May 25, 2012 (Lyon, France) — The combination of low-dose phentermine plus extended-release topiramate (Qnexa, Vivus) might help overweight and obese people lose weight, regardless of their obesity-related risk or the extent of their comorbidities.
Stephan Rössner, MD, PhD, professor emeritus of health-related behavioral science at the Karolinska Institute in Stockholm, Sweden, presented results from the CONQUER trial here at the 19th European Congress on Obesity. Subjects receiving the combination had significantly greater weight loss, regardless of their baseline Edmonton Obesity Staging System (EOSS) stage, than subjects just modifying their lifestyle.
Although body mass index (BMI) denotes the presence and degree of excess weight, it does not give any information about weight-related comorbidities. The EOSS is a classification system that considers the presence and magnitude of weight-related comorbidities and functional status. Stage 0 indicates no apparent risk factors, stage 1 indicates weight-related subclinical risk factors, stage 2 indicates established weight-related chronic disease, and stage 3 indicates established end-organ damage.
The combination of phentermine plus topiramate has previously been shown to be associated with significant weight loss in overweight/obese subjects with 2 or more weight-related comorbidities. Dr. Rössner presented a post hoc analysis of the data in which weight loss was assessed according to a patient's baseline EOSS stage.
CONQUER was a 56-week double-blind phase 3 trial that randomized 2487 overweight/obese adults with 2 or more weight-related comorbidities to 1 of 3 groups: phentermine 7.5 mg plus extended-release topiramate 46 mg (the lower-dose group; n = 498); phentermine 15 mg plus extended-release topiramate 92 mg (the higher-dose group; n = 995); or placebo (n = 994). A lifestyle modification program for weight control was implemented in all groups.
The 3 groups were well matched at baseline for age (mean, 51 years), sex (70% women), race (86% white), weight (mean, 103 kg), and BMI (36.2 to 36.7 kg/m²). The groups were also well matched at baseline for EOSS stage, with the vast majority of subjects (86.7% to 91.0%) in each group being stage 2. Of the remaining subjects, most were stage 3.
Weight Loss for All With the Drug Combination
For all 3 EOSS stages at baseline, weight loss at 56 weeks was significantly greater in the combination groups than in the placebo group, and was dose-dependent. For EOSS stages 1, 2, and 3, the placebo group had mean weight losses of 1.5%, 1.8%, and 2.3%, respectively. The lower-dose group had mean weight losses of 7.3%, 8.6%, and 6.8%, respectively (P < .05, P < .001, P < .05 vs placebo, respectively). The higher-dose group had mean weight losses of 10.0%, 10.5%, and 9.5%, respectively (P < .001 vs placebo for all).
Significantly more subjects achieved a weight loss of 5% or greater and 10% or greater in the combination groups than in the placebo groups for each EOSS stage.
The drug combination was generally well tolerated. The most common adverse effects occurring at a rate greater with the combination than with placebo were dry mouth, constipation, and paresthesias. The proportion of subjects experiencing dry mouth or paresthesias was dose-related.
New Life for Phentermine
Phentermine has been used for weight loss in the past, but at much higher doses and in combination with fenfluramine. The occurrence of pulmonary hypertension and valvular heart disease led to the withdrawal of phentermine from the market.
Now phentermine is being combined with topiramate. "These 2 are combined but at a much, much lower [dosage]," Dr. Rössner said.
In February, a US Food and Drug Administration (FDA) advisory panel voted 20 to 2 to recommend the approval of the combination on the basis of its demonstrated efficacy and favorable risk/benefit profile for treating obesity. In July 2010, an advisory committee had recommended against approval. Despite voting for approval, the more recent panel voiced concerns about adverse effects, including increases in heart rate and potential birth defects, and recommended further study to evaluate cardiovascular morbidity and mortality. They also recommended implementing a Risk Evaluation and Mitigation Strategy to control and monitor its use.
Luca Busetto, MD, from the Department of Medical and Surgical Sciences and the Obesity Center at the University of Padova in Italy, who was not involved in the trial, agrees with the FDA panel, and told Medscape Medical Newsthat "the results on weight loss are very promising. Obviously, we need to be careful, in my opinion, in the clinical use, because we may have problems if you use this type of drug indiscriminately in obese people without strict medical control."
He cited the potential for adverse cardiovascular effects, even with the lower dose. "We still remain cautious. If you think about a drug entering the market of obesity, you need to think about a drug that will potentially be used by millions and millions of people. We need to be careful because a small increment in cardiovascular events will translate into a large number of events," Dr. Busetto cautioned.
Vivus, the manufacturer of Qnexa, funded the study and data analysis and provided editorial support for the authors. Dr. Rössner reports being a consultant for Vivus.
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