NEW ORLEANS—The combination of sustained-release naltrexone and bupropion leads to sustained clinically meaningful weight loss and improves markers of cardiovascular risk in obese patients, according to results released at the 60th Annual Scientific Session of the American College of Cardiology.
Importantly, the benefits are achieved without significant changes in blood pressure (BP), the researchers said.
“Given the growing epidemic of obesity, the availability of naltrexone/bupropion could provide a useful tool for physicians and patients in whom pharmacotherapeutic options are currently extremely limited,” said Jorge Plutzky, MD, Director of the Vascular Disease Prevention Program at Harvard Medical School and Brigham and Women’s Hospital in Boston.
“Blood pressure is of special interest in obese populations because blood pressure has been shown to increase with weight gain,” he added. “Moreover, loss of blood pressure-lowering during nocturnal hours of at least 10%, as seen in type 2 diabetes, predicts poor cardiovascular outcomes.”
The new findings are from the ambulatory BP monitoring (ABPM) substudy of the Contrave Obesity Research (COR-II) study. The COR-II study randomized 1,496 patients to 52 weeks of treatment with 32 mg naltrexone/360 mg bupropion or placebo in a 2:1 ratio, with the study drug gradually escalated to the full dose by the fifth week of treatment.
Naltrexone and bupropion have been used clinically for more than 20 years. Naltrexone has been prescribed primarily to treat opioid and alcohol dependence, and bupropion has been prescribed for nicotine dependence, depression, and seasonal affective disorder. The naltrexone/bupropion combination for obesity is investigational.
Combination therapy has demonstrated a synergistic effect on weight loss and loss of body fat compared with either drug alone, and it also improved subjective control of eating.
Consistent with bupropion’s known pressor effects, patients receiving combination therapy in clinical studies had small increases in BP and heart rate compared with placebo, although weight reduction was associated with decreased mean BP in both treatment groups.
The substudy was undertaken because 24-hour ABPM delineates circadian BP variation, provides a more comprehensive BP profile, and is a better predictor of end-organ damage and cardiovascular events than routine clinic visit measurements.
The 182 patients enrolled in the ABPM substudy had a body mass index (BMI) of 30 to 45 kg/m2 and uncomplicated obesity or BMI of 27 to 45 kg/m2 and uncontrolled hypertension and/or dyslipidemia. All of them were counseled briefly on advice on diet, exercise, and other methods of behavior modification every three months. The primary endpoint was the change from baseline to week 52 in average 24-hour systolic and diastolic BP.
Changes from baseline to week 52 in mean 24-hour BP and pulse were -0.2 mm Hg for systolic BP, +0.8 mm Hg for diastolic BP, and +0.1 beats per minute in patients receiving nalrexone/bupropion. Corresponding changes were -2.8 mm Hg in systolic BP, -2.1 mm Hg in diastolic BP, and -0.5 beats per minute for placebo-treated patients.
The normal circadian variation of BP, including a change between daytime and nighttime BP of at least 10%, was maintained in patients treated with naltrexone/bupropion.
Compared to placebo, naltrexone/bupropion significantly decreased waist circumference and high-sensitivity C–reactive protein (hs-CRP) levels, and significantly increased levels of high-density-lipoprotein (HDL)-cholesterol.
As in the parent study, patients treated with combination therapy had a larger mean weight loss than placebo patients and a larger percentage of patients achieving different weight loss categories. Notably, 53% of patients on combination therapy lost 5% or more of their baseline body weight, 34% lost 10% or more, and 20% lost 15% or more over 52 weeks. Combination therapy was generally well tolerated.
“Despite the growing public epidemic of obesity coupled with the complications of obesity, there are few safe and effective treatments, Dr. Plutzsky commented. “Also, approved therapies produce a weight loss plateau within a few months of use.”
The naltrexone/ bupropion combination provides significant long-lasting weight loss along with improvements in multiple markers of cardiometabolic risk and a good tolerability profile, he said. “As such, it represents an attractive therapeutic option with an acceptable risk-benefit profile.”