Whether the data are enough to change hearts and minds of doctors willing to prescribe the drug for modest weight loss is another question, however.

MUNICH, Germany—A drug already approved in the United States for weight loss in overweight and obese patients does not increase the risk of cardiovascular events, according to the results of a large safety study.

Importantly, in a subset of patients who underwent echocardiographic follow-up, CAMELLIA-TIMI 61 investigators did not observe any of the valve problems that have plagued anti-obesity agents in the past.

“The history with weight-loss agents has been very challenging,” lead investigator Erin Bohula, MD, DPhil (Brigham and Women’s Hospital, Boston, MA). “There have been a number approved for use and then found to have major safety signals and removed. And obesity is clearly a global problem—the rates overall have tripled in the last 40 years. In the US, for example, obesity rates are around 40% so it is a major problem. This is the first time in a rigorous outcomes study we’ve been able to document cardiovascular safety, and for that reason I think it is a milestone and it’s important for patients and providers.”

Presenting the results during a press conference at the European Society of Cardiology Congress 2018, Bohula said lifestyle modification remains the cornerstone of weight-loss therapy for all patients, but adherence is challenging. Having a safe pharmacologic agent is useful and a “step forward” in the field, she said.

Lorcaserin (Belviq, Eisai/Arena Pharmaceuticals), a selective agonist of 5-hydroxytryptamine 2C serotonin receptor (5-HT2C) that modulates appetite, was approved by the US Food and Drug Administration (FDA) in 2012 as an adjunct to a calorie-reduced diet and increased physical activity for weight management. In several trials to date—BLOSSOM, BLOOM, and BLOOM-Diabetes Mellitus—treatment with lorcaserin resulted in better sustained weight loss compared with placebo.

However, given the history of weight-loss drugs, particularly first-generation antiobesity agents such as dexfenfluramine and fenfluramine that increased the risk of pulmonary hypertension and valve problems, determining the long-term safety of lorcaserin was critical, according to investigators.

Other weight-loss agents have faced setbacks, too. Rimonabant was safe from a cardiovascular perspective, but was pulled from several markets, including Europe, because of serious neuropsychiatric side effects (it was never approved in the US), while a cardiovascular safety study testing a naltrexone/bupropion combination (Contrave, Takeda Pharmaceuticals), broke down over leaked interim results, although the drug remains on the market.

Modest Weight Loss With Lorcaserin

In the CAMELLIA-TIMI 61 study, which was presented as a late-breaking clinical trial and published August 26, 2018, in the New England Journal of Medicine, investigators randomized 12,000 overweight or obese patients with atherosclerotic cardiovascular disease or multiple cardiovascular risk factors to treatment with lorcaserin or placebo. Among the treated patients, 75% had established cardiovascular disease, 68% had coronary artery disease, and 40% had a prior MI. Additionally, 57% had diabetes mellitus, and nearly one-third were diagnosed with prediabetes.

The median weight and body mass index of the treated patients was 102 kg (224 lbs) and 35 kg/m2, respectively. After 1 year, weight loss in the lorcaserin- and placebo-treatment groups was 4.2 and 1.4 kg, respectively (P < 0.001). Overall, 38.7% and 14.6% of the lorcaserin-treated patients achieved a weight loss of at least 5% and 10% of their body weight, respectively, compared with 17.4% and 4.8% of patients in the placebo group, (P < 0.001 for both).

After 3.3 years of follow-up, major cardiovascular events—defined as cardiovascular death, MI, or stroke—occurred in 6.1% of the lorcaserin-treated patients and 6.2% of patients treated with placebo (HR 0.99; 95% CI 0.85-1.14). In an extended analysis of major cardiovascular events to include heart failure, unstable angina, or coronary revascularization, there was also no significant difference between the two treatment groups. Patients treated with lorcaserin were more likely to discontinue treatment, mainly because of headaches and nausea. There was no signal of cancer or serious neuropsychiatric side effects.

As part of the trial, investigators conducted an echocardiographic substudy in 3,270 patients to assess new or worsening FDA-defined valvulopathy at 1 year. Overall, there was no difference between the two study arms (1.8% with lorcaserin vs 1.3% in the placebo group; P = 0.24). None of the patients with valvulopathy were hospitalized or required treatment. The change in pulmonary artery systolic blood pressure at 1 year was also similar between the two groups.

