GLP-1 Cardiovascular Outcomes Trials: SELECT, FLOW, and What Came After

Most GLP-1 trial data measures surrogate endpoints — weight, HbA1c, BMI — because they're faster and cheaper to measure than actual clinical events like heart attacks or kidney failure. Two trials, SELECT and FLOW, were specifically designed to answer the harder question directly: does semaglutide actually reduce hard cardiovascular and kidney events, not just the risk factors associated with them.

SELECT: cardiovascular outcomes without diabetes

SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity, NCT03574597) enrolled 17,604 adults with overweight or obesity and established cardiovascular disease, but without diabetes — a population where GLP-1 cardiovascular benefit had not previously been directly established, since earlier CVOTs (LEADER, SUSTAIN-6) had specifically enrolled diabetic populations.[1] Participants were randomized to semaglutide 2.4mg or placebo.

A pre-specified secondary analysis of SELECT, published in Nature Medicine, examined kidney outcomes specifically. The composite kidney endpoint (kidney disease death, kidney replacement therapy initiation, persistent eGFR under 15, persistent ≥50% eGFR reduction, or persistent macroalbuminuria) occurred in 1.8% of the semaglutide group versus 2.2% of placebo — a 22% relative reduction (HR 0.78, 95% CI 0.63–0.96, P=0.02).[2] The eGFR benefit was more pronounced in patients who already had reduced kidney function at baseline: +2.19 mL/min/1.73m² at 104 weeks in patients with baseline eGFR under 60, compared to +0.75 overall.

How many people does this actually apply to?

A population-impact analysis using NHANES data estimated that approximately 3.7 million U.S. adults (95% CI 3.1–4.3 million) meet SELECT's specific eligibility criteria.[3] Notably, this eligible real-world population differs demographically from the trial population itself — a higher proportion Black, older, with somewhat different baseline lab values — a reminder that even a well-designed trial's population isn't a perfect mirror of who becomes eligible for the therapy once approved.

FLOW: the first dedicated GLP-1 kidney outcomes trial

FLOW (NCT03819153) was purpose-built as the first dedicated kidney outcome trial for a GLP-1 receptor agonist, rather than a cardiovascular trial with kidney outcomes as a secondary analysis.[4] It enrolled 30,533 participants with type 2 diabetes and chronic kidney disease across 187 sites in 28 countries, randomized to semaglutide 1mg plus standard of care, or placebo plus standard of care, with a median follow-up of 3.4 years.

The primary endpoint — a composite of ≥50% eGFR reduction, kidney failure, kidney-cause death, or cardiovascular death — showed a 24% relative risk reduction, strong enough that the trial was stopped early for clear efficacy rather than running to its planned completion.[5] A prespecified secondary analysis examining the cardiovascular-specific composite (CV death, non-fatal MI, or non-fatal stroke) found a smaller but still statistically significant absolute risk reduction at week 156 (-0.02, 95% CI -0.04 to -0.002, P=0.035), translating to a number needed to treat of 45 to prevent one such event.[6]

That's why we have FLOW — the first dedicated kidney outcome trial for a GLP-1 receptor agonist.

What SELECT and FLOW together establish

Read together, the two trials extend GLP-1 evidence in complementary directions: SELECT established cardiovascular benefit independent of diabetes status, in a population defined by obesity and existing cardiovascular disease; FLOW established kidney-specific benefit in a diabetic, CKD population, with cardiovascular benefit as a secondary but still statistically significant finding. Between them, the evidence base for semaglutide's cardiovascular and renal benefit now spans diabetic and non-diabetic populations, and both primary cardiovascular and primary kidney trial designs.

Closing note for this series

This is the final article in Source GLP-1's current research cycle, covering topics from the July 2026 secret shopper study through the underlying receptor biology and landmark outcomes trials that justify GLP-1 medications' expanding clinical role. As new primary literature publishes — SURMOUNT-MMO results, the FDA's final 503B determination, LIVERAGE trial data, and more — this research hub will continue tracking the primary sources directly.