The American College of Physicians suggests semaglutide and tirzepatide with lifestyle modifications as first-line pharmacologic treatment for weight management in nonpregnant adult patients with obesity and selected patients with overweight and weight-related comorbidities, according to a living clinical guideline.
The guideline was developed for clinicians in internal medicine or otherwise caring for patients with overweight or obesity in outpatient settings. Investigators in the American College of Physicians (ACP) Clinical Guidelines Committee based their guidance on systematic reviews of pharmacologic treatments in this patient population and used the Grading of Recommendations Assessment, Development, and Evaluation approach. The supporting systematic review searched randomized controlled trials published in English through October 2025 and evaluated all-cause mortality, major adverse cardiovascular events, changes in hemoglobin A1c, health-related quality of life, percentage of total body weight lost, likelihood of achieving at least 10% total body weight loss, weight regain following treatment discontinuation, serious adverse events, and discontinuations because of adverse events. The ACP's Clinical Guidelines Committee considered cost-effectiveness analyses and evidence on patient values and preferences.
Among nonpregnant patients with obesity, defined as a body mass index (BMI) of at least 30 kg/m², the investigators conditionally suggests semaglutide and tirzepatide as first-line pharmacologic treatment with lifestyle modifications. Phentermine-topiramate is suggested as a second-line option, followed by liraglutide as a third-line treatment and naltrexone-bupropion as a fourth-line treatment. Among nonpregnant patients with overweight, defined as a BMI of 27 to 30 kg/m² and either type 2 diabetes, dyslipidemia, hypertension, obstructive sleep apnea, or cardiovascular disease, the guideline conditionally suggests semaglutide and tirzepatide as first-line treatment with lifestyle modifications and liraglutide as a second-line option. The ACP's Clinical Guidelines Committee determined that the evidence was inadequate to recommend phentermine-topiramate or naltrexone-bupropion in patients with overweight and a weight-related comorbidity.
The supporting systematic review found that semaglutide with lifestyle modifications reduced all-cause mortality and major adverse cardiovascular events compared with lifestyle modifications alone and improved percentage of total body weight lost, likelihood of achieving at least 10% total body weight loss, hemoglobin A1c regardless of diabetes status, and physical functioning. Compared with semaglutide, tirzepatide improved percentage of total body weight lost, the likelihood of achieving at least 10% total body weight loss, health-related quality of life. The drug also improved hemoglobin A1c and physical functioning. However, compared with lifestyle modifications alone, low-certainty evidence showed no statistically significant differences in all-cause mortality or major adverse cardiovascular events with tirzepatide. Liraglutide reduced major adverse cardiovascular events and improved weight loss, physical functioning, and health-related quality of life. However, compared with semaglutide, tirzepatide, and phentermine-topiramate, liraglutide produced less weight loss, poorer health-related quality of life, or both. Phentermine-topiramate improved weight loss and health-related quality of life but was not studied in patients with established cardiovascular disease. Naltrexone-bupropion improved weight loss but increased discontinuations because of adverse events and carries a black-box warning for suicidal ideation and behaviors.
The guideline advises clinicians to discuss the potential benefits, harms, costs, access and availability, clinical comorbidities, weight loss goals, life expectancy, values and preferences, contraindications, and warnings of treatments when initiating or changing pharmacologic therapy. The guideline also notes that weight regain occurs following the discontinuation of weight management drugs and that the optimal duration of treatment remains uncertain.
The recommendations are based largely on studies enrolling patients with obesity, most of whom had class 2 obesity. All eligible randomized controlled trials used BMI criteria for enrollment, and none of the eligible studies used waist or hip circumference as primary inclusion criteria. The ACP plans to maintain the topic as a living guideline and update it as new evidence becomes available.
Financial and intellectual conflicts of interest were disclosed and managed according to ACP policies. Paul G. Shekelle, MD, PhD, MPH, and Jeffrey A. Tice, MD, were recused from guideline development activities because of their disclosed conflicts. Full disclosures of the guideline authors are available in the published guideline.
Source: Annals of Internal Medicine