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MUNICH -- Longer-term use of the weight-loss drug lorcaserin (Belviq) revealed no excess major adverse cardiovascular event risk, results of the CAMELLIA-TIMI-61 postmarketing trial found.

At a median of 3.3 years follow-up, there was no difference in major CV events -- a composite of stroke, MI, or death -- between the two study arms, occurring in 6.1% of lorcaserin-treated patients compared with 6.2% among those on placebo (HR 0.99, 95% CI 0.85-1.14, P<0.001 for non-inferiority), reported investigators led by Erin Bohula, MD, DPhil, of Brigham and Women's Hospital in Boston.

Various cardiovascular outcomes among the 12,000 randomized patients were similar across the board, with none significant: cardiovascular death (1.5% with lorcaserin vs 1.4% with placebo), MI (3.8% vs 3.8%), stroke (1.4% vs 1.6%), heart failure (2.4% vs 2.5%), unstable angina (1.5% vs 1.3%), and coronary revascularization (6.8% vs 6.9%).

A key secondary outcome was new-onset diabetes for participants with prediabetes at baseline, which at the end of trial was diagnosed in 8.5% of lorcaserin-treated patients versus 10.3% of those on placebo (HR 0.81, 95% CI 0.66-0.99).

"Lorcaserin is the first pharmacologic weight-loss agent with proven cardiovascular safety for major adverse cardiac and vascular events, supporting its role as an adjunct to lifestyle modification for long-term weight management," said Bohula during a press briefing here, "even in patients who are at particularly high cardiovascular risk."

The study was presented at the European Society of Cardiology (ESC) meeting and published simultaneously in the .

While adverse events of special interest were rare and similar between the two arms, there was a higher incidence of serious hypoglycemia among lorcaserin-treated patients -- 13 versus four cases with placebo, mostly occurring in those with diabetes at baseline (P=0.04).

There was a non-significant increase in suicidal behavior or ideation in the lorcaserin group (0.4% versus 0.2% in placebo group, P=0.08) that appeared to be tied to patients who had depression before entering the trial. There were no deaths by suicide in the trial.

And while there were imbalances in both pulmonary hypertension (1.6% vs 1.0%) and FDA-defined valvulopathy (1.8% versus 1.3%) -- both numerically higher with lorcaserin -- the findings were not significant.

"Clinical experience with the first generation of anti-obesity drugs was not encouraging, despite successful weight loss, because of side effects, both on and off target," wrote Julie R. Ingelfinger, MD, of Tufts University School of Medicine in Boston, and Clifford J. Rosen, MD, of the Maine Medical Center Research Institute in Scarborough, in an . "In particular, agents with a serotonin-agonist mechanism of action, such as dexfenfluramine and fenfluramine, stimulated 5-hydroxytryptamine 2B (5-HT2B) serotonin receptors, which led to pulmonary hypertension and heart-valve problems."

In September 1997, the FDA pulled fenfluramine-phentermine, "Fen-Phen," from the market, roughly 6 months after its approval due to increased risk of symptomatic valvular heart disease. From 1999 to 2012, the agency blocked all weight-loss drugs from hitting the market.

In 2010, sibutramine (Meridia) was also pulled from the market due to an increase in the risk of stroke and MI. But an industry push starting that same year -- which included over $60 million in lobbying -- helped open the doors for new weight-loss drugs, and for some that had previously been rejected by the FDA. In 2012, lorcaserin became the first FDA-approved drug for weight-loss in over a decade. As lorcaserin binds to 5-HT2C receptors, concern remained over its cardiovascular safety.

"The use in general of weight-loss agents is fairly low in the U.S., and I think that speaks to the historical experience with weight-loss agents," said Bohula. "I suspect there may be physicians and patients who are more inclined to use this pharmacologic agent going forward, in light of the safety profile."

Session discussant Peter Nilsson, MD, PhD, of Lund University in Sweden, praised the trial's step-wise approach to cardiovascular safety outcomes -- non-inferiority followed by superiority testing. Lorcaserin failed to show superiority (HR 0.97, 95% CI 0.87-1.07, P=0.55).

But, he said, "the background medication was very fuddled -- 85% were on statin treatment. Whatever you add on top of background treatment versus placebo is difficult when the standard treatment is so effective in itself."

Nilsson also cautioned that with only 13.2% of the patients having a BMI <30, the study really only examined cardiovascular safety in obese patients. "This means that the overweight question was not so much addressed," he said.

From 2014 to 2015, the CAMELLIA-TIMI 61 trial recruited and randomized patients who were overweight or obese to either 10-mg twice daily lorcaserin or placebo. All patients in the trial also had access to a weight-management program and unlimited telephone access with a dietitian.

In terms of weight control, treatment with lorcaserin resulted in ≥5% weight loss in 38.7% of lorcaserin-treated patients compared with 17.4% of those who received placebo (OR 3.01, 95% CI, 2.74-3.30, P<0.001). And ≥10% weight loss occurred in 14.6% of lorcaserin-treated patients compared with 4.8% of those on placebo (P<0.001).

In their editorial, however, Ingelfinger and Rosen expressed skepticism about the drug's wider use. "With respect to efficacy, liraglutide would provide a similar degree of weight loss but a lower risk of diabetes," they noted. "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."

At the end of the study period, the between-group difference in weight loss was just 1.9 kg (4.2 lb) in favor of lorcaserin, highlighted Nilsson.

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