Abstract
Objective
To evaluate the effects of lorcaserin in patients with pre‐existing Food and Drug Administration (FDA)‐defined valvulopathy.
Methods
This is a pooled, post hoc analysis of three Phase 3 studies. BLOOM and BLOSSOM patients were 18 to 65 years of age without diabetes and with a body mass index (BMI) of 27 to 29.9 kg/m2 and ≥1 weight‐related comorbidity or a BMI of 30 to 45 kg/m2. BLOOM‐DM patients had a BMI of 27 to 45 kg/m2 and type 2 diabetes. Patients were treated with placebo, lorcaserin 10 mg once daily, or lorcaserin 10 mg twice daily. Serial echocardiographs were obtained at baseline and every 6 months.
Results
Included patients (N = 169) had FDA‐defined valvulopathy at baseline and a week 52 echocardiogram. At week 52, 35.5% and 52.7% of patients experienced changes from baseline in aortic and mitral regurgitation, respectively. Numerically greater proportions of patients taking lorcaserin versus placebo had decreases in aortic (33.0% vs. 28.3%) or mitral (41.3% vs. 36.7%) regurgitation. Fewer patients taking lorcaserin versus placebo had increases in aortic (2.8% vs. 6.7%) or mitral (8.3% vs. 21.7%) regurgitation. No adverse event‐related discontinuation was due to a valve problem.
Conclusions
These data suggest that lorcaserin does not adversely affect valvular disease in patients with pre‐existing FDA‐defined valvulopathy.
Introduction
The serotonin receptor subtype 5‐hydroxytryptamine 2C (5‐HT2C) regulates satiety and food intake via the hypothalamic melanocortin system and is thus an attractive target for weight loss pharmacotherapy 1. Lorcaserin is a selective 5‐HT2C receptor agonist indicated in the United States for chronic weight management as an adjunct to a reduced‐calorie diet and increased physical activity 2. In preclinical studies, lorcaserin demonstrated ∼61‐fold selectivity for the 5‐HT2C receptor relative to the 5‐HT2B receptor 2. This selectivity is important in light of aortic and mitral valve insufficiency associated with the use of nonselective serotonergic antiobesity compounds 3, 4, 5, 6, 7. Nonselective agents, including fenfluramine and dexfenfluramine, affect serotonin transporters and have potent activity at the 5‐HT2B receptor, which is expressed on cardiac valvular interstitial cells and whose activation has been strongly implicated in serotonergic cardiac valvulopathy 8, 9, 10. In a report of 86 patients exposed to fenfluramine or dexfenfluramine (in combination with mazindol or phentermine) with echocardiograms done before, during, and after treatment, 16.5% of patients developed valvular regurgitation, and its incidence was correlated to duration of treatment 11. In another study, upon cessation of therapy, fenfluramine‐associated valvular regurgitation improved or remained stable, while worsening was infrequent 12.
Due to the historical association of antiobesity agents such as fenfluramine–phentermine (fen‐phen) with valvular heart disease 13, Phase 3 clinical trials evaluating the efficacy and safety of lorcaserin in patients with overweight and obesity incorporated serial echocardiographic assessments to monitor valvular function 14, 15, 16. The primary echocardiographic end point in each study was the proportion of patients developing new Food and Drug Administration (FDA)‐defined valvulopathy at week 52 (i.e., mild or greater aortic regurgitation and/or moderate or greater mitral regurgitation 17 not present at baseline) 14, 15, 16, a prevalence measure (not a clinical measure) used to evaluate fenfluramine‐associated, FDA‐defined valvulopathy in the absence of baseline incidence data. A preplanned, integrated analysis showed that, at 1 year, the proportion of patients developing new FDA‐defined echocardiographic valvulopathy with lorcaserin 10 mg twice daily (BID) (2.4%) was similar to that with placebo (2.0%) 18. The rate of new FDA‐defined valvulopathy was 1.6% in a smaller group of patients receiving lorcaserin 10 mg once daily (QD), and none of these patients with new FDA‐defined valvulopathy was symptomatic 19.
Comprehensive monitoring of more than 20,000 standardized serial echocardiograms in the lorcaserin Phase 3 program ruled out ≥1.25% of risk difference in the development of new valvular regurgitation after 1 year of lorcaserin use 18, 20, but evidence concerning the risk of lorcaserin use in patients with pre‐existing valvular disease has not been published. In this post hoc analysis, we evaluate the effects of lorcaserin in a subset of patients from the Phase 3 program with pre‐existing FDA‐defined valvulopathy at baseline. We also present a sensitivity analysis on the potential confounding influences of weight loss and changes in blood pressure 21, 22 on valvular regurgitation.
