GLP-1 drugs: what the landmark trials actually showed

A hormone that lasts two minutes

Native GLP-1 is released by the gut after a meal. It boosts insulin release, slows stomach emptying and signals fullness. But the body clears it within minutes, mainly through the enzyme DPP-4 — too fast to be a practical drug.

Engineering a peptide to last a week

Semaglutide keeps GLP-1’s shape but swaps the residue at position 8 for a non-standard amino acid (Aib) that DPP-4 can’t easily cut, and attaches a fatty-acid chain that binds albumin in the blood. The result lasts about a week, allowing once-weekly dosing. You can see the sequence — with the Aib shown as X — in our Sequence Explorer.

What the trials found

• STEP 1 (2021): 1,961 adults with overweight or obesity, without diabetes. Over 68 weeks, average body-weight change was −14.9% with semaglutide 2.4 mg vs −2.4% with placebo, both alongside lifestyle support.
• SELECT (2023): 17,604 adults with established cardiovascular disease and overweight or obesity, without diabetes. Semaglutide reduced major adverse cardiovascular events by 20% relative to placebo.
• SURMOUNT-1 (2022): tirzepatide, which acts on both GIP and GLP-1 receptors, produced average weight loss of up to 20.9% at 72 weeks on the highest dose, vs 3.1% on placebo.

What they didn’t show

These are averages — individual responses vary widely. Gastrointestinal side effects such as nausea were common. Follow-up studies found that much of the lost weight tends to return after treatment stops. And these results apply to the approved medicines studied, not to unregulated products sold online.