ACP Names Semaglutide, Tirzepatide as First-Line Pharmacotherapy for Obesity

The American College of Physicians (ACP) has published its first living clinical guideline on pharmacologic treatment of overweight and obesity, positioning semaglutide and tirzepatide as co-equal first-line options when added to lifestyle modifications—while creating a clear therapeutic hierarchy for clinicians navigating a crowded and rapidly evolving drug class.¹

Published today in Annals of Internal Medicine, the conditional recommendations apply to nonpregnant adults in outpatient settings and are grounded in a systematic review and network meta-analysis of 69 randomized controlled trials encompassing more than 112,000 participants.^1,2

A 4-Tier Hierarchy for Obesity (BMI > 30)

For adults with a body mass index (BMI) of 30 kg/m² or higher, the ACP recommends the following tiered approach¹:

• First line: semaglutide or tirzepatide (moderate-certainty evidence)
• Second line: phentermine–topiramate (low-certainty evidence)
• Third line: liraglutide (low-certainty evidence)
• Fourth line: naltrexone–bupropion (low-certainty evidence)

The dual first-line placement of semaglutide and tirzepatide reflects a deliberate clinical trade-off. Tirzepatide produced greater weight loss and health-related quality of life improvements across trials, while semaglutide demonstrated probable reductions in all-cause mortality and major adverse cardiovascular events (MACEs), benefits not established for tirzepatide.^1,2 The ACP Clinical Guidelines Committee concluded that the mortality and cardiovascular signal with semaglutide was sufficiently important to elevate it alongside tirzepatide despite the latter's weight loss advantage.¹

Overweight With Comorbidities (BMI 27–30)

For adults with a BMI of 27 to 30 kg/m² who have type 2 diabetes, dyslipidemia, hypertension, obstructive sleep apnea, or cardiovascular disease (CVD), the ACP suggests semaglutide or tirzepatide as first-line agents, with liraglutide as a second-line option. Phentermine–topiramate and naltrexone–bupropion were not recommended for this population given insufficient evidence of benefit beyond weight loss in patients with overweight.^1,2

Key Clinical Considerations

The guidelines carry several practice-shaping messages beyond the tiered rankings.

Weight regain is the rule upon discontinuation. Evidence across multiple trials showed significant weight regain after stopping semaglutide, tirzepatide, and liraglutide.² The ACP recommends that clinicians have explicit conversations with patients about potential lifelong treatment and cautions against time-limited prescribing.¹

Discontinue if 5% weight loss is not achieved. If a patient does not lose at least 5% of body weight at the maximum tolerated dose, the guidelines suggest discontinuing and reconsidering the approach.

Lifestyle modifications remain foundational. The guidelines emphasize that pharmacotherapy is adjunctive to, not a replacement for, improved nutrition and physical activity. When lifestyle changes are not feasible, however, medications should not be withheld.

Phentermine–topiramate carries important restrictions. Because clinical trials excluded patients with established CVD, and because of teratogenic risk, the drug requires monthly pregnancy tests in those who can become pregnant and should not be used in patients with known CVD.^1,2

Naltrexone–bupropion carries a black-box warning for suicidal ideation and behaviors and produced higher discontinuation rates than other agents in trials.

Shared Decision-Making at Every Step

The ACP frames every prescribing decision as requiring patient-centered discussion of benefits, harms, costs, comorbidities, contraindications, and individual preferences.¹ Cost remains a material barrier: annual wholesale acquisition costs range from roughly $1780 for phentermine–topiramate to nearly $17,000 for semaglutide and $14,100 for tirzepatide. A 2025 cost-effectiveness analysis incorporating payer discounts found tirzepatide was more cost-effective than semaglutide over a lifetime horizon, although both demonstrated high value compared with lifestyle modification alone.³

The guidelines are designated as "living," meaning the ACP Clinical Guidelines Committee will update them as new evidence emerges, particularly as data mature on combination therapies, investigational agents such as cagrilintide–semaglutide and orforglipron, and the long-term safety of GLP-1 receptor agonists, including their effects on lean muscle mass and thyroid C-cell tumor risk.^1,4

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. Published online June 15, 2026. doi:10.7326/ANNALS-25-02714
2. Damen JAA, Idema DL, Vernooij RWM, et al. Benefits and harms of pharmacologic treatments in adults with overweight or obesity: a living systematic review and network meta-analysis for the American College of Physicians. Ann Intern Med. Published online June 15, 2026. doi:10.7326/ANNALS-24-03764
3. Jenniskens K, Huis in 't Veld LF, Lokerse ME, et al. Cost-effectiveness of pharmacologic treatments in adults with overweight or obesity: a systematic review for the American College of Physicians. Ann Intern Med. Published online June 15, 2026. doi:10.7326/ANNALS-24-03766
4. Wee CC, Li T, Batch BC, Wong JB. Treating obesity with pharmacotherapy: making sense of the evolving science when data are vast but direct comparative evidence is sparse. Ann Intern Med. Published online June 15, 2026. doi:10.7326/ANNALS-26-01972