A guidance statement evaluating drugs approved for the treatment of overweight and obesity reports that newer incretin-based therapies, including semaglutide and tirzepatide, are associated with large reductions in body weight and improvements in several obesity-related outcomes in adult patients.
The review summarized evidence from studies assessing pharmacologic treatments used in adult patients with overweight or obesity. The glucagon-like peptide (GLP)-1 receptor agonist semaglutide administered once weekly, produced substantial weight reduction across five studies including 3,179 patients, with about 402 more patients per 1,000 achieving at least 15% weight loss and approximately 332 more per 1,000 achieving at least 20% weight loss compared with control groups. The therapy was also associated with small reductions in cardiovascular mortality and all-cause mortality, including about 4 and 8 fewer deaths per 1,000 patients across one and nine studies including 17,604 and 21,730 patients, respectively. Serious adverse events occurred slightly more frequently with semaglutide, with about 15 additional events per 1,000 patients. Health-related quality-of-life scores improved modestly.
Tirzepatide, a dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist administered once weekly, produced large reductions in body weight percentage. Across five studies involving 2,525 patients, body weight decreased by nearly 12 percentage points compared with control groups. Tirzepatide also increased the proportion of patients achieving clinically meaningful weight loss, including about 870 more patients per 1,000 achieving at least 5% weight loss and large increases in thresholds of 10% and 15%. Serious adverse events occurred slightly less often with tirzepatide, with about 2 fewer events per 1,000 patients across 7 studies including 4,870 patients. Quality-of-life scores increased modestly.
The guidance also reviewed setmelanotide, a melanocortin-4 receptor agonist used for rare genetic obesity syndromes involving the leptin–melanocortin pathway. In two studies including 49 patients, treatment was associated with a reduction in body weight of nearly 4 kg, with greater responses reported among patients with pro-opiomelanocortin or proprotein convertase subtilisin/kexin type 1 mutations and those with Bardet–Biedl syndrome.
Beyond weight reduction, a multidisiplinary panel evaluated several obesity-related conditions. In adult patients with overweight or obesity and obstructive sleep apnea, GLP-1–based therapies reduced the apnea-hypopnea index by about 10 events per hour across three studies involving 747 patients. In patients with heart failure with preserved ejection fraction, GLP-1 receptor agonists probably resulted in small reductions in heart failure events, cardiovascular mortality, and all-cause mortality in studies including up to 18,864 patients.
The guidance also reported evidence suggesting benefits in metabolic dysfunction–associated steatotic liver disease and steatohepatitis. Treatment with GLP-1–based therapies may result in a large increase in the resolution of fatty liver or steatohepatitis, with about 323 additional cases per 1,000 patients across three studies involving 290 patients. In adult patients with osteoarthritis, these therapies reduced symptom severity measured by the Western Ontario and McMaster Universities Osteoarthritis Index and increased the proportion of patients achieving weight loss of at least 5%, 10%, and 15%.
The panel also examined outcomes during weight maintenance. In patients initially treated with obesity drugs for at least 1 year, continued therapy resulted in greater weight reduction compared with stopping therapy. Across two studies including 1,473 patients, continued treatment resulted in more than 16 kg of additional weight loss compared with stopping therapy.
Based on the evidence synthesis, the Obesity Society, Obesity Medicine Association, and Obesity Action Coalition issued strong recommendations for the use of semaglutide and tirzepatide in adult patients with overweight or obesity and recommended continuing obesity drugs during the weight maintenance phase. Conditional recommendations were issued for other agents, including orlistat, phentermine, phentermine-topiramate, and liraglutide. The guidance also suggested considering GLP-1 receptor agonists or dual incretin therapies in adults with conditions such as obstructive sleep apnea, heart failure with preserved ejection fraction, metabolic dysfunction–associated steatohepatitis, osteoarthritis, and type 2 diabetes.
“Obesity medications vary widely in terms of clinical efficacy, safety, accessibility, and economic cost,” wrote lead statement author Lydia Alexander, of Enara Health, and colleagues. The statement authors added: “Important outcomes to be considered include initial weight, achieved weight with medication(s), tolerability, cost and availability, number and severity of obesity-related complications, and degree of response of the complication(s) to the obesity medication intervention.” They also highlighted gaps in evidence, including limited head-to-head trials and the need for longer-term studies.
The work was supported by The Obesity Society, the Obesity Medicine Association, and the Obesity Action Coalition. Full disclosures can be found in the statement.
Source: Obesity