Methods
Ethics
The Phase 3 clinical trial program for lorcaserin consisted of three trials: Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM), Behavioral Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM), and Behavioral Modification and Lorcaserin for Obesity and Overweight Management in Diabetes Mellitus (BLOOM‐DM) 14, 15, 16. These were randomized, placebo‐controlled, double‐blind, multicenter studies conducted from September 2006 to August 2010, in accordance with the guidelines of the Declaration of Helsinki. Institutional review boards reviewed and approved the protocol, and all patients provided written informed consent. Patients did not receive a stipend for participation in these studies, although they could receive a nominal payment to cover time and expenses (generally limited to less than $50 per visit). These studies are registered at Clinicaltrials.gov, identification numbers NCT00395135 (BLOOM), NCT00603902 (BLOSSOM), and NCT00603291 (BLOOM‐DM).
Study populations and designs
This is a pooled analysis of data from the BLOOM, BLOSSOM, and BLOOM‐DM studies. Complete details of randomization and interventions have been previously published 14, 15, 16; briefly, in all three studies, patients were randomized to placebo, lorcaserin 10 mg QD, or lorcaserin 10 mg BID.
Due to the historical association of serotonergic antiobesity agents with valvular disease 7, 13, 23, patients with pre‐existing FDA‐defined valvulopathy were excluded at screening in BLOOM, the first of these three trials 15. BLOOM patients were therefore not included in this analysis, except for three patients who met the criteria for FDA‐defined valvulopathy at baseline, were inadvertently randomized, and had a post‐baseline echocardiographic assessment that could be brought forward to week 52 (last observation carried forward). These three patients were all randomized to the placebo group and presented with trace‐to‐mild aortic regurgitation and mild‐to‐moderate mitral regurgitation at baseline. Their duration in the study ranged from 3 to 193 days. Because lorcaserin use did not increase the incidence of FDA‐defined valvulopathy in the BLOOM trial 16, echocardiographic inclusion/exclusion criteria were not applied in the BLOSSOM and BLOOM‐DM trials 14, 15. However, patients with a history of valve replacement surgery or congestive heart failure caused by insufficiency, damage, or stenosis of any heart valve were excluded from these trials.
BLOSSOM and BLOOM‐DM were both 52‐week, randomized, controlled studies with three arms: lorcaserin 10 mg QD, lorcaserin 10 mg BID, and placebo 14, 15. BLOSSOM patients (N = 4,008) were 18 to 65 years of age without diabetes and with either a body mass index (BMI) of 27 to 29.9 kg/m2 and at least one other weight‐related comorbidity or a BMI of 30 to 45 kg/m2 14. BLOOM‐DM patients (N = 604) were 18 to 65 years of age with a BMI of 27 to 45 kg/m2 and type 2 diabetes poorly controlled by oral agents 15. Both studies were conducted at academic and private research sites in the United States 14, 15.
Race categories were defined by the sponsor in the primary studies, and patients were classified as Caucasian, African American, Asian, Hispanic, or Other for presentation in this analysis. Patients reported their race, and this information was recorded by the investigator. Race data were collected to identify potential differences in safety, efficacy, or population pharmacokinetics on this basis and to provide information on racial distribution between the treatment groups. Sex distribution (male and female) is also reported.
Echocardiographic assessments
Serial echocardiographs were obtained at baseline and every 6 months in BLOSSOM and BLOOM‐DM 14, 15. Each blinded echocardiograph was interpreted by two cardiologists at an independent core lab (Biomedical Systems, St. Louis, MO). The same primary reader was maintained for each patient, and the secondary reader was randomly assigned from a pool of approximately 20 highly experienced level III echocardiographers. In case of a discrepancy, the reading was adjudicated by a third reader. A 5‐level rating scale was applied to aortic and mitral valve regurgitation (absent, trace, mild, moderate, or severe) according to American Society of Echocardiography guidelines 18, 24.
