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Lorcaserin reduces diabetes progression in high-risk adults with obesity, CVD
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Adults with obesity, prediabetes and established cardiovascular disease randomly assigned to the serotonin receptor agonist lorcaserin were less likely to progress to overt type 2 diabetes over 3 years and more likely to revert to normoglycemia compared with similar patients assigned to placebo, according to findings published in The Lancet and presented at the European Association for the Study of Diabetes annual meeting.
The metabolic findings from CAMELLIA-TIMI 61, a randomized, double-blind, placebo-controlled trial of more than 12,000 patients in eight countries, also demonstrated that participants with type 2 diabetes and CVD assigned to lorcaserin (Belviq, Eisai) were 21% less likely to develop a composite of microvascular events, including incident microalbuminuria, diabetic retinopathy or neuropathy.
The analysis follows CV safety findings for lorcaserin presented at the European Society of Cardiology Congress in August and reported by Healio.com, which demonstrated sustained weight loss without excess risk for major adverse CV events in patients assigned the drug vs. those assigned to placebo.
“The analyses presented today and published in The Lancet add to the prior work by demonstrating the consistency of benefit with lorcaserin for glucose control across the populations of patients studied, including those at risk for diabetes and those with established diabetes,” Erin Bohula, MD, DPhil, associate physician at Brigham and Women's Hospital and instructor at Harvard Medical School, told Endocrine Today after a presentation on the findings. “In patients at risk for diabetes, we saw a 19% to 23% reduction in the development of diabetes with lorcaserin compared with placebo. In patients with established diabetes at baseline, we saw an improvement in glycemic control as determined by reductions in HbA1c, increased rates of remission of high glucose (in the absence of glucose-lowering medications) and a reduction in microvascular complications of diabetes, including less kidney impairment (as assessed by microalbuminuria).”
Risk for incident diabetes
Patients enrolled in the study had a BMI of at least 27 kg/m² (median, 35 kg/m²; median age, 64 years; 64% men) and established atherosclerotic CVD or multiple CV risk factors. At baseline, 56.8% of patients had diabetes, 33.3% had prediabetes and 9.9% had normoglycemia.
From February 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. Primary metabolic efficacy endpoint of time to incident diabetes was assessed in patients with prediabetes at baseline. Prespecified secondary outcomes for efficacy included incident diabetes in all patients without diabetes, achievement of normoglycemia in patients with prediabetes and change in HbA1c in patients with diabetes.
Median follow-up time for the cohort was 3.3 years.
At 1 year, researchers found that lorcaserin reduced risk for incident diabetes by 19% in patients with prediabetes (HR = 0.81; 95% CI, 0.66-0.99) and by 23% in patients without diabetes at baseline (HR = 0.77; 95% CI, 0.63-0.94). Additionally, there was a nonsignificant increase in the rate of achievement of normoglycemia among patients with prediabetes assigned to lorcaserin vs. those assigned placebo (HR = 1.2; 95% CI, 0.97-1.49).
Patients assigned lorcaserin also experienced a mean 0.33% reduction HbA1c at 1 year vs. those assigned to placebo, from a mean baseline HbA1c of 7% (P < .0001), according to researchers. Between-treatment differences in HbA1c persisted through 36 months in all groups despite upward trends in HbA1c over time.
Incidence of hypoglycemia with serious complications were rare but occurred more in the lorcaserin group vs. placebo (12 vs. 4).
“It is interesting to note that the CAMELLIA-TIMI 61 trial, as a study of safety, instructed patients to continue therapy regardless of weight loss,” Bohula said. “In that context, we observed a modest but durable weight loss in all glycemic subgroups (ie, patients with and without diabetes). It is notable that even modest weight loss that is sustained over time can lead to an improvement in metabolic health, including glycemic control.”
