efficacy and safety of lorcaserin in obese adults: a meta-analysis of 1-year randomized controlled...

Obesity Treatment

Efficacy and safety of lorcaserin in obese adults: ameta-analysis of 1-year randomized controlled trials(RCTs) and narrative review on short-term RCTs

E. W. Chan, Y. He, C. S. L. Chui, A. Y. S. Wong, W. C. Y. Lau and I. C. K. Wong

Centre for Safe Medication Practice and

Research, Department of Pharmacology and

Pharmacy, The University of Hong Kong,

Hong Kong

Received 13 September 2012; revised 29

November 2012; accepted 10 December

2012

Address for correspondence: Professor ICK

Wong, Department of Pharmacology and

Pharmacy, Li Ka Shing Faculty of Medicine,

University of Hong Kong, 2/F Laboratory

Block, 21 Sassoon Road, Hong Kong.

E-mail: [email protected]

SummaryLorcaserin is a new anti-obesity drug recently approved by US Food and DrugAdministration. We conducted a systematic review and meta-analysis of rand-omized controlled trials (RCTs) to evaluate the association of lorcaserin therapywith weight loss and adverse events in obese adults (18–65 years old). Weight lossof 3.23 kg (95% confidence interval [CI]: 2.70, 3.75) and body mass indexreduction of 1.16 kg m-2 (95% CI: 0.98, 1.34) was observed compared withplacebo in RCTs of 1 year duration. The use of lorcaserin for 8 and 12 weeksreduced weight of 1.60 kg (95% CI: 0.34, 2.86) and 2.9 kg (95% CI: 2.2, 3.5),respectively. In comparison to placebo, lorcaserin decreased waist circumference,blood pressure, total cholesterol, low-density lipoprotein-cholesterol and triglyc-erides, however did not statistically affect heart rate or high-density lipoprotein-cholesterol. Headache, nausea and dizziness were found to be significantly higherin the patients receiving lorcaserin than patients receiving placebo, whereas diar-rhoea is no more likely than in patients receiving placebo. In conclusion, lorca-serin achieves modest weight loss and appears to be well tolerated. Clinical andpharmacovigilance studies with longer study duration are needed to inform of thelong-term efficacy and safety of lorcaserin.

Keywords: Lorcaserin, meta-analysis, treatment outcome, weight loss.

obesity reviews (2013)

Introduction

Obesity, a chronic pathological condition characterized byexcessive body fat accumulation, is now endemic in manydeveloped and developing countries (1). Between 1980 and2008, the prevalence of obesity dramatically increased glo-bally, with predominance in America (2). Obesity is one ofthe major causes of metabolic syndrome which is charac-terized by a cluster of metabolic abnormalities includingglucose intolerance, insulin resistance, central obesity, dys-lipidaemia and hypertension (3). It is claimed that thesemetabolic disturbances are associated with an increasedrisk of cardiovascular disease, rheumatic disease and cancer

(4). Therefore, obesity is expected to become a leadingcause of mortality and morbidity.

The National Institute for Health and Clinical Excellenceguidelines for obesity (NICE CG43) was issued in Decem-ber 2006 (5). The NICE CG43 guideline suggests that thedegree of being overweight or obesity in adults should bedefined based on different body mass index (BMI) as over-weight (25–29.9 kg m-2), obesity I (30–34.9 kg m-2),obesity II (35–39.9 kg m-2) and obesity III (�40 kg m-2). Interms of clinical recommendations, different interventionsfor weight management should be chosen based on theBMI, waist circumference and existing comorbidities. Thefirst step of obesity management is lifestyle interventions

obesity reviews doi: 10.1111/obr.12015

1© 2013 The Authorsobesity reviews © 2013 International Association for the Study of Obesity

including physical exercise, dietary control and behaviouraltherapies. Pharmacological treatment should be consideredonly after these approaches have been tried and evaluated.For patients with severe obesity and metabolic syndrome(especially with diabetes mellitus), anti-obesity drugs playan important role in the treatment of obesity. For patientscategorized in NICE obesity III or obesity II with comor-bidities, surgery should also be considered (5).