Analyses
Echocardiographic data from the lorcaserin 10 mg BID and QD groups were pooled for this analysis, since both doses were pharmacologically active, as demonstrated by statistically significant weight loss as compared with diet and exercise alone 14, 15, 16. Patient characteristics and shifts in valvular regurgitation grade from baseline to week 52 (last observation carried forward) were summarized descriptively. Because previous reports suggested that the prevalence of valvular regurgitation may increase with increases in blood pressure and with decreases in BMI 18, 21, 25, the potential for relationships between shifts in regurgitation and changes in blood pressure and body weight were evaluated. Mean changes in blood pressure and body weight between baseline and week 52 and 95% confidence intervals (CIs) were summarized within each treatment group by category of aortic/mitral regurgitation grade shift.
Results
Patient characteristics and disposition
A total of 169 patients (lorcaserin 10 mg QD, N = 34; lorcaserin 10 mg BID, N = 75; placebo, N = 60) met echocardiographic criteria for FDA‐defined valvulopathy at baseline and were included in the analysis. Patients with pre‐existing FDA‐defined valvulopathy accounted for 2.2% of the total Phase 3 population and 3.6% of the BLOSSOM and BLOOM‐DM populations. Baseline characteristics were similar in patients receiving lorcaserin and those receiving placebo (Table 1). Mean age was 54 years, more than 70% were women, and mean BMI was 35 kg/m2.
Table 1.
Demographic and clinical characteristics of patients with FDA‐defined valvulopathy at baseline
| Lorcaserin 10 mg (N = 109: QD [N = 34]; BID [N = 75]) | Placebo (N = 60) | |
|---|---|---|
| Age (years) | ||
| Mean (SD) | 53.89 (9.01) | 53.50 (8.99) |
| Median (range) | 55.00 (19.0‐65.0) | 55.50 (22.0‐65.0) |
| Age group (years), n (%) | ||
| 18‐24 | 2 (1.8) | 1 (1.7) |
| 25‐34 | 2 (1.8) | 1 (1.7) |
| 35‐44 | 11 (10.1) | 6 (10.0) |
| 45‐54 | 35 (32.1) | 19 (31.7) |
| 55‐65 | 59 (54.1) | 33 (55.0) |
| Sex, n (%) | ||
| Male | 32 (29.4) | 15 (25.0) |
| Female | 77 (70.6) | 45 (75.0) |
| Race, n (%) | ||
| Caucasian | 77 (70.6) | 50 (83.3) |
| African American | 19 (17.4) | 4 (6.7) |
| Asian | 5 (4.6) | 1 (1.7) |
| Hispanic | 8 (7.3) | 4 (6.7) |
| Other | 0 (0.0) | 1 (1.7) |
| Weight (kg) | ||
| Mean (SD) | 99.5 (16.8) | 95.5 (16.1) |
| Median (range) | 98.3 (64.9‐148.7) | 92.9 (59.9‐141.1) |
| BMI (kg/m 2 ) | ||
| Mean (SD) | 35.31 (4.24) | 34.55 (3.57) |
| Median (range) | 34.60 (27.5‐45.0) | 34.60 (28.0‐44.1) |
| BMI group, n (%) | ||
| <30 kg/m2 | 8 (7.3) | 3 (5.0) |
| 30 to <35 kg/m2 | 53 (48.6) | 30 (50.0) |
| 35 to <40 kg/m2 | 29 (26.6) | 23 (38.3) |
| 40 to <45 kg/m2 | 18 (16.5) | 4 (6.7) |
| ≥45 kg/m2 | 1 (0.9) | 0 (0.0) |
| Systolic blood pressure (mm Hg) | ||
| Mean (SD) | 126.18 (12.06) | 127.60 (13.90) |
| Median (range) | 126.00 (97.0‐152.0) | 129.00 (99.0‐156.0) |
| Diastolic blood pressure (mm Hg) | ||
| Mean (SD) | 77.80 (8.89) | 78.53 (9.02) |
| Median (range) | 76.00 (50.0‐94.0) | 79.00 (44.0‐98.0) |
| Current tobacco use, n (%) a | ||
| Yes | 33 (30.3) | 22 (36.7) |
| No | 76 (69.7) | 38 (63.3) |
Patients with non‐missing tobacco use response.
BID, twice daily; BMI, body mass index; QD, once daily; SD, standard deviation.
Fifty of 169 patients (29.6%) withdrew before the end of the study, 26 in the lorcaserin group (23.8%) and 24 in the placebo group (40.0%). This rate of attrition is consistent with other trials for obesity management 26, 27, 28, 29. Major reasons for withdrawal were withdrawn consent (lorcaserin, 12 patients, 11%; placebo, 12 patients, 20%), adverse events (lorcaserin, 7 patients, 6.42%; placebo, 4 patients, 6.67%), and lost to follow‐up (lorcaserin, 4 patients, 3.67%). No adverse event‐related discontinuations were due to a valve problem.
