Lorcaserin Treatment Research Articles

Lorcaserin and phentermine exert anti-obesity effects with modulation of the gut microbiota.

Although drugs have been reported to modulate the gut microbiota, the effects of anti-obesity drugs on the gut microbiota remain unclear. Lorcaserin (LS) and phentermine (PT) are commonly used anti-obesity drugs. However, to our best knowledge, no studies have simultaneously assessed the effects of LS and PT on obesity and gut microbiota. This study aimed to explore the relationship between the anti-obesity effects of LS and PT and re-modulation of host gut microbiota. To test hypothesis, we fed C57BL/6J mice with a high-fat diet supplemented with LS and PT via oral gavage for 8 weeks. After sacrifice, body weight, fat accumulation, and serum biomarkers were measured, and the gut microbial composition was analyzed using 16 s rRNA amplicon sequencing. LS and PT were observed to modulate the gut microbial composition and restore gut microbial dysbiosis, as indicated by an increased Firmicutes/Bacteroidetes ratio. Significantly modulated genera by LS and PT treatment were strongly correlated with obesity-related markers. Additionally, LS and PT increased the mRNA level of G protein-coupled receptor 120 (GPR120) in the colon tissue. ASV3566, which corresponds to Eubacterium coprostanoligenes, was correlated with GPR120 and obesity-related markers such as glutamic pyruvic transaminase (GPT) and serum triglyceride (TG). In conclusion, LS and PT can modulate the gut microbiota dysbiosis and the gut microbiota plays a role in mediating the anti-obesity effect of drugs.

Circulating total and intact GDF-15 levels are not altered in response to weight loss induced by liraglutide or lorcaserin treatment in humans with obesity

BackgroundGrowth differentiation factor 15 (GDF-15) is a stress-response cytokine proposed to be associated with body weight regulation. AimsThe primary aim was to investigate changes of circulating intact GDF-15 (wildtype, non-carrier of the rs1058587 polymorphism coding for the H2O2D mutation) and total GDF-15 (measured irrespective of the mutation) in response to liraglutide (GLP-1 receptor agonist) and lorcaserin (5-HT2C receptor agonist), two pharmacologic agents that induce food intake and weight reduction. In addition, we perform exploratory correlations of total and intact GDF-15 with clinical, hormonal and metabolo-lipidomic parameters in humans with obesity. Materials and methodsWe utilized two studies: 1) Study 1, a randomized, double-blinded, cross-over trial of liraglutide and placebo administration for 5 weeks in subjects with obesity (n = 20; BMI = 35.6 ± 5.9 kg/m2), in escalating doses starting at 0.6 mg/day on week 1 and increased every week, up to the highest dose of 3.0 mg/day during week 5. b) Study 2, a randomized, double-blinded trial of lorcaserin 10 mg twice daily, or placebo for 12-weeks in humans with obesity (n = 34 BMI = 37.4 ± 6.1 kg/m2). Total and intact GDF-15 levels were measured with novel enzyme-linked immunosorbent assays and the metabolomics and lipidomics analysis was performed with nuclear magnetic resonance spectroscopy. ResultsTotal and intact GDF-15 were positively correlated with diabetes risk index and trimethylamine N-oxide and negatively with eGFR. Despite significant changes in body weight, total and intact GDF-15 were not altered in response to liraglutide or lorcaserin treatment in subjects with obesity. ConclusionsTotal and intact GDF-15 levels are not altered in response to liraglutide or lorcaserin therapy and are thus not directly involved in the metabolic feedback loop pathways downstream of GLP1 or 5-HT2C receptor agonists. Since neither total nor intact GDF-15 levels were altered in response to weight loss, future studies are needed to elucidate the pathways activated by GDF-15 in humans and its role, if any, in body weight regulation and energy homeostasis.

Chronic Lorcaserin Treatment Reverses the Nicotine Withdrawal-Induced Disruptions to Behavior and Maturation in Developing Neurons in the Hippocampus of Rats.

