The American College of Physicians suggests semaglutide and tirzepatide, used with lifestyle modifications, as first-line pharmacologic treatment options for weight management in nonpregnant adult patients with obesity or selected patients with overweight and weight-related comorbidities, according to a living clinical guideline published in Annals of Internal Medicine.
The conditional recommendations apply to outpatient management of adult patients with obesity, defined as a body mass index of 30 kg/m² or greater, and adult patients with overweight, defined as a body mass index of 27 to less than 30 kg/m², plus type 2 diabetes, dyslipidemia, hypertension, obstructive sleep apnea, or cardiovascular disease.
For patients with obesity, ACP suggests semaglutide and tirzepatide as first-line treatments, phentermine-topiramate as a second-line treatment, liraglutide as a third-line treatment, and naltrexone-bupropion as a fourth-line treatment. First-line status for semaglutide and tirzepatide was based on moderate-certainty evidence, whereas the recommendations for phentermine-topiramate, liraglutide, and naltrexone-bupropion were based on low-certainty evidence.
For patients with overweight and qualifying comorbidities, ACP suggests semaglutide and tirzepatide as first-line treatments and liraglutide as a second-line treatment.
The guideline was based on systematic reviews of pharmacologic treatments in adult patients with overweight or obesity and used the Grading of Recommendations Assessment, Development and Evaluation approach. Outcomes prioritized for decision-making included all-cause mortality, major adverse cardiovascular events, hemoglobin A1c, health-related quality of life, weight loss, weight regain following treatment discontinuation, serious adverse events, and discontinuations because of adverse events.
The ACP Clinical Guidelines Committee concluded that semaglutide and tirzepatide had the greatest net benefit among the treatments it evaluated. Semaglutide with lifestyle modifications reduced the risk for all-cause mortality and major adverse cardiovascular events compared with lifestyle modifications alone, based on moderate-certainty evidence. Tirzepatide was associated with greater total body weight loss, a higher likelihood of achieving at least 10% total body weight loss, and improved health-related quality of life compared with semaglutide. Evidence for tirzepatide on all-cause mortality and major adverse cardiovascular events was low certainty and showed no difference. Despite greater weight loss with tirzepatide, the committee considered both medications first-line options because reductions in mortality and major adverse cardiovascular events were considered more important for clinical decision-making.
Both semaglutide and tirzepatide improved weight-loss outcomes and hemoglobin A1c, increased discontinuations because of adverse events, nausea, and gallstones, and were associated with weight regain following treatment discontinuation. Semaglutide, tirzepatide, and liraglutide carry a boxed warning for potential thyroid C-cell tumor risk.
Phentermine-topiramate improved weight-loss outcomes and health-related quality of life, but trials excluded patients with established cardiovascular disease. ACP suggests its use only among nonpregnant adult patients with obesity who do not have established cardiovascular disease. Patients who can become pregnant should complete monthly pregnancy testing while receiving phentermine-topiramate because of teratogenic risk.
Liraglutide improved health-related quality of life, physical functioning, and weight-loss outcomes and reduced the risk for major adverse cardiovascular events. However, it was associated with less weight loss, worse health-related quality of life, or both compared with semaglutide, tirzepatide, and phentermine-topiramate.
Naltrexone-bupropion improved only weight loss, increased discontinuations because of adverse events, carried a boxed warning for suicidal ideation and behaviors, and had a higher risk for major adverse cardiovascular events compared with liraglutide.
Evidence for patients with overweight was more limited. All randomized controlled trials enrolling patients with overweight also enrolled patients with obesity, and stratified evidence by body mass index category was limited. ACP determined that evidence was inadequate to recommend phentermine-topiramate or naltrexone-bupropion for patients with overweight and a weight-related comorbidity, and inadequate to recommend pharmacologic treatment for patients with a body mass index below 27 kg/m².
Economic evidence showed mixed value for semaglutide and tirzepatide, with findings varying by publication date and assumptions about manufacturer discounts. Annual wholesale acquisition costs were $16,975 for semaglutide, $14,123 for tirzepatide, $14,284 for liraglutide, $7,607 for naltrexone-bupropion, and $1,780 for phentermine-topiramate.
ACP states that clinicians and patients should discuss benefits, harms, costs, access and availability, clinical comorbidities, weight-loss goals, life expectancy, values and preferences, contraindications, and warnings when initiating or switching weight-management medications.
ACP did not issue recommendations for cagrilintide-semaglutide, orforglipron, retatrutide, dulaglutide, exenatide, lixisenatide, or phentermine monotherapy because of insufficient data, investigational status, or market withdrawal.
The committee noted several evidence gaps, including limited long-term follow-up data, uncertainty about optimal treatment duration, potential harms, combination therapy, switching between medications, treatment following bariatric surgery, weight regain following discontinuation, and effects on all-cause mortality and major adverse cardiovascular events across pharmacologic treatments. Most patients in included studies had class 2 obesity, with a median body mass index of 36 kg/m².
The guideline was funded exclusively by the ACP operating budget. ACP reported that all financial and intellectual disclosures were declared and managed. Two committee members were recused from authorship, discussion, or voting because of conflicts. Full disclosures can be found in the published guidelines.
Source: American College of Physicians