Shifts in valvular regurgitation grade
With respect to regurgitation scores at week 52, 35.5% and 52.7% of patients with baseline FDA‐defined valvulopathy experienced changes in either direction from baseline in aortic and mitral regurgitation, respectively. The majority of shifts in regurgitation scores were single‐grade increases or decreases (Figure 1), and no patient experienced more than a single‐grade increase in aortic or mitral regurgitation. With respect to decreases, although the majority were single grade, some were of 2 or 3 grades. Because the patterns of shifts in the lorcaserin 10 mg QD and BID groups were similar, the data from these two groups were pooled.
Figure 1.
Shifts in (A) aortic and (B) mitral valvular regurgitation scores in patients with FDA‐defined valvulopathy. BID, twice daily; QD, once daily.
Numerically greater proportions of patients taking lorcaserin versus placebo had decreases in aortic regurgitation (lorcaserin, 33.0% [QD, 26.5%; BID, 36.0%] vs. placebo, 28.3%) or mitral regurgitation (lorcaserin, 41.3% [QD, 50.0%; BID, 37.3%] vs. placebo, 36.7%) from baseline to week 52. A numerically smaller proportion of patients taking lorcaserin versus placebo had increases in aortic regurgitation (lorcaserin, 2.8% [QD, 2.9%; BID, 2.7%] vs. placebo, 6.7%) or mitral regurgitation (lorcaserin, 8.3% [QD, 5.9%; BID, 9.3%] vs. placebo, 21.7%) from baseline to week 52. Table 2 provides information on the degree of regurgitation at baseline and week 52. After treatment, aortic valve regurgitation scores improved to absent or trace in 30.3% of lorcaserin‐treated patients and 26.7% of placebo‐treated patients, and mitral valve regurgitation scores improved to absent or trace in 28.4% of lorcaserin‐treated patients and 25.0% of placebo‐treated patients. Thus, lorcaserin‐treated patients exhibited numerically greater improvements in aortic and mitral regurgitation versus placebo, in both the proportions achieving such improvements and their magnitudes.
Table 2.
Changes in valvular regurgitation scores at week 52 among patients with FDA‐defined valvulopathy at baseline
| Lorcaserin 10 mg (N = 109: QD [N = 34]; BID [N = 75])a | Placebo (N = 60)a | |
|---|---|---|
| Aortic valvulopathy | ||
| Improvement (decrease) | ||
| Moderate to absent (−3) | 1 (0.9) | 0 |
| Moderate to trace (−2) | 0 | 0 |
| Mild to absent (−2) | 4 (3.7) | 8 (13.3) |
| Moderate to mild (−1) | 3 (2.8) | 1 (1.7) |
| Mild to trace (−1) | 22 (20.2) | 7 (11.7) |
| Trace to absent (−1) | 6 (5.5) | 1 (1.7) |
| No change | ||
| Absent to absent | 11 (10.1) | 8 (13.3) |
| Trace to trace | 4 (3.7) | 1 (1.7) |
| Mild to mild | 52 (47.7) | 29 (48.3) |
| Moderate to moderate | 3 (2.8) | 1 (1.7) |
| Worsening (increase) | ||
| Absent to trace (+1) | 1 (0.9) | 3 (5.0) |
| Trace to mild (+1) | 0 | 1 (1.7) |
| Mild to moderate (+1) | 2 (1.8) | 0 |
| Moderate to severe (+1) | 0 | 0 |
| Trace to moderate (+2) | 0 | 0 |
| Mitral valvulopathy | ||
| Improvement (decrease) | ||
| Moderate to absent (−3) | 0 | 0 |
| Moderate to trace (−2) | 7 (6.4) | 2 (3.3) |
| Mild to absent (−2) | 3 (2.8) | 1 (1.7) |
| Moderate to mild (−1) | 14 (12.8) | 7 (11.7) |
| Mild to trace (−1) | 13 (11.9) | 7 (11.7) |
| Trace to absent (−1) | 8 (7.3) | 5 (8.3) |
| No change | ||
| Absent to absent | 4 (3.7) | 1 (1.7) |
| Trace to trace | 32 (29.4) | 15 (25.0) |
| Mild to mild | 11 (10.1) | 4 (6.7) |
| Moderate to moderate | 8 (7.3) | 5 (8.3) |
| Worsening (increase) | ||
| Absent to trace (+1) | 2 (1.8) | 4 (6.7) |
| Trace to mild (+1) | 5 (4.6) | 7 (11.7) |
| Mild to moderate (+1) | 2 (1.8) | 1 (1.7) |
| Moderate to severe (+1) | 0 | 1 (1.7) |
| Trace to moderate (+2) | 0 | 0 |
BID, twice daily; QD, once daily.
n (%).