Preclinical data have shown that treatment with serotonin (5-HT)2C receptor agonists inhibits the behavioral effects of nicotine, including self-administration, reinstatement, and locomotor responses to nicotine. Since the data on the effects of 5-HT2C receptor agonism on nicotine withdrawal signs are limited, we aimed to investigate whether 5-HT2C receptor agonism alleviated the behavioral and neurobiochemical (hippocampal neurogenesis) consequences of nicotine withdrawal in Sprague-Dawley rats. Our data indicate that withdrawal from nicotine self-administration induced locomotor hyperactivity, lengthened immobility time (the forced swim test), induced ‘drug-seeking’ behavior and deficits in cognition-like behavior (the novel object recognition task). A two-week exposure to the 5-HT2C receptor agonist lorcaserin attenuated locomotor hyperactivity and induced recovery from depression-like behavior. Analyses of brain slices from nicotine-withdrawn animals revealed that lorcaserin treatment recovered the reduced number of doublecortin (DCX)-positive cells, but it did not affect the number of Ki-67- or 5-bromo-2’-deoxyuridine (BrdU)-positive cells or the maturation of proliferating neurons in drug-weaned rats. To summarize, we show that lorcaserin alleviated locomotor responses and depression-like state during nicotine withdrawal. We propose that the modulatory effect of lorcaserin on the ‘affective’ aspects of nicotine cessation may be linked to the positive changes caused by the compound in hippocampal neurogenesis during nicotine withdrawal.

Lorcaserin treatment for extended-release naltrexone induction and retention for opioid use disorder individuals: A pilot, placebo-controlled randomized trial

BackgroundOpioid Use Disorder (OUD) is a significant public health problem associated with severe morbidity and mortality. While effective pharmacotherapies are available, limitations exist with each. Induction onto extended-release naltrexone (XR-NTX) is more difficult than initiation of buprenorphine or methadone, even in inpatient settings, as it is recommended that patients remain abstinent for at least 7 days prior to initiating XR-NTX. The purpose of this trial was to determine if lorcaserin, a 5HT2c agonist, improves outpatient XR-NTX induction rates. MethodsAn 8-week trial beginning with a brief detoxification period and induction onto XR-NTX. Sixty participants with OUD were enrolled in the trial, with 49 participants at the initiation of detoxification randomized to lorcaserin or placebo for 39 days. Additionally, ancillary medications were provided. The primary outcome was the proportion of participants inducted onto the first XR-NTX injection. Secondary outcomes were withdrawal severity (measured by COWS and SOWS) prior to the first injection and the proportion of participants receiving the second XR-NTX injection. ResultsThe proportion of participants inducted onto the first (lorcaserin: 36 %; placebo: 44 %; p = .67) and the second XR-NTX injection (lorcaserin: 27 %; placebo: 31 %; p = .77) was not significantly different between treatment arms. Prior to the first injection, withdrawal scores did not significantly differ between treatment arms over time (treatment*time interaction COWS: p = .11; SOWS: p = .39). ConclusionsLorcaserin failed to improve outpatient XR-NTX induction rates. Although this study is small, the findings do not support the use of lorcaserin in promoting induction onto XR-NTX or in mitigating withdrawal symptoms.

140-OR: Inhibition of Serotonin 2c Receptor Internalization Potentiates Lorcaserin Effect on Body Weight Loss

As a body weight management medicine, lorcaserin, a selective agonist of serotonin 2C receptor (5-HT2CR) which is a G protein-coupled receptor, fails to maintain its effect on body weight loss after a long term administration. Thus, it is necessary to find a way to strengthen its effect on obesity treatment. It has been reported that the effect of lorcaserin on body weight loss is by activating Pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARH). However, how POMCARH neuron activity changes after long term lorcaserin treatment remains unknown. In the present study, we found that POMCARH neurons cannot maintain its sensitivity to further lorcaserin stimulation after a long term lorcaserin treatment. By using in vitro electrophysiology recording and c-Fos immunostaining in the brain slice from control mice, we found that acute lorcaserin application significantly increased POMCARH neuron activity. However, this activation effect significantly decreased in mice with lorcaserin administration for consecutive 20 days. By in vivo fiber photometry calcium recording, we found that lorcaserin significantly increased POMCARH neuron activity in vivo at first day, but this activation effect decreased after 10 days lorcaserin treatment and almost disappeared after 20 days lorcaserin treatment. We further showed that this desensitization of POMCARH neurons to lorcaserin stimulation is mainly due to a beta-arrestin-mediated excessive internalization of 5-HT2C receptor in POMCARH neurons. Barbadin, a novel selective β-arrestin/adaptor protein 2 interaction inhibitor, maintains POMCARH neuron sensitivity to further lorcaserin stimulation by blocking prolonged lorcaserin-induced aberrant 5-HT2C receptor internalization. Co-treatment with barbadin also prolongs lorcaserin’s effect on body weight loss and food intake reduction in mice. Overall, our results may provide a potential strategy for facilitating obesity treatment by lorcaserin. Disclosure Y. He: None. H. Liu: None. Y. Xu: None.

