GLP-1 research: SELECT trial and the published evidence base
The short version: the GLP-1 evidence base grew steadily from diabetes outcomes (SUSTAIN, LEADER) to weight management (STEP) to cardiovascular outcomes (SELECT). Each trial answered a different question.
TL;DR
- SELECT showed a 20% relative reduction in major adverse cardiovascular events with semaglutide 2.4 mg.
- STEP trials documented average weight reductions of about 15% with semaglutide and higher with tirzepatide.
- All published trials studied branded FDA-approved products — compounded versions are not the same medication.
What the trials are
The GLP-1 evidence base is a stack of large randomized trials (in plain English: studies that randomly assign participants to drug or placebo to compare outcomes). The four most-cited families are SUSTAIN (diabetes outcomes), STEP (weight management), LEADER (cardiovascular outcomes in diabetes), and SELECT (cardiovascular outcomes in adults with obesity but without diabetes). Each addressed a different question and built on the prior generation of data.
How the evidence built
Think of the GLP-1 evidence as a four-step staircase. Step one: SUSTAIN-6 in 2016 showed cardiovascular safety in adults with type 2 diabetes (Marso et al., NEJM, 2016). Step two: STEP-1 in 2021 documented average weight reductions of about 15% over 68 weeks in adults with obesity. Step three: tirzepatide trials (SURMOUNT) added a second mechanism — GIP plus GLP-1. Step four: SELECT in 2023 connected weight reduction to fewer heart attacks and strokes in people without diabetes (Lincoff et al., NEJM, 2023).
Who asks about it
People come to this question after seeing news headlines and wanting to know what the actual data show. About 1 in 8 U.S. adults reports having taken a GLP-1 medication, and a much larger group is considering it. The trials are the reason these conversations are happening.
What the research says
SELECT enrolled over 17,000 adults with prior cardiovascular disease and overweight or obesity, randomized to semaglutide 2.4 mg or placebo. The primary outcome — a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke — occurred in 6.5% of the semaglutide group versus 8.0% of placebo over a mean of 39.8 months (Lincoff et al., NEJM, 2023). STEP-1 reported a mean weight change of -14.9% with semaglutide vs -2.4% with placebo (Wilding et al., NEJM, 2021). Side effects were common and primarily gastrointestinal.
What to know before considering it
These trials studied branded FDA-approved products at specific doses. Compounded GLP-1 medications, prepared by state-licensed 503A compounding pharmacies from FDA-approved active pharmaceutical ingredients, are not themselves FDA-approved and have not been studied in this trial format. Compounded GLP-1 products are also the subject of ongoing litigation (Novo Nordisk v. Hims & Hers, Feb 2026). A licensed clinician evaluation is required.
The Halftime POV
The headline “GLP-1s reduce heart attacks” comes from one trial in a specific population. Reading SELECT carefully — population, dose, duration, outcome — is more useful than reading the headline. The evidence base is real and substantial. It is also product-specific.
Related reading:
- GLP-1: what this gut hormone actually is
- How semaglutide activates GLP-1 receptors: the mechanism
- GLP-1 side effects in the published literature
FAQ
Q: What did the SELECT trial show? A: SELECT was a large cardiovascular outcomes trial of semaglutide 2.4 mg in adults with overweight or obesity and established cardiovascular disease but without diabetes. It found a 20% relative reduction in major adverse cardiovascular events compared with placebo.
Q: Is the evidence stronger for diabetes or for weight management? A: Both have substantial evidence. The diabetes evidence base is older (SUSTAIN, LEADER trials). The obesity evidence base built rapidly with STEP-1 through STEP-4 from 2021 forward and SELECT in 2023.
Q: Are these trials about compounded GLP-1 or branded GLP-1? A: All major published trials studied branded FDA-approved products. The compounded versions of semaglutide are not the same as the branded products and have not been studied directly in randomized trials. Compounded GLP-1 medications are not FDA-approved.
Disclaimer
This article is educational and is not medical advice. Compounded GLP-1 medications are prepared by state-licensed 503A compounding pharmacies from FDA-approved active pharmaceutical ingredients and are not themselves FDA-approved. GLP-1 therapies are available only with a valid prescription following a licensed clinician evaluation. Clinical outcomes depend on individual factors including baseline health, adherence, diet, and physical activity. Individual results vary. Side effects are common and may include nausea, injection-site reactions, and gastrointestinal symptoms. Compounded GLP-1 products are the subject of ongoing litigation (Novo Nordisk v. Hims & Hers, Feb 2026). Halftime Health is launching soon — join the waitlist to get updates.
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