Effects may seem moderate
In commentary published in The Lancet accompanying the study, Xabier Unamuno, MSc, and Gema Frühbeck, MD, PHD, RNutr, both of the Metabolic Research Laboratory at the University of Navarra in Pamplona, Spain, wrote that the study findings, namely the magnitude of effect of lorcaserin across stratified glycemic groups, were “somewhat puzzling” from an endocrinologist’s point of view.
“For some physicians, the overall magnitude of the effects of lorcaserin might seem moderate; the resulting weight loss might be disappointing, especially if it does not lower the risk of cardiovascular disease, and evidence exists that effective weight management delivered in the primary care setting can produce sustained remission in type 2 diabetes,” Unamuno and Frühbeck wrote. “Physicians might be uncomfortable prescribing lorcaserin on a general basis and might, instead, prefer to prescribe it on a temporary basis.”
Bohula said the findings suggest that weight loss, regardless of magnitude, can be beneficial for patients with obesity.
“The key is to find safe strategies,” Bohula told Endocrine Today. “This study offers clinicians another option to add to diet and exercise that is safe from the perspective of major adverse CV events and improves metabolic health.” – by Regina Schaffer
Reference s :
Bohula EA. Oral presentation S33.4. Presented at: European Association for the Study of Diabetes Annual Meeting; Oct. 1-5, 2018; Berlin.
Bohula EA, et al. Lancet. 2018;doi:10.1016/s0140-6736(18)32328-6.
Unamuno X, et al. Lancet. 2018;doi:10.1016/s0140-6736(18)32460-7.
For more information:
Erin Bohula, MD, DPhil, can be reached at Brigham and Women’s Hospital, Cardiovascular Division, 75 Francis St., Boston, MA 02115; email: ebohula11@bwh.harvard.edu.
Disclosures: Eisai sponsored the study. Bohula reports she has received grants from Eisai and personal fees from Lexicon, Merck, Novartis and Paradigm and grants from Amgen, AstraZeneca and Merck. Unamuno and Frühbeck report receiving grants from the Spanish Health Institute ISCII, Fondos FEDER and Ciberobn. Please see the study for the other authors’ relevant financial disclosures.
Perspective
Back to TopKen Fujioka, MD
The finding that putting people with prediabetes on the weight-loss medication lorcaserin resulted in a decrease in the progression to type 2 diabetes comes as no surprise. Many studies, including the classic Diabetes Prevention Program trial, have shown that weight loss will decrease the number of patients converting from prediabetes to overt type 2 diabetes.
What makes this study unique is that the progression to diabetes was reduced in very high-risk patients. These were patients with known coronary artery disease (> 90%), hypertension (> 86%) and elevated lipids (> 90%), with an average age of close to 65 years. To show an improvement in this group is impressive. This will be important as the demographics of the world change with our aging population.
Another more fascinating finding was that weight loss in patients with diabetes on antidiabetic medications can be substantial. The reason I say this is that, for many years, diabetologists and obesity experts have noted that people with diabetes have a harder time losing weight. This was not seen in this study. If one looks closely at the weight-loss curves of participants with diabetes compared with those without diabetes, one sees more weight loss among those with diabetes. This is the first time I have ever seen this in a well-designed study. What is truly impressive is that the patients with diabetes are continuing to lose weight even at the end of the study, which is well over 3 years. This is incredibly rare in a long-term weight-loss study. The exact opposite is seen in participants with prediabetes and normoglycemia. After 1 year, they are actually regaining weight. The reason for this continued weight loss beyond 1 year in participants with diabetes is not obvious; however, it is probably related to the use of the newer GLP-1 receptor agonists and SGLT2 inhibitors. There is no doubt that the newer diabetic agents are great therapeutic options, as well as weight-loss agents on their own.
For many years, we have known that the future of weight loss will be combinations of various agents used together to increase weight loss. As an obesity researcher, these findings are exciting and confirm the direction of research to produce meaningful weight loss and, more importantly, weight loss in the patient with diabetes or at risk for diabetes.
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