Weight & Metabolic
Do GLP-1s Affect Heart Health?
The short answer
In the SELECT trial — 17,604 adults with obesity and preexisting cardiovascular disease, but not diabetes — semaglutide reduced the combined rate of cardiovascular death, non-fatal heart attack, and non-fatal stroke from 8.0% to 6.5% over a mean follow-up of 39.8 months (hazard ratio 0.80, P<0.001). That is real evidence of cardiovascular benefit, not just weight loss, in people who already had heart disease. It has not been tested in people without existing cardiovascular disease, and no equivalent placebo-controlled cardiovascular outcomes trial has been completed for tirzepatide.
Quick answers
- What is it?
- Whether GLP-1 drugs like semaglutide actually reduce heart attack and stroke risk, or just help people lose weight.
- Why are people interested in it?
- People want to know if these drugs protect their heart, not just their waistline.
- What has actually been studied?
- The SELECT trial, a 17,604-person randomized, placebo-controlled trial in adults with obesity and existing cardiovascular disease but not diabetes, followed for a mean of nearly 40 months.
- How strong is the evidence?
- Strong randomized controlled trial evidence for a specific population — but it only covers people who already had cardiovascular disease, and no equivalent placebo-controlled trial has reported results for tirzepatide.
- What don't we know yet?
- Whether semaglutide prevents a first cardiovascular event in people without prior heart disease, tirzepatide's actual cardiovascular effect, and how much of the benefit comes from weight loss itself versus a direct drug effect.
- Where can I read the original research?
- Sources at the bottom of this page: Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT) and Comparison of tirzepatide and dulaglutide on major adverse cardiovascular events (SURPASS-CVOT design).
The short answer: Yes, in a specific, well-defined population: adults with obesity or overweight who already had cardiovascular disease. In the SELECT trial, 17,604 such adults were randomized to weekly semaglutide 2.4 mg or placebo and followed for a mean of nearly 40 months. Semaglutide reduced the combined rate of cardiovascular death, non-fatal heart attack, and non-fatal stroke from 8.0% to 6.5% — a 20% relative risk reduction (hazard ratio 0.80, 95% CI 0.72-0.90, P<0.001). That is the strongest cardiovascular evidence that exists for any GLP-1 drug in a non-diabetic obesity population. It does not extend to people without existing heart disease, and no comparable placebo-controlled trial has reported results for tirzepatide.
What the research shows
The trial: SELECT
SELECT was a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial. It enrolled patients 45 years of age or older with a body-mass index of 27 or greater and preexisting cardiovascular disease, but no history of diabetes. 8,803 were assigned to once-weekly subcutaneous semaglutide 2.4 mg and 8,801 to placebo. Mean drug exposure was 34.2 (±13.7) months, and mean follow-up was 39.8 (±9.4) months — this was not a short trial.
The primary endpoint — a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, counted as a time-to-first-event — occurred in 569 of 8,803 semaglutide patients (6.5%) versus 701 of 8,801 placebo patients (8.0%). The hazard ratio was 0.80 (95% CI, 0.72 to 0.90; P<0.001): semaglutide patients had a 20% lower relative rate of these events over the trial period. Because SELECT specifically enrolled people who already had cardiovascular disease, this is secondary-prevention evidence — it shows semaglutide reduced further cardiovascular events in people who had already had one, not that it prevents a first event in someone with no cardiovascular history.
What it cost in tolerability
The cardiovascular benefit came alongside a higher rate of treatment discontinuation than shorter obesity trials show. 16.6% of the semaglutide group (1,461 patients) permanently stopped the drug because of adverse events, compared with 8.2% of the placebo group (718 patients) — a statistically significant difference (P<0.001). That figure is substantially higher than the 4-7% discontinuation rates reported in 68-72 week obesity trials, which likely reflects both the older, cardiovascular-disease population enrolled in SELECT and roughly three times the length of drug exposure.
