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Beyond the scale: what the outcome trials show for the heart, kidneys and heart failure
SELECT, FLOW, SUMMIT, SOUL, SURPASS-CVOT and ACHIEVE-4: where the hard-outcome evidence stands, which drugs have it, and why the newest drugs with the biggest weight loss still have none.
Published Oct 23, 2026 ยท 4 min read
Weight loss gets the headlines, but it is not what doctors and insurers ultimately pay for. The question that decides how these drugs are used is whether they prevent the things that kill or disable people with obesity and diabetes: heart attacks, strokes, kidney failure and heart failure. That evidence comes from large outcome trials, which take years and tens of thousands of patients. Here is where it stands in October 2026.
How to read a hazard ratio
Outcome trials report a hazard ratio: the rate of events on the drug divided by the rate on the comparator. A hazard ratio of 0.80 means about 20% fewer events. The 95% confidence interval shows the plausible range; if it stays below 1.0 the benefit is statistically clear, and if it crosses 1.0 the trial cannot rule out no effect.
The decade of diabetes trials
Between 2015 and 2021, eight cardiovascular outcome trials tested GLP-1 drugs in people with type 2 diabetes. Results ranged from neutral (lixisenatide in ELIXA, 1.02) to clear benefit (semaglutide in SUSTAIN-6, 0.74; efpeglenatide in AMPLITUDE-O, 0.73). Pooled across 60,080 people, GLP-1 drugs cut major cardiovascular events by about 14% (hazard ratio 0.86, 0.80 to 0.93). Drugs built on human GLP-1 did slightly better (0.84) than those built on exendin, a lizard-derived peptide (0.90, with an interval crossing 1).
The trials that changed the field
| Trial | Drug and comparator | People | Outcome | Hazard ratio (95% CI) |
|---|---|---|---|---|
| SELECT, 2023 | Semaglutide 2.4 mg vs placebo | 17,604 with overweight or obesity and heart disease, no diabetes | Heart attack, stroke, CV death | 0.80 (0.72 to 0.90) |
| FLOW, 2024 | Semaglutide 1.0 mg vs placebo | 3,533 with type 2 diabetes and kidney disease | Major kidney events | 0.76 (0.66 to 0.88) |
| SUMMIT, 2024 | Tirzepatide vs placebo | 731 with obesity and heart failure with preserved ejection fraction | CV death or worsening heart failure | 0.62 (0.41 to 0.95) |
| SOUL, 2025 | Oral semaglutide vs placebo | 9,650 with type 2 diabetes and CV or kidney disease | Major cardiovascular events | 0.86 (0.77 to 0.96) |
| SURPASS-CVOT, 2025 | Tirzepatide vs dulaglutide | 13,165 with type 2 diabetes and atherosclerotic disease | Heart attack, stroke, CV death | 0.92 (0.83 to 1.01, 95.3% CI) |
| ACHIEVE-4, 2026 | Orforglipron vs insulin glargine | 2,749 with type 2 diabetes, overweight and raised CV risk | Heart attack, stroke, CV death, unstable angina | 0.84 (0.59 to 1.20) |
SELECT was the turning point: the first proof that an obesity drug prevents heart attacks and strokes in people without diabetes. FLOW extended the benefit to the kidneys, and SUMMIT showed fewer heart failure events in a smaller trial whose interval is wide but stays below 1.
The two newest trials used active comparators, which sets a higher bar. SURPASS-CVOT showed tirzepatide is at least as protective as dulaglutide, itself a drug with proven benefit (REWIND), but the 8% advantage did not reach statistical significance. ACHIEVE-4 met its safety goal against insulin. Its striking secondary result, 57% fewer deaths from any cause (hazard ratio 0.43, 0.25 to 0.75), was a pre-planned analysis not controlled for multiple testing, so it is a signal rather than a finding.
The gap: newer drugs have no outcome data yet
Almost all of the hard-outcome evidence belongs to semaglutide, with tirzepatide close behind. The drugs with the largest weight loss have none yet. Retatrutide's TRIUMPH-3 trial, in people with severe obesity and heart disease, reported cardiovascular results that were inconclusive (MACE-5 hazard ratio 0.82, MACE-3 1.12, both with wide intervals). Outcome trials still running or awaiting results include:
SURMOUNT-MMO (tirzepatide in people with obesity and no diabetes), REDEFINE 3 (CagriSema in people with cardiovascular disease) and SYNCHRONIZE-CVOT (survodutide), whose results are not yet public.
Why it matters
Outcome data shape labels, guidelines and insurance coverage. Semaglutide's cardiovascular indication carries over to the Wegovy pill label; a new drug with more weight loss but no outcome trial starts at a disadvantage with payers, however impressive its scale results. Until retatrutide, CagriSema or survodutide show hard-outcome benefit, it is an assumption, though a reasonable one, that more weight loss means more protection.
All of these trials are in our outcome trials map, which you can filter by outcome and by comparator.
General information, not medical advice. Sources: ACC, SELECT; ACC, FLOW; ACC, SUMMIT; ACC, SOUL; ACC, SURPASS-CVOT; Eli Lilly, ACHIEVE-4; Sattar et al., meta-analysis of GLP-1 outcome trials; PharmExec, TRIUMPH-2 and TRIUMPH-3.