TRIUMPH-3: Retatrutide in Severe Obesity With Cardiovascular Disease

Study Overview

TRIUMPH-3 evaluated retatrutide for weight management in adults with Class II/III obesity (BMI ≥35 kg/m²) and established cardiovascular disease, with and without type 2 diabetes. It is the TRIUMPH trial that enrolled the sickest population, and the one that produced the first look at cardiovascular events on retatrutide.

Eli Lilly announced topline results on July 23, 2026, alongside TRIUMPH-2. The trial enrolled 1,949 participants and ran for 80 weeks. Participants entered with a mean body weight of 111.4 kg (245.6 lb) and a mean BMI of 40.4 kg/m².

Scientific Rationale

Obesity and Cardiovascular Risk

Class II/III obesity is associated with substantially elevated cardiovascular risk, including higher rates of heart failure, coronary artery disease, stroke and cardiovascular mortality. Weight reduction in this population can act through several pathways at once: lower blood pressure, better lipid profiles, reduced systemic inflammation and lower cardiac workload.

Why This Population Matters

The overlap of severe obesity and established cardiovascular disease is one of the highest-risk groups in metabolic medicine. Semaglutide’s SELECT trial showed a 20% reduction in major adverse cardiovascular events in people with overweight or obesity and established cardiovascular disease, setting the precedent that weight-management therapy can change cardiovascular outcomes. TRIUMPH-3 tested whether retatrutide’s larger weight loss and broader mechanism are safe and effective in the same kind of patient, without being designed to prove an outcomes benefit.

Study Design

TRIUMPH-3 is a randomized, double-blind, placebo-controlled, multicenter trial.

Participant Population

• Adults with Class II/III obesity (BMI ≥35 kg/m²)
• Established cardiovascular disease (for example prior myocardial infarction, stroke or documented atherosclerotic disease)
• Participants with and without type 2 diabetes

Dose Selection

Two maintenance doses were tested against placebo:

• 9 mg once weekly
• 12 mg once weekly

The 4 mg dose was not included, reflecting the judgment that people with severe obesity and cardiovascular disease are most likely to benefit from the higher doses.

Endpoints

Primary endpoint: percent change in body weight from baseline at 80 weeks.

Secondary and exploratory endpoints: weight-loss responder thresholds; blood pressure, lipids and inflammatory markers; A1C in participants with diabetes; and an in-study adjudication of major adverse cardiovascular events (MACE), which was exploratory rather than a powered endpoint.

Topline Results (July 23, 2026)

Weight results were reported under the efficacy estimand (participants assumed to remain on treatment without prohibited weight-management therapies). Treatment-regimen figures have not yet been disclosed.

Weight loss at 80 weeks

The result is roughly six points below TRIUMPH-1’s -28.3% at 12 mg, which is expected: this population was heavier, older in cardiovascular terms, more medicated and included people with diabetes. It nonetheless matches or exceeds the best tirzepatide result in any population (-22.5% in SURMOUNT-1, a lower-risk group), a cross-trial comparison only.

Cardiometabolic markers (12 mg arm)

The 37% triglyceride reduction and the halving of hsCRP are the largest reported for retatrutide in any Phase 3 trial and are consistent with the glucagon-receptor contribution to hepatic lipid handling seen in the Phase 2 liver-fat substudy.

In-study cardiovascular events (exploratory)

TRIUMPH-3 adjudicated cardiovascular events during the 80-week study. Pooling both retatrutide arms against placebo:

Neither result is statistically significant, and both confidence intervals include harm as well as benefit. That is what an 80-week trial of about 2,000 people should be expected to show: it was powered for weight, not for events. The reassuring reading is that the point estimate on the broader MACE-5 endpoint favours retatrutide and there is no signal of excess events despite the well-documented resting heart-rate increase with this class. The cautious reading, which analysts voiced on the day, is that the MACE-3 estimate leans the other way on a small number of events. The question is only answerable by TRIUMPH-Outcomes, the roughly 10,000-participant, event-driven cardiovascular outcomes trial that remains ongoing.

Safety Profile

Gastrointestinal adverse events

Dysesthesia

Dysesthesia occurred in 6.4% of participants at both 9 mg and 12 mg, versus 1.3% on placebo. Alongside TRIUMPH-2 (7.3% at 12 mg), this is well below the 12.5% of TRIUMPH-1 and the 20.9% of TRIUMPH-4, and confirms that the very high TRIUMPH-4 rate was the outlier in the program rather than the norm.

Treatment discontinuation

Discontinuation because of adverse events was 9.8% at 9 mg and 13.5% at 12 mg, versus 4.8% on placebo.

Relationship to TRIUMPH-Outcomes

TRIUMPH-3 is an efficacy trial with an exploratory look at cardiovascular events. TRIUMPH-Outcomes is the separate, large cardiovascular outcomes trial designed to determine whether retatrutide reduces major adverse cardiovascular events over a longer horizon. TRIUMPH-3 supplies safety and efficacy evidence in the cardiovascular-disease population for the initial obesity submission; a cardiovascular risk-reduction claim would depend on TRIUMPH-Outcomes.

Clinical and Regulatory Significance

With TRIUMPH-3, Lilly has efficacy data in the highest-risk obesity population and an early, if inconclusive, cardiovascular safety read. The company has stated that its obesity data package is complete and that it plans to submit a Biologics License Application in Q1 2027. For clinicians, the practical message is that roughly 22% weight loss with large reductions in triglycerides, blood pressure and inflammation is achievable in patients with a BMI around 40 and existing heart disease, at the cost of a 13.5% adverse-event discontinuation rate at the top dose.

Publication Status

Topline results were announced by Eli Lilly press release on July 23, 2026. Lilly has said the detailed results “will be presented at future medical meetings and published in peer-reviewed journals”; as of September 2026 no meeting date has been announced for TRIUMPH-3 (the EASD 2026 symposium on September 30 is focused on TRIUMPH-2).

Timeline

• Enrollment start: early 2024
• Topline results: July 23, 2026
• Full presentation: not yet scheduled
• Regulatory use: part of the BLA Lilly plans to submit in Q1 2027