In the last several decades, a wide range of anti-obesitydrugs have been developed to target different mechanisms,including sympathomimetic adrenergic drugs such asfenfluramine and dexfenfluramine; selective cannabinoid1 receptor blocker, rimonabant; and serotonin (5-HT)reuptake inhibitor, sibutramine. However, these drugs haveall been withdrawn by the US Food and Drug Administra-tion (FDA) due to their severe adverse events (AEs), per-taining to valvular heart disease, pulmonary hypertension,psychiatric disorders and cardiovascular risks. To date,orlistat, the pancreatic lipase inhibitor is the only availablemedication for long-term weight management in manycountries (6).

Lorcaserin (APD356 (7), also called Lorqess (8) duringearly development) is a new anti-obesity drug with thecommercial name Belviq. It was approved by the FDA on27 June 2012. The approved indications were for use inadults with a BMI �30 kg m-2 or those with a BMI�27 kg m-2 with at least one weight-related pathologicalcondition, such as hypertension, type 2 diabetes or dyslipi-daemia (9). Unlike the non-selective serotonergic agonistsfenfluramine and dexfenfluramine which can also activate5-HT2b receptors expressed in cardiac valvular interstitialcells (10), lorcaserin is a selective serotonin 2c (5-HT2c)receptor agonist, which selectively activates the central5-HT2c receptors and decreases food intake through theproopiomelanocortin system of neurons (11,12). The lit-erature to date shows that lorcaserin has few AEs impact-ing the cardiovascular system, likely due to its selectivityfor 5-HT2c receptors. The most common AEs of lorcaserinare transient headache, nausea and dizziness (13).

Lorcaserin is the first anti-obesity drug approved by theFDA in the last 13 years, and there is heightened interest inits use, application and AEs. Several research teams haveconducted randomized controlled trials (RCTs) in obese/overweight adults to investigate the efficacy and safety oflorcaserin in the treatment of patients using different studyperiods within 2 years (14–16). Data from these RCTsshow that lorcaserin administered in patients resulted instatistically significant weight loss. It is proposed that theseeffects are achieved through reduced energy intake (17).Further, lorcaserin also led to improvements in glycaemiccontrol in patients with type II diabetes (18). However,prior to its FDA approval, there was controversy about itsuse due to the moderate efficacy in reducing body weight aswell as its potential carcinogenicity in pre-clinical studies

in rodents (10,19,20). Therefore, further post-approvalstudies are required to confirm its safety, especially in thelong-term.

There are few clinical studies investigating lorcaserin inthe clinical setting and no meta-analysis has been con-ducted to summarize its efficacy and associated AEs. Inthis study, we undertook a systematic review with a meta-analysis of RCTs to investigate the efficacy and safety oflorcaserin.

Methods

The literature search was performed in Ovid MEDLINE(R)(1946 to July Week 4 2012), EMBASE (1996 to 2012 Week31), the Cochrane Central Register of Controlled Trials(CENTRAL) and PubMed electronic databases. Keywordsand truncations were used and combined as follows: (‘lor-caserin’ or ‘Lorqess’ or ‘Belviq’ or ‘APD356’). Trial regis-ters: the metaRegister of Controlled Trials (mRCT) (http://www.controlled-trials.com), the US National Institutes ofHealth Clinical Trials Registry (http://www.clinicaltrials.gov) and the World Health Organization (WHO) Interna-tional Clinical Trials Registry (http://apps.who.int/trialsearch/) were also searched to identify potentiallyrelevant studies. Titles, abstracts and the content of thearticles were screened to determine whether the articles metthe inclusion criteria. The snowballing technique was alsoused to identify potentially relevant studies by reviewingthe reference list of retrieved studies.

