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No excess CV risk with lorcaserin for weight loss
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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.”
CV outcomes
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.
Weight loss
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).
Other findings
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.”
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
References:
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.
Perspective
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Caroline M. Apovian, MD
This study showed that 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. The Obesity Society and the American Medical Association have proclaimed obesity to be a disease and not a matter of willpower. Lorcaserin and the GLP-1 agonist liraglutide have now be shown to be safe in those with CVD risk, In the case of liraglutide, in a CV outcomes trial, the dose for type 2 diabetes had been shown to reduce risk as compared with placebo.
Lorcaserin and liraglutide 3 mg for obesity have seen limited usage in the United States for obesity treatment, chiefly because of lack of insurance coverage. Since this new study highlights both the safety and efficacy of long-term use of lorcaserin in those who suffer from obesity and CVD risk, efforts should be heightened to secure insurance coverage and allow more of the population suffering from obesity to obtain access to this and other drugs for obesity.
Director, Nutrition and Weight Management Center, Boston Medical Center
Perspective
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Ken Fujioka, MD
In simple terms, this means that lorcaserin is as safe as giving a placebo to high-risk CV patients trying to lose weight.
It may be hard for some readers to be comfortable with the small amount of weight loss. It needs to be remembered this study was designed for safety and not for weight loss. In addition, patients with (57% of the patients enrolled) always seem to lose less weight, and the patients were on beta-blockers which significantly slow metabolic rate and weight loss.
This study is unique and important for a number of reasons. The patient population had very serious CVD. The study population was also older and over half were men. These are patient populations that are very rarely studied and to show safety in these groups is important as the world’s population begins to shift to a much older population. Another unique group of patients that were allowed into the group were patients on depression medications from the serotonin reuptake inhibitor (SSRI) class. Many patients who struggle with weight management are on SSRIs and, until now, it has not been known whether it would be safe to use lorcaserin in this group. Serotonin syndrome was an adverse event of special interest and no increase in this adverse event was noted. This opens up a large number of patients who could potentially benefit from this medication.
Lastly, the study underlines the importance of adjusting down insulin and sulfonylureas in diabetics trying to lose weight. Although rare, a statistical difference in serious hypoglycemia was observed in patients taking lorcaserin relative to placebo. Weight loss is a great treatment for lowering elevated blood sugars. It has also been proposed that lorcaserin may have its own beneficial effect on blood sugars. It is important to adjust down these medications when a patient has good glycemic control and starts weight loss.
Director of the Nutrition and Metabolic Research Center
Scripps Clinic, Department of Diabetes and Endocrine
San Diego, California
Perspective
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Scott Kahan, MD, MPH, FTOS
Over the past two decades, the FDA has progressively strengthened its requirements for approval of obesity and diabetes medications. Notably, in 2010, FDA denied approval to three new obesity medications — one of which was lorcaserin — and shortly thereafter began requiring long-term outcomes trials to rule out excess CV risk for all new medications. Lorcaserin, a selective serotonin-2c receptor agonist, was approved in mid-2012 with requirement for a long-term postmarketing study, despite its favorable impact on CV intermediate endpoints. Six years later, the results of this study are now published, showing that lorcaserin does not increase CV risk.
The CAMELLIA-TIMI 61 trial randomized 12,000 individuals who had existing CVD or who were at high CV risk to either lorcaserin or placebo. The primary outcome was a composite of major CV events, HF, hospitalization for unstable angina or coronary revascularization. After a median follow-up of 3.3 years, there was no difference in CV events between the groups, supporting the long-term safety of lorcaserin for the treatment of obesity. Additionally, there was no statistical increase in risk for valvulopathy or pulmonary hypertension, conditions with an incidence that was increased by prior serotonergic agents for obesity. The rates of serious adverse events and premature discontinuation of was statistically identical between lorcaserin and placebo, countering the common assumption that obesity medications are poorly tolerated. In addition to three-times-greater odds of losing at least 5% and 10% of starting weight in individuals assigned to lorcaserin, compared with placebo, there was slight improvements in most CV risk factors and significantly decreased risk for developing diabetes.
Perhaps most importantly, this result may start to moderate the overwhelming beliefs — rooted in several older medications taken off the market for safety concerns — that obesity medications are inherently unsafe.
Medical Director, S.T.O.P. Obesity Alliance
George Washington University Milken Institute School of Public Health
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