To TCTMD, Bohula said that none of the 30 patients who developed valvulopathy in the study period with lorcaserin had symptoms or required valve repair or replacement. Moreover, the numerical increase in the lorcaserin arm was largely attributable to new-onset, mild aortic insufficiency. When compared with historical experience, Bohula said the development of symptomatic valve problems with prior agents typically occurred in the first year of treatment.

“At least the severity of what we’re seeing does not seem to correspond with what we’ve seen with the prior agents,” said Bohula.

Although the results are reassuring, Stephan Achenbach, MD (University of Erlangen, Germany), who chaired the press conference, said physicians have been burned by weight-loss agents in the past. Physicians don’t even know the details of the older trials, but the image of damaged valves is firmly lodged in their memory. “We’re so scared of the old drugs and valve damage,” he told TCTMD. “That’s what we all have in our minds. . . . So this is a relief. This is a drug that is safe.”

Kurt Huber, MD (Sigmund Freud University Medical School, Vienna, Austria), who was not involved in the study, also said the results are reassuring, but questioned whether the follow-up is sufficient to identify long-term side effects, particularly valve-related problems. “It’s safe for a bit more than 3 years,” he told TCTMD, “but what happens when we double the length of treatment?”

In an editorial, Julie Ingelfinger, MD, and Clifford Rosen, MD (Tufts University School of Medicine, Boston, MA), state that lorcaserin may be best used on a cautious basis according to the needs of individual patients. They advise continued follow-up, particularly since the drug is likely to be used for many years to maintain weight loss.

Potential Clinical Experiences

Speaking with the media, Bohula acknowledged that weight loss with lorcaserin is limited, especially when compared with bariatric surgery. In the first year, the between-group weight-loss difference was just 2.8 kg, but it was sustained during the 3.3 years follow-up. Trials to date with other weight-loss agents have only followed patients for 1 to 2 years, she said.

“It is modest, but it is something on top of diet and lifestyle, and it’s sustainable,” said Bohula. “And that’s the challenge—very often diet and lifestyle is not sustainable. We usually see some nadir in weight at 6 months and then people tend to regain [weight], and possibly regain [more] from where they started out. So something that helps maintain that weight loss for a longer period of time is something that moves the needle.”

To TCTMD, Huber cautioned that the modest weight loss was largely observed in the first year and the clinical significance of the change is unknown. “The drug supports things, but it doesn’t really help to lose weight in the range that is necessary,” said Huber. Lifestyle, he suggested, really needs to be altered for significant weight loss so a drug that helps patients lose weight in the first year could help patients get more active to make more sustained long-term changes. “Whether you should take it for a very long time is another question,” he said.

For Achenbach, it was slightly disappointing that treatment with lorcaserin didn’t lower the risk of cardiovascular events given the weight loss. “Is this a cosmetic drug now? It makes you thinner, but it doesn’t lower your risk of heart attack,” he commented to TCTMD. “Maybe we need to wait longer? Maybe the positive cardiovascular effects won’t occur in 3 years, but maybe they’ll take 5 or 10 years before they occur.”

Based on CAMELLIA-TIMI 61, Achenbach said he is comfortable enough with the safety data to keep a patient on lorcaserin if they were taking it, but he wouldn’t start a patient on the drug given the modest weight loss and absence of cardiovascular benefit. In addition to weight loss, Bohula noted there were improvements in systolic blood pressure, heart rate, and a 19% reduction in new-onset diabetes. The full metabolic data will be presented next month at the European Association for the Study of Diabetes (EASD) meeting in Berlin, Germany.

In the United States, weight-loss agents, including lorcaserin, are used infrequently, largely stemming from the poor safety profiles and/or lack of data. Without evidence of safety, physicians are reluctant to prescribe the drugs—they know the history and it scares them, said Bohula—and patients are reluctant to take them.

“I think these are important findings, where we can now confidently say that [lorcaserin] is safe in terms of major adverse cardiovascular events,” said Bohula. “I suspect there might be physicians and patients who are more inclined to use this pharmacologic agent going forward.”