New data on metabolic & cardiovascular safety and efficacy
Worldwide, the incidence of obesity is increasing dramatically having almost tripled in the last 40 years . In 2016, 39% of adults aged 18 years and older were overweight - 13% were obese. Because obesity is associated with an array of metabolic pathologies, including cardiovascular disease, type 2 diabetes, musculoskeletal disorders, and even some cancers, identifying effective strategies for sustained weight loss are imperative.
In 2012, the Food and Drug Administration (FDA) approved lorcaserin - a selective serotonin 2C receptor agonist that modulates appetite - as an adjunct to lifestyle changes for chronic weight management. Although available in the US, the application for marketing authorisation was withdrawn in the EU by the drug manufacturer. The post-marketing requirements of the FDA included the evaluation of long-term cardiovascular and metabolic safety as well as efficacy of lorcaserin, which have been addressed in the CAMELLIA-TIMI 61 trial .
The CAMELLIA-TIMI 61 trial was a randomized, double-blind, placebo-controlled, multinational clinical trial in which patients at 473 sites in eight countries were randomized. Eligible patients were overweight or obese (with a BMI of 27 kg/m2 or higher), along with either established atherosclerotic cardiovascular disease or multiple cardiovascular risk factors. They were randomly assigned to either lorcaserin (10 mg twice daily) or placebo. All patients were encouraged to participate in a weight-management program, consisting of multicomponent behaviour therapy including dietary and exercise information. The trial was planned to continue until at least 1,401 adjudicated MACE+ events (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, heart failure, or any coronary revascularization) had accrued and the median treatment duration exceeded 2.5 years.
The primary cardiovascular efficacy outcome was MACE+ events.
The primary safety outcome was 3-point MACE (a composite of cardiovascular death, myocardial infarction, or stroke).
The primary metabolic efficacy endpoint was time to incident diabetes (in patients with prediabetes at baseline).
Secondary outcomes for efficacy were incident diabetes in all patients without diabetes, achievement of normoglycaemia in patients with prediabetes, and change in glycated haemoglobin (HbA1c) in patients with diabetes.
Between February 2014 and November 2015, a total of 12,000 patients were randomized (6,000 patients per group) of whom 64.2% were men and 35.8% were women. The median age was 64 years (IQR 58-69) and body mass index 35 kg/m2 (IQR 32-39). Patients had a high burden of coexisting conditions, including diabetes (56%), prediabetes (33.3%), hypertension (90.4%), hyperlipidemia (93.6%) and chronic kidney disease (19%). A total of 8,958 (74.7%) had established atherosclerotic cardiovascular disease .
Cardiovascular safety and efficacy. During a median follow-up of 3.3 years (IQR 3.0 to 3.5), the rate of the major cardiovascular events was 2.0% per year in the lorcaserin group and 2.1% in the placebo group (hazard ratio, 0.99; 95% CI, 0.85 to 1.14; P<0.001 for non-inferiority). The rate of extended major cardiovascular events was 4.1% per year and 4.2% per year, respectively (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P = 0.55). Adverse events of special interest were uncommon, the rates were generally similar in both groups, except for a higher number on patients with serious hypoglycemia in the lorcaserin group (13 vs. 4, P=0.004) .
Effect on weight. From a median weight at baseline of 102.0 kg (IQR 90.0-116.2), at 1 year, patients treated with lorcaserin had a net weight loss beyond placebo of 2.8 kg (P<0.001). Notably, in 38.7% of patients in the lorcaserin group a weight loss of at least 5% had occurred, in comparison to 17.4% of patients in the placebo group. Weight loss of at least 10% had occurred in 14.6% and 4.8% in the lorcaserin and placebo group, respectively. After the median follow-up period of 3.3 years, the between-group difference remained significant, with a net weight loss of 1.9 kg (95% CI, −2.3 to −1.6; P<0.001).
Effect on prevention and remission of type 2 diabetes. Lorcaserin reduced the risk of incident diabetes by 19% in patients with prediabetes (172 [8.5%] of 2015 vs 204 [10.3%] of 1976; hazard ratio 0.81, 95% CI 0.66–0.99; p=0.038) and by 23% in patients without diabetes (174 [6.7%] of 2615 vs 215 [8.4%] of 2569; 0.77, 0.63–0.94; p=0.012). Lorcaserin resulted in a non-significant increase in the rate of achievement of normoglycaemia in patients with prediabetes (185 [9.2%] vs 151 [7.6%]; 1·20, 0.97–1.49; p=0.093). In patients with diabetes, lorcaserin resulted in a reduction of 0.33% (95% CI 0.29−0.38; p<0.0001) in HbA1c compared with placebo at 1 year from a mean baseline of 53 mmol/mol (7.0%) .
In a high-risk population of overweight and obese patients, 1 year treatment with lorcaserin led to a net weight loss of 2.8 kg compared to placebo. After the follow-up period of 3.3 years, a difference of 1.9 kg remained.
Non-inferiority was shown for the rate of major cardiovascular events and MACE+ events when compared with placebo.
Lorcaserin decreased the risk for incident diabetes and led to a reduction of HbA1c, which was accompanied by a higher number of patients who experienced serious hypoglycemia.