Inclusion criteria

The inclusion criteria for systematic review were publishedRCTs investigating the efficacy and safety of lorcaserin inobese adults (aged 18–65 years) with BMI of 27–45 kg m-2.We excluded non-human and drug abuse potential studiesby scanning titles and abstracts. There were no restrictionson language. Full texts were evaluated for inclusion assess-ment. Studies with study periods of �1 year were includedin the meta-analysis. Studies that did not meet the analysisinclusion criteria were included in the narrative review.

Data extraction

Electronic searches and screening were performed by twoindependent reviewers (AYSW and CSLC). AYSW per-formed the initial electronic searches and screened abstractsfor eligibility. Full texts of potential articles were retrievedand screened for relevance by AYSW and CSLC. The rel-evant articles were assessed independently by both review-ers for inclusion in the meta-analysis. Data of includedstudies were then extracted by CSLC and a standardizedsummary table of the data was generated. Non-statisticaldata extracted from the eligible studies included the

2 Efficacy and safety of lorcaserin E. W. Chan et al. obesity reviews

© 2013 The Authorsobesity reviews © 2013 International Association for the Study of Obesity

objective, places conducted, group assignment, duration ofthe study, sample size and the mean age, sex and BMI of thesubjects. Statistical data included weight loss, percentage ofcholesterol, low-density lipoprotein-cholesterol (LDL-C),high-density lipoprotein-cholesterol (HDL-C), triglycer-ides, blood pressure (BP) and heart rate. Data on AEs,relative risks and the standard deviation of headache forlorcaserin were also extracted. Lastly the assessment ofintention-to-treat (ITT) was recorded. Another two review-ers (YH and WCYL) independently checked the data tablefor data accuracy.

Quality assessment

A Jadad Score was assigned to each of the included articlesfor RCT quality assessment (Table 1). CSLC and AYSWmade the assessment independently and the results wereconsistent. Studies with a score of three or above are con-sidered eligible for inclusion (21).

Statistical analysis

The primary outcomes of interest include changes in bodyweight (kg) and BMI (kg m-2). Weighted mean differencesand risk ratios were calculated for continuous outcomes(e.g. weight and BMI) and dichotomous outcomes (e.g.AEs) from baseline to the end of follow-up, respectively.Secondary outcomes include changes in waist circumfer-ence, heart rate, BP and lipids. The meta-analysis used theDerSimonian and Laird random-effects model to deal withpossible heterogeneity between studies (22). I2 statistic wasused to describe the proportion of the variability that is dueto heterogeneity rather than sampling error. We used ITTdata for the analyses of primary outcomes. For secondaryoutcomes and AEs, analyses were based upon ITT or com-pleter analysis when ITT data were not available. Whenstandard deviations were not provided, they were calcu-lated using standard errors and sample sizes. Unit conver-sions for cholesterol and triglycerides from milligrams perdecilitre (mg dL-1) to millimoles per litre (mmol L-1) were

achieved by simple conversion. We were unable to assesspublication bias by Funnel plot due to the low number ofincluded studies. All statistical analyses were conductedusing Review Manager 5.1 (Copenhagen: The NordicCochrane Centre, The Cochrane Collaboration, 2011).

Results

Figure 1 summarizes the review flowchart in accordancewith Preferred reporting items for systematic reviews andmeta-analyses (PRISMA statement) (23). The electronicsearch in PubMed, Medline, EMBASE and CENTRALyielded a total of 235 studies. Six records were identifiedfrom the mRCT, the US National Institutes of Health Clini-cal Trials Registry and the WHO International ClinicalTrials Registry; and all of them have publications available(Appendix). Twenty-three duplicate studies were excludedand a total of 212 records were screened. Of these, sixarticles were considered relevant after scanning titles andabstracts, and the remaining 206 were not clinical trialsand were therefore excluded. Six studies were retrieved for

Table 1 Jadad Score summary for included studies

Smith2009 (14)

Smith2010 (15)

Fidler2011 (16)

Martin2011 (17)

O’Neil2012 (18)

Randomization 1 1 2 1 1Blinding 2 2 2 1 1Fate of all patients 1 1 1 1 1Total 4 4 5 3 3

Additional ratingLevel of blindness 3 3 3 3 3Analysis ITT 1 1 1 0 1

ITT, intention-to-treat.

