Characteristics of the Patients

Table 1. Table 1. Characteristics of the Patients at Baseline.

From January 2014 through November 2015, a total of 12,000 patients underwent randomization. The median follow-up period was 3.3 years (interquartile range, 3.0 to 3.5). The patients’ baseline characteristics were well balanced between the two groups (Table 1). Overall, the median age was 64 years, 64.2% of the patients were male, and the median BMI was 35. Patients had a high burden of coexisting conditions, including diabetes (in 56.8% of the patients), hypertension (90.4%), hyperlipidemia (93.6%), and chronic kidney disease (19.0%). A total of 8958 patients (74.7%) had established atherosclerotic cardiovascular disease. The baseline characteristics according to cardiovascular disease status are provided in Table S1 in the Supplementary Appendix.

The rate of premature discontinuation of a trial agent was 12.0% per year in the lorcaserin group (2248 of 6000 patients over a median of 3.3 years of follow-up) and 12.7% per year in the placebo group (2363 of 6000). The majority of premature discontinuations were due to patient choice unrelated to an adverse event (Table S2 in the Supplementary Appendix). The rate of withdrawal of consent was 0.6% per year (116 of 6000 patients) in the lorcaserin group and 0.7% per year (139 of 6000) in the placebo group; the rates of loss to follow-up were 0.2% per year (42 of 6000) and 0.3% per year (50 of 6000), respectively (Fig. S1 in the Supplementary Appendix). A final vital status was known for 97.4% of the patients.

Effect of Lorcaserin on Weight

Figure 1. Figure 1. Weight Loss. Panel A shows the change in weight from baseline (as least-squares means) among patients in the lorcaserin group and the placebo group. 𝙸 bars indicate 95% confidence intervals. Panel B shows the percentage of patients with weight loss of at least 5% or at least 10% from baseline at 1 year in the lorcaserin group and the placebo group. The analyses included all the patients for whom data regarding weight were available at baseline and at 1 year (5135 patients in the lorcaserin group and 5083 in the placebo group).

In a pooled analysis of the two trial groups, the median weight at baseline was 102.0 kg (interquartile range, 90.0 to 116.2). At 1 year, the least-squares mean change in weight from baseline was −4.2 kg in the lorcaserin group and −1.4 kg in the placebo group, for a between-group difference of 2.8 kg (P<0.001) (Figure 1A). At 1 year, weight loss of at least 5% had occurred in 1986 of 5135 patients (38.7%) in the lorcaserin group and in 883 of 5083 (17.4%) in the placebo group; weight loss of at least 10% had occurred in 748 of 5135 patients (14.6%) and in 243 of 5083 (4.8%), respectively (P<0.001 for both comparisons) (Figure 1B).

Although the between-group difference in weight loss was largest at approximately 1 year, the difference remained significant through 40 months, with a change from baseline of −4.0 kg (95% confidence interval [CI], −4.3 to −3.8) with lorcaserin and −2.1 kg (95% CI, −2.3 to −1.8) with placebo, for a between-group difference of −1.9 kg (95% CI, −2.3 to −1.6; P<0.001). At 1 year, patients in the lorcaserin group had a greater reduction from baseline in BMI and waist circumference than those in the placebo group (Table S3 in the Supplementary Appendix).

Effect on Other Cardiovascular Risk Factors

Table 2. Table 2. Primary and Other Outcomes.

At 1 year, the rates of several cardiovascular and metabolic risk factors were slightly lower in the lorcaserin group than in the placebo group, including systolic blood pressure (between-group difference, −0.9 mm Hg), diastolic blood pressure (difference, −0.8 mm Hg), heart rate (difference, −1.0 beat per minute), low-density lipoprotein cholesterol (difference, −1.2 mg per deciliter [0.03 mmol per liter]), triglycerides (difference, −11.7 mg per deciliter [0.13 mmol per liter]), non–high-density lipoprotein cholesterol (difference, −2.6 mg per deciliter [0.07 mmol per liter]), and glycated hemoglobin (difference, −0.2% in the entire population; −0.3% in patients with diabetes at baseline) (Table S3 in the Supplementary Appendix). Among the patients who had prediabetes at baseline, new-onset diabetes was diagnosed in 172 of 2015 patients (8.5%, or 3.1% per year) in the lorcaserin group and in 204 of 1976 patients (10.3%, or 3.8% per year) in the placebo group (Table 2).