Effects of changes in weight and blood pressure on valvular regurgitation
We evaluated the effects of changes in weight on valvular regurgitation in patients with FDA‐defined valvulopathy at baseline. In the total population, mean weight change (95% CI) was −5.2% (−6.2 to −4.2); when stratifying by treatment group (lorcaserin, N = 109; placebo, N = 60), greater weight loss was achieved in lorcaserin‐treated patients versus placebo (lorcaserin, −6.2% [−7.5 to −4.9] vs. placebo, −3.4% [−4.8 to −2.0]). Also in the total population, mean change from baseline in weight was −5.2% (−6.7 to −3.7) in patients who showed improvement in mitral regurgitation (N = 67) and −5.9% (−9.2 to −2.6) in patients who showed worsening in mitral regurgitation (N = 22). Mean change from baseline in weight was −4.8% (−6.5 to −3.2) in patients who showed improvement in aortic regurgitation (N = 53) and −8.2% (−16.1 to −0.3) in patients who showed worsening in aortic regurgitation (N = 7). Therefore, no association was detected between weight loss and valvular regurgitation.
We also evaluated the effects of changes in blood pressure on valvular regurgitation in these patients. In the total population, mean change in systolic/diastolic blood pressure was −2.2 mm Hg (−4.1 to −0.3)/−0.5 mm Hg (−2.0 to 1.0); when stratifying by treatment group (lorcaserin, N = 109; placebo, N = 60), slightly greater reductions in systolic/diastolic blood pressure were achieved in lorcaserin‐treated patients versus placebo (lorcaserin, −2.4 mm Hg [−4.6 to −0.1]/−0.5 mm Hg [−2.3 to 1.3] vs. placebo, −2.0 mm Hg [−5.6 to 1.7]/−0.5 mm Hg [−3.3 to 2.2]). In the total population, mean change from baseline in systolic/diastolic blood pressure was −4.0 mm Hg (−7.0 to −1.1)/−0.2 mm Hg (−2.6 to −2.3) in patients that showed improvement in mitral regurgitation (N = 67) and −2.0 mm Hg (−7.0 to −3.0)/−0.8 (−5.3 to −3.8) in patients that showed worsening in mitral regurgitation (N = 22). Mean change from baseline in systolic/diastolic blood pressure was −1.6 mm Hg (−4.9 to 1.7)/−1.0 mm Hg (−4.1 to 2.1) in patients that showed improvement in aortic regurgitation (N = 53) and −11.3 (−18.4 to −4.2)/−2.9 mm Hg (−8.4 to −2.7) in patients that showed worsening in aortic regurgitation (N = 7). In this analysis, no association was detected between blood pressure changes and valvular regurgitation.
Discussion
Previous nonselective serotonergic agents implicated in FDA‐defined cardiac valvulopathy have potent activity at the 5‐HT2B receptor 8, 9, 10. Lorcaserin, a highly selective serotonergic antiobesity agent that is clinically available for use in patients with obesity or with overweight with a comorbidity, was designed to selectively activate 5‐HT2C receptors at therapeutic doses, with a functional selectivity of approximately 14 times that for 5‐HT2A receptors and 61 times that for 5‐HT2B receptors 2, 30. At therapeutic doses, free (unbound to plasma proteins) drug levels of lorcaserin are well below the in vitro activation constant for the 5‐HT2B receptor 30, 31, 32. Thus, the theoretical risk of valvular heart disease associated with lorcaserin use is low.
Analyses reported in a previous publication demonstrated that lorcaserin use was not associated with a meaningfully greater incidence of new echocardiographically identified FDA‐defined valvulopathy versus placebo 18. Applying multiple statistical techniques to the data, a consistent risk ratio of approximately 1.1 (lorcaserin BID vs. placebo) was identified 18. Consistent with these data, the current analysis demonstrates that lorcaserin use does not worsen aortic or mitral regurgitation in patients with pre‐existing FDA‐defined valvulopathy after 1 year of treatment, relative to placebo. Small changes, limited to 1‐grade increases and 1‐ to 3‐grade decreases in regurgitation, were noted in similar proportions of lorcaserin‐ and placebo‐treated patients at each valve. Furthermore, a sensitivity analysis showed that neither weight loss nor changes in blood pressure were associated with changes in valvular regurgitation in this population.
The Endocrine Society Clinical Practice Guideline for the Pharmacological Management of Obesity suggests the use of lorcaserin for weight management in patients with established cardiovascular disease 33, since, unlike some other antiobesity agents 29, 34, it is not a sympathomimetic agent 33. The current analysis, coupled with the previous analysis of lorcaserin use in patients without FDA‐defined valvulopathy at baseline 18, provides additional support for the Endocrine Society recommendation. Combined, these two analyses provide a comprehensive analysis of cardiac valvular safety with lorcaserin use, which may facilitate clinical decision making.
In a pool of more than 20,000 echocardiograms conducted during the Phase 3 clinical trials of lorcaserin, only a small number of patients (2.7%) had FDA‐defined valvulopathy at baseline 20. Therefore, these data should be interpreted within the limitations of this analysis. This is a retrospective, post hoc subgroup analysis of a limited number of patients with pre‐existing FDA‐defined valvulopathy. As such, this analysis was not powered to conduct statistical testing between treatment groups. Furthermore, pre‐existing valvulopathy was not considered a characteristic for stratification in randomization, so this post hoc analysis cannot be considered randomized. Therefore, it is unknown whether the subtle differences in baseline characteristics between the treatment groups introduce bias. Larger prospective studies looking at a diverse population of patients are needed to confirm these results and to conduct subgroup analyses to examine the effects of blood pressure and weight changes on valvular regurgitation. Furthermore, this is not a complete cardiovascular evaluation of lorcaserin use. Valvular regurgitation is only one aspect of cardiovascular health, and general assumptions regarding overall cardiovascular health should not be made based on these data. A 12,000‐patient, multiyear assessment of cardiovascular outcomes with lorcaserin use, including serial echocardiographic evaluations in a large subset of the trial population, is ongoing (NCT02019264).
This study provides further data to support that use of lorcaserin does not adversely affect valvular heart disease in patients with pre‐existing FDA‐defined valvulopathy.
Acknowledgments
Authors gratefully acknowledge the scientific guidance of William Soliman and Yuhan Li. The authors thank Caryn Trbovic, PhD, of Imprint Science for assistance with editing the manuscript for nonintellectual content. Please refer to the primary publications 14, 15, 16 for a complete list of investigators who participated in the clinical trials.
Funding agencies: Editorial support was provided by Imprint Science, New York, NY, USA, with funding from Eisai Inc. The clinical trials were funded by Arena Pharmaceuticals, Inc., and this post hoc analysis was funded by Eisai Inc., who, in addition to the authors, was responsible for design and conduct of the study; management, analysis, and interpretation of the data; and approval of the manuscript.Disclosure: NJW receives grant support from Abbott Vascular, St. Jude Medical Inc., Medtronic, Edwards Lifesciences, Sorin Group, Boston Scientific, and Direct Flow Medical; he previously received grant support from Arena Pharmaceuticals, Inc. He serves on the steering committee for the CAMELLIA‐TIMI 61 trial of lorcaserin. SRS has received research grant support from Eli Lilly and Company, Eisai Inc., Takeda Pharmaceuticals, Ionis Pharmaceuticals, Pfizer Inc., Sanofi, and NuSI; has served as a consultant/advisor to Amylin Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol‐Meyers Squibb, Eisai Inc., Elcelyx, Eli Lilly and Company, Five Prime Therapeutics, Inc., GSK, NGM Biopharmaceuticals, Novo Nordisk, Orexigen Therapeutics, Inc., Piramal Life Sciences, Takeda Pharmaceuticals, and Zafgen; and is an equity stakeholder in Jenrin Discovery and Zafgen. He also serves on the steering committee for cardiovascular outcomes trials CAMELLIA‐TIMI 61 of lorcaserin and the LIGHT study of naltrexone‐bupropion. RF is a former employee and NH is a current employee of Eisai Inc. WRS is a former employee of Arena Pharmaceuticals, Inc.
