TRIUMPH-Outcomes: the heart and kidney trial, due 2029

Losing weight lowers blood pressure and cholesterol, and that should mean fewer heart attacks. "Should" is not proof. TRIUMPH-Outcomes is the trial designed to find out whether retatrutide actually prevents heart attacks, strokes and kidney failure. It is following about 10,000 people and is not expected to finish before 2029.

What an outcomes trial is

The obesity trials on this site measure weight, blood pressure, cholesterol and similar things over one or two years. Those are called surrogate outcomes: they are markers that usually track with health, but they are not health itself. What people actually want to avoid is a heart attack, a stroke, kidney failure or an early death. Those are "hard" outcomes, and they are rare enough that a trial has to be very large and very long to count enough of them.

An outcomes trial is built for exactly that. Instead of running for a fixed number of weeks, it is "event-driven": it continues until a pre-set number of heart attacks, strokes and deaths has occurred across both groups, because that number, not the number of participants, is what gives the answer its precision. In TRIUMPH-Outcomes the retatrutide group has its dose stepped up to the highest each person can tolerate, and the placebo group gets matching dummy injections, for an expected four to five years.^[1]

Why weight loss is not proof

It is reasonable to expect that a drug which cuts weight by a quarter, lowers blood pressure and improves cholesterol will prevent heart attacks. But drugs have surprised people before, and this class has a specific reason for caution: it raises resting heart rate, and retatrutide's glucagon action appears to raise it more than earlier drugs did.^[3] Whether the benefits outweigh that in people who already have heart disease is an empirical question. Regulators treat it as one, which is why every major weight-loss drug has had to run an outcomes trial.

TRIUMPH-3 is a good illustration of what a smaller trial cannot do. It enrolled 1,949 people with heart disease and counted heart events as an extra analysis. The result for cardiovascular death, heart attack or stroke was 27 events on retatrutide versus 23 on placebo, a hazard ratio of 1.12 with a confidence interval of 0.64 to 1.96.^[2] That range covers everything from a large benefit to a near-doubling of risk. With only 50 events in total, it could not be otherwise. Lilly's release said as much: events "occurred less frequently than anticipated". TRIUMPH-3 was not powered for this question, and it would be wrong to read either reassurance or alarm into it.

What SELECT showed for semaglutide

The best model for what TRIUMPH-Outcomes is trying to do is the SELECT trial of semaglutide, published in the New England Journal of Medicine in 2023. It enrolled 17,604 people aged 45 or over with a BMI of 27 or more and existing cardiovascular disease, but no diabetes, and assigned them at random to weekly semaglutide at its licensed weight-management dose or to placebo. After an average follow-up of 39.8 months, a first cardiovascular death, heart attack or stroke had occurred in 6.5% of the semaglutide group and 8.0% of the placebo group: a hazard ratio of 0.80, with a confidence interval of 0.72 to 0.90.^[4]

Three things are worth noticing. The benefit was real and statistically solid, a 20% relative reduction. It was also modest in absolute terms, 1.5 percentage points over about three years. And 16.6% of the semaglutide group stopped because of side effects, against 8.2% on placebo.^[4] That is what a positive outcomes result looks like: not a miracle, but proof of a benefit that weight loss alone could only suggest. Semaglutide is a different drug from retatrutide; SELECT says nothing about retatrutide except what kind of evidence to expect, and to wait for.

The trial in detail

To join, participants need a BMI of 27 or more and at least one of: coronary artery disease, cerebrovascular disease, peripheral arterial disease, or chronic kidney disease defined by a combination of reduced kidney filtration rate and protein in the urine. People with type 2 diabetes are eligible if their HbA1c is 10% or below; type 1 diabetes is excluded. Anyone who has had a heart attack, stroke or artery procedure in the previous 90 days is excluded, as are people on dialysis, people with a kidney transplant, and people with a history of pancreatitis or medullary thyroid cancer.^[1]

The two primary outcomes are the time to the first of nonfatal heart attack, nonfatal stroke, cardiovascular death or a hospital or urgent visit for heart failure; and the time to the first of end-stage kidney disease, a sustained 40% or greater fall in kidney function, cardiovascular death or death from kidney disease.^[1] Having a kidney outcome as a co-primary measure is unusual and reflects the fact that chronic kidney disease is common in people with obesity and that no retatrutide trial has yet studied it. See liver and kidney.

The trial will also be the largest and longest source of retatrutide safety data by a wide margin: 10,000 people for four to five years, compared with 2,339 for 80 weeks in TRIUMPH-1. Rare harms that the shorter trials could not detect, if they exist, are most likely to show up here. See what we don't know yet.

Where to check

Search NCT06383390 on ClinicalTrials.gov. Because the trial is event-driven, the completion date is an estimate and may move in either direction depending on how quickly events accumulate.^[1] The how to read a trial page explains what to look for on the registry entry.