A recent network meta-analysis published in Obesity has found that tirzepatide and semaglutide are more effective for weight loss than other FDA-approved obesity medications. The study, which analyzed data from 31 randomized controlled trials, suggests these newer medications may offer significant benefits for patients struggling with obesity and related cardiometabolic conditions.
The meta-analysis included 35,458 adults and compared the weight change achieved with tirzepatide (Zepbound, Eli Lilly), semaglutide (Wegovy, Novo Nordisk), liraglutide (Saxenda, Novo Nordisk), phentermine/topiramate (Qsymia, Vivus), naltrexone/bupropion (Contrave, Nalpropion Pharmaceuticals), and orlistat (Xenical, Roche). Researchers used surface under the cumulative ranking curve (SUCRA) analysis to rank each medication's efficacy.
Weight Loss Efficacy
The SUCRA analysis revealed that phentermine/topiramate had the highest ranking for achieving 5% or greater (SUCRA = 0.979) and 10% or greater weight loss (SUCRA = 0.9308). However, for a 15% or greater weight loss, tirzepatide 15 mg ranked first (SUCRA = 0.9451), followed by tirzepatide 10 mg (SUCRA = 0.878) and semaglutide 2.4 mg (SUCRA = 0.7959). Tirzepatide 15 mg also ranked first when assessing weight reduction compared to placebo (SUCRA = 0.9928).
Cardiometabolic Changes
Tirzepatide 15 mg also demonstrated the best results in reducing waist circumference (SUCRA = 0.9941), total cholesterol (SUCRA = 0.7867), triglycerides (SUCRA = 0.9843) and systolic blood pressure (SUCRA = 0.9457). While Orlistat 120 mg topped the rankings for lowering LDL cholesterol (SUCRA = 0.8789), Tirzepatide was also best at lowering HbA1c, with the 15 mg dose (SUCRA = 0.848), 10 mg dose (SUCRA = 0.841) and 5 mg dose (SUCRA = 0.6725) ranked in the top three spots. Naltrexone/bupropion conferred the greatest HDL cholesterol increase (SUCRA = 0.8757).
Safety Considerations
Naltrexone/bupropion was associated with a higher risk of any adverse event compared to placebo (RR = 1.45; 95% CI, 1.26-1.68). Orlistat 120 mg (RR = 2.63; 95% CI, 1.37-5.06) and semaglutide 2.4 mg (RR = 1.37; 95% CI, 1.1-1.72) showed a higher risk for serious adverse events than placebo. All medications except phentermine/topiramate were tied to higher risks for gastrointestinal adverse events.
According to Dr. Priyanka Majety, assistant professor at Virginia Commonwealth University Health System, "I think we should prioritize tirzepatide, followed by the GLP-1 receptor agonists whenever possible, especially in patients where they have coexisting cardiometabolic diseases."
Clinical Implications
While tirzepatide and semaglutide appear to be the most effective options for weight loss, Dr. Majety noted that older medications may still be appropriate for some patients, particularly those with contraindications to GLP-1 receptor agonists or limited insurance coverage. "There are some patients with contraindications, [if] they may have pancreatitis or any family history of medullary thyroid cancers, we can’t use these medications, both tirzepatide and GLP-1s," she explained.
Dr. Majety also emphasized the need for more data on the long-term safety and potential loss of lean body mass associated with obesity medications.