Lorcaserin maintenance fails to attenuate heroin vs. food choice in rhesus monkeys

BackgroundThe current opioid crisis has reinvigorated preclinical research in the evaluation of non-opioid candidate treatments for opioid use disorder (OUD). Emerging evidence suggests 5-HT2C receptor agonists may attenuate the abuse-related effects of opioids. This study evaluated effectiveness of 7-day treatment with the clinically available 5-HT2C agonist lorcaserin (Belviq®) on heroin-vs.-food choice in rhesus monkeys. Lorcaserin effects were compared to effects produced by 7-day saline substitution and by 7-day treatment with the opioid antagonist naltrexone. MethodsAdult male (1) and female (6) rhesus monkeys were trained to respond under a concurrent schedule of food delivery (1 g pellets, fixed-ratio 100 schedule) and intravenous heroin injections (0-0.032 mg/kg/injection, fixed-ratio 10 schedule) during daily 2 h sessions. Heroin choice dose-effect functions were determined daily before and following 7-day saline substitution or 7-day continuous treatment with naltrexone (0.0032-0.032 mg/kg/h, IV) or lorcaserin (0.032-0.32 mg/kg/h, IV). ResultsUnder baseline conditions, increasing heroin doses maintained a dose-dependent increase in heroin choice. Both saline substitution and 7-day naltrexone treatment significantly attenuated heroin choice and produced a reciprocal increase in food choice. Continuous lorcaserin (0.32 mg/kg/h) treatment significantly increased heroin choice. ConclusionsIn contrast to saline substitution and naltrexone, lorcaserin treatment was ineffective to reduce heroin-vs.-food choice. These preclinical results do not support the therapeutic potential and continued evaluation of lorcaserin as a candidate OUD treatment.

2096-P: Real-World Examination of Lorcaserin Treatment in Patients with Type 2 Diabetes, Prediabetes, and Metabolic Syndrome

Background: Lorcaserin is a serotonin 2C receptor agonist approved in the U.S. as adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in patients with a BMI ≥ 30 or ≥ 27 with at least one weight-related comorbidity. To date, there is limited data on the real-world use of lorcaserin for weight management, including in patients diagnosed with T2DM, prediabetes, and metabolic syndrome. Methods: A retrospective chart review was performed at the Scripps Clinic Weight Management Center. Patients were identified if they had at least one prescription for lorcaserin and were ≥ 18 years old. Weight change at 90 days and reason for discontinuation were assessed for patients with at least one day on pharmacotherapy. Patients with weight loss of ≥ 5% at 90 days were defined as medication “responders.” Results: A total of 118 overweight and obese patients filled a prescription for lorcaserin. Of these, 69 (58%) remained on lorcaserin ≥ 90 days (median follow-up was 306 days). Mean age was 53 years old, 73% were female, and mean baseline weight was 102 kg (BMI= 36). For patients who had follow-up weight information available (N=65), overall mean weight loss at 90 days was -3.5 kg (-4%) from baseline, responders had a decrease -7 kg (-7%, n=24) versus -1 kg (-2%) for non-responders (n=41). For patients diagnosed with metabolic syndrome (n=25), mean weight loss for responders (n=10, 40%) was -6.7 kg (-7%) versus -2.1 kg (-2%) for non-responders (n=15). Similar weight loss was observed in patients with T2DM and prediabetes. Conclusion: These "real world" results represent a group of commercially insured overweight and obese patients and demonstrate that weight loss programs can use lorcaserin and expect to get significant weight loss when used according to the label. Disclosure S.R. Harris: Consultant; Self; Sanofi. Research Support; Self; Eisai Inc. R.L. Knoth: Employee; Self; Eisai Inc. X. Li: Employee; Self; Eisai Inc. I. Khilfeh: Employee; Self; Eisai Inc. J. Choi: Employee; Self; Eisai Inc. Stock/Shareholder; Self; Johnson & Johnson. A. Philis-Tsimikas: Advisory Panel; Self; AstraZeneca, Lilly Diabetes, Novo Nordisk A/S, Sanofi. Employee; Spouse/Partner; Ionis Pharmaceuticals, Inc. Research Support; Self; Dexcom, Inc., Glooko, Inc., National Institute of Diabetes and Digestive and Kidney Diseases. Stock/Shareholder; Spouse/Partner; Ionis Pharmaceuticals, Inc., Novo Nordisk Inc. K. Fujioka: Consultant; Self; Eisai Inc. Funding Eisai Inc.

