Semaglutide outperforms its GLP-1 rivals, at a cost to the stomach

GLP-1 receptor agonists have become a cornerstone treatment for type 2 diabetes, and the class now contains several competing drugs. Most trials test each drug against a placebo, which tells you little about which one to choose when several are on the table. Semaglutide has attracted enormous attention for its effects on blood sugar and weight, so the obvious question is whether it genuinely outperforms its siblings when tested against them directly. This review set out to answer exactly that by pooling only head-to-head comparisons.

The authors searched PubMed, the Cochrane Library and grey literature sources up to 8 February 2023 for phase 3 randomised controlled trials that compared semaglutide directly against another GLP-1 receptor agonist in people with type 2 diabetes. Five trials met the criteria, covering 3760 randomised participants in total. The pooled outcomes included HbA1c, fasting plasma glucose, body weight and body mass index, along with the odds of reaching glycaemic targets, losing more than 5% or 10% of body weight, suffering gastrointestinal side effects and stopping treatment.

Semaglutide beat the other GLP-1 drugs on every efficacy measure pooled. It cut HbA1c by an extra 0.44%, fasting plasma glucose by 0.48 mmol/L, body weight by 2.53 kg and body mass index by 0.91 kg/m2. People on semaglutide also had significantly greater odds of reaching target and optimal HbA1c levels, and of losing more than 5% and 10% of their body weight. The advantage was not free: those randomised to semaglutide had significantly greater odds of gastrointestinal adverse events and of discontinuing treatment altogether.

This pooled analysis puts numbers on something individual trials had hinted at: within its own drug class, semaglutide sits at the top for both glycaemic control and weight. Because it draws only on head-to-head phase 3 trials, it avoids the guesswork of comparing separate placebo-controlled studies against each other. What it cannot say is whether the extra improvement in risk factors translates into fewer heart attacks, strokes or deaths, since those hard outcomes were not assessed here. How individuals weigh benefit against tolerability remains an open question.

If you have type 2 diabetes and GLP-1 therapy is on the table, this is a reason to think the differences between drugs in the class are real rather than marketing. Semaglutide delivered measurably better blood sugar and weight results in direct comparisons, but it also drove more stomach upset and pushed more people off the drug entirely. That balance between extra benefit and extra side effects is exactly the sort of thing worth raising with a clinician rather than deciding from a headline.