Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): Arandomised, placebo-controlled, phase 3 trial

Obesity Clinical Trials Programme, Duke University Medical Center, Durham, NC 27710, USA.
The Lancet (Impact Factor: 45.22). 04/2011; 377(9774):1341-52. DOI: 10.1016/S0140-6736(11)60205-5
Source: PubMed


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.
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/m(2) 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, number NCT00553787.
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.
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.

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    • "Subjects were randomized 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 centers in the USA. The combination of phentermine and topiramate, with office-based lifestyle interventions, was associated with a significant decrease in A1c (−0.4%) compared with the control group (−0.1%).172 These benefits were sustained in the double-blind 52-week extension study, where the annualized incidence rates for progression to T2DM among subjects without diabetes at baseline were 3.7%, 1.7%, and 0.9% in the placebo, 7.5/46 mg, and 15/92 mg treatment groups, respectively. "
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    ABSTRACT: Clinical trials have demonstrated that it is possible to prevent diabetes through lifestyle modification, pharmacological intervention, and surgery. This review aims to summarize the effectiveness of these various therapeutic interventions in reducing the risk of progression of prediabetes to diabetes, and address the challenges to implement a diabetes prevention program at a community level. Strategies focusing on intensive lifestyle changes are not only efficient but cost-effective and/or cost-saving. Indeed, lifestyle intervention in people at high risk for type 2 diabetes mellitus (T2DM) has been successful in achieving sustained behavioral changes and a reduction in diabetes incidence even after the counseling is stopped. Although prediabetes is associated with health and economic burdens, it has not been adequately addressed by interventions or regulatory agencies in terms of prevention or disease management. Lifestyle intervention strategies to prevent T2DM should be distinct for different populations around the globe and should emphasize sex, age, ethnicity, and cultural and geographical considerations to be feasible and to promote better compliance. The translation of diabetes prevention research at a population level, especially finding the most effective methods of preventing T2DM in various societies and cultural settings remains challenging, but must be accomplished to stop this worldwide epidemic.
    Therapeutics and Clinical Risk Management 03/2014; 10(1):173-188. DOI:10.2147/TCRM.S39564 · 1.47 Impact Factor
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    • "In EQUIP and CONQUER, there were small increases in mean heart rate: EQUIP, –0.2, –0.3, and 1.2 bpm with placebo, 3.75/23, and 15/92, respectively (Allison et al., 2012); CONQUER, –0.1, 0.1, and 1.7 bpm with placebo, 7.5/46, and 15/92, respectively (Gadde et al., 2011; Garvey et al., 2012). However, mean BP was decreased with PHEN/ TPM ER treatment vs placebo and there were no adverse events reported that were associated with changes in heart rate (Allison et al., 2012; Gadde et al., 2011; Garvey et al., 2012). 3.4. "
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    ABSTRACT: Moderate weight loss (>5%), which has been associated with improvements in glycemic parameters in patients with dysglycemia, also reduces the presence of other comorbidities, including dyslipidemia and hypertension, culminating in a reduced risk of cardiovascular disease. Lifestyle changes are the recommended preliminary approach to weight loss, with an initial weight-loss goal of 10% of body weight achieved over 6 months at a rate of 1-2 pounds per week selected as an appropriate target to decrease the severity of obesity-related risk factors. Implementing and maintaining the lifestyle changes associated with weight loss can, however, be challenging for many patients. Therefore, additional interventions sometimes may be necessary. Bariatric surgery can also be a highly effective option for weight loss and comorbidity reduction, but surgery carries considerable risks and is still applicable only to selected patients with type 2 diabetes. Thus, attention is turning to the use of weight-loss medications, including 2 recently approved compounds: twice-daily lorcaserin and a once-daily combination of phentermine and topiramate extended-release, both shown to be safe and effective therapies in the management of obesity in patients with type 2 diabetes.
    Journal of diabetes and its complications 05/2013; 27(5). DOI:10.1016/j.jdiacomp.2013.04.011 · 3.01 Impact Factor
    • "Recently, combination of topiramate with phentermine has been evaluated in two big studies for weight loss which demonstrated near 10% weight loss and 0.3-0.7% reduction in HgA1C.[2021] "
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    ABSTRACT: Obesity has been associated with several co-morbidities such as diabetes and increased mortality. In general, the use of medication promotes only a modest weight loss in the range of 2 to 10 kg, usually most effective during the first 6 months of therapy; however, studies have shown positive effects on other risk factors such as blood pressure and serum glucose levels, but there are fewer studies in patients with diabetes. The aim of this study was to assess the effect of topiramate on weight reduction patients with type 2 diabetes. This was a 32-week randomized clinical trial study of 69 subjects during 2008-2010. Patients, in two treatment groups were given topiramate (39 patients) and Placebo (30 patients) and were subjected to participation in a non-pharmacologic lifestyle intervention program; which were randomly allocated in our two groups. The percentage change in body weight and Body Mass Index (BMI) at the end of the study was the primary efficacy endpoint and secondary indicators were changes in blood pressure (BP), proportion of subjects who achieved 5% or 10% weight loss, changes in lipid profile (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides); and changes in glycosylated hemoglobin (HgA1c). Paired samples and independent samples t-test was used for statistical analysis. (RCT code: IRCT201112036027N2). All results were extracted on base of 69 (Intended to treat) ITT patients. Mean BMI changes was significantly higher in patients treated with topiramate (-1.08 1.90 vs. +0.086 ± 1.05 kg/m², P = 0.006). Mean weight loss percentage was significantly different between active and placebo groups (-3.02 ± 5.78% vs. +0.32 ± 3.54%, P = 0.005) and systolic blood pressure and HgA1C significantly decreased in patients treated with topiramate (P = 0.021 and P = 0.047, respectively). Topiramate induced weight loss and improved glycemic control in obese, diabetic patients.
    Journal of research in medical sciences 04/2013; 18(4):297-302. · 0.65 Impact Factor
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