Abstract and Introduction
Abstract
Objective: To evaluate over 108 weeks the effect of phentermine and topiramate extended release (PHEN/TPM ER) treatment on progression to type 2 diabetes and/or cardiometabolic disease in subjects with prediabetes and/or metabolic syndrome (MetS) at baseline.
Research Design and Methods: Subanalysis of a phase 3, randomized, placebo-controlled, double-blind study of overweight/obese subjects (BMI ≥27 to ≤45 kg/m) with two or more comorbidities. Subjects were randomized to placebo, PHEN 7.5 mg/TPM ER 46 mg (7.5/46), or PHEN 15 mg/TPM ER 92 mg (15/92) plus lifestyle modifications for 108 weeks. Percent weight loss in the intent-to-treat population using multiple imputation (ITT-MI), annualized incidence rate of progression to type 2 diabetes, and changes in glycemia, lipid parameters, blood pressure, and waist circumference were evaluated.
Results: At baseline, 475 subjects met the criteria for prediabetes and/or MetS. After 108 weeks, subjects with prediabetes and/or MetS in the placebo, 7.5/46, and 15/92 groups experienced mean percent weight loss of 2.5, 10.9, and 12.1%, respectively (ITT-MI; P < 0.0001 vs. placebo), associated with reductions of 70.5 and 78.7% in the annualized incidence rate of type 2 diabetes for those receiving 7.5/46 and 15/92, respectively (ITT, P < 0.05), versus placebo. The ability of PHEN/TPM ER to prevent diabetes was related to degree of weight lost and was accompanied by significant improvements in cardiometabolic parameters. PHEN/TPM ER was well tolerated by this subgroup over 2 years.
Conclusions: PHEN/TPM ER plus lifestyle modification produced significant weight loss and markedly reduced progression to type 2 diabetes in overweight/obese patients with prediabetes and/or MetS, accompanied by improvements in multiple cardiometabolic disease risk factors.
Introduction
The increased prevalence of type 2 diabetes, together with its burden of patient suffering and societal costs, underscores the importance of finding effective strategies for both treatment and prevention of this disease. Two clinical constructs for identifying individuals at high risk of developing type 2 diabetes are prediabetes and metabolic syndrome (MetS). Prediabetes is a state of dysglycemia defined by impaired fasting glucose (IFG) and/or impaired glucose tolerance. It is estimated that 79 million Americans aged 20 years or older have prediabetes, with 25% of them progressing to type 2 diabetes within 3–5 years. Type 2 diabetes is associated with abdominal obesity and insulin resistance (diagnostic criteria were established by the Advanced Treatment Panel III of the National Cholesterol Education Program); MetS is a cluster of risk factors for cardiovascular disease. Individuals with MetS are at a fivefold increased risk of developing type 2 diabetes. Because IFG is one of the constituent traits used to identify MetS, overlap with criteria for prediabetes exists, and the risk of progression to type 2 diabetes is further increased in individuals who satisfy both sets of criteria. Thus, effective treatment of these at-risk individuals is imperative for the prevention of type 2 diabetes.
Sustained loss of 5–10% of body weight in obese and overweight patients has proven to be effective in preventing progression from prediabetes and MetS to type 2 diabetes. It also ameliorates the cardiometabolic disease process, as shown by an increase in insulin sensitivity and a reduction in cardiovascular disease risk factors. However, achieving sustained weight loss at a clinically meaningful level sufficient to reduce risk remains a challenge for many patients. The primary approach to treating obesity and its related complications involves lifestyle modifications, including reductions in caloric intake (by 500–1,000 calories/day) combined with increases in physical activity. Bariatric surgery can also be an effective weight loss option for patients meeting specific criteria and may reduce the incidence of type 2 diabetes, but the approach entails risks associated with surgery, nutritional deficiencies, and weight regain in some patients.
In patients for whom lifestyle changes alone are insufficient and bariatric surgery is not an option, pharmacotherapies may be considered. Phentermine and topiramate extended release (PHEN/TPM ER; Qsymia; VIVUS, Inc., Mountain View, CA) have been shown to induce significant weight loss when combined with lifestyle modification in overweight/obese adults. The CONQUER study assessed effectiveness of PHEN/TPM ER for weight loss in overweight/obese adults with two or more weight-related comorbidities over 56 weeks (clinicaltrials.gov, NCT00553787) and was followed by SEQUEL, a 52-week blinded extension study (NCT00796367). In order to assess the ability of PHEN/TPM ER to reduce progression to type 2 diabetes and improve cardiometabolic parameters in patients at high risk of developing type 2 diabetes, we analyzed the subpopulation of patients meeting the criteria at baseline for prediabetes and/or MetS who elected to enroll in SEQUEL.