Pharmacotherapy for Adults With Overweight and Obesity

Quick Takes

  • Phentermine–topiramate and GLP-1 receptor agonists appear to be the most effective for weight loss among overweight and obese adults.
  • Semaglutide, a GLP-1 receptor agonist, appears effective for weight loss among overweight and obese adults.
  • Phentermine–topiramate and naltrexone–bupropion were associated with the highest risk for adverse events resulting in discontinuation.

Study Questions:

Which weight loss medications are the most effective among obese and overweight adults?


This was a systematic review and network meta-analysis. References were identified using PubMed, Embase, and Cochrane Library (CENTRAL) searches from inception to March 23, 2021. Studies were included if they used a randomized controlled trial design to evaluate weight-lowering drugs in adults who were overweight or obese. The primary comparator used was lifestyle modification. The primary outcome was weight loss as a percent of body weight.


A total of 14,605 references were identified, from which 143 trials met eligibility criteria. A total of 49,810 participants were included in these trials. The median age of participants was 47 (interquartile range, 43–54) years, women comprised 75% (54–89%) of participants, and median baseline body mass index was 35.3 (33.1–36.8) kg/m2. The median length of follow-up was 24 (24–52) weeks. Except for levocarnitine, all drugs lowered bodyweight compared with lifestyle modification alone. Moderate to high evidence of efficacy was observed for phentermine–topiramate in reducing weight (odds ratio [OR] of ≥5% weight reduction, 8.02; 95% confidence interval [CI], 5.24-12.27; mean difference [MD] of percentage bodyweight change, −7.97; 95% CI, −9.28 to −6.66) compared to lifestyle modification. Glucagon-like peptide-1 (GLP-1) receptor agonists also appeared effective for weight loss (OR, 6.33; 95% CI, 5.00-8.00; MD, −5.76; 95% CI, −6.30 to −5.21). Naltrexone–bupropion (OR, 2.69; 95% CI, 2.11-3.43), phentermine–topiramate (OR, 2.40; 95% CI, 1.69-3.42), GLP-1 receptor agonists (OR, 2.17; 95% CI, 1.71-2.77), and orlistat (OR, 1.72; 95% CI, 1.44-2.05) were associated with increased adverse events leading to drug discontinuation. In a post hoc analysis, semaglutide, a GLP-1 receptor agonist, showed substantially larger benefits than other drugs with a similar risk of adverse events as other drugs, for both likelihood of weight loss of ≥5% (OR, 9.82; 95% CI, 7.09-13.61) and percentage body weight change (MD, −11.41; 95% CI, −12.54 to −10.27).


The investigators concluded that among adults with overweight or obesity, phentermine–topiramate and GLP-1 receptor agonists proved the best drugs in reducing weight. For the drug class of GLP-1 agonists, semaglutide might be the most effective. Among adults with obesity, weight reductions ranged from 6-11% of body weight.


This well-done systematic review and meta-analysis suggest phentermine–topiramate and GLP-1 receptor agonists (particularly semaglutide) are more effective for weight loss than the other medications evaluated. However, it should be noted that this is a meta-analysis, and data on quality of life and clinical parameters, including hemoglobin A1c, lipids, and blood pressure, were not uniformly collected. Additionally, these trials were of short duration, and the comparator was lifestyle modification. These limitations suggest that trials, which directly evaluate drugs against each other and in combination with lifestyle modification, are warranted.

Keywords: Anti-Obesity Agents, Blood Pressure, Body Mass Index, Bupropion, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Life Style, Lipids, Metabolic Syndrome, Naltrexone, Obesity, Orlistat, Overweight, Pharmaceutical Preparations, Phentermine, Primary Prevention, Quality of Life, Topiramate, Weight Loss, Weight Reduction Programs

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