Where tirzepatide stands
No placebo-controlled cardiovascular outcomes trial for tirzepatide has reported results. The trial designed to establish tirzepatide's cardiovascular profile, SURPASS-CVOT, is a different kind of study altogether: it randomized 13,299 people with type 2 diabetes and established atherosclerotic cardiovascular disease to tirzepatide versus dulaglutide — an active GLP-1 comparator with its own established cardiovascular benefit — not placebo. Its primary analysis is designed to show non-inferiority to dulaglutide (which would also, by extension, demonstrate superiority to a hypothetical placebo), and secondarily to test whether tirzepatide beats dulaglutide outright. As of its design and baseline-characteristics publication, the trial was fully recruited across 640 sites in 30 countries but still ongoing, with no outcome results published. In short: there is currently no SELECT-equivalent trial for tirzepatide, and none is expected imminently.
A broader signal, beyond the heart itself
A 2026 prespecified pooled analysis combined participant-level data from SELECT with two other large semaglutide trials — FLOW, in people with chronic kidney disease, and SOUL, in people with type 2 diabetes and cardiovascular disease — for a combined 30,787 participants followed a mean of roughly 39.5 to 47.5 months. Across the pooled population, semaglutide reduced a composite kidney outcome (major eGFR decline, kidney failure, kidney-related death, or cardiovascular death) with a hazard ratio of 0.84 (95% CI, 0.77-0.91). The authors noted this pooled benefit appeared consistent regardless of baseline characteristics across the cardio-kidney-metabolic spectrum, suggesting the drug's protective effect isn't fully explained by glycemic control or weight loss alone — though this analysis, spanning three separately designed trials with different doses and routes of administration, is not a direct substitute for a dedicated mechanistic study.
What we don't know yet
Whether semaglutide prevents a first cardiovascular event. SELECT enrolled only people who already had cardiovascular disease. Whether the same drug reduces cardiovascular risk in people with obesity but no prior heart attack, stroke, or diagnosed cardiovascular disease has not been tested by this trial.
Tirzepatide's actual cardiovascular effect. SURPASS-CVOT is active-comparator, not placebo-controlled, is limited to people with type 2 diabetes, and has not yet reported results. There is no completed, published trial answering whether tirzepatide reduces cardiovascular events the way SELECT showed for semaglutide.
How much of the benefit comes from weight loss itself versus a direct drug effect. SELECT was not designed as a mediation study. It cannot separate how much of the 20% relative risk reduction traces to weight loss, blood pressure change, direct vascular or anti-inflammatory effects of the drug, or some combination.
What happens beyond roughly four years of exposure. SELECT's mean follow-up was under 40 months. Cardiovascular risk and drug tolerability over five, ten, or more years of continuous treatment fall outside what this trial measured.
Why discontinuation for side effects was so much higher here than in shorter trials. The 16.6% figure in SELECT was more than double the discontinuation rates seen in shorter obesity trials, and the trial data don't isolate how much of that gap is age, comorbidity, or longer exposure time.
Sources
- Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, Hardt-Lindberg S, Hovingh GK, Kahn SE, Kushner RF, Lingvay I, Oral TK, Michelsen MM, Plutzky J, Tornøe CW, Ryan DH. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. New England Journal of Medicine, 2023;389(24):2221-2232. DOI
- Nicholls SJ, Bhatt DL, Buse JB, et al. Comparison of tirzepatide and dulaglutide on major adverse cardiovascular events in participants with type 2 diabetes and atherosclerotic cardiovascular disease: SURPASS-CVOT design and baseline characteristics. American Heart Journal, 2023;267:1-11. DOI
- Mann JFE, Badve SV, Baeres FMM, et al. Effect of semaglutide on kidney outcomes in the SELECT, FLOW, and SOUL trials: a prespecified pooled analysis. Lancet Diabetes & Endocrinology, 2026. DOI00134-8)
Article records maintained via PubMed. Peptide Proof reports what studies found. It does not provide medical advice, dosing guidance, or treatment recommendations.
Topic: Weight & Metabolism | Evidence Index: semaglutide · tirzepatide
Sources
- Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT)
- New England Journal of Medicine, 2023 · n=17604 · DOI
- Comparison of tirzepatide and dulaglutide on major adverse cardiovascular events (SURPASS-CVOT design)
- American Heart Journal, 2023 · n=13299 · DOI
- Effect of semaglutide on kidney outcomes in the SELECT, FLOW, and SOUL trials: a prespecified pooled analysis
- Lancet Diabetes & Endocrinology, 2026 · n=30787 · DOI
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