ORIGINAL RESEARCH

Reduction of Excessive Visceral Fat and Safetywith 52-Week Administration of Lipase InhibitorOrlistat in Japanese: Long-Term Clinical Study

Kohji Shirai . Michitaka Tanaka . Toru Fujita . Yuka Fujii .

Masatsugu Shimomasuda . Soichi Sakai . Yoshishige Samukawa

Received: August 22, 2018 / Published online: November 1, 2018� The Author(s) 2018

ABSTRACT

Introduction: Orlistat is an inhibitor of pan-creatic lipase and is used as an anti-obesity drugin many countries. However, there are no dataavailable regarding the effects of orlistat onvisceral fat (VF) accumulation in Japanese indi-viduals. Therefore, this study aimed to analyzethe efficacy and safety of 52 weeks of orlistatadministration in Japanese individuals.Methods: Orlistat 60 mg was administeredorally three times daily for 52 weeks to Japaneseparticipants with excessive VF accumulationand without dyslipidemia, diabetes mellitus,and hypertension (metabolic diseases). Partici-pants were also counseled to improve their dietand to maintain exercise habits. We definedexcessive VF accumulation as a waist

circumference (WC) of C 85 cm for males andC 90 cm for females, which corresponds to a VFarea of 100 cm2. Adverse reactions, clinicallaboratory tests, VF, WC, body weight (BW),etc., were monitored throughout the studyperiod.Results: VF, WC, and BW were significantlyreduced at week 52 from baseline; the mean ±standard error rate of change was - 21.52% ±1.89%, - 4.89% ± 0.45%, and - 5.36% ±0.56%, respectively, and continued to reducethroughout the 52 weeks; these significantlyreduced at whole term compared with baseline.Most adverse reactions were defecation-relatedsymptoms such as oily spotting and flatus withdischarge (flatus with small amounts of stool oroil) due to the pharmacologic effects of thelipase inhibitor. These symptoms were mostlymild, reversible, and recognizable by the par-ticipants; none were serious or severe. No par-ticipants discontinued by medical judgmentabout adverse reactions, and the drug could beadministered continuously.Conclusion: VF, WC, and BW were reducedfrom week 4 to week 52, indicating the effect oflong-term orlistat administration. Moreover, itwas well tolerated with an acceptable safetyprofile. Long-term administration of orlistatmay be efficacious in reducing VF accumulationwith safety when used in combination with dietand exercise.

Enhanced digital features To view enhanced digitalfeatures go to https://doi.org/10.6084/m9.figshare.7223543.

Electronic supplementary material The onlineversion of this article (https://doi.org/10.1007/s12325-018-0822-x) contains supplementary material, which isavailable to authorized users.

K. ShiraiDepartment of Internal Medicine, Mihama Hospital,Chiba, Japan

M. Tanaka (&) � T. Fujita � Y. Fujii �M. Shimomasuda � S. Sakai � Y. SamukawaTaisho Pharmaceutical Co., Ltd, Tokyo, Japane-mail: t-michitaka@taisho.co.jp

Adv Ther (2019) 36:217–231

https://doi.org/10.1007/s12325-018-0822-x

http://dx.doi.org/10.6084/m9.figshare.7223543http://dx.doi.org/10.6084/m9.figshare.7223543http://dx.doi.org/10.1007/s12325-018-0822-xhttp://dx.doi.org/10.1007/s12325-018-0822-xhttp://dx.doi.org/10.1007/s12325-018-0822-xhttp://dx.doi.org/10.1007/s12325-018-0822-xhttps://doi.org/10.1007/s12325-018-0822-xhttp://crossmark.crossref.org/dialog/?doi=10.1007/s12325-018-0822-x&domain=pdfhttp://crossmark.crossref.org/dialog/?doi=10.1007/s12325-018-0822-x&domain=pdf

Trial Registration: This study is registered withthe Japan Pharmaceutical Information Center(identifier: JapicCTI-184004).Funding: Funding for this study was providedby Taisho Pharmaceutical Co., Ltd.

