Elsevier

The Lancet

Volume 377, Issue 9774, 16–22 April 2011, Pages 1341-1352
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(11)60205-5Get rights and content

Summary

Background

Obesity is associated with a reduction in life expectancy and an increase in mortality from cardiovascular diseases, cancer, and other causes. We therefore assessed 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 were overweight and obese, with two or more risk factors.

Methods

In this 56-week phase 3 trial, we randomly assigned overweight or obese adults (aged 18–70 years), with a body-mass index of 27–45 kg/m2 and two or more comorbidities (hypertension, dyslipidaemia, diabetes or prediabetes, or abdominal obesity) to placebo, once-daily phentermine 7·5 mg plus topiramate 46·0 mg, or once-daily phentermine 15·0 mg plus topiramate 92·0 mg in a 2:1:2 ratio in 93 centres in the USA. Drugs were administered orally. Patients were randomly assigned by use of a computer-generated algorithm that was implemented through an interactive voice response system, and were stratified by sex and diabetic status. Investigators, patients, and study sponsors were masked to treatment. 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. This study is registered with Clinical Trials.gov, number NCT00553787.

Findings

Of 2487 patients, 994 were assigned to placebo, 498 to phentermine 7·5 mg plus topiramate 46·0 mg, and 995 to phentermine 15·0 mg plus topiramate 92·0 mg; 979, 488, and 981 patients, respectively, were analysed. At 56 weeks, change in bodyweight was −1·4 kg (least-squares mean −1·2%, 95% CI −1·8 to −0·7), −8·1 kg (−7·8%, −8·5 to −7·1; p<0·0001), and −10·2 kg (−9·8%, −10·4 to −9·3; p<0·0001) in the patients assigned to placebo, phentermine 7·5 mg plus topiramate 46·0 mg, and phentermine 15·0 mg plus topiramate 92·0 mg, respectively. 204 (21%) patients achieved at least 5% weight loss with placebo, 303 (62%; odds ratio 6·3, 95% CI 4·9 to 8·0; p<0·0001) with phentermine 7·5 mg plus topiramate 46·0 mg, and 687 (70%; 9·0, 7·3 to 11·1; p<0·0001) with phentermine 15·0 mg plus topiramate 92·0 mg; for ≥10% weight loss, the corresponding numbers were 72 (7%), 182 (37%; 7·6, 5·6 to 10·2; p<0·0001), and 467 (48%; 11·7, 8·9 to 15·4; p<0·0001). The most common adverse events were dry mouth (24 [2%], 67 [13%], and 207 [21%] in the groups assigned to placebo, phentermine 7·5 mg plus topiramate 46·0 mg, and phentermine 15·0 mg plus topiramate 92·0 mg, respectively), paraesthesia (20 [2%], 68 [14%], and 204 [21%], respectively), constipation (59 [6%], 75 [15%], and 173 [17%], respectively), insomnia (47 [5%], 29 [6%], and 102 [10%], respectively), dizziness (31 [3%], 36 [7%], 99 [10%], respectively), and dysgeusia (11 [1%], 37 [7%], and 103 [10%], respectively). 38 (4%) patients assigned to placebo, 19 (4%) to phentermine 7·5 mg plus topiramate 46·0 mg, and 73 (7%) to phentermine 15·0 mg plus topiramate 92·0 mg had depression-related adverse events; and 28 (3%), 24 (5%), and 77 (8%), respectively, had anxiety-related adverse events.

Interpretation

The combination of phentermine and topiramate, with office-based lifestyle interventions, might be a valuable treatment for obesity that can be provided by family doctors.

Funding

Vivus.

Introduction

Obesity is associated with reduced life expectancy and increased mortality from cardiovascular disease, cancer, and other causes.1, 2, 3, 4 About 90% of cases of type 2 diabetes are attributable to excess weight, and there is a five-to-six times increase in hypertension among obese individuals compared with those with normal weight.5, 6, 7

In patients with diabetes, a weight reduction of 5–10% improves obesity-related risk factors and comorbidities,8 with substantial improvements in glycaemia, blood pressure, and lipid concentrations.9 Intensive lifestyle-modification programmes that produce significant weight loss, and concomitant benefits, in obese patients with prediabetes or diabetes have to be implemented by trained counsellors during frequent office visits, and are not readily incorporated into visits to the family doctor.10, 11 An effective pharmacological intervention that can produce 5–10% greater weight loss than does brief office-based counselling alone could meet the need for improved medical management of the obese patient.

Phentermine, a central norepinephrine-releasing drug, approved in 1959 for short-term obesity treatment at 15·0–37·5 mg/day, remains the most widely prescribed antiobesity drug in the USA.12 No long-term (≥1 year) randomised controlled trials of phentermine have been reported. At approved doses, phentermine has no serotonergic activity and has negligible effects on dopamine release.13 Topiramate has several pharmacological mechanisms of action, and is marketed for the treatment of epilepsy and migraine prophylaxis. It was assessed alone for weight reduction in obese patients without and with type 2 diabetes and hypertension.14, 15, 16, 17, 18, 19 However, dose-dependent neuropsychiatric adverse events, mainly memory and mood events including depression, hindered its development as monotherapy for obesity.

Since several neuronal and peripheral pathways are implicated in the regulation of food intake, satiety, and energy homoeostasis, combinations of drugs with additive or synergistic effects could overcome the biological compensatory mechanisms.20 Furthermore, drug combinations might improve tolerability if doses could be carefully modulated. In the CONQUER study, we assessed efficacy and safety of two doses of a once-daily, controlled-release phentermine plus topiramate combination for weight reduction during 56 weeks in adults who were overweight or obese, and had weight-related comorbidities.

Section snippets

Patients and study design

CONQUER was a randomised, double-blind, placebo-controlled study undertaken in 93 centres in the USA. Patients (aged 18–70 years) were eligible if they were overweight or obese with a body-mass index (BMI) of 27–45 kg/m2. No lower BMI limit was set for patients diagnosed with diabetes at baseline. Inclusion criteria were two or more of the following comorbidities at baseline: systolic blood pressure 140–160 mm Hg (130–160 mm Hg in patients with diabetes), diastolic blood pressure 90–100 mm Hg

Results

The study was undertaken between Nov 1, 2007, and June 30, 2009. Figure 1 shows the trial profile. Patient characteristics at baseline were similar in the three groups (table 1). Most patients were women (n=1737 [70%]) and were white (n=2140 [86%]). Mean age for the whole group was 51·1 years (SD 10·4), bodyweight was 103·1 kg (17·9), and BMI was 36·6 kg/m2 (4·5). According to protocol-specified definitions, 1305 (52%) patients had hypertension, 897 (36%) had hypertriglyceridaemia, 1684 (68%)

Discussion

The results of this study show robust efficacy of the phentermine plus topiramate combination for weight loss (as assessed with change in bodyweight and proportion of patients who achieved a weight loss of at least 5%) that was shown in a preliminary trial.26 A major strength of our study was that we were able to assess the effects of weight loss on weight-related comorbidities—half the patients had at least three comorbidities, and a substantial proportion was receiving several concomitant

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