JAMA network meta-analysis ranks the approved weight drugs
A 2016 JAMA analysis of nearly 29,000 patients found phentermine-topiramate and liraglutide were the most effective FDA-approved weight-loss pills of their era, a benchmark that shaped years of prescribing before newer GLP-1 drugs arrived.
A large analysis published in JAMA in July 2016 compared five weight-loss drugs approved by the FDA at the time and found real differences in how well they worked. The study, led by Khera and colleagues, pooled data from 28 clinical trials covering more than 29,000 patients who were followed for at least one year [1].
The drugs compared were orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, and liraglutide, an early GLP-1 medication now sold as a component of some diabetes and weight-loss regimens [1]. All five outperformed placebo. In the placebo group, 23% of participants lost at least 5% of their body weight after a year. Among people taking one of the five drugs, that share ranged from 44% to 75% [1].
Phentermine-topiramate came out on top, with 75% of patients reaching the 5% weight-loss mark and an odds ratio of 9.22 compared with placebo, meaning those patients were about nine times more likely to hit that target [1]. Liraglutide ranked second, with 63% of patients reaching 5% weight loss, making them roughly six times more likely than placebo patients to do so [1]. On average, people taking any of the five drugs lost between 3 and 19 pounds more than those on placebo [1].
The study also flagged a tradeoff. Liraglutide and naltrexone-bupropion had the highest rates of patients stopping treatment because of side effects, even though liraglutide ranked near the top for effectiveness [1]. The authors said their findings support all five drugs as reasonable options for adults with overweight or obesity, especially alongside diet and lifestyle changes, but they cautioned that the trials only tracked patients for one year, so longer-term safety and effectiveness remained unclear [1].
Why it matters for patients
This analysis became a reference point for doctors and patients weighing options in the years before the current generation of GLP-1 drugs, such as semaglutide (sold as Ozempic, Wegovy, and Rybelsus) and tirzepatide (sold as Mounjaro and Zepbound), reshaped the weight-loss drug market. At the time, liraglutide's second-place ranking helped establish GLP-1 medications as a serious option for weight management, not just diabetes care.
The study also underscored that effectiveness and tolerability don't always move together. A drug that helps more people lose weight, like liraglutide, may also cause more people to quit treatment because of side effects. That kind of tradeoff remains relevant today as patients and doctors compare newer, more potent GLP-1 drugs, which the sources note came after this comparison and were not part of it [1].
The one-year timeframe of the trials means the study could not answer questions about what happens to weight loss, side effects, or health outcomes over many years of use — a limitation the study's authors themselves flagged [1].
What happens next
The sources reviewed do not describe follow-up studies extending this comparison to newer GLP-1 drugs like semaglutide, tirzepatide, or orforglipron. How those medications stack up against phentermine-topiramate and liraglutide in a similarly rigorous, head-to-head analysis is not established in the material available here.
Sources
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