MUNICH — Full details of the CAMELLIA-TIMI 61 cardiovascular outcomes study with the obesity drug lorcaserin (Belviq, Eisai) have been reported here at the European Society of Cardiology (ESC) 2018 Congress and simultaneously published in the New England Journal of Medicine.
Added to a background of diet and exercise, the drug led to modest weight loss compared with placebo and did not increase the risk for major adverse cardiovascular events (MACE) in the trial, which lasted a median of 3.3 years, in 12,000 overweight and obese patients with established cardiovascular disease, type 2 diabetes, or cardiovascular risk factors.
“It was safe; this is the first time, in a rigorous outcome study, that we’ve been able to demonstrate cardiovascular safety…for a pharmacologic weight loss agent,” said lead author, Erin A. Bohula, from the Brigham and Women’s Hospital, Boston, Massachusetts, presenting the findings during a press briefing.
This supports the role of lorcaserin “as an adjunct to lifestyle modification for long-term weight management even in patients at high cardiovascular risk,” she observed.
Of interest, the rate of new-onset diabetes was 19% lower in the active treatment group than in the placebo group among those who had prediabetes at baseline (around a third of the study population). Bohula said, “We are not sure if this is just due to weight loss” or whether there are other metabolic effects of lorcaserin. Full details of these aspects of the trial will be reported at the European Association for the Study of Diabetes (EASD) meeting in Berlin on October 4, she said.
Bohula admitted during questions after her presentation at the hotline session that the team was a little disappointed not to have seen cardiovascular benefit with lorcaserin. Given the net weight loss of 2.8kg with lorcaserin compared with placebo at 1 year in the trial, “we had hoped we would see efficacy,” she said.
Yet she stressed that while “Diet and exercise are still the cornerstones for weight loss,” obesity agents “are guideline-recommended adjuncts to lifestyle.”
And although weight loss with this agent is admittedly only “modest,” lorcaserin did more than triple the odds of achieving either a 5% or greater or a 10% or greater weight loss, and the effects were sustained throughout the 3 years of the study. This is “novel,” so overall this drug “does move the needle to some extent,” she indicated.
Use of Weight Loss Agents Low in General; Will This Now Change?
As background, Bohula explained to assembled journalists that the use, in general, of weight loss agents “is fairly low, given the history [of withdrawal from the market of a number of obesity drugs] so this is a “challenging” field, with much reluctance on the part of physicians to prescribe these drugs.
Indeed, in a poll conducted before her hotline session, only 14% of the audience said they “do include drug treatment to achieve weight reduction in…patients with obesity in some situations,” and a further 4% said they “frequently” did this.
Now that safety in terms of cardiovascular events is proven, this should encourage more physicians and patients to want to use lorcaserin going forward, Bohula said.
After her presentation, 26% of respondents at ESC said they “would consider to more frequently use medical treatment for weight loss,” while 41% said the CAMELLIA-TIMI 61 results still wouldn’t encourage them to use obesity drugs more and 33% said “more data” are needed.
Discussant of the trial, Peter M. Nilsson, MD, PhD, from Lund University, Malmö, Sweden, wasn’t certain himself. He said CAMELLIA-TIMI 61 is an “impressive” trial and provides “much needed safety data” on an antiobesity drug.
And yet, although safety “is nice, we need something more.” He likened the results to those “of the story of the DPP-4 [dipeptidyl peptidase-4] inhibitors” in type 2 diabetes, which, although effective and safe, for the most part have failed to show cardiovascular benefit.
And in an editorial accompanying the published report, Julie R. Ingelfinger, MD, and Clifford J. Rosen, MD, are also circumspect: “Whether this trial will lead to enhanced utilization of lorcaserin by providers is uncertain,” they write, “as is the ultimate role of this drug in the treatment of patients who are overweight or obese.”
There was also a question during the press briefing as to why someone would prescribe a weight loss agent with no proven cardiovascular benefit over and above one which is likely to have some efficacy in this regard, for example, the glucagon-like peptide-1 agonist liraglutide (Novo Nordisk).
The lower dose of liraglutide approved for type 2 diabetes, marketed as Victoza, significantly reduced the rate of major cardiovascular adverse events in the LEADER trial, and a higher 3-mg dose has now been approved in the United States and Europe as Saxenda for obesity. Importantly, cardiovascular risk reduction has been added to the label for Victoza in the United States and to the labels of both Victoza and Saxenda in the European Union.
Is Lorcaserin Different From Older Serotonin Agonists?
The older obesity drugs that were withdrawn from the market, dexfenfluramine and fenfluramine, caused relatively rapid development of symptomatic valvular heart disease and pulmonary hypertension.
These drugs were serotonin receptor (5HT-2B) receptor agonists, whereas lorcaserin, as a selective agonist of the 5HT-2C receptor, “does not alter the release or metabolism of serotonin,” Bohula and her coauthors explain in their paper. Instead, it suppresses appetite by hypothalamic activation of the pro-opiomelanocortin (POMC) pathway.
With respect to any effects on the heart valve, the story with lorcaserin “seems very different” from what was seen with prior obesity agents, Bohula noted.