Author contributions: NJW: conception of work, design of work, data analysis, interpretation of data; drafting of work, critical revision of work for important intellectual content; final approval of the version to be published. He had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. SRS: conception of work, design of the work, data analysis, interpretation of data; critical revision of work for important intellectual content; final approval of the version to be published. RF: conception of work, design of work, data analysis, interpretation of data; drafting of work, critical revision of work for important intellectual content; final approval of the version to be published. NH: design of work, statistical/data analysis, interpretation of data; critical revision of work for important intellectual content; final approval of the version to be published. WRS: conception of work, design of work, data analysis, interpretation of data; drafting of work, critical revision of work for important intellectual content; final approval of the version to be published.
Clinical trial registration: ClinicalTrials.gov identifiers NCT00395135, NCT00603902, NCT00603291.
References
- 1. Xu Y, Jones JE, Kohno D, et al. 5‐HT2CRs expressed by pro‐opiomelanocortin neurons regulate energy homeostasis. Neuron 2008;60:582‐589. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Eisai Inc . BELVIQ (lorcaserin hydrochloride) US Prescribing Information. Eisai Inc: Woodcliff Lake, NJ; 2014. [Google Scholar]
- 3. Hopkins PN, Polukoff GI. Risk of valvular heart disease associated with use of fenfluramine. BMC Cardiovasc Disord 2003;3:5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Jick H, Vasilakis C, Weinrauch LA, Meier CR, Jick SS, Derby LE. A population‐based study of appetite‐suppressant drugs and the risk of cardiac‐valve regurgitation. N Engl J Med 1998;339:719‐724. [DOI] [PubMed] [Google Scholar]
- 5. Jollis JG, Landolfo CK, Kisslo J, Constantine GD, Davis KD, Ryan T. Fenfluramine and phentermine and cardiovascular findings: effect of treatment duration on prevalence of valve abnormalities. Circulation 2000;101:2071‐2077. [DOI] [PubMed] [Google Scholar]
- 6. Palmieri V, Arnett DK, Roman MJ, et al. Appetite suppressants and valvular heart disease in a population‐based sample: the HyperGEN study. Am J Med 2002;112:710‐715. [DOI] [PubMed] [Google Scholar]
- 7. Sachdev M, Miller WC, Ryan T, Jollis JG. Effect of fenfluramine‐derivative diet pills on cardiac valves: a meta‐analysis of observational studies. Am Heart J 2002;144:1065‐1073. [DOI] [PubMed] [Google Scholar]
- 8. Rothman RB, Baumann MH, Savage JE, et al. Evidence for possible involvement of 5‐HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 2000;102:2836‐2841. [DOI] [PubMed] [Google Scholar]
- 9. Roth BL. Drugs and valvular heart disease. N Engl J Med 2007;356:6‐9. [DOI] [PubMed] [Google Scholar]
- 10. Rothman RB, Baumann MH. Therapeutic and adverse actions of serotonin transporter substrates. Pharmacol Ther 2002;95:73‐88. [DOI] [PubMed] [Google Scholar]
- 11. Ryan DH, Bray GA, Helmcke F, et al. Serial echocardiographic and clinical evaluation of valvular regurgitation before, during, and after treatment with fenfluramine or dexfenfluramine and mazindol or phentermine. Obes Res 1999;7:313‐322. [DOI] [PubMed] [Google Scholar]
- 12. Mast ST, Jollis JG, Ryan T, Anstrom KJ, Crary JL. The progression of fenfluramine‐associated valvular heart disease assessed by echocardiography. Ann Intern Med 2001;134:261‐266. [DOI] [PubMed] [Google Scholar]
- 13. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine‐phentermine. N Engl J Med 1997;337:581‐588. [DOI] [PubMed] [Google Scholar]
- 14. Fidler MC, Sanchez M, Raether B, et al. A one‐year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab 2011;96:3067‐3077. [DOI] [PubMed] [Google Scholar]
- 15. O'Neil PM, Smith SR, Weissman NJ, et al. Randomized placebo‐controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM‐DM study. Obesity (Silver Spring) 2012;20:1426‐1436. [DOI] [PubMed] [Google Scholar]