Cardiovascular Safety and Efficacy

Figure 2. Figure 2. Major Adverse Cardiovascular Outcomes. Shown are the cumulative incidences of the primary safety outcome of major cardiovascular events (a composite of cardiovascular death, myocardial infarction, or stroke) (Panel A) and the primary cardiovascular efficacy outcome of major cardiovascular events plus hospitalization for unstable angina, heart failure, or coronary revascularization (extended major cardiovascular events) (Panel B) among patients in the lorcaserin group and the placebo group. The insets show the data on an expanded y axis. The hazard ratios are for noninferiority of lorcaserin regarding major cardiovascular events and for superiority of lorcaserin regarding extended major cardiovascular events.

At the time of trial completion, major cardiovascular events had occurred in 364 patients (6.1%, or 2.0% per year) in the lorcaserin group and 369 (6.2%, or 2.1% per year) in the placebo group (hazard ratio, 0.99; 95% CI, 0.85 to 1.14; P<0.001 for noninferiority) (Figure 2A). Similar results were seen at the time of the interim analysis (Table 2) and at trial completion in the as-treated analysis (Table S4 in the Supplementary Appendix).

The primary efficacy outcome of extended major cardiovascular events occurred in 707 patients (11.8%, or 4.1% per year) in the lorcaserin group and in 727 (12.1%, or 4.2% per year) in the placebo group (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P=0.55 for superiority) (Figure 2B). Individual components of the composite outcome are shown in Table 2. The results were consistent with respect to cardiovascular safety and efficacy in prespecified subgroups (Figs. S3 and S4 in the Supplementary Appendix).

Additional Safety Assessments

Table 3. Table 3. Adverse Events.

No significant between-group differences were seen in the overall incidence of serious adverse events (Table 3). Adverse events that were deemed by investigators to be possibly related to a trial agent and leading to discontinuation of lorcaserin or placebo were more frequent in the lorcaserin group than in the placebo group (in 433 of 5995 patients [7.2%] vs. 220 of 5992 [3.7%]). The most commonly reported adverse events leading to discontinuation in the lorcaserin group were dizziness, fatigue, headache, diarrhea, and nausea (Table 3). The occurrence of prespecified adverse events of special interest was low (<1% for most events). Suicidal ideation or behavior was reported in 21 patients (0.4%) in the lorcaserin group and 11 patients (0.2%) in the placebo group (P=0.08); the numerical imbalance in suicidal ideation or behavior appeared to be restricted to patients with depression at baseline (in 15 patients [1.2%] and 6 patients [0.5%], respectively; P=0.06). There were no deaths by suicide. Hypoglycemia occurred in 232 patients (3.9%) in the lorcaserin group and 202 (3.4%) in the placebo group (P=0.14) (Table 3). Severe hypoglycemia with serious complications (i.e., that required hospitalization, were life-threatening or disabling, or resulted in death) was rare but more common with lorcaserin than with placebo (in 13 patients [0.2%] vs. 4 patients [0.1%]), with the imbalance restricted to hypoglycemia requiring hospitalization (11 patients vs. 2 patients). All but 1 event occurred in patients with diabetes who were receiving insulin or a sulfonylurea at baseline (12 vs. 4 events, P=0.054).

Echocardiographic Substudy

Among the 3270 patients for whom echocardiographic data were available at baseline and at 1 year, new or worsening FDA-defined valvulopathy had occurred in 30 of 1624 patients (1.8%) in the lorcaserin group and in 22 of 1646 (1.3%) in the placebo group (P=0.24) (Table 3). The nonsignificant numerical imbalance between the groups was due to more patients in the lorcaserin group than in the placebo group with new-onset, mild aortic-valve insufficiency (23 patients vs. 15 patients). None of the patients with valvulopathy were symptomatic, were hospitalized, or required valve replacement or repair. Findings were similar in a sensitivity analysis with the use of multiple imputation that included all 4318 patients in the echocardiographic substudy (see the Supplementary Appendix).

In the total population of 12,000 patients, symptomatic valvular heart disease of any type was diagnosed in 58 patients in the lorcaserin group and in 64 in the placebo group. Of these patients, 20 in the lorcaserin group and 23 in the placebo group met the specific FDA-defined criteria for valvulopathy.

The change in pulmonary artery systolic pressure at 1 year was similar in the two groups (least-squares mean change, −1.0 mm Hg [95% CI, −1.4 to −0.5] with lorcaserin and −0.7 mm Hg [95% CI, −1.1 to −0.3] with placebo; P=0.32). At 1 year, new or worsening pulmonary hypertension occurred in 13 of 813 patients (1.6%) in the lorcaserin group and in 8 of 825 (1.0%) in the placebo group (P=0.26). Two patients in each group had symptoms leading to mild limitation in activity; the remainder of patients were asymptomatic. Pulmonary vasodilator therapy for pulmonary hypertension was not initiated in any of the patients, and none of the patients were hospitalized.