She stressed that in the overall study population of 12,000 in CAMELLIA-TIMI-61, followed for a median of 3.3 years, there was no imbalance in cases of symptomatic valvular heart disease of any type — with 58 patients in the lorcaserin group and 64 in the placebo group affected. And in terms of incident pulmonary hypertension, all but 4 patients (2 in the lorcaserin group and 2 in the placebo group) were asymptomatic.
And in an echocardiographic substudy performed at 1 year, there were numerically higher numbers of patients with US Food and Drug Administration (FDA)–defined heart valvulopathy 30 of 1624 patients (1.8%) in the lorcaserin group vs 22 of 1646 (1.3%) in the placebo group, but this difference was not significant (P = .024), “and none of the patients with valvulopathy were symptomatic, were hospitalized or required valve replacement or repair.”
In contrast, with dexfenfluramine and fenfluramine, “patients tended to present by a year with symptomatic valvular disease,” she said.
E. Magnus Ohman, MD, associate director of the Duke Heart Center at Duke University Medical Center, Durham, North Carolina, who was chair of the independent data monitoring committee for CAMELLIA-TIMI-61, told theheart.org | Medscape Cardiology: “The fact that nobody developed severe valvulopathy was encouraging.”
Also of importance, rates of any cancer did not differ between lorcaserin and placebo in the CAMELLIA-TIMI-61 study. Concern about tumors in animal models was one of the reasons that regulators in Europe declined to approve lorcaserin there some years back.
“We did not see any difference in rates of malignant neoplasms between the two treatment groups,” observed Bohula.
Lorcaserin: Sustained Weight Loss Without Higher MACE
Lorcaserin has been on the market in the United States since 2012, as a 10-mg twice-daily agent for weight loss. In 2016, an extended-release once-daily 20-mg dosing option (Belviq XR) was also approved.
Despite safety concerns about the drug, the FDA decided to allow use of lorcaserin, pending results of a postmarketing study. Indeed, the agency is now requiring cardiovascular outcomes trials for all obesity drugs, similar to the requirement for type 2 diabetes drugs.
In the trial, 12,000 patients with a median baseline body mass index of 35 mg/kg2 and existing cardiovascular disease or multiple cardiovascular risk factors (one of which could be type 2 diabetes) were randomly assigned, on top of diet and exercise, to lorcaserin 10 mg twice daily, or placebo, for a median of 3.3 years.
Patients in the active treatment group (n = 6000) lost an average of 4.2 kg after 1 year, compared with a 1.4-kg loss in the placebo group (n = 6000), for a between-group difference of –2.8 kg (P < .001).
At 1 year, weight loss of at least 5% had occurred in 38.7% of the lorcaserin group compared with 17.4% among placebo patients (odds ratio, 3.01; P < .001).
And as already explained by Bohula, the weight loss with lorcaserin, while largest at 1 year compared with placebo, was sustained so that the difference between the groups remained significant out to 3.3 years, with a between-group difference of –1.9kg in favor of lorcaserin at that time point.
There was no difference in the primary safety outcome of MACE (a composite of cardiovascular death, myocardial infarction, or stroke) between groups: 2.0% in the lorcaserin group at 3.3 years compared with 2.1% in the placebo patients (hazard ratio, 0.99).
The was also no difference in the primary efficacy endpoint, the secondary extended outcome, a composite of MACE, heart failure, hospitalization for unstable angina, or coronary revascularization: 4.1% with lorcaserin vs 4.2% per year, respectively (hazard ratio, 0.97).
Adverse events that were thought by the investigators to be possible related to the study drug and that lead to discontinuation were twice as common in the lorcaserin group (7.2%) as in the placebo group (3.7%) and were most commonly dizziness, fatigue, headache, diarrhea, and nausea.
In conclusion, say the authors, among overweight or obese patients with atherosclerotic cardiovascular disease, or multiple cardiovascular risk factors, “those who received lorcaserin had better long-term rates of weight loss than those who received placebo and the higher weight loss rates were achieved without an accompanying increase in the risk of CV events.”
And yet Ingelfinger and Rosen still wonder: “Will lorcaserin prove to be helpful over the long haul?”
“It would appear that long-term data remain very important with regard to cardiovascular safety, given that the use of lorcaserin is likely to extend for years to maintain weight loss.
“For now the drug may be best used on a cautious basis according to the needs of individual patients,” they conclude.
The study was supported by Eisai. Bohula reports grants from Eisai, during the conduct of the study; personal fees from Servier, personal fees from Merck, personal fees from the National Institutes of Health, personal fees from Lexicon, personal fees from Medscape, personal fees from Academic CME, personal fees from MD Conference Express, personal fees from Paradigm, personal fees from Novartis, grants from Amgen, grants from Astra Zeneca, grants from Merck, outside the submitted work. Disclosures for other authors appear online in the New England Journal of Medicine. J Ohman Nilsson has disclosed no relevant financial relationships.
European Society of Cardiology (ESC) 2018 Congress. Presented August 26, 2018.