Obesity drugs deliver weight loss, but broader benefits vary

Clinical takeaway: Match obesity drug selection to patient goals. Tirzepatide and CagriSema* produced the greatest weight loss, while subcutaneous semaglutide had the strongest evidence for reducing death, myocardial infarction, and heart failure risk. Discuss gastrointestinal adverse effects, lean mass loss, and the likelihood of long-term treatment before prescribing.

As use of anti-obesity medications accelerates, clinicians increasingly need to weigh not only weight loss, but also cardiovascular benefits, tolerability, quality of life, costs, and long-term treatment burden.

In a systematic review and network meta-analysis of 262 randomized trials involving nearly 100,000 adults with overweight or obesity, investigators compared 19 approved and emerging obesity drugs across weight, cardiometabolic outcomes, quality of life, and safety.

At 1 year, the greatest weight loss was seen with tirzepatide (14.9%) and cagrilintide-semaglutide (CagriSema; 14.8%), followed by oral semaglutide (10.9%), orforglipron (9.9%), subcutaneous semaglutide (9.8%), and phentermine-topiramate (8.1%). Several investigational agents, including retatrutide, ecnoglutide, and mazdutide, showed similarly large effects, although evidence remains less certain.

Weight loss came with trade-offs. Tirzepatide reduced fat mass most (25.7%) but also lean mass most (8.3%). Discontinuations due to adverse events were highest with orforglipron, naltrexone-bupropion, liraglutide, phentermine-topiramate, CagriSema, and oral semaglutide; GI adverse events were most increased with naltrexone-bupropion, oral semaglutide, orforglipron, and tirzepatide.

Notably, no drug improved quality of life beyond the 10-point minimally important threshold. Subcutaneous semaglutide was the only agent associated with lower all-cause mortality (19% reduction) and myocardial infarction risk (28% reduction), while both semaglutide and tirzepatide were linked to roughly 50% lower heart failure risk. No drug convincingly reduced kidney failure.

“Treatment decisions for obesity should be individualised, balancing expected benefits, harms, treatment burden, costs, availability, and patient preferences,” the authors concluded. The accompanying editorial called the analysis “an important step” toward more individualized obesity care.

*CargriSema is not yet approved in the US.

Source: Nong K, et al. (2026 July 8) BMJ. Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis