{'fraction_non_alphanumeric': 0.033193031061857316, 'fraction_numerical': 0.015877244392349086, 'mean_word_length': 5.674964438122333, 'pattern_counts': {'":': 0, '<': 4, '<?xml version=': 0, '>': 5, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Lorcaserin and metabolic disease: weight‐loss dependent and independent effects

Summary Objective Weight management pharmacotherapies can improve metabolic diseases through weight‐dependent and weight‐independent effects. Lorcaserin is a selective 5‐hydroxytryptamine 2C receptor agonist. The objective of this analysis is to quantify the relative contribution of weight loss to the treatment effects of lorcaserin 10 mg twice a day on key metabolic parameters. Methods This retrospective analysis evaluated 6,897 patients with overweight or obesity (with or without diabetes mellitus) across three randomized, placebo‐controlled, double‐blind, 52‐week clinical trials that evaluated lorcaserin 10 mg twice daily (BID; NCT00395135, NCT00603902, and NCT00603291); 509 patients from only one of the studies had type 2 diabetes mellitus. A mediation analysis was applied to help rank the relative contribution of weight loss to metabolic study outcomes. Results According to this mediation analysis, lorcaserin 10 mg BID improved a spectrum of adiposopathic metabolic abnormalities with varying contributions attributable to weight loss. Improvements in waist circumference and blood pressure were almost exclusively attributable to weight loss. Less than 50% of the improvement in glucose parameters (fasting blood glucose and haemoglobin A1c) were attributable to weight loss. Conclusions Across Phase III clinical trials, lorcaserin 10 mg BID improved multiple cardiometabolic parameters through both weight‐loss dependent and independent mechanisms.


Introduction
Obesity affects a multitude of individuals worldwide. Since 1980, its prevalence has doubled in more than 70 countries and continues to increase (1). Management of patients with overweight and obesity usually begins with implementing appropriate nutrition and physical activity, addressing potential secondary causes of fat weight gain, and engaging patients in behaviour modification. However, as with treatment of other metabolic diseases (e.g. high blood sugar, high blood pressure and abnormal lipid blood levels), these measures alone are often insufficient. In such cases, pharmacotherapy and perhaps even bariatric surgery may be beneficial in both reducing body weight and improving adiposopathic metabolic diseases. The overall objective in treating obesity is to not only improve the weight of patients but also improve the health of patients (2).
Some existing anti-obesity pharmacotherapies not only reduce body fat but also improve metabolic diseases such as diabetes mellitus, hypertension and dyslipidemia, which are all major cardiovascular disease risk factors (3,4). Lorcaserin is a selective 5-hydroxytryptamine (5-HT or serotonin) 2C receptor agonist that was approved by the US Food and Drug Administration for weight management pharmacotherapy in 2012. During the clinical trial development, lorcaserin not only reduced body weight, but also improved multiple metabolic parameters often caused or promoted by obesity (5). Clinical trials have suggested lorcaserin may be especially effective in improving glucose levels. Behavioral Modification and Lorcaserin for Obesity and Overweight Management in Diabetes Mellitus (BLOOM-DM) was a 1-year, randomized, placebo-controlled study that evaluated 604 patients with type 2 diabetes mellitus (T2DM) treated with metformin, a sulfonylurea or both (6). Patients in the lorcaserin 10 mg twice daily (BID) group experienced significantly greater weight reduction (À4.5%) than the placebo group (À1.5%). The lorcaserin 10 mg BID group also experienced a significant reduction (27 mg dL À1 ) in fasting glucose compared with the reduction found with placebo (12 mg dL À1 ). Lorcaserin also promoted a significant reduction in haemoglobin A1c (HbA1c) of 0.9%, compared with a reduction of 0.4% with placebo (difference of 0.5%). A subsequent post hoc analysis of this Phase III BLOOM-DM study supported the hypothesis that the glucose-lowering effect of lorcaserin in patients with T2DM occurs with or without weight loss (7). This suggested lorcaserin may have beneficial metabolic effects (especially with regard to glucose parameters) independent of lorcaserin-promoted weight loss.
