1. GLP-1 receptor agonists, such as semaglutide, and phentermine-topiramate were shown to cause the greatest percent decrease in body weight.

2. GLP-1 receptor agonists, phentermine-topiramate, and naltrexone-bupropion were also associated with increased adverse effects.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Over two-thirds of Americans are considered to be in the overweight or obese body-mass index (BMI) ranges. Despite this, there are limited pharmacotherapy options for weight loss when lifestyle interventions are not sufficient. This systematic review selected randomized control trials (RCTs) which evaluated weight lowering drugs versus lifestyle modification. A total of 143 studies were identified. Of the drugs studied, phentermine-topiramate and GLP-1 receptor agonists demonstrated the highest efficacy for lowering total body weight. However, these drugs, along with naltrexone-bupropion were associated with the greatest number of adverse events leading to discontinuation. Of all the drugs, semaglutide (a GLP-1 receptor agonist) showed the greatest benefit with a similar risk of adverse events as the other drugs. Limitations of this study include the heterogeneity of the study populations, but no differences were seen across baseline BMI, follow-up durations and co-morbid diabetes. Nonetheless, this study provides high quality evidence regarding pharmacotherapy options for weight loss.

Click to read the study in the Lancet

Relevant Reading: Once-Weekly Semaglutide in Adults with Overweight or Obesity

In-Depth [systematic review and meta-analysis]: This systematic review identified eligible RCTs that evaluated lifestyle modifications versus pharmacotherapy in overweight or obese adults. The studies must have recorded absolute or percentage weight change after at least 12 weeks of treatment. Exclusion criteria included studies relating to psychiatric conditions including schizophrenia. 143 RCTs (n = 49810) were selected after full text review. The median age of participants was 47 with 75% female and an average BMI of 35.3 at baseline. The drugs identified included GLP-1 agonists, SGLT2 inhibitors, metformin, orlistat, naltrexone-bupropion, pramlintide, and levocarnitine. All drugs except levocarnitine reduced body weight except levocarnitine. All drugs except metformin, SGLT2 inhibitors and pramlintide led to greater than 10% decrease in weight in the majority of participants. The greatest mean difference of percent body weight change was seen with semaglutide (-11.41%, 95% CI -12.54 to -10.27) and phentermine-topiramate (-7.97%, 95% CI -9.28 to -6.66). However, the drugs with the greatest risk (odds ratio) of discontinuation due to adverse events were semaglutide (Odds ratio 2.45), naltrexone-bupropion (2.69), and phentermine-topiramate (2.40).

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