GLP-1 receptor agonists

Outcome measured: Disease outcome — A diagnosed condition or clinical event was measured.

SELECT randomised 17,604 adults with overweight or obesity and established cardiovascular disease — but no diabetes — to weekly semaglutide or placebo and found fewer major cardiovascular events over about three years. A landmark trial; the grade reflects our replication requirement, not doubt about its conduct. A mortality signal appeared among secondary outcomes, which is exactly the kind of result a dedicated trial should now test.

Limitations. One trial, in a high-risk secondary-prevention population, funded by the manufacturer. It does not establish benefit for metabolically healthy people, which is how longevity use is being marketed.

Outcome measured: Surrogate biomarker — A laboratory marker measured as a stand-in for health. A change here does not by itself demonstrate a health benefit.

STEP 1 randomised 1,961 adults with obesity to weekly semaglutide or placebo alongside lifestyle support: roughly 15% average body-weight loss versus 2.4% on placebo at 68 weeks. The wider STEP programme repeated the pattern. Body weight is recorded here as a surrogate — the health value of drug-induced weight loss depends on what happens to composition, and to the weight after discontinuation.

Limitations. Weight regain after stopping is well documented, and a meaningful fraction of the loss is lean mass. Trials are manufacturer-funded.

Outcome measured: Lifespan — Death from any cause was measured.

No trial has tested a GLP-1 agonist with lifespan as a primary outcome, in any population — let alone in healthy people. The longevity-clinic framing of these drugs runs ahead of that entirely.

Limitations. Untested as a primary endpoint; secondary mortality signals in high-risk populations do not transfer to healthy users.