Figure 1 Review flowchart (PRISMA flowchart).

obesity reviews Efficacy and safety of lorcaserin E. W. Chan et al. 3


detailed evaluation, five of which were included in thisreview. The remaining one was considered irrelevant, sinceit was about the abuse potential of lorcaserin and hencewas excluded. No additional publication was identifiedfrom the reference lists of the retrieved studies. Since therewas only one study lasting 8 weeks (17) and another lasting12 weeks (14), the data reported in these studies wereexcluded from the meta-analysis but included in the narra-tive review. As a result, three eligible studies were includedin the meta-analysis, contributing a total sample size of7,789. Table 2 shows the characteristics of RCT includedin the meta-analysis and narrative review.

Methodological quality

All studies were of similar quality. All studies specifiedthe eligibility criteria and included an ITT analysis.Co-interventions and baseline characteristics were similarfor the lorcaserin and placebo groups for all studies. Moststudies did not state the details of the randomizationprocess and blinding methods. However, all studiesreported that they were double-blind. There were varia-tions in the dosages and duration of lorcaserin used in allstudies; however, each reported the effects of receiving10 mg lorcaserin twice daily at 1 year. The data from Smithet al. (15) generally had a larger effect size compared withthe other two studies, and we investigated the impact ofexcluding it in a sensitivity analysis.

Primary outcomes

The pooled mean estimate of weight loss between the treat-ment and placebo groups was 3.23 kg (95% CI: 2.70, 3.75)with heterogeneity across the studies (I2 = 59%) (Fig. 2).Lorcaserin significantly reduced mean BMI by 1.16 kg m-2

(95% CI: 0.98, 1.34) compared with placebo (Fig. 3).Heterogeneity was detected across studies (I2 = 62%).

Secondary outcomes and adverse effects

The secondary outcome analyses are reported in Table 3.Lorcaserin decreased waist circumference (on average) by2.51 cm (95% CI: 1.99, 3.04) when compared withplacebo. For BP, the pooled mean estimate of the reductionin systolic and diastolic BP were 0.61 mmHg (95% CI:0.07, 1.16) and 0.49 mmHg (95% CI: 0.11, 0.88), respec-tively, when compared with placebo. There was no signifi-cant difference in the change in heart rate between bothgroups. Significant percentage reductions in total choles-terol, LDL-C and triglycerides between the treatment andplacebo groups were found. The increase in HDL-C wasnot significant. The association between lorcaserin and AEsincluding headache, nausea and dizziness was found to bestatistically significant.

Sensitivity analysis

The estimated mean reduction of 3.23 kg (95% CI: 2.70,3.75), did not materially alter with the exclusion of datafrom Smith et al. (15) (2.93 kg, 95% CI: 2.51, 3.35)however, the heterogeneity was significantly reduced to 0%(Table 4). Similarly, the pooled mean BMI reduction esti-mate of 1.16 kg m-2 (95% CI: 0.98, 1.34), did not changesignificantly (1.07 kg m-2, 95% CI: 0.93, 1.21) however, asignificant drop in heterogeneity (I2 = 0%) was noted(Table 4). In summary, although the inclusion of Smithet al. (15) led to substantial heterogeneity, it did not mate-rially alter the estimates.

Narrative review of short-term trials results

We reviewed two studies which evaluated the short-termeffects of lorcaserin. In the study of 8-week duration,57 subjects aged between 18 and 65 and with BMI27–45 kg m-2 were randomized to receive 10 mg twicedaily lorcaserin (n = 29) or placebo (n = 28). Participantsalso followed a diet and exercise plan. After 8 weeks, themean weight loss between the lorcaserin and placebogroups was 1.60 kg (95% CI: 0.34, 2.86). The data forchanges in BMI were not reported. No significant changesin heart rate, BP, HDL-C and triglycerides between lorca-serin and placebo were detected. Compared with placebo,total cholesterol and LDL-C were found to be significantlyreduced by 0.35 mmol L-1 (95% CI: 0.11, 0.59) and0.35 mmol L-1 (95% CI: 0.16, 0.54), respectively. Mostfrequent AEs included headache, nausea and dizziness.Headache occurred in 37.9% (n = 11) of lorcaserin groupand 32.1% (n = 9) of placebo group. Nausea and dizzinessoccurred in, 6.9% (n = 2) and 10.3% (n = 3) of the lorca-serin group; and 3.6% (n = 1) and 3.6% (n = 1) of placebogroup, respectively.

