SURMOUNT-5: tirzepatide outperforms semaglutide head-to-head (20.2% vs 13.7%) over 72 weeks

SURMOUNT-5 (Aronne et al., NEJM April 2025; PMID 40353578) is the head-to-head trial the GLP-1 class needed. 751 adults with obesity were randomised to maximum-tolerated tirzepatide vs maximum-tolerated semaglutide and treated for 72 weeks.

Primary endpoint — mean percent weight loss

Tirzepatide: −20.2% (95% CI −21.4 to −19.1). Semaglutide: −13.7% (95% CI −14.9 to −12.6). Difference −6.5 percentage points, p<0.001.

Secondary — proportion achieving ≥15% loss

Tirzepatide: 65% of patients. Semaglutide: 32% of patients. The mean-difference and the proportion-achieving difference both favor tirzepatide by roughly 2x.

Tolerability

Discontinuation rates from adverse events were similar between arms (8% on tirzepatide vs 7% on semaglutide). Nausea was slightly more common with tirzepatide; injection-site reactions slightly more common with semaglutide. Neither difference reached the threshold for clinical relevance.

What this changes

For patients prioritizing weight loss as the primary goal, SURMOUNT-5 makes tirzepatide the evidence-supported first choice. For patients prioritizing cardiovascular outcomes, semaglutide retains the larger SELECT trial as evidence base — tirzepatide's CV outcomes trial is still maturing. The choice now reflects different evidence strengths for different endpoints.