RetatrutideWeight Loss / GLP-1

Retatrutide (development code LY3437943) is an investigational, once-weekly peptide from Eli Lilly that activates three metabolic-hormone receptors at once: GIP, GLP-1 and glucagon. It is given by subcutaneous injection and has a half-life of roughly 6 days (phase 1b, Lancet 2022). It is now in late-stage phase 3: five phase 3 trials have reported positive results, three of them in peer-reviewed journals. Lilly is finishing its manufacturing data and plans to submit a Biologics License Application to the FDA in the first quarter of 2027. As of October 2026 it is not approved by the FDA and has not yet been submitted. It is listed here as research-use-only and is not a prescription medicine.

Retatrutide is a "triple agonist" engineered from the glucagon/GIP/GLP-1 peptide family, with a fatty-diacid modification that enables albumin binding and prolonged exposure. GLP-1 and GIP receptor activity drive appetite suppression and glucose-dependent insulin secretion, while glucagon-receptor agonism is hypothesized to add increased energy expenditure — a combination intended to produce additive effects on body weight and glycemia. This mechanism was characterized in vitro and in rodent models before first-in-human study (Coskun et al., Cell Metabolism 2022).

Phase 3, peer-reviewed. The pivotal obesity trial, TRIUMPH-1 (NEJM 2026; n=2,339 adults with obesity and without diabetes; 80 weeks), reported mean body-weight changes of −17.6%, −23.7% and −25.0% at 4, 9 and 12 mg versus −3.9% for placebo (treatment-regimen estimand). It also reduced knee-osteoarthritis pain and sleep-apnea events in its dedicated subgroups. Lilly additionally reports −28.3% versus −2.2% using the efficacy estimand, which models the result had everyone stayed on treatment. In adults with obesity and type 2 diabetes, TRIUMPH-2 (Lancet 2026; n=1,152; 80 weeks) reported −11.9%, −16.8% and −18.8% versus −5.1% for placebo (treatment-regimen estimand). TRANSCEND-T2D-1 (Lancet 2026; n=537; 40 weeks) lowered HbA1c by 1.69–1.94 percentage points versus 0.81 for placebo, with weight changes of −11.5% to −15.3% versus −2.6%.

Phase 3, topline press releases only (not yet peer-reviewed). TRIUMPH-4 (obesity with knee osteoarthritis; 68 weeks) reported −23.7% at 12 mg versus −4.6% for placebo (treatment-regimen estimand; −28.7% versus −2.1% on the efficacy estimand). TRIUMPH-3 (severe obesity with established cardiovascular disease; 80 weeks) reported −21.6% and −22.6% at 9 and 12 mg versus −3.2% for placebo (efficacy estimand).

Still running. A head-to-head comparison with tirzepatide (TRIUMPH-5), a weight-maintenance trial, trials in chronic low back pain and MASLD, and a roughly 10,000-person cardiovascular and kidney outcomes trial, which is not expected to complete before 2029.

Earlier evidence. A 48-week phase 2 obesity trial (Jastreboff et al., NEJM 2023; n=338) reported −24.2% at 12 mg versus −2.1% for placebo. Phase 2 trials in type 2 diabetes (Lancet 2023) and in liver fat in MASLD (Nature Medicine 2024) were also positive. A prespecified body-composition substudy (Lancet Diabetes & Endocrinology 2025) and a post hoc analysis of cardiovascular-risk biomarkers (2026) have since been published.

Across phase 2 and phase 3, the most common adverse events were gastrointestinal (nausea, diarrhea, constipation, vomiting). They were dose-dependent, mostly mild to moderate, and concentrated during dose escalation. Lilly reported nausea in 42.4% at 12 mg versus 14.8% on placebo in TRIUMPH-1.

Dysesthesia (abnormal or uncomfortable skin sensation) is a dose-related signal. Skin hyperesthesia and sensitivity were already reported in phase 2 (about 7% versus 1% on placebo). In phase 3 it was 7% at 12 mg versus 1% in the peer-reviewed TRIUMPH-2 paper, and Lilly reported 12.5% versus 0.9% in TRIUMPH-1 and 20.9% versus 0.7% in TRIUMPH-4. Lilly describes these events as generally mild, mostly resolving during treatment. Urinary tract infections were more frequent than on placebo in TRIUMPH-1 (7.5–8.8% versus 5.3%), and the TRIUMPH-2 paper reported more hypotension with retatrutide.

Discontinuation due to adverse events was generally higher at the 9 and 12 mg doses: 11.3% at 12 mg versus 4.9% on placebo in TRIUMPH-1, and 18.2% versus 4.0% in TRIUMPH-4, which Lilly partly attributes to perceived excessive weight loss.

Cardiovascular. In TRIUMPH-3, the one trial in people with established cardiovascular disease, there were too few major cardiovascular events to draw conclusions (MACE-3 hazard ratio 1.12, 95% CI 0.64–1.96). Cardiovascular safety will be answered by the outcomes trial. The phase 2 obesity trial reported dose-dependent heart-rate increases that peaked around week 24 and then declined. No severe hypoglycemia was reported in TRANSCEND-T2D-1. Deaths in the published phase 3 trials were judged unrelated to the study drug.

Retatrutide is investigational and not FDA-approved, and its long-term safety is not yet established. Research use only; this is not therapeutic or dosing guidance.