Because anti-obesity agents may have metabolic effects beyond reducing body fat alone, it may be useful to quantify the relative weight-dependent and weightindependent effects of anti-obesity agents. Mediation analysis is a statistical application that quantifies multiple mechanisms that may help explain a cause-and-effect relationship (8). In a mediation analysis, key factors influencing the relationship between an independent variable (e.g. anti-obesity agent) and a dependent variable (e.g. metabolic parameter) are examined via inclusion of a mediating variable (e.g. weight loss) (9). However, mediation analyses have limitations in that definitive proof of the findings of the mediation analysis requires clinical trials designed specifically to test the hypothesis. Nonetheless, the application of a mediation analysis can provide hypothesis-generating insights into potential mechanisms of causality and rank the relative contributions of an independent variable mediator, on a dependent variable (9).
For example, a prior mediation analysis of liraglutide (an injectable, glucagon-like peptide-1 agonist) supported weight loss-dependent and weight lossindependent metabolic effects (9). Liraglutide-induced weight loss was predominantly associated with improvements in waist circumference, triglycerides, diastolic blood pressure and high-density lipoprotein (HDL) cholesterol levels, as well as Apnea-Hypopnea Index and Impact of Weight on Quality of Life (IWQoL)-Lite total and physical function scores (ranked 88-100%) (9). Liraglutide-induced weight loss had an intermediate effect on systolic blood pressure, low-density lipoprotein (LDL) cholesterol, total cholesterol and Short-Form-36 general health and physical function scores (ranked 59-67%) (9). Approximately 26-32% of the reductions in glucose parameters (e.g. fasting plasma glucose levels and HbA1c) were attributable to liraglutide-promoted weight loss (9). This was expected, given that liraglutide is not only approved as a weight management pharmacotherapy but also as an anti-DM agent. Thus, the findings of this prior mediation analysis were consistent with the known clinical effects of liraglutide (enhanced glucosedependent insulin secretion by the pancreatic beta cell, suppression of inappropriately elevated glucagon secretion and slowing of gastric emptying). It was also supportive of the potential for a weight-management pharmacotherapy to have both weight loss-dependent and weight loss-independent effects.
The purpose of this report is to quantify the relative weight loss-dependent and weight loss-independent effects of lorcaserin. Lorcaserin clinical trial data were subjected to a mediator analysis to better quantify the relative contribution of lorcaserin to weight loss on metabolic parameters. In this case, the mediator analysis evaluated the association between an independent variable (i.e. treatment with lorcaserin 10 mg BID) and a dependent variable (outcome) through a third variable called a mediator (i.e. weight loss). The hypothesis prior to application of this mediator analysis was that lorcaserin would have both weight loss-dependent and weight lossindependent effects, especially with regard to glucose and HbA1c parameters.
Non-HDL cholesterol was calculated as total cholesterol less the cholesterol carried by HDL (total cholesterol -HDL cholesterol). Remnant cholesterol was calculated as total cholesterol less the cholesterol carried by LDL and HDL (total cholesterol -LDL cholesterol -HDL cholesterol). The American College of Cardiology/American Heart Association (ACC/AHA) Risk Score was performed on patients without T2DM and with/without metabolic syndrome (n = 5,658; ACC/AHA Risk Score non-DM/ non-MetSyn) and patients with T2DM or metabolic syndrome (n = 2,097; ACC/AHA Risk Score DM/MetSyn).
Metabolic syndrome was defined as the presence of at least three of the following five parameters: waist circumference >35 in. in women and >40 in. in men; fasting plasma glucose levels >100 mg dL À1 ; triglyceride levels ≥150 mg dL À1 ; HDL cholesterol <50 mg dL À1 in women or <40 mg dL À1 in men; and/or systolic blood pressure >130 mmHg or diastolic blood pressure >85 mmHg.
Mediation analysis investigates the association between an independent variable (exposure) and a dependent variable (outcome) through a third variable called a mediator (12). The independent variable was an exposure to treatment with lorcaserin 10 mg BID or placebo. The dependent variable (outcome) was assessed for changes from baseline at Week 52 last observation carried forward (LOCF). The mediator in this analysis was weight change from baseline to Week 52 LOCF (12).
