1/2, Clinical Coordinating Center for the Long-term Effectiveness of the Anti-obesity medication Phentermine: the LEAP Trial

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PROJECT SUMMARY/ABSTRACT Over one-third of adults in the US have obesity, many with comorbidities including hypertension and diabetes. Comprehensive lifestyle change is the first-line approach to treating obesity, but as many as half of patients are non-responsive to behavior change interventions, and the majority of initial responders go on to regain lost weight within 2 years. Pairing lifestyle intervention with an antiobesity medication (AOM) can enhance weight loss and promote weight loss maintenance. However, despite the recent availability of several AOMs in the US, these medications are rarely prescribed. Among the small subset of patients who do receive an AOM prescription, the generic medication Phentermine accounts for 76% of fills. Phentermine is only approved for short-term use, while current guidelines for treatment of obesity recommend long-term AOM prescribing. Concerns about longer-term use of phentermine stem from the fact that it can increase heart rate and blood pressure, theoretically increasing risk of incident cardiovascular disease. Despite these concerns, and despite the pressing need for affordable and effective long-term obesity pharmacotherapy, there have been no high-quality, randomized controlled trials of phentermine monotherapy to examine its efficacy, impact on risk factors, or potential adverse events if used long-term. At 5 centers across the United States, we will conduct the Long-term Effectiveness of the Anti-obesity medication Phentermine (LEAP) trial—a placebo-controlled, randomized trial, enrolling 1,000 adults with BMI 27-44.9kg/m2. In an intent-to-treat fashion, with all participants provided with an evidence-based online lifestyle intervention, we will compare participants receiving 24 mg/day of phentermine vs. placebo for up to 24 months. We will examine co-primary outcomes of percent weight loss and change in systolic blood pressure at 24 months. Additionally, we will compare between groups changes in drivers of energy balance, including resting metabolic rate, caloric intake, physical activity and dietary composition. Because weight loss can improve cardiometabolic health, we will also compare changes in heart rate, hemoglobin A1c, lipids, waist circumference, atherosclerotic cardiovascular disease (ASCVD) risk score, and novel ECG markers of cardiac strain. Finally, we will examine overall adverse event and serious adverse event rate, including rates of incident cardiovascular disease or death. The potential impact of our findings is large regardless of whether they are positive or negative. If phentermine were shown to be safe and effective for long-term use in patients with obesity, it could provide an immediately available low-cost option for weight management. In contrast, if shown ineffective, the trial could reduce off-label prescribing of the medication and promote a shift to drugs with proven, albeit costly, long-term effectiveness.