- 16. Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo‐controlled trial of lorcaserin for weight management. N Engl J Med 2010;363:245‐256. [DOI] [PubMed] [Google Scholar]
- 17. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: U.S. Department of Health and Human Services interim public health recommendations, November 1997. MMWR Morb Mortal Wkly Rep 1997;46:1061‐1066. [PubMed] [Google Scholar]
- 18. Weissman NJ, Sanchez M, Koch GG, Smith SR, Shanahan WR, Anderson CM. Echocardiographic assessment of cardiac valvular regurgitation with lorcaserin from analysis of 3 phase 3 clinical trials. Circ Cardiovasc Imaging 2013;6:560‐567. [DOI] [PubMed] [Google Scholar]
- 19. Weissman NJ, Smith SR, Fain R, et al. Effects of lorcaserin on preexisting valvulopathy in two phase 3 lorcaserin trials: a pooled analysis Presented at: 63rd Annual Scientific Session & Expo of the American College of Cardiology; March 29‐31, 2014; Washington, DC; pp. 1122‐1339. [Google Scholar]
- 20. Aronne L, Shanahan W, Fain R, et al. Safety and efficacy of lorcaserin: a combined analysis of the BLOOM and BLOSSOM trials. Postgrad Med 2014;126:7‐18. [DOI] [PubMed] [Google Scholar]
- 21. Singh JP, Evans JC, Levy D, et al. Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the Framingham Heart Study). Am J Cardiol 1999;83:897‐902. [DOI] [PubMed] [Google Scholar]
- 22. ACC/AHA guidelines for the management of patients with valvular heart disease. A report of the American College of Cardiology/American Heart Association. Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease). J Am Coll Cardiol 1998;32:1486‐1588. [DOI] [PubMed] [Google Scholar]
- 23. Weissman NJ, Tighe JF Jr, Gottdiener JS, Gwynne JT. An assessment of heart‐valve abnormalities in obese patients taking dexfenfluramine, sustained‐release dexfenfluramine, or placebo. Sustained‐Release Dexfenfluramine Study Group. N Engl J Med 1998;339:725‐732. [DOI] [PubMed] [Google Scholar]
- 24. Zoghbi WA, Enriquez‐Sarano M, Foster E, et al. Recommendations for evaluation of the severity of native valvular regurgitation with two‐dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003;16:777‐802. [DOI] [PubMed] [Google Scholar]
- 25. Shively BK, Roldan CA, Gill EA, Najarian T, Loar SB. Prevalence and determinants of valvulopathy in patients treated with dexfenfluramine. Circulation 1999;100:2161‐2167. [DOI] [PubMed] [Google Scholar]
- 26. Dalle Grave R, Calugi S, Molinari E, et al. Weight loss expectations in obese patients and treatment attrition: an observational multicenter study. Obes Res 2005;13:1961‐1969. [DOI] [PubMed] [Google Scholar]
- 27. Gadde KM, Allison DB, Ryan DH, et al. Effects of low‐dose, controlled‐release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo‐controlled, phase 3 trial. Lancet 2011;377:1341‐1352. [DOI] [PubMed] [Google Scholar]
- 28. Greenway FL, Fujioka K, Plodkowski RA, et al. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR‐I): a multicentre, randomised, double‐blind, placebo‐controlled, phase 3 trial. Lancet 2010;376:595‐605. [DOI] [PubMed] [Google Scholar]
- 29. Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional weight loss with liraglutide after low‐calorie‐diet‐induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond) 2013;37:1443‐1451. [DOI] [PubMed] [Google Scholar]
- 30. Thomsen WJ, Grottick AJ, Menzaghi F, et al. Lorcaserin, a novel selective human 5‐hydroxytryptamine(2C) agonist: in vitro and in vivo pharmacological characterization. J Pharmacol Exp Ther 2008;325:577‐587. [DOI] [PubMed] [Google Scholar]
- 31. Miller KJ. Serotonin 5‐HT2C receptor agonists: potential for the treatment of obesity. Mol Interv 2005;5:282‐291. [DOI] [PubMed] [Google Scholar]
- 32. Kaumann AJ, Levy FO. 5‐hydroxytryptamine receptors in the human cardiovascular system. Pharmacol Ther 2006;111:674‐706. [DOI] [PubMed] [Google Scholar]
- 33. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2015;100:342‐362. [DOI] [PubMed] [Google Scholar]
- 34. Apovian CM, Aronne L, Rubino D, et al. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity‐related risk factors (COR‐II). Obesity (Silver Spring) 2013;21:935‐943. [DOI] [PMC free article] [PubMed] [Google Scholar]