Introduction: Given that various neuronal and peripheral pathways are believed to play a role in obesity, drug combinations using lower doses and controlled-release formulations may improve tolerability and help overcome compensatory mechanisms that prevent weight loss.
Methods: The phase 3 trial involved 2,487 patients aged 18 to 70 years who were overweight or obese (body mass index 27-45 kg/m2) and had at least 2 comorbidities (hypertension, dyslipidemia, diabetes or prediabetes, or abdominal obesity). The patients were randomized to once-daily treatment with placebo, phentermine 7.5 mg plus topiramate 46.0 mg, or phentermine 15.0 mg plus topiramate 92.0 mg in a 2:1:2 ratio. The agents were given for 56 weeks in addition to diet and lifestyle changes.
Results: At 56 weeks, both phentermine plus topiramate groups showed a significantly greater change in body weight (-8.1 kg with the low-dose group and -10.2 kg with the high-dose group) compared with the placebo group (-1.4 kg; P<0.0001). In addition, a significantly greater percentage of patients in the combination groups achieved a 5% weight loss compared with the placebo group (62%, 70%, and 21%, respectively). Improvements in blood pressure, lipid levels, glucose levels, and inflammatory markers also were found. A dose-related increase in the incidence of psychiatric and cognitive adverse events was noted.
Conclusion: Both doses of phentermine plus topiramate, in combination with lifestyle intervention, resulted in significant weight loss and comorbid risk reduction. The weight loss was sustained for the duration of the 56-week trial.
Commentary by Louis Kuritzky MD
For the first time in many years, we enjoy the approval of two new pharmacologic weight-loss entities: lorcaserin (Belviq, approved in June 2012) and controlled-release phentermine plus topiramate (Qsymia, approved in July 2012). The CONQUER trial explored the effects of phentermine/topiramate in overweight or obese adults. Importantly, inclusion criteria also required two or more cardiometabolic comorbidities (hypertension, dyslipidemia, diabetes, prediabetes, or abdominal obesity).
At the conclusion of the trial, both low- and high-dose phentermine/topiramate were associated with significantly better weight loss than placebo. Another pre-specified endpoint was the percentage of subjects able to achieve at least a 5% weight loss. For this metric, both doses of phentermine/topiramate were statistically superior to placebo, with approximately two-thirds of treated patients achieving at least a 5% weight loss. The side-effect profiles of topiramate and phentermine are already well established, and in this trial largely reflect what has been seen in clinical experience with these agents as monotherapy: dry mouth, paresthesias, constipation, insomnia, dizziness, and dysgeusia. Efficacy of phentermine/topiramate is well demonstrated here, although the discontinuation rate due to adverse effects (approximately 10%) should prompt a high level of vigilance for such adversities.