ACP Recommends Semaglutide and Tirzepatide as First-Line Pharmacotherapy for Obesity and Overweight

The global prevalence of obesity and overweight continues to rise, posing significant public health challenges due to associated comorbidities like type 2 diabetes, dyslipidemia, hypertension, and cardiovascular disease. While lifestyle modifications are foundational, they often yield insufficient or unsustainable weight loss for many patients. Clinicians have historically lacked clear, evidence-based guidelines for integrating pharmacologic treatments into comprehensive weight management strategies, leading to variability in care and underutilization of effective therapies. This guideline addresses that gap by providing a structured, evidence-backed framework for outpatient pharmacotherapy.

The American College of Physicians (ACP) developed this living clinical guideline for internal medicine physicians and other clinicians managing nonpregnant adults with overweight or obesity in outpatient settings. The recommendations are based on systematic reviews of pharmacologic treatments, utilizing the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to assess evidence certainty. The guideline specifically targets adults with obesity (body mass index ≥30 kg/m2) and those with overweight (body mass index ≥27 to 30 kg/m2) who also have comorbidities such as type 2 diabetes, dyslipidemia, hypertension, obstructive sleep apnea, or cardiovascular disease.

The ACP issued two conditional recommendations for initiating pharmacologic treatments alongside lifestyle modifications. For nonpregnant adults with obesity (BMI ≥30 kg/m2), semaglutide (moderate-certainty evidence) and tirzepatide (moderate-certainty evidence) are recommended as first-line treatments. Second-line is phentermine-topiramate (low-certainty evidence), third-line is liraglutide (low-certainty evidence), and fourth-line is naltrexone-bupropion (low-certainty evidence). For nonpregnant adults with overweight (BMI ≥27 to 30 kg/m2) and specific comorbidities, semaglutide (moderate-certainty evidence) and tirzepatide (moderate-certainty evidence) are also recommended as first-line. Clinicians are advised to engage in shared decision-making with patients, discussing benefits, harms, costs, access, comorbidities, weight loss goals, life expectancy, values, preferences, and contraindications. > For example, specific warnings include the requirement for monthly pregnancy tests with phentermine-topiramate, its contraindication in those with cardiovascular disease, and the risk of suicidal ideation with naltrexone-bupropion.