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).
This 2026 American College of Physicians (ACP) living clinical guideline synthesizes systematic reviews on pharmacologic treatments combined with lifestyle modifications for weight management in nonpregnant adults with overweight or obesity in outpatient settings, using the GRADE framework. For adults with obesity (BMI ≥30 kg/m²), the ACP issued conditional recommendations favoring semaglutide and tirzepatide as first-line agents (moderate-certainty evidence), phentermine-topiramate as second-line (low-certainty), liraglutide as third-line (low-certainty), and naltrexone-bupropion as fourth-line (low-certainty). For adults with overweight (BMI ≥27–30 kg/m²) who also have type 2 diabetes, dyslipidemia, hypertension, obstructive sleep apnea, or cardiovascular disease, the guideline conditionally recommends semaglutide and tirzepatide as first-line and liraglutide as second-line. All recommendations are conditional, reflecting the importance of shared decision-making around benefits, harms, costs, access, comorbidities, contraindications (e.g., cardiovascular contraindication and monthly pregnancy-test requirement for phentermine-topiramate; suicidal ideation risk with naltrexone-bupropion), and patient preferences. The living guideline format signals ongoing updates as new evidence emerges.
Why this grade: This is a professional society clinical practice guideline derived from systematic reviews and GRADE evidence synthesis, not an original clinical trial, so it is graded as a review rather than direct human evidence.
The American College of Physicians (ACP) developed this clinical guideline for internal medicine physicians and other clinicians caring in outpatient settings for adults with overweight or obesity. This guideline is based on systematic reviews of pharmacologic treatments in adults with overweight or obesity and used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. ACP suggests initiating one of the following pharmacologic treatments with lifestyle modifications for weight management in nonpregnant adults with obesity (body mass index ≥30 kg/m2) in outpatient settings (conditional recommendation): First-line treatments are semaglutide (moderate-certainty evidence) and tirzepatide (moderate-certainty evidence); second-line treatment is phentermine-topiramate (low-certainty evidence); third-line treatment is liraglutide (low-certainty evidence); fourth-line treatment is naltrexone-bupropion (low-certainty evidence). When initiating a recommended medication for weight management or switching to another recommended medication because of an inadequate response, clinicians and patients should discuss benefits, harms, costs, access and availability, clinical comorbidities, weight loss goals, life expectancy, values and preferences, and contraindications and warnings (for example, the requirement for monthly pregnancy tests with use of phentermine-topiramate, the contraindication to phentermine-topiramate in those with cardiovascular disease, and suicidal ideation with naltrexone-bupropion). ACP suggests initiating one of the following pharmacologic treatments with lifestyle modifications for weight management in nonpregnant adults with overweight (body mass index ≥27 to 30 kg/m2) and type 2 diabetes, dyslipidemia, hypertension, obstructive sleep apnea, or cardiovascular disease (conditional recommendation): First-line treatments are semaglutide (moderate-certainty evidence) and tirzepatide (moderate-certainty evidence); second-line treatment is liraglutide (low-certainty evidence). When initiating a recommended medication for weight management or switching to another recommended medication because of an inadequate response, clinicians and patients should discuss benefits, harms, costs, access and availability, clinical comorbidities, weight loss goals, life expectancy, values and preferences, and contraindications and warnings (for example, use in pregnancy).
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