Giving patients a combination of low-dose, controlled-release phentermine plus topiramate could be a much-needed and valuable adjunct to labor-intensive, office-based diet and lifestyle interventions for the management of obesity. “A greater understanding of obesity, and effective treatment strategies, is critical to addressing [the obesity] epidemic. New tools have not been forthcoming, so promising therapies are really exciting for the field,” explains Kishore Gadde, lead author on the multicenter phase 3 CONQUER trial.

Phentermine was approved by the FDA for short-term treatment of obesity in 1959, but no randomized controlled trials have reported its use in the long term. By contrast, topiramate is approved for the treatment of epilepsy and migraine prophylaxis; its effect on weight reduction in obese patients with or without type 2 diabetes and hypertension has been studied, but its potential as a monotherapy for obesity has been held back by associated dose-dependent neuropyschiatric adverse events.

Gadde et al. adopted a combined treatment approach as phentermine and topiramate have different mechanisms of action and could, therefore, have an additive or synergistic effect. Indeed, this combination achieved greater weight loss than either drug alone in a phase 2 study. Combined treatment could also improve treatment tolerability by modulating the drug dose and controlling its release.

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In the CONQUER trial, 2,487 overweight and obese individuals were randomly allocated (2:1:2) to receive placebo, once-daily phentermine 7.5 mg plus topiramate 46.0 mg or once-daily phentermine 15.0 mg plus topiramate 92.0 mg for 56 weeks. To reflect the 'typical' obese patients seen in clinical practice, adults aged 18–70 years who had a BMI of 27–45 kg/m2 and two or more comorbidities (diabetes or prediabetes, hypertension, dyslipidemia or abdominal obesity) were recruited.

In the intention-to-treat analysis, the decrease in bodyweight was significantly greater for combined treatment with either dose of phentermine plus topiramate than for placebo—the decrease in bodyweight was slightly higher for the highest dose of combined treatment. For those who completed 1 year of treatment, the absolute decrease in bodyweight was even greater.

Weight loss of at least 5% was achieved by 21% of patients in the placebo group, compared with 62% in the phentermine 7.5 mg plus topiramate 46.0 mg group and 70% in the phentermine 15.0 mg plus topiramate 92.0 mg group. 7% of patients in the placebo group, 37% in the phentermine 7.5 mg plus topiramate 46.0 mg group and 48% in the phentermine 15.0 mg plus topiramate 92.0 mg group achieved weight loss of at least 10%. “This degree of weight loss has not been seen [with] other pharmacotherapies, and in light of the fact that only one long-term medication treatment is currently available for obesity, additional treatment options could equip physicians with more tools,” says Gadde.

Combined treatment also conferred significant improvements in blood pressure, waist circumference, lipid concentrations and inflammatory biomarkers compared with placebo; patients who had pre-existing cormorbidities seemed to benefit most.

Overall, 38% of patients discontinued treatment (including placebo). The treatment was generally well tolerated, but dose-related increases in discontinuations due to adverse events were noted for the combination treatment compared with placebo. Treatment-related adverse events included dry mouth, constipation, dysgeusia, parasthesia, insomnia, dizziness, anxiety, irritability and disturbances in attention, but these were as expected and also seemed to be dose related. All groups had a similar rate of serious adverse events.

An extension of this study, in which a subset of patients were followed up for a full second year, has recently been completed and the findings are now being prepared for publication.