In another study of 12-week duration, 469 subjects aged18–65 and with BMI 30–45 kg m-2 were randomized toreceive placebo (n = 118), lorcaserin 10 mg once (n = 117)or twice daily (n = 116), or 15 mg once daily (n = 118) for12 weeks. They were counselled to maintain their usual dietand activity. At the end of the study, a significant meanweight loss of 2.9 kg (95% CI: 2.2, 3.5) between lorcaserinand placebo group was observed. The BMI reduction was1.20 kg m-2 (95% CI: 0.91, 1.49). Changes in heart rate,BP and LDL-C were found to be statistically non-significantcompared with placebo. The mean reduction in total cho-lesterol, HDL-C and triglycerides between lorcaserin andplacebo groups were 0.22 mmol L-1 (95% CI: 0.07, 0.37),0.10 mmol L-1 (95% CI: 0.05, 0.15) and 0.20 mmol L-1

(95% CI: 0.01, 0.39), respectively. Headache was the mostfrequent AE occurring in 26.7% (n = 31) of lorcaseringroup and 17.8% (n = 27) of placebo group, followed bynausea and dizziness, which occurred in 11.2% (n = 13)



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and 7.8% (n = 9) of lorcaserin group and 3.4% (n = 4) and0% (n = 0) of placebo group, respectively.

Discussion

The meta-analysis of RCTs of lorcaserin in overweightand obese adults showed that use of lorcaserin resulted in

statistically significant but moderate absolute weight lossand BMI reduction compared with placebo. Lorcaserintreatment demonstrates an approximate average of 3 kgweight loss in a patient weighting 100 kg body weight or areduction of 1.16 kg m-2 in BMI where the basal mean BMIis 36.1 kg m-2.

Figure 2 Mean reduction in weight (kg) with lorcaserin.

Figure 3 Mean reduction in body mass index (kg m-2) with lorcaserin.

Table 3 Secondary outcomes and adverse reactions with lorcaserin

Secondary outcomes Number ofstudies

Sample size (total:lorcaserin, placebo)

Weighted meandifference (95% CI)

Waist circumference (cm) 3 6,638: 3,350, 3,288 -2.51 (-3.04, -1.99)Systolic blood pressure (mm Hg) 3 6,638: 3,350, 3,288 -0.61 (-1.16, -0.07)Diastolic blood pressure (mm Hg) 3 6,638: 3,350, 3,288 -0.49 (-0.88, -0.11)Heart rate (beats per minute) 2 3,676: 1,844, 1,832 0.80 (-1.92, 0.31)Cholesterol total (%) 3 6,638: 3,350, 3,288 -1.06 (-1.07, -0.42)

LDL 3 6,638: 3,350, 3,288 -1.29 (-2.32, -0.25)HDL 3 6,638: 3,350, 3,288 1.82 (-0.05, 3.70)

Triglycerides (%) 3 6,638: 3,350, 3,288 -4.70 (-6.53, -2.87)

Adverse events Number ofstudies


Risk ratio (95% CI)

Headache 3 6,888: 3,451, 3,437 1.68 (1.48, 1.90)Nausea 3 6,888: 3,451, 3,437 1.51 (1.26, 1.90)Dizziness 3 6,888: 3,451, 3,437 1.97 (1.45, 2.66)Fatigue 3 6,888: 3,451, 3,437 1.99 (1.61, 2.46)Urinary tract infection 3 6,888: 3,451, 3,437 1.25 (1.04, 1.50)Constipation 2 6,380: 3,195, 3,185 1.48 (1.19, 1.85)Dry mouth 2 6,380: 3,195, 3,185 2.29 (1.75, 3.00)Diarrhoea 2 6,380: 3,195, 3,185 1.15 (0.95, 1.40)

CI, confidence intervals; HDL, high-density lipoprotein; LDL, low-density lipoprotein.



