Semaglutide and Tirzepatide Lead Internists’ First Ranking of Weight-Loss Medicines

CATEGORY: DIET & WEIGHT

America’s internists have published their first ranking of the weight-loss medicines, and two drugs share the top spot: semaglutide and tirzepatide.¹ The American College of Physicians issued the guidance in June in the Annals of Internal Medicine. Behind it sits a review of 69 randomized trials covering more than 112,000 adults. The question it answers reaches far beyond any clinic. By the guideline’s own count, 68.5% of US adults have overweight or obesity.¹

Why First Place Is Shared

The two winners earned it differently. Tirzepatide, a weekly injection that mimics two gut hormones, produced the largest weight loss in trials and the biggest gains in quality of life. Semaglutide, a weekly injection that mimics one of them, is the drug with evidence that it probably lowers deaths and major cardiac events. The committee weighed bigger losses against a survival signal and declined to choose. Both sit on moderate-certainty evidence. Everything below them sits on low.¹

The Rest of the List, and the Price Problem

For adults with obesity, meaning a body mass index of 30 or higher, the order continues: phentermine-topiramate second, liraglutide third, naltrexone-bupropion fourth. For adults in the overweight range with at least one weight-linked condition, such as type 2 diabetes, high blood pressure or sleep apnea, only the top two and then liraglutide are suggested at all. The caveats are stated plainly. Phentermine-topiramate requires pregnancy testing and is kept away from anyone with heart disease. Naltrexone-bupropion carries a black-box warning about suicidal thoughts. Then there’s money. The guideline cites yearly list prices near $17,000 for semaglutide and about $14,100 for tirzepatide, against roughly $1,780 for phentermine-topiramate.¹ Cost and access are built directly into the choice physicians and patients are supposed to make together.

Built to Be Rewritten

Trials show weight returning once these drugs stop, so the document frames prescribing as a long-term commitment rather than a short course. It tells physicians to counsel about muscle and bone loss, above all in older adults, and to stop a medicine that hasn’t produced at least 5% weight loss at its highest tolerated dose.¹ An independent comparison published this year in The BMJ lands the same way, rating tirzepatide the strongest of the current drugs for weight itself.² This is also a living guideline, rewritten as evidence arrives. Combination therapies and daily pills such as orforglipron are already waiting in that queue.

Key Takeaways

• The ACP’s first obesity-medication guideline makes semaglutide and tirzepatide joint first choices: tirzepatide for larger weight loss, semaglutide for its probable reduction in deaths and heart events.
• The ranking rests on 69 randomized trials in more than 112,000 adults, with moderate-certainty evidence at the top of the list and low-certainty evidence below it.
• Cost sits inside the recommendation itself: the first-line drugs list near $14,000 to $17,000 a year, and affordability counts as part of the decision.

References

1. Qaseem A, Cross JT Jr, Harrod CS, et al. Pharmacologic Treatments With Lifestyle Modifications in Nonpregnant Adults With Overweight or Obesity in Outpatient Settings: A Living Clinical Guideline From the American College of Physicians (April 2026). Ann Intern Med. 2026;ANNALS-25-02714. link
2. Nong K, Shi Q, Xie X, et al. Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis. BMJ. 2026;394:e372161. link