Keywords: Body weight; Efficacy; Japanese;Lipase inhibitor; Long-term administration;Obesity; Orlistat; Safety; Visceral fat; Waistcircumference

INTRODUCTION

Excessive accumulation of body fat is frequentlyassociated with metabolic disorders, such asdiabetes mellitus, hypertension, and dyslipi-demia, and these disorders are known to causecoronary artery disease and cerebrovasculardisorders [1, 2]. In addition, comorbidities suchas sleep apnea, kidney damage, bone and jointdiseases, and menstrual disorders can also occurwith obesity [1, 2]. The Organisation for Eco-nomic Co-operation and Development hasranked obesity as the greatest emerging threatto public health worldwide and forecasted asharp rise in medical expenditures based on theincreased number of individuals with obesity-related diseases [3]. The increased incidence ofdyslipidemia, diabetes mellitus, and hyperten-sion caused by obesity as well as obesity-relatedcardiovascular diseases is a global problem, andprevention and treatment of obesity have beenearnestly implemented in many countries.Although various indicators, including bodyweight, body mass index (BMI), waist circum-ference, and body fat, are considered for theassessment of obesity in Europe and the USA,BMI is the main indicator to identify individu-als for treatment [4, 5].

In Japan, despite a low grade of obesity incomparison to the US and European popula-tions, the incidence of dyslipidemia, diabetesmellitus, and hypertension (metabolic diseases)caused by obesity is relatively high, indicatingthat metabolic diseases caused by obesity candevelop even with relatively mild obesity. Fur-thermore, body fat distribution types are divi-ded into the visceral fat type and subcutaneousfat type, and metabolic diseases caused by

obesity are more likely to be linked to visceralfat accumulation than subcutaneous fat accu-mulation [2].

Several clinical studies have demonstratedthat the number of obesity-related cardiovas-cular risk factors increases with an increase invisceral fat accumulation [2, 6], suggesting aclose relationship between excessive visceral fatand the development of metabolic diseasescaused by obesity [7, 8]. The adverse healtheffects of visceral fat accumulation are mainlybelieved to result from insulin resistance causedby an insulin resistance factor, such as tumornecrosis factor-a, among others [2]. Severalstudies have also demonstrated that reductionsin visceral fat accumulation and body weightlead to decreased risk of metabolic diseasescaused by obesity [9, 10]. Therefore, visceral fataccumulation is used as an index for the diag-nosis and treatment of obesity in Japan [2].

The initial management regimen for reduc-ing visceral fat should start with lifestyleadjustments including improvements in dietand exercise [2]. Individuals with metabolicdiseases should receive medical treatment fromphysicians, but those without metabolic dis-eases despite excessive visceral fat accumulationare generally required to manage their ownhealth regimens by improving lifestyle. How-ever, lifestyle improvements are often insuffi-cient to achieve significant body weight loss,and long-term control of body weight is diffi-cult to maintain [11–14]. Consequently, thedevelopment of new, effective, and safe meth-ods to reduce visceral fat in Japanese partici-pants with excessive visceral fat accumulationand without metabolic diseases is required.

One of the options is drug. There are severaldrugs affecting body weight, among whichorlistat inactivates pancreatic lipase in thedigestive tract, thereby inhibiting the absorp-tion of dietary fat and enhancing the excretionof undigested fat in the stool, resulting in bodyweight reduction by decreasing energy uptake.Orlistat is available as both a prescription drugand an over-the-counter drug for weight loss inmore than 120 countries of Europe and theUSA. An important feature of orlistat is that ithas no effect on the central nervous system;therefore, addiction or emotional side effects

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are expected to be few. A clinical study con-ducted mainly in the white and black popula-tions demonstrated that orlistat successfullyreduced visceral fat [15]. Similar results wouldbe expected in Japanese populations; however,data regarding the effects of orlistat on visceralfat in Japan are limited.

We confirmed from another study thatadministration of orlistat 60 mg three timesdaily for 24 weeks showed a reduction in vis-ceral fat area, waist circumference, and bodyweight and was safe and tolerable in Japaneseparticipants.

Due to orlistat’s mechanism of action, theabsorption of dietary fat-soluble vitamins couldpotentially be inhibited in individuals takingorlistat. Consequently, the over-the-counterformulation of orlistat (Alli�, GlaxoSmithKline,Brentford, UK) includes a warning in the pack-age insert that recommends taking a multivita-min once a day at bedtime. In addition,defecation-related symptoms such as oily spot-ting and flatus with discharge can occur whentaking orlistat. These effects may become par-ticularly significant with extended use of orlis-tat; however, clinical evidence of the safety oflong-term administration of orlistat in theJapanese population has not been reported.

Therefore, we conducted a 52-week study toevaluate the efficacy and safety of long-termorlistat administration in Japanese participantswith excessive visceral fat accumulation andwithout metabolic diseases.

