Clinical Pearls & Morning Reports
On the basis of findings in weight-loss trials, lorcaserin was approved by the Food and Drug Administration as an adjunct to a reduced-calorie diet and increased physical activity for long-term weight management. The cardiovascular safety and efficacy of lorcaserin are undefined. Bohula et al. investigated the long-term cardiovascular and metabolic safety and efficacy of lorcaserin in obese or overweight patients with established atherosclerotic cardiovascular disease or multiple cardiovascular risk factors. Read the latest NEJM Original Article here.
Q: Are there any available weight loss medications with proven cardiovascular benefits?
A: Many weight-loss guidelines recommend the use of pharmacologic agents as adjuncts to lifestyle modification for long-term weight management in some patients. However, no pharmacologic strategy has yet shown cardiovascular safety or benefit. Indeed, several agents have precipitated various cardiovascular or neuropsychiatric complications, which has led to their removal from markets by regulatory agencies and left clinicians without a pharmacologic weight-loss agent with proven cardiovascular safety.
Q: What is the mechanism of action of lorcaserin?
A: Lorcaserin is a selective agonist of the 5-hydroxytryptamine 2C serotonin receptor (5-HT2C), which regulates appetite through hypothalamic activation of the anorexigenic proopiomelanocortin (POMC) pathway.
A: The primary safety outcome in the trial by Bohula et al. was major cardiovascular events (a composite of cardiovascular death, myocardial infarction, or stroke). The primary cardiovascular efficacy outcome was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, heart failure, or any coronary revascularization (extended major cardiovascular events). A two-step procedure was used in which the primary assessment was for cardiovascular safety, followed by an assessment of cardiovascular efficacy. The primary cardiovascular safety assessment for the noninferiority of lorcaserin versus placebo was conducted at an interim analysis after the prespecified number of events had accrued. If the criteria for noninferiority were met, the trial was to continue to assess the superiority of lorcaserin over placebo with respect to extended major cardiovascular events. At the time of trial completion, major cardiovascular events had 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 (hazard ratio, 0.99; 95% CI, 0.85 to 1.14; P<0.001 for noninferiority). The primary efficacy outcome of extended major cardiovascular events occurred 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 (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P=0.55 for superiority).
A: No significant between-group differences were seen in the overall incidence of serious adverse events. The occurrence of prespecified adverse events of special interest was low (<1% for most events). 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); the numerical imbalance in suicidal ideation or behavior appeared to be restricted to patients with depression at baseline (in 15 patients [1.2%] and 6 [0.5%], respectively; P=0.06). There were no deaths by suicide. Severe hypoglycemia with serious complications (i.e., that required hospitalization, were life-threatening or disabling, or resulted in death) was rare but more common with lorcaserin than with placebo (in 13 patients [0.2%] vs. 4 [0.1%]), with the imbalance restricted to hypoglycemia requiring hospitalization (11 patients vs. 2 patients). All but 1 event occurred in patients with diabetes who were receiving insulin or a sulfonylurea at baseline (12 vs. 4 events, P=0.054).