Retatrutide (LY3437943): the triple GIP/GLP-1/glucagon agonist in phase 3

Retatrutide (development code LY3437943) is an investigational peptide from Eli Lilly that activates three hormone receptors simultaneously: the GIP receptor, the GLP-1 receptor, and the glucagon receptor. In phase 2 trials it produced the largest mean weight-loss signal seen in any incretin peptide to date. It is not FDA-approved for any indication, cannot legally be compounded in the US, and all current use should be in the context of formal clinical trials.

What is retatrutide and why add glucagon?

Retatrutide builds on the dual GIP/GLP-1 framework established by tirzepatide by adding glucagon receptor agonism as a third axis. Glucagon is typically associated with raising blood sugar, but at the receptor and tissue level it also drives significant increases in energy expenditure and fat oxidation, particularly in the liver. The hypothesis behind triple agonism is that adding this energy-expenditure component on top of the appetite and glycemic effects of dual agonism could push the weight-loss ceiling substantially higher.

The GLP-1 receptor component drives appetite suppression, glucose-dependent insulin secretion, glucagon suppression, and satiety signaling in the central nervous system. The GIP receptor component adds complementary incretin effects on beta-cell function, adipose tissue insulin sensitivity, and central appetite pathways. The glucagon receptor component is intended to increase hepatic glucose output in the fasting state (which requires careful balance in a therapeutic context), stimulate fatty acid oxidation, and increase energy expenditure through thermogenic pathways [9]. The relative contribution of each receptor to net clinical outcomes is still being characterized as phase 3 data matures; mechanistic partitioning at this stage remains inferential.

What do the phase 2 trials show?

Two peer-reviewed phase 2 publications and a phase 2a liver substudy provide the current evidence base. The obesity trial (NEJM 2023) reported approximately 24% mean weight loss at 48 weeks at the highest dose, the type 2 diabetes trial (Lancet 2023) showed dose-dependent HbA1c and weight reduction, and the MASLD substudy (Nature Medicine 2024) reported striking liver-fat reductions at higher doses.

The phase 2 obesity trial (NCT04881760, n=338) randomized adults without type 2 diabetes across multiple dose and escalation arms. Mean weight change at 24 weeks reached approximately -17.5% in the 12 mg arm versus -1.6% for placebo. At 48 weeks, the 12 mg arm reached approximately -24.2% mean weight loss versus -2.1% for placebo [2]. The most common adverse events were gastrointestinal and dose-related, with most events mild to moderate. A notable finding was a dose-dependent heart-rate increase that peaked around week 24 and then declined, a signal not seen with the dual agonists, plausibly related to glucagon receptor-mediated cardiac effects, and a priority monitoring item for the ongoing phase 3 program.

The phase 2 type 2 diabetes trial (NCT04867785, Lancet 2023, n=281) showed dose-dependent HbA1c improvements reaching approximately -2.0 percentage points in high-dose escalation arms at 24 weeks, with body weight also falling dose-dependently into the mid-to-high-teen percentage range by 36 weeks [3]. No severe hypoglycemia and no deaths were reported in either phase 2 publication.

A phase 2a MASLD substudy (Nature Medicine 2024) examined liver-fat changes in participants from the obesity trial. Strong relative liver-fat reductions were reported at 24 weeks in higher-dose arms, with large proportions reaching normal liver-fat thresholds below 5%, compared with none in the placebo group in the reported analysis [4]. This is a promising hepatic signal with biological plausibility from both the weight-loss and glucagon-mediated hepatic fat-oxidation mechanisms, but hard liver outcomes and long-term fibrosis endpoints remain under investigation.

The TRIUMPH phase 3 program and what it will answer

The TRIUMPH and TRANSCEND programs span obesity without diabetes, type 2 diabetes, obesity with cardiovascular disease, obesity with osteoarthritis, and a head-to-head comparison with tirzepatide. Four trials have now reported: TRIUMPH-4 in December 2025, TRIUMPH-1 in May 2026, and TRIUMPH-2 and TRIUMPH-3 together in July 2026. All four are sponsor toplines rather than peer-reviewed publications, and the head-to-head against tirzepatide and the cardiovascular and kidney outcomes trial are both still running.

