Effects of Low-Dose, Controlled-Release, Phentermine Plus Topiramate Combination on Weight and Associated Comorbidities in Overweight and Obese Adults (CONQUER): A Randomised, Placebo-Controlled, Phase 3 Trial

Study Questions:

What is the efficacy and safety of two doses of phentermine plus topiramate controlled-release combination as an adjunct to diet and lifestyle modification for weight loss and metabolic risk reduction in individuals who are overweight and obese, with two or more risk factors?


The CONQUER trial is a 56-week phase 3 placebo-controlled trial that randomly assigned overweight or obese adults (ages 18-70 years), with a body mass index (BMI) of 27-45 kg/m2 and two or more comorbidities (hypertension, dyslipidemia, diabetes or prediabetes, or abdominal obesity) to placebo, once-daily phentermine 7.5 mg plus topiramate 46 mg (low dose), or once-daily phentermine 15 mg plus topiramate 92 mg (high dose) in a 2:1:2 ratio in 93 centers in the United States. Randomized patients were stratified by sex and diabetic status. Primary endpoints were the percentage change in bodyweight and the proportion of patients achieving at least 5% weight loss. Analysis was by intention to treat.


Data were available on 2,448 patients for analysis. Of these, 70% were women and 86% were white. Mean age was 51.1 years (standard deviation, 10.4), weight was 103.1 kg (17.9), and BMI was 36.6 kg/m2 (4.5). At 56 weeks, change in bodyweight was –1.4 kg (least-squares mean, –1.2%; 95% confidence interval [CI], –1.8 to –0.7), –8.1 kg (least-squares mean, –7.8%; –8.5 to –7.1; p < 0.0001), and –10.2 kg (least-squares mean, –9.8%; –10.4 to –9.3; p < 0.0001) in the patients assigned to placebo, low dose, and high dose, respectively. Twenty-one percent of the patients achieved at least 5% weight loss with placebo; 62% (odds ratio [OR], 6.3; 95% CI, 4.9-8.0; p < 0.0001) with low dose; and 70% (OR, 9.0; 95% CI, 7.3-11.1; p < 0.0001) with high dose. For ≥10% weight loss, the corresponding numbers were 7%, 37%, and 48%. The most common side effects in active drug groups were dry mouth and paresthesias (21% in each), constipation (17% with high dose), insomnia (10% with high dose), dizziness (10% with high dose), and dysgeusia (10% with high dose). Four percent of patients assigned to placebo, 4% with low dose, and 7% with high dose had depression-related adverse events; and 3%, 5%, and 8%, respectively, had anxiety-related adverse events. Significant improvements were noted in blood pressure, waist circumference, concentrations of lipids, glycemia, and high-sensitivity C-reactive protein and adiponectin with phentermine plus topiramate compared with placebo.


The authors concluded that the combination of phentermine and topiramate, with office-based lifestyle interventions, might be a valuable treatment for obesity that can be provided by primary care physicians.


Phentermine is a safe anorexigen, and topiramate is an anticonvulsant used in children and adults for seizures and migraine. The magnitude of weight loss and improvement in coronary risk factors and risk markers with both the low- and high-dose combination is at least as great as any of the other weight loss agents available and in published clinical trials. The major issue with phentermine plus topiramate for the Food and Drug Administration (FDA) is the symptom of depression, concern with inadvertent use in pregnancy, and the need to assess effect on QTc. I am hopeful that this agent will be available soon, along with the FDA requirement of a phase IV long-term outcome study of safety and efficacy.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Diet, Hypertension

Keywords: Obesity, Abdominal, Outcome Assessment (Health Care), Sleep Initiation and Maintenance Disorders, Phentermine, Overweight, Risk Reduction Behavior, Lipids, Body Weight, Comorbidity, Body Mass Index, United States Food and Drug Administration, Obesity, Diet, Migraine Disorders, Anti-Obesity Agents, Hypertension, United States

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