In preliminary analyses among multiple baseline covariates in a stepwise linear regression model, age and diastolic blood pressure were significantly associated with weight change at Week 52 LOCF. Therefore, linear regression models applicable to age and diastolic blood pressure were applied to both outcomes (dependent variables) and weight loss (mediator). The mediation Rpackage was used to conduct all analyses (13). The 95% confidence intervals were estimated using the quasi-Bayesian Monte Carlo method, based on normal approximation (14).
The results of the mediation analysis are shown in Table 1 and Figure 1. A mediation analysis should be considered hypothesis generating, and thus, definitive statements of causality require confirmation by definitive clinical trials that test the hypothesis. In this mediation analysis, lorcaserin-associated weight loss accounted for almost all the reductions in waist circumference and systolic and diastolic blood pressure. Other measured parameters that ranked ≥80%, as mediated by lorcaserin-associated weight loss, included a reduction in the ACC/AHA Risk Score among patients without T2DM, reduction in triglyceride levels, improvement in the IWQoL survey, reduction in insulin blood levels, reduction in aspartate aminotransferase (AST), increase in HDL cholesterol and reduction in remnant cholesterol.
Measured parameters wherein lorcaserin-associated weight loss had an intermediate effect (50-79%) included reductions in ACC/AHA Risk Score among patients with T2DM, reduction in heart rate, reduction in non-HDL cholesterol, reduction in total cholesterol, reduction in alanine aminotransferase (ALT), reduction in AST/ALT ratio, reduction in homeostatic model assessment-insulin resistance and reduction in LDL cholesterol. In addition, measured parameters wherein lorcaserin effects were mostly independent of weight loss (ranked <50%) included the glycaemic parameters of reduced fasting plasma glucose (33.7%) and reduced HbA1c (46.6%).

Obesity Science & Practice
Lorcaserin weight-loss dependent effects H. Bays et al. 501

Discussion
Serotonin or 5-HT is a neurotransmitter that not only regulates food intake and energy expenditure but also mediates glucose homeostasis (16)(17)(18). Lorcaserin is a selective 5-HT2C receptor agonist. Human data support the hypothesis that lorcaserin-mediated improvement in metabolic parameters may be mediated by both weight loss-dependent and weight loss-independent effects, especially regarding improvements in glycaemic parameters (7). This report further explores this hypothesis via application of a statistical model of mediation analysis, which helps quantify and rank the relative contribution of weight loss to various metabolic and clinical parameters. According to this mediation analysis, the reduction in waist circumference plus diastolic and systolic blood pressure were almost entirely due to lorcaserin-associated weight loss. Conversely, <50% of the lorcaserin-associated improvements in glucose parameters (fasting plasma glucose levels and HbA1c) were attributable to weight loss.
No therapeutic agent that specifically targets serotonergic pathways is yet approved for treatment of DM. However, due to the reported effects of serotonergic agents in improving glucose metabolism, the serotonin pathway has often been considered a therapeutic treatment target for novel anti-DM agents (19). In human clinical trials, data support various serotonergic agents as favourably affecting glucose metabolism via mechanisms that appear to be independent of weight loss and not associated with increased insulin levels (20)(21)(22). Such effects would be consistent with the tissue expression and metabolic effects of serotonergic receptors, both in peripheral tissues and in the central nervous system (5,23). However, many serotonergic agents previously reported to favourably affect glucose and other metabolic parameters were not specific in their binding to serotonergic receptors.
So how might serotonergic agents affect glucose parameters? Lorcaserin is highly selective for the 5-HT2C central receptors (24), which are G-coupled receptors found in the brain choroid plexus, cerebral cortex, basal ganglia and limbic system. Lorcaserin is thought to act upon the arcuate nucleus area of the hypothalamus via neural areas having energy balance functions (e.g. proopiomelanocortin [POMC], agouti-related peptide and cocaine-regulated and amphetamine-regulated transcript). Specifically, lorcaserin is believed to activate POMC neurons, resulting in second-order signalling via melanocortin 4 (MC4) receptors (25,26). Centrally,  activation of MC4 receptors may reduce appetite and thus contribute to weight loss. Increased MC4-receptor activation may also increase sympathetic nerve activity (27), which may promote adipose tissue lipolysis (28). Adipocytes and adipose tissue are not inert; they are metabolically active. During positive caloric balance and onset of overweight and obesity, adipocyte hypertrophy and visceral adiposity become the anatomical findings of adiposopathy (i.e. fat cell and fat organ endocrine and immune dysfunction) (29). Reductions in adipocyte size and adipose tissue expansion with MC4 activation potentially improve adipocyte and adipose tissue functionality and thus improve metabolic parameters such as hyperglycaemia (30). Furthermore, during calorie restriction, sympathetic nervous system activity (as might be promoted by MC4 activation) may be required for energy liberation and reduction in adipose tissue, especially for visceral-fat reduction during early weight loss (31). These mechanisms may help explain why weight loss via MC4 activation (as occurs with lorcaserin) may improve metabolic parameters such as markers of glucose homeostasis.