TRIUMPH-4 (NCT05931367, n=445) was the first to read out, on 11 December 2025, in adults with obesity or overweight and knee osteoarthritis. Lilly reported co-primary endpoints met at 68 weeks in both the 9 mg and 12 mg groups, with up to 28.7% mean weight reduction (about 71 lb from a mean baseline of 249 lb) and a WOMAC pain-score drop of up to 4.5 points versus placebo [5]. That 28.7% is the efficacy estimand, which asks what the result would have been had everyone stayed on treatment; the treatment-regimen estimand, which counts everyone randomized whatever they did next, was 23.7%. The roughly five-point gap inside a single dose arm is why a topline percentage means little without knowing which estimand produced it. TRIUMPH-1 (NCT05929066, n=2,335) followed on 21 May 2026 in adults with obesity or overweight without diabetes: at 80 weeks the 4 mg, 9 mg and 12 mg arms reported 19.0%, 25.9% and 28.3% mean weight loss on the efficacy estimand, 25.0% at 12 mg on the treatment-regimen estimand, with 65.3% of the 12 mg group falling below a BMI of 30. A pre-specified 104-week extension limited to participants with a baseline BMI of 35 or above reached 30.3% [7]. TRIUMPH-2 (NCT05929079, n=1,152, type 2 diabetes with obesity or overweight) and TRIUMPH-3 (NCT05882045, n=1,946, severe obesity with established cardiovascular disease) reported together on 23 July 2026: 12.7%, 19.1% and 20.8% across the three doses in TRIUMPH-2 with HbA1c reductions of up to 1.6 points, and up to 22.6% in TRIUMPH-3, all on the efficacy estimand [8]. None of the four has a peer-reviewed manuscript yet, so every figure above is a company-reported estimate.

TRIUMPH-5 (NCT06662383) is a direct head-to-head comparison of retatrutide versus tirzepatide, which will provide the first controlled head-to-head efficacy and safety comparison between the dual and triple agonist strategies. TRIUMPH-Outcomes (NCT06383390) is the event-driven cardiovascular and kidney outcomes trial, with estimated primary completion in 2029 [6]. The TRANSCEND programs (TRANSCEND T2D-1, TRANSCEND T2D-3) cover type 2 diabetes and type 2 diabetes with renal impairment, and further phase 3b work is looking at weight-maintenance and dose-escalation schemes.

Regulatory status and access

Retatrutide is not FDA-approved for any indication as of 2026. FDA has stated it cannot be used in compounding under federal law, and any commercially sold product labeled as retatrutide represents an illegally marketed unapproved drug. The only legitimate access is participation in a registered clinical trial.

The FDA has issued warning actions related to illegally marketed products containing GLP-1 class peptides including retatrutide, and warns against products sold as "research use only" but promoted for human use. Unlike semaglutide and tirzepatide, which had compounding-pharmacy availability during shortage periods, retatrutide has never had an approved commercial product and thus has never had a legitimate shortage-based compounding pathway. Lilly said alongside the July 2026 toplines that it intends to submit a Biologics License Application to the FDA in the first quarter of 2027 [8]. A submission is not an approval: FDA review follows, and a reviewed label remains a future event rather than a current one.

Where retatrutide fits in the incretin landscape

Retatrutide represents the next step beyond tirzepatide in the incretin evolution: from GLP-1-only (semaglutide) to dual GIP/GLP-1 (tirzepatide) to triple GIP/GLP-1/glucagon. If the phase 3 data confirm the phase 2 efficacy signal, it would represent the highest weight-loss efficacy of any approved incretin medicine. The key unknowns are the long-term cardiovascular safety of glucagon receptor activation at therapeutic doses and whether the heart-rate signal seen in phase 2 resolves or requires management in longer-term use.

Tirzepatide currently has the strongest approved evidence and the head-to-head superiority over semaglutide from SURMOUNT-5, but its weight-loss ceiling (~22.5% in SURMOUNT-1) is lower than what the retatrutide phase 2 data suggest is achievable with triple agonism. Survodutide (Boehringer Ingelheim) is a different dual GLP-1/glucagon agonist in phase 3 with a particular focus on liver disease; it takes a different combination than retatrutide and may carve out a distinct niche. For context on how GH-axis peptides like tesamorelin interact with this incretin landscape, the underlying biology is covered in our free peptides and your body module.