Effect of lorcaserin in different age groups: a post hoc analysis of patients from the BLOOM, BLOSSOM and BLOOM-DM studies.

SummaryIntroductionThe elderly population is projected to be the fastest growing group of individuals with obesity group in the United States. As such, there is merit in examining factors that contribute to healthy aging and weight management. The effects of newer weight loss medications approved after 2013 have been studied but are not often assessed specifically in older persons.MethodsThis post hoc analysis evaluated the magnitude of weight loss in adults across age quartiles with lorcaserin, a serotonin (5‐HT) 2C receptor agonist indicated as an adjunct to a reduced‐caloric diet and increased physical activity for chronic weight management. Data from three lorcaserin pivotal phase 3 studies were used in this analysis. Data for patients with overweight/obesity without type 2 diabetes (T2D; BLOOM/BLOSSOM; body mass index [BMI] 27.0–29.9 kg/m2 and ≥1 comorbidity or BMI 30.0–45.0 kg/m2) and patients with overweight/obesity with T2D (BLOOM‐DM; BMI 27.0–45.0 kg/m2) were used. Patients were randomized to receive lorcaserin 10 mg twice daily or placebo in addition to diet and exercise for 52 weeks. Age quartiles between the studies differed as the T2D population was on average, 9 years older.ResultsThis analysis shows that lorcaserin was associated with improved weight loss relative to placebo regardless of age. Importantly, these results were consistent for patients with and without T2D. Interestingly, the magnitude of weight loss for lorcaserin appeared to increase with increasing age. In patients without T2D, odds of achieving ≥5% and ≥10% reduction in body weight at 52 weeks were significantly higher for patients >36 years. Lorcaserin was well tolerated in all patients across all quartiles including the oldest quartile.ConclusionsIn summary, this post hoc analysis demonstrates that lorcaserin treatment in patients with and without T2D was safe and effective at reducing weight across all age groups analysed. Weight loss appeared to be greater for older patients; additional analyses are warranted to confirm these findings and to better understand the factors for improved weight loss.

Lorcaserin treatment decreases body weight and reduces cardiometabolic risk factors in obese adults: A six-month, randomized, placebo-controlled, double-blind clinical trial.

Lorcaserin is a serotonin 2c receptor agonist that promotes weight loss while contributing to the prevention and improvement of type 2 diabetes and improvement of atherogenic lipid profiles, without higher rates of major cardiovascular events. The full spectrum of possible lorcaserin-induced improvements in cardiometabolic health remains to be clarified. Thus, we investigated the way in which lorcaserin treatment may alter cardiovascular disease risk, either independently or through changes in body weight. We measured, for the first time, lipid particle quantification, lipid peroxidation, appetite-regulating hormones and mRNA expression of the 5-hydroxytryptamine 2c receptor (5-HT2c receptor). A total of 48 obese participants were enrolled in this six-month, randomized (1:1), placebo-controlled, double-blinded clinical trial. Lorcaserin treatment reduced fat mass (P < 0.001), the fatty liver index (P < 0.0001) and energy intake (P < 0.03) without affecting energy expenditure or lean mass. Total low-density lipoprotein (LDL) (P < 0.04) and small LDL particles (P < 0.03) decreased, while total high-density lipoprotein (HDL) P < 0.02) increased and heart rate significantly decreased with lorcaserin treatment. No mRNA expression of the 5-HT2c receptor was observed in peripheral organs. These data suggest that lorcaserin treatment for six months improves cardiometabolic health in obese individuals, acting mainly through the brain.