Comparison to orlistat or sibutramine

The effect of weight loss was less pronounced for lorcaserinrelative to other anti-obesity drugs like sibutramine. Fourmeta-analyses showed that the use of sibutramine resultedin greater weight loss, over 4–5 kg (24–27). The effect ofweight loss for orlistat was similar to that of lorcaserin,with a significant mean weight loss of 3 kg (26,27). Franzet al. also showed the most significant weight loss was at 12months for both orlistat (3.1 � 8.7 kg) and sibutramine(5.1 � 4 kg) treatment compared with diet alone (24). Theweight loss for the treatment group of orlistat and sibu-tramine were small when the trials were conducted over ashorter duration of 6 months (24). Yet, the duration of thetwo trials included in our study for short-term use of lor-caserin were only 8 and 12 weeks, respectively. The totalmean difference in weight loss for 8 and 12 weeks were alsosmaller to that of relatively longer term (i.e. 1 year) use oflorcaserin. In our study, the decrease in BMI was observedin three trials but no meta-analysis reported the mean BMIchange for orlistat and sibutramine in adults. Hence, nocomparison could be made for the change of BMI.

In terms of secondary outcomes, lorcaserin marginallyincreased the percentage of HDL-C and significantlydecreased the percentage of triglycerides and LDL-C(Table 3). Several studies indicated that orlistat alsosignificantly improved LDL-C (28), HDL-C (27), whilesibutramine induced beneficial changes on HDL-C andtriglycerides (26–28). Padwal et al. reported that orlistatincreased HDL-C levels by 0.03 mmol L-1 (95% CI: 0.02,0.04). They further concluded that sibutramine increasedHDL-C levels by 0.04 mmol L-1 (95% CI: 0.01, 0.08) andreduced triglycerides by 0.18 mmol L-1 (95% CI: 0.07,0.30) (27). This suggests that lorcaserin may improveLDL-C, HDL-C and triglycerides to a similar extent asorlistat and sibutramine. Sibutramine is known to increasesystolic BP, diastolic BP (28) and heart rate (29). Studiesrecorded the mean weighted difference of systolic BPfrom +0.5 to +1.7 mmHg and diastolic BP from +1.7 to+2.4 mmHg (25,27,30). Moreover, heart rate increased byapproximately 4.5 beats per minute (27). On the contrary,lorcaserin was found to decrease systolic BP and diastolicBP significantly at 12 months. Heart rate was also reduced

but the results were not statistically significant. Despitethis, these findings suggested lorcaserin may have a lowercardiovascular risk than that of sibutramine. Like lorca-serin, orlistat can also decrease BP (25,28–30). The degreeof reduction was even greater than that of lorcaserin wherethe decrease in systolic and diastolic BP was 2.5 mmHg and1.9 mmHg, respectively. The use of orlistat was found tohave statistically significant gastrointestinal AE in severalstudies (26,27,30). Li et al. showed that the relative risk ofdiarrhoea among orlistat-treated patients was 3.4 whencompared with the placebo group (26). However, patientstreated with lorcaserin for 12 months were no more likelythan placebo to have diarrhoea as the risk ratio was notstatistically significant (Table 3).

