Semaglutide and Phentermine/Topiramate Linked to Greatest Body Weight Reduction

Semaglutide and phentermine/topiramate were associated with the greatest amount of weight loss and reduction of waist circumference in patients with obesity when compared with placebo and other drugs, according to study results published in Diabetes Obesity and Metabolism. 

Researchers conducted a systematic review of studies examining the efficacy and safety of medications approved for the management of obesity. The searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to February 26, 2023. The following drugs were compared against each other, placebo, and standard management practices: orlistat, liraglutide, semaglutide, phentermine/topiramate, naltrexone/bupropion, and lorcaserin. Primary and secondary outcomes included cardiovascular death, all-cause death, non-fatal stroke, non-fatal myocardial infarction, diabetes onset, loss of body weight, reduction of waist circumference, reductions in body mass index (BMI), and lipid profile. Body weight loss, waist circumference, and BMI were measured at 6, 12, 24, and 60 months.

Overall, 168 trials with a total of 97,938 patients were eligible for inclusion.  Patients had a median age of 46.9 years, and the median proportion of men was 25.5%. The median BMI at baseline was 35.8 kg/m² with a median duration follow-up of 12 months. A total of 47 trials included patients with diabetes. The researchers observed the network inconsistency for the percentage of body weight loss at 12 months (P =.03). 

Of the included trials, 69 (N=59,037) reported cardiovascular death as a primary outcome. The researchers found naltrexone/bupropion was associated with a lower risk of cardiovascular death compared with placebo (OR, 0.62; 95% CI, 0.39-0.99). However, no significant differences with relation to cardiovascular death were found between all drugs. Additionally, no significant associations were found between the drugs for all-cause mortality, non-fatal stroke, lipid levels, or non-fatal myocardial infarction.

The researchers noted that all drugs were associated with increased weight loss compared to placebo at 12 months. However, semaglutide (MD, -9.02 kg; 95% CI, 10.42-7.63) and phentermine (MD, 8.10 kg; 95% CI, 10.14-6.05) resulted in the highest weight loss effects.

Similarly, all drugs were associated with a reduction in waist circumference at 12 months compared to placebo. Again, the researchers noted that semaglutide (MD, -7.84 cm; 95% CI, 9.34-6.34) and phentermine (MD, -6.20 cm; 95% CI, 7.46-4.94) resulted in the greatest reductions.

The risk of withdrawal was also increased with all drugs compared to placebo. Naltrexone/bupropion was associated with the highest odds of withdrawal and semaglutide and phentermine/topiramate had the lowest odds of withdrawal compared with other drugs. The researchers noted that semaglutide (MD, -0.58%; 95% CI, -0.81 to -0.34), liraglutide (MD, -0.43%; 95% CI, -0.59 to -0.26) and orlistat (MD, -0.31%; 95% CI, -0.51 to -0.12) showed the greatest reductions in HbA1c levels compared with placebo.

Study limitations included the high risk of bias in several of the randomized trials included in the analysis; additionally, the primary outcome of cardiovascular death was not prevalent in enough studies to be evaluated appropriately. 

“Semaglutide and phentermine/topiramate were associated with greater body weight loss and waist circumference reduction at 12 months than all other drugs, and lower or no significant difference in risks of withdrawal.” The researchers concluded.