How does lorcaserin facilitate weight loss and who will benefit?

Pharmacotherapy for obesity, as an adjunct to targeted behavioural modifications, can facilitate weight loss. Previous serotonergic candidates have been withdrawn owing to undesirable cardiovascular effects. A new study in a large sample of high-risk patients shows lorcaserin treatment leads to no greater increase in cardiovascular problems than placebo — what does this result mean for personalized pharmacotherapy for obesity?

Lorcaserin decreases the reinforcing effects of heroin, but not food, in rhesus monkeys

Preclinical studies indicate that lorcaserin (Belviq®), an FDA-approved serotonin 2 C receptor agonist, may be a promising medication for the treatment of stimulant addiction. However, few studies have investigated its effects on self-administration of drugs of abuse from other pharmacological classes, including opioids. Here, adult male rhesus macaques (N = 3) responded under a fixed ratio 30 schedule of food (1-g banana-flavored pellets) and IV heroin delivery. Following stable self-administration of a range of heroin doses (0.32–32 μg/kg/inj, IV), the effects of acute pretreatment with lorcaserin (0.32–1.0 mg/kg, IM) on heroin- and food-maintained responding was determined. The ability of repeated treatment with lorcaserin (1.0 mg/kg) to produce sustained decreases in heroin and/or food intake and reinforcing strength were then analyzed using behavioral economic demand procedures. Results show that self-administration of intravenous heroin was dose-dependent, with peak responding maintained, on average, by the unit dose of 3.2 μg/kg/inj. Lorcaserin pretreatment produced a dose-dependent flattening of the dose-response function for heroin self-administration in each subject. On the other hand, lorcaserin did not decrease food-maintained responding. Repeated lorcaserin treatment reduced heroin intake by selectively decreasing its reinforcing strength, as evidenced by a leftward shift in the demand curves for heroin and the absence of comparable changes in the reinforcing strength of food. These results indicate that serotonin 2 C receptor agonists, such as lorcaserin, have behaviorally selective effects on IV self-administration behavior, and deserve further consideration as candidates for the management of opioid use disorder.

Effects of lorcaserin (Belviq®) on nicotine- and food-maintained responding in non-human primates

BackgroundAccumulating evidence suggests that the FDA-approved serotonin 5-HT2C receptor agonist, lorcaserin (Belviq®), may be a promising candidate for the management of substance use disorders, including nicotine addiction. The present study was conducted to determine the efficacy and selectivity of acute or continuous lorcaserin treatment for decreasing the reinforcing effects of nicotine in a primate species. MethodsAdult rhesus monkeys (n=4) with a history of nicotine self-administration (>2years) responded for injections of nicotine (0.32–100μg/kg IV) or food pellets under a fixed-ratio schedule of reinforcement during daily 100-min sessions. When responding was stable, lorcaserin was administered either as an acute pretreatment (0.1–1.0mg/kg, IM) or by continuous infusion (0.1mg/kg/hr, SC for 3–5days). Daily activity patterns were also monitored immediately following experimental sessions. ResultsResults indicate that acute lorcaserin pretreatment produced significant and dose-dependent decreases in nicotine-maintained responding across a >100-fold range of self-administered nicotine doses. Continuous lorcaserin treatment decreased intake of 10μg/kg/inj nicotine to about 50% of baseline values. Food-maintained responding was only moderately decreased in 3 of 4 subjects after acute administration and unaffected in all subjects during continuous treatment. Daily activity also was significantly decreased—to ≤50% of control values—following experimental sessions in which acute lorcaserin was administered. ConclusionsThese data indicate that lorcaserin reduces IV self-administration of nicotine at a dose that decreases motoric activity but less consistently disrupts food-maintained responding. Further research into lorcaserin’s potential utility for the management of nicotine dependence is warranted.