METHODS

Participants

Japanese participants without metabolic dis-eases aged 18 years or older with excessive vis-ceral fat accumulation were eligible for thisstudy. We defined excessive visceral fat accu-mulation as a waist circumference C 85 cm formales and C 90 cm for females, which corre-sponds to a visceral fat area of 100 cm2 [2].Participants had not received medical treatmentfor obesity, diabetes mellitus, dyslipidemia,hypertension, hyperuricemia/gout, or fattyliver. Major exclusion criteria were the presence

of secondary obesity; BMI B 22.0 kg/m2 (opti-mal BMI in Japan is defined as 22.0 kg/m2 [16]);BMI C 35.0 kg/m2; judged necessary to treatwith cyclosporine, warfarin, amiodarone, orother drugs capable of interfering with orlistat’seffects during the study period; and presence ofor a history of malabsorption syndrome, pan-creatitis, cholestasis, cholecystitis, gallstones,kidney stones, or hyperoxaluria.

Study Design

This was an open-label, uncontrolled study tomainly evaluate the safety of 52-week adminis-tration of orlistat based on ‘‘The Extent of Popu-lationExposure toAssessClinical Safety forDrugsIntended for Long-Term Treatment of Non-Life-Threatening Conditions’’ [International CouncilforHarmonisationofTechnicalRequirements forPharmaceuticals for Human Use—Efficacy 1(ICH-E1) guidelines] [17], which requires 100participants for 1-year administration. Account-ing for possible dropouts, target enrollment wasdetermined to be 120 participants. Participantswere scheduled to take an oral capsule of orlistat60 mg three times daily for 52 weeks with meals(during or within 1 h after breakfast, lunch, anddinner).

This study included a 12-week observationterm and a 52-week treatment term. Partici-pants were counseled to improve diet and tomaintain exercise habits from the beginning ofthe observation term through the end of thestudy. All participants, except those whosewaist circumference increased or reduced suffi-ciently during the observation term, moved onto the treatment.

Every 4 weeks, the participants underwentinterviews, body measurements, blood pressureassessments, and routine clinical laboratorytesting. Only glycated hemoglobin (HbA1c) wasmeasured at the beginning of the observationterm, at the beginning of treatment, and attreatment weeks 12, 24, 36, and 52. Body mea-surements consisted of height (measured onlyat the beginning of the observation term), bodyweight, and waist circumference. The measure-ment of waist circumference was performedaccording to the guidelines published by the

Adv Ther (2019) 36:217–231 219

Japan Society for the Study of Obesity [2]. BMIwas calculated from height and body weight.Visceral and subcutaneous fat areas were mea-sured at the beginning of the observation term,at the beginning of treatment, and at treatmentweeks 24 and 52 using computed tomography(CT) images of the umbilical plane with visceralfat area measurement software (FatScan Ver.5.0, East Japan Institute of Technology Co.,Ltd., Ibaraki, Japan). The imaging was per-formed according to the guidelines publishedby the Japan Society for the Study of Obesity [2].Participants fasted for at least 10 h prior to bodymeasurements, abdominal CT, and clinical lab-oratory tests.

Throughout the study period, participantswere counseled to improve the quality of theirdiet and reduce their daily calorie intake by200–400 kcal per day, depending on bodyweight. They recorded their achievement levelof calorie reduction on a daily basis using thecategories ‘‘almost attained,’’ ‘‘partiallyattained,’’ ‘‘attempted but not attained,’’ and‘‘not attempted.’’ Participants were also advisedto maintain their exercise habits withoutimplementing significant changes throughoutthe study period.

Adverse events were defined as any unfa-vorable event or the presence or signs of medi-cally unintended complications that occurredbetween the beginning and the end of treat-ment. All adverse events were recorded duringphysician examinations or by self-reportingfrom the participants. The investigator deter-mined whether a causal relationship existedbetween the adverse event and investigationaldrug; all events except those that were judged tobe ‘‘not related’’ were regarded as adversereactions.

This study is registered with the JapanPharmaceutical Information Center (identifier:JapicCTI-184004). It was implemented inaccordance with Good Clinical Practiceguidelines and the ethical principles of theHelsinki Declaration of 1964, as revised in2013, concerning human and animal rights.Springer’s policy concerning informed consenthas been followed. This study was approved bythe Institutional Review Board of each partic-ipating institution. After receiving sufficient

explanation and achieving a full understand-ing of the study, all potential participantsprovided written consent to voluntarily par-ticipate in this study.

