GLP-1s and Cardiovascular Outcomes Beyond SELECT

The SELECT trial was a turning point for GLP-1 receptor agonists. Published in the New England Journal of Medicine in 2023 (Lincoff et al.), it randomized 17,604 people with overweight or obesity and established cardiovascular disease — but without diabetes — to semaglutide 2.4 mg or placebo. Over a mean of about 40 months, the rate of major adverse cardiovascular events (cardiovascular death, nonfatal heart attack, or nonfatal stroke) fell from 8.0% on placebo to 6.5% on semaglutide: a 20% relative risk reduction (hazard ratio 0.80, 95% CI 0.72–0.90). That result mattered because the benefit appeared in a non-diabetic, obesity-driven population — not just as a side effect of treating diabetes.

But SELECT is one chapter, not the whole book.

Doctor checking a patient’s blood pressure with a stethoscope during a clinical exam

The wider trial landscape

Other large trials have extended the cardiometabolic story to kidneys and heart failure.

Trial	Drug	Population	Key result
SELECT (NEJM 2023)	Semaglutide	Obesity + prior CVD, no diabetes	20% fewer MACE (HR 0.80)
FLOW (NEJM 2024)	Semaglutide	Type 2 diabetes + chronic kidney disease	24% lower risk of major kidney/CV events (HR 0.76)
SUMMIT (NEJM 2025)	Tirzepatide*	HFpEF + obesity	38% lower risk of CV death or worsening HF (HR 0.62)

*Tirzepatide is a dual GIP/GLP-1 receptor agonist, not a pure GLP-1 drug.

The FLOW trial (Perkovic et al.) was stopped early for efficacy: among 3,533 patients with type 2 diabetes and chronic kidney disease, semaglutide cut the composite of major kidney events and cardiovascular death by 24%. SUMMIT (Packer et al.) tested tirzepatide in 731 people with heart failure with preserved ejection fraction and obesity, reducing the composite of cardiovascular death or worsening heart failure by 38% (HR 0.62, 95% CI 0.41–0.95).

The honest synthesis: cardiovascular and cardiorenal benefit across this drug class is one of the better-supported findings in modern cardiometabolic medicine — but it’s clearest in higher-risk populations, and benefit size for any given person depends heavily on baseline risk.

Laboratory vial and sample tube used for clinical trial blood analysis

Where the mechanism gets interesting

A natural question is how these drugs help. Weight loss, better glucose control, and lower blood pressure are obvious contributors, but the magnitude and timing of benefit in some trials hint at effects beyond weight alone — possibly anti-inflammatory or direct vascular actions. The mechanism is plausibly multifactorial, and confident single-cause explanations outrun the evidence.

Researcher in a lab coat and gloves examining samples on a laboratory bench

Reading it responsibly

A few caveats keep this grounded. Most trial populations were higher-risk by design, so impressive relative risk reductions translate into larger absolute benefits for them than for a healthier person — in SELECT, a 20% relative reduction was a 1.5-percentage-point absolute reduction over more than three years. The evidence is strongest for the specific agents tested in outcome trials; it isn’t automatically a class-wide guarantee. And SUMMIT used tirzepatide, a GIP/GLP-1 agent, so its result extends the cardiometabolic theme without being a pure-GLP-1 finding.

The takeaway

SELECT rightly drew attention, but it sits within a larger and reassuringly consistent body of evidence — strongest in people with diabetes, established cardiovascular disease, or kidney disease, with extensions into heart failure. For the right patient, this is one of the more compelling cardiometabolic stories in current medicine. The discipline is in remembering that “benefit in high-risk trial populations” is the claim the data supports, not “good for every heart.”