Abstract P456: Examining Framingham Coronary Heart Disease 10-year Risk Reduction in Individuals Treated With Lorcaserin, a Selective 5HT 2C Receptor Agonist for Weight Management

Introduction: Obesity contributes significantly to cardiovascular disease (CVD) risk and weight management is associated with CVD risk reduction. Lorcaserin, a selective 5HT 2C receptor agonist, is indicated as an adjunct to a reduced-calorie diet and increase physical activity for weight management in adults with obesity (BMI≥30) and overweight (BMI 27-29.9 and ≥1 weight-related comorbidity). This analysis used the Framingham 10-year CVD risk to examine the impact of lorcaserin treatment on CVD risk and risk reduction. Method: Pooled data from two randomized, double-blind studies (BLOOM &amp; BLOSSOM) investigating the efficacy of lorcaserin vs. placebo among non-diabetic patients with overweight or obesity, were used in this analysis. Framingham CVD risk was calculated for those whose lipid values were available at baseline and at one year. A Framingham CVD risk of &lt;5% was classified as low risk. Patients were stratified by cohort, lorcaserin (LOR) vs. placebo (PBO) and response at week 12 (≥5% weight loss vs. &lt; 5%) for calculating the 10-year CVD risk at one year. Logistic regression was used to adjust for baseline risk and determine if proportional differences in risk reduction were significant. Results: A total of 5,658 patients were evaluated, 51% treated with LOR. Among the LOR-treated patients, 43% achieved ≥5% weight loss at week 12 (compared to 19% treated with PBO). At one year, more patients in the LOR cohort had reduced CVD risk (from high to low risk, 21% vs. 15%, respectively). The regression analysis showed LOR-treated patients were 34% more likely to have low CVD risk (p&lt;0.001). Similarly, for patients who lost ≥5% baseline body weight at 12 weeks, more patients in the LOR cohort had reduced CVD risk (from high to low risk, 26% vs. 16% respectively) at one year. The regression showed LOR-treated patients were 23% more likely to have low CVD risk (p&lt;0.05). Conclusion: The analysis suggests that patients treated with LOR are more likely to have low CVD risk at one year than those treated with PBO. The effect is magnified if patients have ≥5% weight loss at 12 weeks.

The atypical antipsychotic olanzapine causes weight gain by targeting serotonin receptor 2C.

Atypical antipsychotics such as olanzapine often induce excessive weight gain and type 2 diabetes. However, the mechanisms underlying these drug-induced metabolic perturbations remain poorly understood. Here, we used an experimental model that reproduces olanzapine-induced hyperphagia and obesity in female C57BL/6 mice. We found that olanzapine treatment acutely increased food intake, impaired glucose tolerance, and altered physical activity and energy expenditure in mice. Furthermore, olanzapine-induced hyperphagia and weight gain were blunted in mice lacking the serotonin 2C receptor (HTR2C). Finally, we showed that treatment with the HTR2C-specific agonist lorcaserin suppressed olanzapine-induced hyperphagia and weight gain. Lorcaserin treatment also improved glucose tolerance in olanzapine-fed mice. Collectively, our studies suggest that olanzapine exerts some of its untoward metabolic effects via antagonism of HTR2C.

Lorcaserin decreases the reinforcing effects of 3,4‐methylenedioxypyrovalerone (MDPV) and cocaine in Sprague‐Dawley rats

