LY3437943
Evidence Grade C — Moderate human evidence. 130 published studies, 84 human. 32 registered clinical trials.
Retatrutide is a once-weekly injection in Phase III development by Eli Lilly that simultaneously activates three gut hormone receptors — GIP, GLP-1, and glucagon — making it the first triple-action treatment for obesity. The first Phase III trial reported an average weight loss of 28.7% (about 71 pounds) at the highest dose, the largest ever recorded for any obesity medication in a clinical trial.
130 published studies: 84 human, 4 animal, 1 in-vitro, 83 reviews
Retatrutide is in Phase III development (not yet approved). In a Phase II trial (338 patients, 48 weeks), the highest dose achieved 24.2% body weight loss compared to 2.1% with placebo, with 100% of participants at higher doses achieving at least 5% weight loss. A sub-study showed dramatic liver fat reduction.
Phase III trials are ongoing. If approved, retatrutide would represent an escalation from dual to triple receptor targeting in the incretin-based obesity treatment approach. The glucagon receptor component's ability to increase energy expenditure and reduce liver fat addresses limitations of GLP-1-only approaches. Gastrointestinal side effects (nausea, diarrhoea) are the most common adverse events, consistent with the drug class.
Retatrutide activates three complementary metabolic pathways simultaneously. GLP-1 receptor activation suppresses appetite and slows gastric emptying (the mechanism used by semaglutide). GIP receptor activation enhances insulin secretion and may improve metabolic efficiency (as with tirzepatide). Glucagon receptor activation — the novel addition — increases the body's energy expenditure and promotes liver fat burning, potentially addressing metabolic liver disease alongside weight loss.
The first Phase III results (TRIUMPH-4, 445 patients, 68 weeks) confirmed and exceeded the already striking Phase II data. At the 12 mg dose, patients lost an average of 28.7% of their body weight, with nearly 40% of participants losing 30% or more. The trial also showed substantial improvements in knee osteoarthritis pain, systolic blood pressure reductions of 14 mmHg, and improvements in cardiovascular risk markers. A new safety signal emerged: dysesthesia (abnormal tingling or pain sensations) was reported in 21% of patients at the highest dose — a side effect not seen in Phase II. Gastrointestinal side effects were significant (nausea 43%, diarrhoea 33%, vomiting 21%). Discontinuation rates of 12-18% were driven partly by perceived excessive weight loss in some patients. Seven additional Phase III trials are expected to report in 2026, covering obesity, diabetes, sleep apnoea, liver disease, and cardiovascular outcomes. Approval is projected for late 2027 at earliest.
Effect of LY3437943 Versus Placebo in Participants Who Have Obesity or Are Overweight
A Study of Retatrutide (LY3437943) in Participants Without Type 2 Diabetes Who Have Obesity or Overweight
A Study of Retatrutide (LY3437943) in Participants With Obesity or Overweight
A Master Protocol of Multiple Agents in Adults With Metabolic Dysfunction-Associated Steatotic Liver Disease (SYNERGY-Outcomes)
A Study to Investigate the Response of Participants With Type 2 Diabetes Mellitus on Once-Weekly Retatrutide to Hypoglycemia
The information on this page is provided for educational and research reference purposes only. This is not medical advice. Always consult a qualified healthcare professional before making any health-related decisions.
Liraglutide is marketed as Victoza for type 2 diabetes (approved 2010) and Saxenda for weight management (approved 2014). The LEADER trial, involving over 9,300 patients followed for nearly four years, established that liraglutide reduced the risk of major cardiovascular events by 13% — a landmark finding that helped establish GLP-1 treatments as a class with heart benefits. Saxenda is also approved for adolescents aged 12 and older. While historically significant, liraglutide has been substantially surpassed by newer agents. In a direct comparison, semaglutide achieved 15.8% weight loss compared to liraglutide's 6.4%. Liraglutide remains relevant as a lower-intensity option and as a benchmark against which newer treatments are measured. It has over a decade of real-world safety data, making it one of the best-understood medications in this class.
Setmelanotide is marketed as Imcivree (Rhythm Pharmaceuticals; approved November 2020 for POMC, PCSK1, or LEPR deficiency; June 2022 for Bardet-Biedl syndrome; December 2024 expanded to patients aged 2 years and older). Genetic testing confirming an eligible mutation is required before treatment. In patients with POMC or PCSK1 deficiency, approximately 80% achieved at least 10% weight loss in clinical trials. In Bardet-Biedl syndrome, 32.3% achieved the same threshold. The most common side effects are injection-site reactions and skin darkening (due to the melanocortin pathway's connection to pigmentation). Setmelanotide exemplifies precision medicine — it is highly effective in the specific genetic populations it targets but is not indicated for common obesity.
HGH Fragment 176-191 has no marketing authorisation. A Phase IIa trial in obesity (approximately 300 patients) failed to demonstrate statistically significant weight loss at any dose tested. The clinical development programme was discontinued. The disconnect between animal data (which showed significant fat reduction in obese mice) and the failed human trial is the defining feature of this compound's development history. Products available through unregulated channels lack pharmaceutical quality assurance. The failed Phase II trial represents the highest level of clinical evidence available.
