-1, produced 8.4 kg of loss versus 2.8 kg with placebo at 56 weeks⁷. The European Medicines Agency authorized Wegovy (semaglutide) for weight management on 6 January 2022¹⁸.

GLP-1, GIP and amylin: what each pathway does

GLP-1 acts on hunger and satiety centers and slows gastric emptying. Tirzepatide adds the GIP receptor: one peptide that activates both². In SURMOUNT-1 (2,539 adults, 72 weeks), mean change was −15.0%, −19.5% and −20.9% with 5, 10 and 15 mg, versus −3.1% with placebo². For the mechanism in depth, see Tirzepatide mechanism of action.

Amylin is the third pathway. Cagrilintide, a weekly amylin analog, reduced weight by 6.0% to 10.8% over 26 weeks in phase 2, versus 3.0% with placebo⁵. In REDEFINE 1 (3,417 participants), combining it with semaglutide reached −20.4% at 68 weeks, with gastrointestinal events in 79.6% of the combination group versus 39.9% with placebo⁴. More in Cagrilintide and amylin.

Semaglutide versus tirzepatide: the head-to-head

Percentages from different trials are not comparable: population, duration and statistical method all differ. That is why SURMOUNT-5 matters, an open-label phase 3b trial of 751 adults with obesity and no diabetes that compared both drugs at maximum tolerated doses for 72 weeks: −20.2% with tirzepatide and −13.7% with semaglutide, with a waist-circumference difference too (−18.4 cm versus −13.0 cm)³. It was funded by tirzepatide's manufacturer and was open-label, two caveats worth keeping in mind.

Investigational peptides: retatrutide and mazdutide

Peptides that activate three or two receptors at once are the next generation. Retatrutide (GIP, GLP-1 and glucagon) showed, in a phase 2 trial of 338 adults, a weight change of −24.2% with 12 mg at 48 weeks versus −2.1% with placebo, with heart-rate increases that peaked at 24 weeks⁶. Mazdutide, which combines GLP-1 and glucagon, produced −14.01% with 6 mg at 48 weeks in Chinese adults, versus +0.30% with placebo¹¹. These are trial results, not approvals available everywhere. For context on retatrutide, see the GLP-1 guide.

Other peptides that show up in searches

Tesamorelin, a growth hormone–releasing factor analog, was studied in patients with HIV and excess abdominal fat: visceral fat fell 15.2% versus a 5.0% increase with placebo, but that is a different population and goal from common obesity¹². Setmelanotide was investigated in obesity caused by the MC4R pathway, a rare genetic cause, including a 1-year open-label phase 3 trial in children aged 2 to 5¹³.

AOD9604, a growth hormone fragment, is mentioned constantly online. The literature we could verify on it centers on detection methods and analysis of seized preparations, for example a case in which Belgian authorities identified it in an unknown product¹⁴. Phase 3 weight-loss trial evidence to support it is missing.

Limits the headlines skip

• Rebound. One year after stopping semaglutide, participants regained two-thirds of the weight lost, and cardiometabolic improvements drifted back toward baseline⁸.
• Maintenance. In SURMOUNT-4, people who continued tirzepatide lost another 5.5%, while those switched to placebo regained 14.0%⁹.
• Persistence. In a US cohort of 125,474 adults, 64.8% of those without type 2 diabetes had stopped treatment within a year¹⁵.
• Tolerability. Nausea, diarrhea and other gastrointestinal effects are the most common, especially during dose escalation¹².
• Product quality. The FDA warns that unapproved drugs do not go through its review for safety, effectiveness and quality, and that illegally marketed online versions could contain too little, too much or no active ingredient¹⁶. WHO alerted to falsified batches of Ozempic in the Americas and Europe regions¹⁹.

Beyond weight: what was measured in outcomes

For a physician, the question is not only how many kilos. In SELECT (17,604 patients with cardiovascular disease and overweight or obesity, without diabetes), semaglutide reduced the primary cardiovascular endpoint: 6.5% versus 8.0% with placebo (hazard ratio 0.80), with more discontinuations for adverse events (16.6% versus 8.2%)¹⁰. That kind of data, from approved drugs in defined populations, does not exist for most catalog peptides. Tirzepatide received FDA approval for chronic weight management on 8 November 2023¹⁷.