Lorcaserin is a serotonin (5‐HT) 2C receptor‐preferring agonist that is currently approved by the Food and Drug Administration to treat obesity; however, its behavioral effects are also mediated by 5‐HT 2A and 1A receptors. Agonists acting at 5‐HT2C receptors are known to dampen dopamine neurotransmission, an effect that could be beneficial for treating drug abuse. 3,4‐Methylenedioxypyrovalerone (MDPV) is a cocaine‐like monoamine reuptake inhibitor that is commonly found in abused bath salt preparations. Recent studies have demonstrated lorcaserin decreases the reinforcing effects of cocaine in rats and monkeys, and the present study aimed to: (1) determine whether lorcaserin was equally effective at decreasing the reinforcing effects of MDPV and cocaine; and (2) determine the receptor(s) responsible for the effects of lorcaserin on cocaine and MDPV self‐administration. Male Sprague‐Dawley rats (n=6) were injected with lorcaserin (0.1–5.6 mg/kg, IP) 25 minutes before the initiation of MDPV or cocaine self‐administration sessions. Lorcaserin was equipotent at suppressing responding for MDPV and cocaine; however, individual differences in sensitivity to lorcaserin were observed. To determine which receptor mediated the effects of lorcaserin, rats were administered 5‐HT1A (WAY100635, 0.178 mg/kg), 5‐HT2A (MDL100907, 0.1 mg/kg), or 5‐HT2C (SB242084, 0.1 mg/kg) receptor antagonists (IP) 15 minutes prior to lorcaserin treatment. Antagonism of 5‐HT2C (but not 5‐HT1A or 5‐HT2A) receptors reversed the effects of lorcaserin on MDPV and cocaine self‐administration. Taken together, these data indicate lorcaserin may be an effective pharmacotherapy against MDPV and cocaine abuse through its agonist actions at 5‐HT2C receptors.Support or Funding InformationThis research was supported by the National Institutes of Health (NIH) and the National Institute on Drug Abuse (NIDA) R01DA039146 (GTC) and T32DA031115 and the NIH Intramural Research Programs of the NIDA and the National Institute of Alcohol Abuse and Alcoholism (NIAAA) (KCR).

Lorcaserin treatment allows for decreased number needed to treat for weight and glycemic parameters in week 12 responders with ≥5% weight loss

ABSTRACTObjectives: Lorcaserin is a serotonin 2C receptor agonist approved for chronic weight management. This analysis explores the number of patients needed to be treated (NNT) with lorcaserin for one more patient to achieve weight loss and glycemic goals.Methods: This is a post hoc analysis of three Phase 3 studies in adults with and without type 2 diabetes mellitus (T2DM) treated with lorcaserin 10 mg BID or placebo. NNT is reported for patients achieving ≥5% or ≥10% weight loss, achievement of either HbA1c <5.7% or FPG <100 mg/dL in patients with prediabetes, and reduction of HbA1c to <7% in patients with T2DM at Week 52.Results: In the modified intention-to-treat (MITT) population, NNTs for ≥5% and ≥10% weight loss were 3.6 and 6.2 (without T2DM) and 4.3 and 7.5 (with T2DM); in Week 12 responders (≥5% weight loss at Week 12), NNTs were 1.7 and 2.6 (without T2DM) and 1.9 and 3.2 (with T2DM). In patients with prediabetes, NNTs to achieve HbA1c <5.7% were 9.9 (MITT) and 5.2 (Week 12 responders). In patients with T2DM, NNTs to achieve HbA1c <7% were 4.2 (MITT) and 2.3 (Week 12 responders).Conclusion: In addition to weight management, lorcaserin improved glycemic control in patients with prediabetes and facilitated targeted HbA1c reduction in patients with T2DM, especially for those who achieved ≥5% weight loss by Week 12. Assessment of treatment response at Week 12 is a valuable tool to achieve efficient use of healthcare resources.Clinical trial registration: www.clinicaltrials.gov identifiers are NCT00395135, NCT00603291, and NCT00603902

Characterization of the 5-HT2C receptor agonist lorcaserin on efficacy and safety measures in a rat model of diet-induced obesity.

The 5-HT2C receptor agonist lorcaserin (Belviq®) has been Food and Drug Administration (FDA) approved for the treatment of obesity. The present study is a back translational investigation into the effect of 28-day lorcaserin treatment in a diet-induced obesity (DIO) model using male, Sprague–Dawley rats. An assessment of drug effect on efficacy and multiple safety endpoints including cardiac function was undertaken. Lorcaserin (1–2 mg/kg SC b.i.d.) significantly reduced percentage body weight gain compared to vehicle-treated controls (VEH: 10.6 ± 0.4%; LOR 1: 7.6 ± 1.2%; LOR 2: 5.4 ± 0.6%). Measurement of body composition using quantitative magnetic resonance (QMR) imaging indicated this change was due to the selective reduction in body fat mass. Modest effects on food intake were recorded. At the completion of the treatment phase, echocardiography revealed no evidence for valvulopathy, that is, no aortic or mitral valve regurgitation. The pharmacokinetics of the present treatment regimen was determined over a 7-day treatment period; plasma Cmin and Cmax were in the range 13–160 ng/mL (1 mg/kg b.i.d.) and 34–264 ng/mL (2 mg/kg b.i.d.) with no evidence for drug accumulation. In sum, these studies show an effect of lorcaserin in the DIO model, that in the context of the primary endpoint measure of % body weight change was similar to that reported clinically (i.e., 3.0–5.2% vs. 3.2%). The present studies highlight the translational value of obesity models such as DIO, and suggest that assuming consideration is paid to nonspecific drug effects such as malaise, the DIO model has reasonable forward translational value to help predict clinical outcomes of a new chemical entity.