While fat weight loss alone may help improve multiple metabolic parameters (32), MC4 activity may affect glucose levels beyond its effects upon body weight. In rodent models of MC4 deficiency, young, lean MC4knockout mice have impaired insulin tolerance and increased insulin levels before onset of detectable hyperphagia or obesity (33). Potential weight-independent mechanisms explaining how MC4 activation may improve glucose metabolism include increased insulin sensitivity, increased glucose transporter 4 expression and reduced hepatic glucose production (33)(34)(35). MC4 activation may also facilitate leptin-promoted improvement in glucose metabolism (36). With specific regard to lorcaserin, murine models of T2DM suggest lorcaserin improves glycaemic control in the absence of reduction in food intake or body weight. These improvements in glycaemic parameters require sufficient POMC activity and functional MC4-receptor signalling, both of which contribute to lorcaserin-mediated increased insulin sensitivity, reduction in hepatic glucose production and increased glucose disposal (37,38).
Given all the aforementioned information, it may not be surprising that, at least since 2007 (before the development and approval of lorcaserin), 5-HT2C receptor agonists were proposed as having the potential to improve glucose tolerance and reduce plasma insulin levels in murine models of obesity and T2DM. In these earlier studies, improvement in glucose metabolism was found even at concentrations of 5-HT2C receptor agonists that had no effect on ingestive behaviour, energy expenditure, locomotor activity, body weight or fat mass (38).
Regarding non-glycaemic metabolic parameters in this mediation analysis, lorcaserin-associated weight loss accounted for almost all reductions in waist circumference and systolic and diastolic blood pressure. Metabolic parameters that ranked ≥80%, as mediated by lorcaserinassociated weight loss, included a reduction in the ACC/AHA Risk Score among patients without T2DM, Figure 1 Relative contribution of weight loss (data truncated at 100%) on cardiometabolic parameters from Phase III clinical trials, ranked by effect size from smallest (least weight dependent) to largest (most weight dependent). ACC/AHA, American College of Cardiology/American Heart Association; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DM, diabetes mellitus; HbA1c, haemoglobin A1c; HDL, high-density lipoprotein; HOMA-IR, homeostatic model assessment-insulin resistance; IWQoL, impact of weight on quality of life; LDL, low-density lipoprotein; MetSyn, metabolic syndrome. reduction in triglyceride levels, improvement in the IWQoL survey, reduction in insulin blood levels, reduction in AST, increase in HDL cholesterol and reduction in remnant cholesterol. Lorcaserin-associated weight loss had an intermediate effect (50-79%) on reduction in ACC/AHA Risk Score among patients with T2DM, a reduction in heart rate, a reduction in non-HDL cholesterol, a reduction in total cholesterol, a reduction in ALT, a reduction in AST/ALT ratio, a reduction in homeostatic model assessment-insulin resistance and a reduction in LDL cholesterol.

Conclusion
This report of a mediation analysis of lorcaserin is generally consistent with clinical trial data collected over the past several decades regarding the potential weight loss-independent effects of serotonergic agents, especially with regard to improving glycaemic parameters. This mediation analysis of lorcaserin is also consistent with specific animal and human studies that have examined the effects of lorcaserin, with the greatest evidence of weight loss-independent effects being those related to glycaemic control. Further information regarding the effects of lorcaserin on glucose metabolism, and/or patients with DM, will likely be found pending the results of the ongoing Cardiovascular And Metabolic Effects of Lorcaserin In Overweight And Obese Patients-Thrombolysis in Myocardial Infarction 61 (CAMELLIA-TIMI61) lorcaserin cardiovascular outcomes trial.