Eliza is a 65-year-old woman with a history of hypertension, hyperlipidemia, and obesity (body mass index, 34) who comes to your office for a follow-up visit. You’ve been her primary care doctor for 5 years, and together you have chosen a variety of lifestyle interventions to address her weight and cardiovascular risk factors, but these have simply not worked. At her last visit, Eliza resolved to walk around her neighborhood at least three times a week, but today her weight is unchanged. She asks if there are any new and safe medications for weight loss that she can try.
Weight loss medications have a complicated history in terms of safety profile. In the 1990s, dexfenfluramine and fenfluramine, both 5-hydroxytryptamine 2B receptor agonists, were approved by the FDA for weight loss, but then were removed from the market due to increased rates of pulmonary hypertension and cardiac valvulopathies. Given these adverse effects, anti-obesity drugs that have been developed since then are closely monitored for long-term safety, particularly from a cardiovascular standpoint. Lorcaserin, a selective agonist of the 5-hydroxytryptamine 2C serotonin receptor (5-HT2C), was FDA-approved in 2012 as an adjunct to lifestyle modification for long-term weight management, but its cardiovascular safety profile is uncertain.
Bohula and colleagues examined the safety of lorcaserin in the Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients—Thrombolysis in Myocardial Infarction 61 (CAMELLIA-TIMI) trial, published in NEJM this week. In a double-blind controlled study, the authors randomized 12,000 patients (median age, 64; median BMI, 35) to receive either lorcaserin or placebo. Most patients had existing medical conditions such as hypertension, hyperlipidemia, diabetes, and established atherosclerotic cardiovascular disease. The primary safety outcome was major cardiovascular events (a composite of cardiovascular death, myocardial infarction, or stroke).
The good news is, after a median follow up of 3.3 years, lorcaserin was noninferior to placebo in terms of major cardiovascular events (2.0% vs. 2.1% per year; hazard ratio, 0.99, P<0.001 for noninferiority). The unsurprising news is that significantly more patients in the lorcaserin group than in the placebo group demonstrated a weight loss of at least 5%, with the largest between-group difference noted at the 1-year time point (38.7% vs. 17.4%; odds ratio, 3.01; 95% CI, 2.74- 3.30; P<0.001). New-onset type 2 diabetes, a key secondary outcome in the study, occurred in 8.5% of patients in the lorcaserin group and 10.3% of patients in the placebo group.
In an accompanying editorial, NEJM Deputy Editor Julie R. Ingelfinger and Associate Editor Clifford J. Rosen, emphasize the importance of obtaining and evaluating long-term cardiovascular safety data on lorcaserin and understanding lorcaserin’s role in diabetes. They note limitations of a subset analysis of de novo or progressive FDA-defined valvulopathies assessed by echocardiography and an imbalance in pulmonary hypertension that was worsening at 1 year. In relation to lorcaserin’s uncertain effect on glucose control, they state, “preclinical data have suggested that lorcaserin has glucose-lowering properties independent of weight loss… But clinical trials, including this one, have shown less impressive results, in part because of confounding from other medications…” They conclude, “with respect to efficacy, liraglutide [an agonist of glucagon-like peptide 1 receptor] would provide a similar degree of weight loss but with a lower risk of diabetes.”
Although the CAMELLIA-TIMI trial provides useful 3-year cardiovascular safety data for lorcaserin in high-risk overweight and obese patients, long-term data are still needed. When discussing lorcaserin and other FDA-approved weight loss medications with Eliza, it will be important to discuss the limitations of the safety data and adverse event profile and to review other approved medications for weight loss in the context of her cardiovascular risk factors.
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Angela Castellanos is a general pediatrician and editorial fellow at the NEJM.