Safety and Efficacy of Lorcaserin: A Combined Analysis of the BLOOM and BLOSSOM Trials

Background: Lorcaserin, a novel selective 5-HT2C receptor agonist, is approved by the US Food and Drug Administration (FDA) for weight management in combination with lifestyle modification for adults with obesity and adults with overweight and ≥ 1 weight-related comorbid condition. The safety and effectiveness of lorcaserin in adult patients without type 2 diabetes mellitus was established based on 2 phase III clinical trials of similar design: Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) and Behavioral Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM). This report presents a prespecified analysis of pooled data from these trials. Methods: Co-primary end points in this analysis include the proportion of patients with a reduction in baseline body weight of ≥ 5% and ≥ 10%, and a change in weight from baseline. Key secondary end points include changes from baseline values in lipid parameters, quality-of-life measures, glycemic indicators, and vital signs. Results: At week 52, more than twice as many lorcaserin-treated patients achieved a weight loss of ≥ 5% compared with placebo (lorcaserin, 47.1%; placebo, 22.6%), and lorcaserin-treated patients lost significantly more body weight (lorcaserin, −5.8%; placebo, −2.5%). A significantly greater proportion of lorcaserin-treated patients achieved a weight loss of ≥ 10% (lorcaserin, 22.4%; placebo, 8.7%). There were statistically significant improvements in lipid parameters, glycemic indicators, quality-of-life measures, and vital signs in the lorcaserin group compared with placebo. The most common adverse events associated with lorcaserin treatment were headache, upper respiratory tract infection, and nasopharyngitis. Lorcaserin-treated patients had a rate of FDA-defined valvulopathy similar to placebo. Conclusions: This pooled analysis of the phase III BLOOM and BLOSSOM trials shows that lorcaserin 10 mg twice daily, in combination with diet and exercise, is safe and tolerable, and is associated with statistically significant weight loss and clinically relevant improvements in cardiometabolic parameters.

Evaluation of chemically diverse 5-HT2C receptor agonists on behaviours motivated by food and nicotine and on side effect profiles

Selective 5-HT2C receptor agonists, such as lorcaserin, are being developed for the treatment of obesity. Studies suggest that they may also have therapeutic potential for addictive behaviours including nicotine dependence, although few drugs of this class have been evaluated. The primary aim was to evaluate the highly selective 5-HT2C agonist, CP-809101, against food-motivated (operant FR5 and progressive ratio schedules, palatability-induced feeding) and nicotine-motivated (intravenous self-administration, drug discrimination) behaviours in rats and to compare with equivalent findings for the structurally distinct 5-HT2C receptor agonists lorcaserin and Ro 60-0175. The secondary aims were to evaluate the side effect profiles of lorcaserin and CP-809101 and to determine the plasma levels of lorcaserin at a dose (1 mg/kg) that reduces both food and nicotine reinforcement for comparison to plasma concentrations reported in human trials. CP-809101 (0.3-3 mg/kg SC) reduced responding for both nicotine and food and blocked the discriminative stimulus properties of nicotine in a similar manner to lorcaserin and Ro 60-0175. Behaviours such as hypolocomotion, chewing and ptosis became evident following both CP-809101 and lorcaserin administration at higher doses. Plasma levels of lorcaserin were of similar range to those reported in obesity trials. These studies support the utility of 5-HT2C agonists as a therapeutic approach to treat nicotine dependence. Plasma exposure levels after acute lorcaserin treatment suggest that equivalent dosages could be used to evaluate these drugs in obesity and smoking cessation trials. Finally, there may be differences in the side effect profiles between lorcaserin and CP-809101, raising the possibility for tolerability differences amongst 5-HT2C agonists.