Annals of Internal MedicinePharmacologic 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)

✅ Guideline Update

The ACP’s first clinical guideline on pharmacologic obesity treatment establishes a tiered formulary framework for outpatient weight management, ranking five agents by net benefit across weight loss, mortality, MACE reduction, and harm profiles. Semaglutide carries the only moderate-certainty evidence for all-cause mortality and MACE reduction; tirzepatide shows superior weight loss and quality of life but insufficient mortality data.

Clinician Considerations

• Semaglutide and tirzepatide share first-line status across both obesity and overweight-with-comorbidity populations, but their MACE and mortality evidence profiles diverge: semaglutide holds moderate-certainty mortality reduction; tirzepatide data are insufficient or show no difference, a distinction that affects therapeutic substitution conversations
• Phentermine-topiramate is contraindicated in established cardiovascular disease and requires monthly pregnancy tests in adults who can become pregnant; as a Schedule IV controlled substance, prescribing duration limits vary by state, creating dispensing verification obligations at the community level
• Naltrexone-bupropion carries a black-box warning for suicidal ideation and behaviors; pharmacist counseling at dispensing should address this risk explicitly, particularly in patients with comorbid depression or substance use history
• Weight regain on discontinuation is documented for semaglutide, tirzepatide, and liraglutide at low-certainty evidence; this supports long-term adherence counseling and flags therapeutic substitution requests driven by cost or supply interruption as clinically consequential

Practice Applications

• Verify formulary tier placement and prior authorization requirements for semaglutide and tirzepatide before dispensing, as access remains the primary barrier identified in this guideline
• Recognize phentermine-topiramate as a controlled substance with state-specific prescribing duration limits requiring prescription validity review
• Flag naltrexone-bupropion dispensing for black-box counseling on suicidal ideation, particularly at initiation and dose escalation
• Counsel patients initiating GLP-1 receptor agonists on nausea, gallstone risk, and the clinical consequences of self-discontinuation
• Clarify that race- and ethnicity-specific BMI thresholds affect eligibility determination, particularly for South Asian, Southeast Asian, and East Asian patients (obesity threshold: BMI 25 kg/m2)