Comparison to non-pharmacological interventions

Lifestyle interventions for prevention or treatment ofobesity usually refer to diet, physical exercise and psycho-logical or behavioural interventions (31). It was reportedthat the impact of dietary intervention in absolute meanweight loss varies from 1.09 kg to 2.63 kg in different typesof dietary control (32,33) In particular, very low caloriediets (<800 kcal d-1) produced 16.1 � 1.6% of bodyweight loss in the short-term (12.7 � 6.4 weeks) and6.3 � 3.2% of body weight loss for �1 year (1.9 � 1.6years) in obesity II patients (34). Studies also showed thatincreasing exercise intensity resulted in 1.5 kg weight loss(95% CI: 0.7, 2.3) (35). A recent Cochrane meta-analysisreview also claimed that the ‘transtheoretical model’ fordietary and physical activity interventions had limitedeffect on weight loss which was about 2 kg or less,however, there was no conclusive evidence for sustainableweight loss (36). For those obese patients who acceptedpsychological and behavioural interventions, a 2.5 kgweight loss (95% CI: 1.7, 3.3) was achieved, whichincreased significantly to 4.9 kg (95% CI: 2.4, 7.3) whencombined with dietary and exercise intervention (37).Based on results of these studies and our finding, it issuggested that the use of very low calorie diets showed agreater effect on the percentage of weight loss compared tolorcaserin. Despite its comparatively desirable effect, thevery low calorie diets should be received under thorough

Table 4 Sensitivity analysis (exclusion of Smith et al. (15)) of primary outcomes

Primary outcomes Original model Exclusion of Smith et al. 2010 (15)



I2 Sample size (total:lorcaserin, placebo)


I2

Weight (kg) 6,638: 3,350, 3,288 -3.23 (-3.75, -2.70) 59% 3,601: 1,812, 1,789 -2.93 (-3.35, -2.51) 0%BMI (kg m-2) 6,638: 3,350, 3,288 -1.16 (-1.34, -0.98) 62% 3,601: 1,812, 1,789 -1.07 (-1.21, -0.93) 0%

BMI, body mass index; CI, confidence intervals.



medical supervision to monitor the patients’ health and tosustain the effect, which may increase the costs consider-ably. It is estimated that a 12-week very-low-calorie dietprogramme costs approximately US$1,000 (34) comparedto lorcaserin which costs about US$3.57 per tablet or perday (US$300–600 for 12 weeks) (38). Additionally, com-pared with general lifestyle interventions alone, it is sug-gested that lorcaserin to be superior in terms of weightloss; however, combination of different lifestyle interven-tions might lead to greater weight loss. Consequently,non-pharmacological strategies remain important consid-erations in the management of obesity.

Strengths and limitations

We undertook a rigorous systematic review and meta-analysis using independent reviewers for data extractionand statistical analysis. It is the first meta-analysis of theRCTs investigating lorcaserin and includes all relevantliterature to date.

However, there are several potential limitations. First,there is scant published literature on the topic of lorcaserin,with a total of only five RCT studies available for analysis.Second, all published studies have reported statistically sig-nificant absolute weight loss and BMI reduction with lor-caserin in treating obese adults; hence this suggests thepossibility of publication bias. Although we have generatedfunnel plots to access publication bias, the paucity of theliterature makes it difficult to warrant its reliability. Third,there is substantial statistical heterogeneity between studiesin the primary outcomes, including changes in absolutebody weight and BMI values. This apparent heterogeneityis likely attributed to data from a single study by the Smithet al. (15). However, sensitivity analysis shows that itsexclusion results in a dramatic reduction in heterogeneitywithout affecting the overall estimates. Since the setting ofthis study is similar to that of Fidler et al. (16) in terms ofco-interventions, study duration and study populations, itimplies that the heterogeneity may be due to the randomeffect as there were only three papers included in our meta-analysis. Fourth, all included studies were conducted in theUS and have only included obese adults, which limits thegeneralizability of study findings. Fifth, the available datasuggest that lorcaserin appears to have a favourable safetyprofile. However, the number of patients exposed to lorca-serin is small and long-term data are still lacking. Thereforelong-term studies are needed to address the above safetyissues.

Conclusion

Lorcaserin treatment for 1 year duration in obese adultsproduces a statistically significant although modest reduc-tion in both absolute body weight and BMI. Compared

with the available anti-obesity management strategies,lorcaserin is well tolerated as no significant AEs impact-ing the cardiovascular or gastrointestinal system wereobserved. Further investigation of lorcaserin in differentpatient groups such as children and adolescents are neededto inform of its place in the management of obesity. Clinicaland pharmacovigilance studies with longer study durationsare required to inform of the long-term efficacy and safetyof lorcaserin.

