ESC 2018 - Munich

Cardiovascular Safety of Lorcaserin in Overweight or Obese Patients

Presented at the ESC congress 2018 by Bohula EA

Introduction and methods

Obesity is associated with the development and progression of several diseases, including hypertension, dyslipidemia, type 2 diabetes, coronary artery disease, stroke, and heart failure, as well as a risk of death from any cause. Medical guidelines on weight-loss recommend the use of drugs as adjuncts to lifestyle modification for long-term weight management, although no weight-loss medicine has been proven to provide cardiovascular (CV) safety or benefit.

Lorcaserin, a selective agonist of the 5-hydroxytryptamine 2C serotonin receptor (5-HT2C), regulates appetite and is approved as an adjunct to a reduced-calorie diet and increased physical activity for long-term weight management. The CAMELLIA–TIMI 61 (Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients–Thrombolysis in Myocardial Infarction 61) trial was set up to assess the long-term CV and metabolic safety and efficacy of lorcaserin in obese or overweight patients with established atherosclerotic CV disease or multiple CV risk factors.

CAMELLIA–TIMI 61, a randomized, double-blind, placebo-controlled trial, recruited patients with a body mass index (BMI) ≥27 kg/m2, and established atherosclerotic CV disease or multiple CV risk factors. Eligible patients were randomly assigned 1:1 to either lorcaserin (10 mg twice daily) or placebo, on a background of lifestyle interventions. The primary safety outcome was major CV events (MACE), defined as a composite of CV death, myocardial infarction, or stroke. The primary CV efficacy outcome was a composite of MACE, hospitalization for unstable angina, heart failure, or any coronary revascularization. A subgroup of patients were echocardiographically controlled for the development or progression of valvulopathy and pulmonary pressure. A total of 12,000 patients underwent randomization and were followed-up for a median of 3.3 years (IQR: 3.0-3.5).

Main results

• At 1 year, patients in the lorcaserin group showed 4.2 kg weight loss, as compared with 1.4 kg in the placebo groups (net difference: 2.8 kg, P<0.001). The weight loss was maintained over the course of the trial.
• At 1 year, 38.7% of patients in the lorcaserin group and 17.4% in the placebo group achieved weight loss of at least 5% (OR: 3.01; 95%CI: 2.74-3.30; P <0.001).
• The primary safety endpoint occurred in 364 patients (6.1%, or 2.0% per year) in the lorcaserin group and 369 (6.2%, or 2.1% per year) in the placebo group (HR: 0.99; 95%CI: 0.85-1.14; P <0.001 for non-inferiority)
• The primary efficacy outcome was observed in 707 patients (11.8%, or 4.1% per year) in the lorcaserin group and in 727 (12.1%, or 4.2% per year) in the placebo group (HR: 0.97; 95%CI, 0.87-1.07; P = 0.55 for superiority).
• The most common adverse events in the lorcaserin group, which led to therapy discontinuation, were dizziness, fatigue, headache, diarrhea, and nausea.
• Suicidal ideation or behavior was reported in 21 patients (0.4%) in the lorcaserin group and 11 patients (0.2%) in the placebo group (P = 0.08).

Conclusion

The authors conclude that compared to placebo, lorcaserin was not associated with an increased CV risk in obese patients with established CV disease or multiple CV risk factors.

Discussion

During the press conference, the non-inferiority concept of the study was discussed, and it was questioned whether it is enough to safely use lorcaserin for weight-management. There is a long history of trying to get success in this field, and a number of agents that were found to yield improvement, were later found to have safety issues and were retracted from the market. This is the first time that safety has been demonstrated in a rigorous outcome study, which may be considered a milestone. Anything that can be offered to patients and providers, will likely be welcomed, dr. Bohula said.

There was also discussion about the added value of lorcaserin over the lifestyle changes that should remain the cornerstone in weight loss, including physical activity and healthy diet. This agent may represent a reasonable extra option for patients, as it is always a challenge to maintain weight loss achieved with diet and exercise. The weight loss was seen only in the first year, but it was sustained, which is a new finding. Moreover, some risk factor improvements were seen. They did not alter the number of CV events, but they seemed to alter the CV risk profile a bit.

-Our reporting is based on the information provided at the ESC congress -

The CAMELLIA trial was published simultaneously in NEJM