More CAMELLIA: Obesity Drug Lorcaserin May Avert Diabetes

Miriam E. Tucker

October 05, 2018

BERLIN — The weight-loss drug lorcaserin (Belviq, Eisai) improved blood glucose levels among overweight and obese patients at high cardiovascular risk, new data show. 

The findings, from a subanalysis of the CAMELLIA-TIMI 61 trial, were presented October 4 here at the European Association for the Study of Diabetes (EASD) 2018 Annual Meeting and simultaneously published in The Lancet.

The primary results of CAMELLIA-TIMI 61 were presented in August 2018 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, lorcaserin produced modest weight loss compared with placebo and did not raise the risk for major adverse cardiovascular events in the trial, although it didn't reduce them.

CAMELLIA-TIMI 61 lasted a median of 3.3 years and involved 12,000 overweight and obese individuals with atherosclerotic cardiovascular disease or multiple cardiovascular risk factors. Overall, 57% of patients had type 2 diabetes, 33% had prediabetes, and the remaining 10% had normal blood glucose levels.

At EASD, new data for prespecified metabolic efficacy and safety outcomes were presented by study coauthor Benjamin M. Scirica, MD, associate professor of medicine, Brigham and Women's Hospital, Boston, Massachusetts.

Overall, lorcaserin produced modest but sustained weight loss among patients with diabetes, prediabetes, and normoglycemia, decreased incident diabetes among those with prediabetes or no diabetes at baseline, and improved glycemia among those with diabetes or prediabetes at baseline.

"Taken together, these findings reinforce the notion that modest, durable weight loss can improve cardiometabolic health and supports the role of lorcaserin as an adjunct to lifestyle modification for chronic management of weight and metabolic health," Scirica said.

Although the glycemic benefit of lorcaserin is believed to be primarily because of weight loss, preclinical data suggest that lorcaserin may also downregulate hepatic gluconeogenesis via agonism of the 5-HT2C receptor, although "it's very hard to disentangle that," Sciricasaid in response to an audience member's question.

The US Food and Drug Administration approved lorcaserin 10 mg twice daily in 2012. In 2016, the agency approved an extended-release 20-mg once-daily dosing option of lorcaserin (Belviq XR). Lorcaserin has not, to date, been approved in the European Union, however.

Competitors Have Advantages

Naveed Sattar, MD, professor of metabolic medicine at the University of Glasgow, UK, who was the commentator for the study at EASD, called it "fantastically well-conducted," and noted that "there is absolutely a need for safe and effective obesity drugs."

However, he also noted that although there were no major safety issues in the study, there were increases in dizziness, headaches, and fatigue with lorcaserin. "I would like to see a bit more safety data," he said.

Sattar also questioned what role lorcaserin would play in clinical management of diabetes and prediabetes, considering that "competitors have advantages." And he pointed out that "we're getting better at lifestyle modification," which has been shown to dramatically reduce the incidence of type 2 diabetes among people at risk.

Moreover, cheaper drugs such as orlistat and metformin also produce weight loss, and the newer type 2 diabetes medications, SGLT2 inhibitors and GLP-1 receptor agonists, aren't cheap, but do reduce weight and provide cardiovascular benefit. And, he noted, bariatric surgery is also a weight-loss option that has been shown to improve glycemia.

"My gut feeling is that the clinical role for lorcaserin is probably at best a down-the-line adjunct in some who are still obese, for additional weight reduction on top of other drugs and lifestyle, maybe particularly for those who are super responders," Sattar said.   

In an accompanying editorial, Xabier Unamuno, MSc, and Gema Frühbeck, MD, of the Department of Endocrinology and Nutrition, Clínica Universidad de Navarra, Pamplona, Spain, say that the mechanism of action of lorcaserin indicates it "might be particularly useful in patients who turn to food to satisfy emotional needs rather than hunger (ie, emotional eaters)."

And they agree that physicians might be "uncomfortable prescribing lorcaserin on a general basis and might instead prefer to prescribe it on a temporary basis (ie, for 6 to 12 months). Patients who respond well and for whom treatment should be continued could be identified within the first few months of treatment."

Glycemic Benefit Seen in Those With and Without Diabetes

CAMELLIA-TIMI 61 was a randomized, double-blind, placebo-controlled trial conducted at 473 sites in eight countries. The total 12,000 patients enrolled were aged 40 years or older, had a body mass index of 27 kg/m2 or greater, and had or were at high risk for atherosclerotic vascular disease.

At baseline, 56.8% of the patients had diabetes, 33.3% had prediabetes, and 9.9% were normoglycemic.

Participants were randomly assigned to lorcaserin 10 mg twice daily or placebo, and also had access to a lifestyle modification program for weight management.  

Over an average 3.3 years' follow-up, lorcaserin reduced incident diabetes by 19% among those with prediabetes at baseline (hazard ratio, 0.81; P = .038). Among all patients without diabetes — prediabetes and normoglycemia — the reduction was 23%.

At 1 year, the net weight loss was significantly greater with lorcaserin compared with placebo in each subgroup: -2.6 kg (5.7 lb) for those with diabetes, -2.8 kg for the prediabetes group, and -3.3 kg for those with normoglycemia.  

HbA1c at 1 year was reduced by 0.33 percentage points among those with diabetes (P < .0001) and by 0.09 and 0.08 percentage points among those with prediabetes and normoglycemia, respectively (both P < .0001).

The between-treatment difference in HbA1c remained significant through at least 3 years among all three groups, although it did trend upward with time.   

Patients who took lorcaserin also used less glucose-lowering medication compared with the placebo group and were less likely to initiate a new glucose-lowering drug at 1 year (13.1% versus 20.1%; P < .0001). And more patients with diabetes discontinued glucose-lowering medications at 1 year compared with placebo (10.1% vs 7.9%; P = .0045). 

Severe hypoglycemia, occurring primarily among those taking insulin, was rare but occurred more often among those taking lorcaserin, in 12 patients (0.4%), than placebo, in four patients (0.1%) (P = .054). None of the hypoglycemic episodes were fatal.   

Data on renal outcomes in CAMELLIA-TIMI 61 will be presented at the American Heart Association meeting in November 2018, Scirica said.

The study was funded by Eisai. Scirica reports receiving grants from Eisai during the conduct of the study and from AstraZeneca, Novartis, and Merck; personal fees from AstraZeneca, Biogen Idec, Boehringer Ingelheim, Covance, Dr Reddy's Laboratory, Eisai, Elsevier Practice Update Cardiology, GlaxoSmithKline, Merck, Novo Nordisk, Sanofi, and St Jude Medical. Sattar is on the advisory board and/or is a speaker for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi. He has also received grants from Boehringer Ingelheim. Disclosures for the other authors are listed in the article.

European Association for the Study of Diabetes (EASD) 2018 Annual Meeting; October 4, 2018; Berlin, Germany.

Lancet. Published online October 4, 2018. Abstract, Editorial

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