Conflict of interest statement

None to declare.

Acknowledgement

None to declare.

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Appendix

mRCT, ClinicalTrials.gov and WHO International Clinical Trials Registry: completed clinical trials (RCTs)

Scientific title Registrationdate

Location Responsible partyand study director

Study type Study design Estimatedenrolment

Relatedpublication

A randomized,double-blind,double-dummy, placebo-and active-controlledcrossover study toevaluate the abusepotential of single dosesof lorcaserin in healthyrecreational polydrugusers

22 January2009

Canada,Ontario

Christen Anderson,MD, PhD, ArenaPharmaceuticals,Inc.

Interventional Allocation: RandomizedEndpoint Classification:Pharmacodynamics StudyIntervention Model:Crossover AssignmentMasking: Double Blind(Subject, Investigator)

35 Shram MJ,2011



Appendix Continued

Scientific title Registrationdate

Location Responsible partyand study director

Study type Study design Estimatedenrolment

Relatedpublication

A 56-day, double-blind,randomized,placebo-controlled,parallel-group study toassess the effect oflorcaserin hydrochlorideon energy metabolismand food intake inoverweight and obesepatients (TULIP)

22 January2009

UnitedStates,Louisiana

Christen AndersonMD, PhD, ArenaPharmaceuticals, Inc.Principal Investigator:Eric Ravussin, PhDPenningtonBiomedical ResearchCenter

Interventional Allocation: RandomizedIntervention Model:Parallel AssignmentMasking: Double Blind(Subject, Investigator)

56 Martin CK,2011

A 52-week, double-blind,randomized,placebo-controlled,parallel-group study toassess the safety andefficacy of lorcaserinhydrochloride inoverweight and obesepatients

16 January2008

UnitedStates,California

Vice President andChief Medical Officer,ArenaPharmaceuticalsStudy Director:Christen M Anderson,MD, PhD ArenaPharmaceuticals

Interventional Allocation: RandomizedEndpoint Classification:Safety/Efficacy StudyIntervention Model:Parallel AssignmentMasking: Double Blind(Subject, Caregiver,Investigator, OutcomesAssessor)Primary Purpose:Treatment

3000 Filder MC,2011

A 52-week, double-blind,randomized,placebo-controlled,parallel-group study toassess the safety andefficacy of lorcaserinhydrochloride inoverweight and obesepatients with type 2diabetes mellitusmanaged with oralhypoglycaemic agent(s)

17 January2008


Vice President andChief Medical Officer,ArenaPharmaceuticalsStudy Director:Christen M Anderson,MD, PhD ArenaPharmaceuticals


750 O’Neil2012

BLOOM: BehavioralModification andLorcaserin for Overweightand Obesity Management;A 104-week, double-blind,randomized,placebo-controlled,parallel-group study toassess the safety andefficacy of lorcaserinhydrochloride in obesepatients

31 October2006


Vice President andChief Medical Officer,ArenaPharmaceuticalsStudy Director:Christen Anderson,MD, PhD ArenaPharmaceuticalsPrincipal Investigator:Steven Smith, MDPenningtonBiomedical ResearchCenter; NeilWeissman, MD


3,182 Smith SR2010

A 12-week, dose-ranging,double-blind, randomized,placebo-controlled,parallel-group study toassess the safety andefficacy of apd356 inobese patients

30 June2005

UnitedStates,Louisiana

ArenaPharmaceuticalsWilliam R Shanahan,Jr, MD ArenaPharmaceuticals

Interventional Allocation: RandomizedEndpoint Classification:Safety/Efficacy StudyIntervention Model:Parallel AssignmentMasking: Double BlindPrimary Purpose:Treatment

400 Smith SR2009



efficacy and safety of lorcaserin in obese adults: a meta-analysis of 1-year randomized controlled...

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