Cardiovascular Safety of Lorcaserin in Overweight or Obese Patients
Kaity Bader, Pharm.D., Apple Valley Medical Clinic, Fairview Physician Associates
Background: Obesity is associated with several other medical conditions including hypertension, coronary artery disease, heart failure, type 2 diabetes, and dyslipidemia. Lorcaserin, a selective agonist of the 5-hydroxy-tryptamine 2C serotonin receptor (5-HT2C), in conjunction with a reduced calorie diet and increased physical activity has shown efficacy for weight loss. Yet, the cardiovascular safety of lorcaserin in overweight or obese patients is not known.
Objective: The cardiovasular and metabolic effects of lorcaserin in overweight and obese patients-thrombolysis in myocardial infarction 61 trial (CAMELLIA-TIMI 61) was designed to measure the cardiovascular and metabolic safety and efficacy of lorcaserin in overweight or obese patients with high cardiovascular risk.
Study Design: CAMELLIA-TIMI 61 was a multisite trial enrolling participants in eight countries. Study participants had a body mass index (BMI) ≥27, were willing to comply with reduced caloric diet and increased physical activity regimen, and had established cardiovascular risk. Cardiovascular risk was defined as either 1) age ≥40 years with established cardiovascular disease (history of myocardial infarction, ischemic stroke, revascularization, peripheral artery disease, or significant unrevascularized coronary artery stenosis), or 2) women age ≥55 years or men age ≥50 years with type 2 diabetes, without established cardiovascular disease, but at least one additional cardiovascular risk factor (hypertension, dyslipidemia, impaired glomerular filtration rate (GFR), high sensitivity C-reactive protein (hsCRP) >3 mg/L, or urinary albumin-to-creatinine ratio (ACR) ≥30 µg/mg). Randomization to either lorcaserin 10 mg twice daily or matched placebo was double-blind and stratified by cardiovascular disease status. All participants were strongly encouraged to participate in a weight management program (behavioral therapy with dietary and exercise guidance).
The primary safety composite outcome of major cardiovascular events was defined as either cardiovascular death, myocardial infarction, or stroke. The primary cardiovascular efficacy outcome was also composite, including cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, heart failure, or any coronary revascularization. Statistical analysis was performed using the intention-to-treat method. The non-inferiority margin was set at 1.4 for lorcaserin v. placebo.
Results: A total of 12,000 participants were randomized, with 64.2% being male and an overall high burden of coexisting conditions such as hypertension, hyperlipidemia, diabetes and chronic kidney disease. The median age was 64 years and median BMI was 35. The median follow-up period was 3.3 years. At the time of trial completion, the primary safety outcome of major cardiovascular events had occurred in 364 patients in the lorcaserin group (6.1%) and 369 patients in the placebo group (6.2%), HR 0.99 [95% CI 0.85 - 1.14] for non-inferiority. The primary efficacy outcome result for lorcaserin v. placebo was HR 0.97 [95% CI 0.87 - 1.07]. Considering weight changes, the difference in weight loss between study arms was -1.9 kg at 40 months, remaining significant. Participants in the lorcaserin arm had -4.0 kg weight change and participants in the placebo arm had -2.1 kg weight change. Majority of the participants who discontinued prematurely, 12% per year in the lorcaserin and 12.7% per year in the placebo group, stopped because of patient choice unrelated to an adverse event. However, dizziness, fatigue, headache, diarrhea, and nausea were the most commonly reported side effects that resulted in trial discontinuation.
Conclusions: Lorcaserin demonstrated non-inferiority for cardiovascular safety when compared to placebo in the CAMELLIA-TIMI 61 trial. Therefore, lorcaserin may be an optimal therapy choice for weight management overweight or obese patients with established cardiovasular disease or multiple risk factors for cardiovasular disease.
Key Point: Lorcaserin is an effective pharmacotherapy option for weight management in high cardiovascular risk patients with BMI ≥27 who are also committed to non-pharmacotherapy improvements, with no significant difference in cardiovascular safety outcomes when compared with placebo.
Bohula EA, Wiviott SD, McGuire DK, et al. Cardiovascular safety of lorcaserin in overweight or obese patients. N Engl J Med. 2018;379(12):1107-1117. doi: 10.1056/NEJMoa1808721.