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Obesity is a growing epidemic with multiple associated comorbidities including type 2 diabetes, hypertension and hyperlipidaemia. Multiple studies have shown that weight loss can improve these obesity RR factors. But weight loss is difficult. There is an urgent need for new and more efficacious pharmacological treatments to help curtail this growing epidemic. There have been previous studies looking at the use of phentermine and topiramate as single agents for weight loss. In the CONQUER trial, Gadde and colleagues have asked whether a combination of these two agents could provide a more effective treatment option for obesity with fewer side effects.
The CONQUER trial is a randomised controlled trial to assess the effects of two different doses of the combination of controlled-release (CR) phentermine plus topiramate versus placebo on weight loss. The multicentred study enrolled 2487 patients with a body mass index between 27 and 45 kg/m2 with at least two obesity-related comorbidities at baseline (including hypertension, hypertriglycerideamia, diabetes or increased waist circumference). The primary outcome was the percentage change in body weight from baseline and the proportion of patients achieving at least 5% weight loss. It excluded patients who had uncontrolled hypertension, major depression or diabetes requiring treatment other than monotherapy with metformin.
Participants were randomised to either placebo or once daily CR phentermine 7.5 mg plus topiramate 46 mg or once daily CR phentermine 15 mg plus topiramate 92 mg. All patients had a dose titration during the first 4 weeks and were then maintained on their assigned dose for the duration of the study (52 weeks).
Patient characteristics at baseline were similar across all three groups. The majority of patients were women (70%), White (86%), with a mean age of 51 years.
At 56 weeks, all participants had significant changes in body weight with all between-group differences being statistically significant (−1.4, −8.1 and −10.2 kg for the patients assigned to placebo, phentermine 7.5 mg plus topiramate 46 mg and phentermine 15 mg plus topiramate 92 mg, respectively). A total of 21% of patients achieved at least 5% weight loss with placebo, 62% with phentermine 7.5 mg plus topiramate 46 mg and 70% with phentermine 15 mg plus topiramate 92 mg (the medication groups were significantly different from the placebo group). There were improvements in the medication groups compared with placebo in blood pressure, waist circumference, lipid concentrations, glycaemia and blood inflammatory biomarkers that were significant in the higher dose group and significant for all but diastolic blood pressure and low-density lipoprotein cholesterol in the lower dose group. In addition, in patients with diabetes, there were greater reductions in haemoglobin A1c at both doses of phentermine plus topiramate (−0.4) than with placebo (−0.1).
Dose-related trends were noted for rates of dry mouth, constipation, paraesthesia, insomnia, anxiety, irritability and disturbance in attention. However, rates of serious adverse events were similar across all groups (3–5%). There were dose-related increases in discontinuation rates because of adverse events. The discontinuation rate due to adverse events was 9%, 12% and 19% for placebo, phentermine 7.5 mg plus topiramate 46 mg and phentermine 15 mg plus topiramate 92 mg, respectively. A concern of the Food and Drug Administration, possible teratogenicity of topiramate when used during pregnancy, was not observed in this trial.
The results of the CONQUER trial demonstrate the efficacy of the combination of phentermine plus topiramate for the treatment of obesity. The use of both agents together provides more robust weight loss than either agent alone and also provides a treatment option that is more efficacious than anything currently on the market. Although both doses were efficacious in terms of weight loss, the lower dose had better tolerability. The higher dose did improve some cardiometabolic risk factors to a greater extent. It is possible that the dose should be tailored to the individual patient.
The study also reveals the positive impact that an effective medical treatment has on obesity-related comorbidities. In particular, it supports the use of treatment in those patients with pre-existing disease as demonstrated by the inclusion criteria of the study, although longer term data are necessary before drawing firm conclusions. Moreover, it is worth noting that, although not specified as an outcome, most patients in the trial likely remained overweight or obese at the end of the trial. Nonetheless, this combination has the most robust percentage weight loss of any other drug combination since ‘fen-phen’, but unlike ‘fen-phen’ it has been studied in clinical trials to assure safety.
One might argue that the discontinuation rate for the higher dose, 19%, which is quite acceptable, could have been minimised if downtitration to the lower dose was permitted if side effects developed. In clinical practice, we adjust the dosage of medications according to patient tolerability; thus, the likelihood of discontinuation of treatment may be lower in practice where tailored therapy can occur.
There are multiple neuronal and peripheral pathways implicated in the regulation of energy homeostasis, food intake and satiety. The use of combination therapy for obesity is one attempt not only to overcome this complex circuitry and provide more robust weight loss but also to improve the safety and tolerability of the treatment by allowing lower doses of the drugs to be used.
Competing interests LJA is a consultant, speaker and advisor and receives research support from Abbott, Amylin, Arena, BMIQ, GI Dynamics, GSK, Novo Nordisk, Orexigen, Vivus. CMA has participated on the advisory boards of Allergan, Amylin, Orexigin, Merck, Johnson & Johnson, Arena and Sanofi-Aventis, and has received research funding from Lilly, Amylin, Pfizer, Sanofi-Aventis, Orexigen, MetaProteomics and the Dr Robert C and Veronica Atkins Foundation.