Semaglutide and the Heart: What the SELECT Trial Showed, Who It Applies To, and Whether Compounded Semaglutide Delivers the Same Benefit

The trial that changed what the drug is for

Until November 2023, semaglutide for obesity was a weight-loss drug whose cardiovascular effects were inferred from diabetes trials and from the known benefits of losing weight. SELECT made it a cardiovascular drug in its own right, and the FDA indication that followed in March 2024 — the first for a weight-management medication to reduce cardiovascular death, heart attack and stroke — is the reason semaglutide retains a claim on patients that tirzepatide, for now, cannot match.

Design

SELECT enrolled 17,604 adults aged 45 or older with a BMI of 27 or higher and established cardiovascular disease — a prior heart attack, prior stroke, or symptomatic peripheral artery disease — and without diabetes (HbA1c below 6.5%). Participants at 804 sites in 41 countries were randomized to semaglutide titrated to 2.4 mg weekly or placebo, on top of standard cardiovascular care, and followed for a mean of 39.8 months. The primary outcome was the first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. The trial was event-driven and funded by Novo Nordisk.

The result

The primary outcome occurred in 569 of 8,803 participants on semaglutide (6.5%) and 701 of 8,801 on placebo (8.0%): a hazard ratio of 0.80, a 20% relative reduction, with a 95% confidence interval of 0.72 to 0.90. The absolute reduction was 1.5 percentage points over about three years, corresponding to a number needed to treat of roughly 67. Cardiovascular death fell 15% (not statistically significant on its own); non-fatal heart attack fell 28%; non-fatal stroke fell 7% (not significant). Death from any cause fell 19%. A composite heart-failure outcome fell 18%. Prespecified kidney analysis showed a 22% reduction in a composite of kidney events.

Mean weight loss was 9.4% on semaglutide versus 0.9% on placebo, less than in STEP 1 because the population was older, had cardiovascular disease and was not selected for weight-loss motivation. Adverse events leading to discontinuation were more common on semaglutide (16.6% versus 8.2%), mostly gastrointestinal; serious adverse events were less common on semaglutide, driven by fewer cardiovascular events.

Was it the weight?

Two features of the data suggest the benefit was not simply weight loss. The event curves separated early, within the first months, before most of the weight had been lost. And the benefit was consistent across baseline BMI categories and across the amount of weight lost, in a prespecified analysis; participants who lost little weight still benefited. Proposed mechanisms include reductions in inflammation (C-reactive protein fell about 38% relative to placebo), blood pressure, lipids and glucose, and direct effects on vascular and cardiac tissue via GLP-1 receptors. The practical implication is that a patient does not have to lose a large amount of weight to obtain the cardiovascular benefit, and that the benefit is a property of the drug at the dose tested, not of the number on the scale.

Who it applies to

The evidence covers what the trial enrolled: adults 45 and over with existing cardiovascular disease and BMI 27 or higher, without diabetes. For people with diabetes, SUSTAIN-6 (semaglutide injection) and the broader GLP-1 outcome trial literature showed similar reductions. For people with obesity and no cardiovascular disease — the primary prevention population, which is most telehealth patients — SELECT does not directly apply. The mechanisms and the risk-factor improvements make a benefit plausible; a trial has not shown it. STEP-HFpEF showed symptom and function improvements in heart failure with preserved ejection fraction, which extends the picture but is a different question.

The gap between SELECT and compounded semaglutide

SELECT tested Wegovy: a manufactured product with a verified 2.4 mg dose delivered by a pen, under FDA oversight, for three years. Compounded semaglutide is a different thing in three respects that matter for cardiovascular outcomes. The dose delivered depends on the pharmacy's concentration and the patient's syringe technique (see units vs mg). The product's identity and purity are not FDA-verified, and the FDA has documented salt-form substitutions and potency problems. And no compounded product has been tested for any outcome. A patient taking compounded semaglutide for weight loss is probably obtaining a similar drug at a similar dose; a patient taking it specifically for cardiovascular protection is relying on an assumption the evidence does not cover. For a patient with established cardiovascular disease, the FDA-approved product is the one the trial supports, and insurance coverage for Wegovy under the cardiovascular indication is the route many such patients now use; insurance-first programs such as Ro handle the prior authorization.

What it means for the tirzepatide question

Tirzepatide is the more effective weight-loss drug (SURMOUNT-5). Semaglutide is the drug with the cardiovascular outcome trial in obesity. For a patient without cardiovascular disease choosing on weight loss, tirzepatide has the direct evidence. For a patient with established cardiovascular disease, semaglutide has the outcome evidence and the indication, and tirzepatide's SURMOUNT-MMO trial, when it reports, will show whether the gap closes. Until then, the choice for cardiovascular patients is not a close call.

Cost

Compounded semaglutide is the cheapest GLP-1 in our database (NexLife's 12-month plan is $119; see the cheapest semaglutide guide). But the SELECT benefit belongs to Wegovy, and for the patients SELECT describes, the relevant comparison is Wegovy through insurance, or through NovoCare's self-pay pricing, against the compounded product's cost and uncertainty. The semaglutide reference covers the full trial program.

Sources

1. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med 2023;389:2221-2232
2. Deanfield J et al. Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial. Lancet 2024;404:773-786
3. Colhoun HM et al. Long-term kidney outcomes of semaglutide in obesity and cardiovascular disease in the SELECT trial. Nat Med 2024;30:2058-2066
4. Wegovy prescribing information, indication for MACE risk reduction (March 2024)
5. Marso SP et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN-6). N Engl J Med 2016;375:1834-1844
6. Kosiborod MN et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity (STEP-HFpEF). N Engl J Med 2023;389:1069-1084

Citations are to primary sources (peer-reviewed trials, FDA labeling and announcements, and provider pricing pages). See our sources policy and corrections log.