MUNICH — Treatment with the serotonin receptor agonist lorcaserin yielded sustained weight loss over a median follow-up of 3 years without an excess risk for major adverse CV events in adults with overweight or obesity at high CV risk, according to new data from the CAMELLIA-TIMI 61 study.
In the randomized, double-blind, placebo-controlled trial of more than 12,000 patients in eight countries with atherosclerotic CVD or multiple CV risk factors, researchers also found no increased risk for new or worsening valvulopathy in patients assigned lorcaserin (Belviq, Eisai) compared with placebo, which has been a concern with other weight-loss drugs.
“Weight-loss agents are guideline-recommended adjuncts to lifestyle modification; however, no agent has convincingly demonstrated cardiovascular safety in a rigorous cardiovascular outcomes study,” Erin Bohula, MD, DPhil, associate physician at Brigham and Women's Hospital and instructor at Harvard Medical School, said during a press conference at the European Society of Cardiology Congress. “In fact, several agents, historically, have proven to precipitate cardiovascular and psychiatric side effects and where therefore removed from the market.”
Patients enrolled had a BMI of at least 27 kg/m² (median, 35 kg/m²) and established atherosclerotic CVD or multiple CV risk factors. The median age was 64 years and 64% were men. Nearly 57% presented with diabetes and 75% established atherosclerotic CVD.
From January 2014 to November 2015, patients underwent random assignment to lorcaserin 10 mg twice daily (n = 6,000) or placebo (n = 6,000). Participation in a standardized weight-management program that included multicomponent behavioral therapy was also recommended.
At the median follow-up of 3.3 years, the primary safety outcome of major adverse CV events — a composite of CV death, MI or stroke — occurred in 6.1% of the lorcaserin group vs. 6.2% of the placebo group (HR = 0.99; 95% CI, 0.85-1.14; P < .001 for noninferiority). The annualized rate of major adverse CV events was 2% for the lorcaserin group vs. 2.1% for the placebo group, according to data presented here.
The primary efficacy outcome was a composite of CV death, MI, stroke, hospitalization for unstable angina, HF or any coronary revascularization, which occurred in 11.8% of the lorcaserin group vs. 12.1% of the placebo group (HR = 0.97; 95% CI, 0.87-1.07; P = .55 for superiority). The annualized rate of extended major CV events was 4.1% for the lorcaserin group vs. 4.2% for the placebo group.
At 1 year, the least-squares mean change in weight was –4.2 kg for the lorcaserin group vs. –1.4 kg for placebo, for a between-group difference of 2.8 kg, with weight change persisting at 40 months for both groups (between-group difference, –1.9 kg; P < .001).
Additionally, researchers found that patients assigned lorcaserin experienced a more than threefold increased odds for meeting the FDA-defined threshold of 10% weight loss from baseline at 1 year (14.6% vs. 4.8%), Bohula said. Weight loss of at least 5% occurred in 38.7% of those assigned lorcaserin vs. 17.4% of those assigned placebo (OR = 3.01; 95% CI, 2.74-3.3).
Researchers also observed small but significant improvements in in BP, heart rate, triglyceride levels and HbA1c during the course of the study, Bohula said.
The most commonly reported adverse events leading to drug discontinuation were dizziness, fatigue, headache, diarrhea and nausea. There were no between-group differences in prespecified adverse events of special interest, including malignant neoplasms, psychosis, serotonin syndrome or euphoria. Severe hypoglycemia requiring hospitalization, while rare, occurred more frequently in the lorcaserin group vs. placebo (0.2% vs. 0.1%), Bohula said; however, all but one hypoglycemic event occurred in patients with diabetes prescribed insulin or a sulfonylurea.
New-onset diabetes in patients with prediabetes at baseline was a secondary outcome of the trial. Among this group, new-onset diabetes was diagnosed in 8.5% of the lorcaserin group vs. 10.3% of the placebo group (HR = 0.81; 95% CI, 0.66-0.99).
“[Lorcaserin] was safe; it did not increase the risk of major adverse cardiac events, and there were favorable effects seen in glycemic control as well,” Bohula said.
In a dedicated echocardiographic analysis of 3,270 patients at 1 year, new or worsening FDA-defined valvulopathy was observed in 1.8% of the lorcaserin group vs. 1.3% of the placebo group (P = .24). However, the nonsignificant numerical imbalance (30 vs. 22) was due to more patients in the lorcaserin group with new-onset mild aortic-valve insufficiency, according to the researchers.
“All of these cases were asymptomatic and were found by screening,” Bohula said.
‘Cautious use is good advice for all medications’
Lorcaserin was approved in 2012 by the FDA in a landmark decision after 2 years of scrutiny. It is indicated for weight management in patients with obesity or overweight, in addition to a reduced-calorie diet and exercise.
Bohula said the findings support the role of lorcaserin as an adjunct to lifestyle modification for long-term weight management, even in patients with particularly high CV risk.
“I do think that providers may be more inclined to prescribe a weight-loss agent that has proven safety for major adverse cardiovascular events,” Bohula told Cardiology Today. “I think that cautious use is good advice for all medications.”
Treatment with the weight-loss drug lorcaserin resulted in sustained weight loss without excess risk for major adverse CV events
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In an editorial accompanying the study publication in The New England Journal of Medicine, Julie R. Ingelfinger, MD, of Tufts University School of Medicine, and Clifford J. Rosen, MD, senior scientist and director for the Center for Clinical and Translational Research at Maine Medical Center Research Institute in Scarborough, noted that lorcaserin may best be used on a “cautious basis” according to the needs of individual patients. Ingelfinger and Rosen acknowledged, however, that the side effects of lorcaserin, including headache, fatigue, dizziness, diarrhea and nausea, led to twice the number of discontinuations vs. placebo, although overall discontinuation rates were similar between groups.
“With respect to efficacy, liraglutide (Saxenda, Novo Nordisk) would provide a similar degree of weight loss but a lower risk of diabetes,” Ingelfinger and Rosen wrote. “Thus, whether this trial will lead to enhanced utilization of lorcaserin by providers is uncertain, as is the ultimate role of this drug in the treatment of patients who are overweight or obese.”
A 2015 guideline released by the Endocrine Society, cosponsored by the European Society of Endocrinology and The Obesity Society, recommends lorcaserin over sympathomimetic amines, such as phentermine and diethylpropion, in patients with CVD. However, for patients with obesity and depression on a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI), lorcaserin is not recommended due to the potential for serotonin syndrome. – by Regina Schaffer
Bohula EA. Hot Line Session 1. Presented at: European Society of Cardiology Congress; Aug. 25-29, 2018; Munich.
Bohula EA, et al. N Engl J Med. 2018; doi:10.1056/NEJMoa1808721.
Ingelfinger JR; Rosen CJ. N Engl J Med. 2018; doi:10.1056/NEJMe1810855.
Apovian CM, et al. J Clin Endocrinol Metab. 2015; doi:10.1210/jc.2014-3415.
Disclosures: The study was sponsored by Eisai. Bohula reports she has received consultant fees from Daiichi Sankyo, Lexicon, Merck, MD Conference Express and Novartis. Please see the study for a list of the other authors’ relevant financial disclosures. Ingelfinger and Rosen report no relevant financial disclosures.