Assessments

End points for efficacy were the percent changeand the amount of change in visceral fat area,waist circumference, body weight, BMI, andsubcutaneous fat area from baseline to eachstudy term; the achievement rates were 3%reduction in waist circumference and 3%reduction in body weight (defined as the per-centage of participants whose waist circumfer-ence/body weight changed by - 3% or lower ateach assessment compared with baseline); theachievement rates were 5% reduction in waistcircumference and 5% reduction in bodyweight. ‘‘Baseline’’ was defined as the beginningof the treatment term; the primary study termwas week 52 of the treatment.

The primary safety end point was the fre-quency of adverse reactions.

In addition, the clinical laboratory tests,blood pressure, compliance rate for dietaryimprovement (the level of calorie reduction on adaily basis using the categories was rated ‘‘almostattained, partially attained, or attempted but notattained’’), and change in the number of meta-bolic disease risk factors from baseline to week 52of treatment were assessed. Metabolic diseaserisk factors for diabetes mellitus, dyslipidemia,and hypertension were defined as blood glu-cose C 126 mg/dl or HbA1c C 6.5%; low-densitylipoprotein (LDL) cholesterol C 140 mg/dl,high-density lipoprotein (HDL) cholesterol\40 mg/dl, or triglycerides C 150 mg/dl; andsystolic blood pressure C 140 mmHg or diastolicblood pressure C 90 mmHg, respectively.

Efficacy end points, compliance rate fordietary improvement, and change in metabolicdisease risk factors were analyzed using theefficacy analysis set (full analysis set), andadverse reactions, clinical laboratory tests, andblood pressure were analyzed using the safetyanalysis set (all participants who were adminis-tered even one investigational drug and had

220 Adv Ther (2019) 36:217–231

observed safety data after administration of theinvestigational drug).

Statistical Analysis

The percent change and amount of change inthe visceral fat area, waist circumference, bodyweight, BMI, and subcutaneous fat area wereanalyzed using the paired t test. Achievementrates of 3% and 5% reductions in waist cir-cumference and body weight from baselinewere obtained by calculating the proportion ofparticipants whose percent change was - 3% orlower and - 5% or lower, respectively; 95% two-sided confidence intervals (CIs) were also cal-culated. Differences in clinical laboratory testsand blood pressure from baseline to each termwere analyzed using the Wilcoxon signed ranktest. The change in the number of metabolic

disease risk factors was analyzed using the Wil-coxon signed rank test. Because analyses otherthan the primary end point are also included toachieve the results or understand the cause,multiplicity was not considered, with a p\0.05considered significant. All analyses were per-formed using SAS 9.2 and SAS 9.3 (SAS InstituteInc., Cary, NC, USA).

RESULTS

Participants

Among 241 potential participants selected forthis study, 120 (the target enrollment number)were found to be eligible and subsequentlyreceived orlistat (Fig. 1). Six participants (5.0%)withdrew from the study during the treatment

Fig. 1 Disposition of participants

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term at their request. Of the 120 participantswho received orlistat, none were excluded fromthe safety analysis set or the efficacy analysis set(both consisted of all 120 participants).

Baseline characteristics of the participantsare shown in Table 1. The age of the partici-pants was 47.3 ± 6.7 years [mean ± standarddeviation (SD)], 22.5% were female, and visceralfat area was 130.90 ± 40.13 cm2.

Efficacy

Efficacy End PointsVisceral fat area showed a significant change of- 21.52% ± 1.89% [mean ± standard error(SE)] from baseline to week 52 (p\ 0.001;Fig. 2). The change in waist circumference frombaseline to week 52 was - 4.89% ± 0.45%, andthe change in body weight was - 5.36% ±0.56%, both of which were significant reduc-tions (p\0.001 for all parameters; Figs. 3, 4).The visceral fat area, waist circumference, andbody weight reduced during the 12-weekobservation term and reduced throughout the52-week treatment term, with significant

reductions in all three parameters at each periodcompared with baseline.

The amountof change in visceral fat area frombaseline to week 52 was - 28.05 ± 2.71 cm2

(mean ± SE); waist circumference reduced by- 4.73 ± 0.45 cm, and body weight reduced by- 4.22 ± 0.45 kg. BMI reduced by - 5.35% ±0.56%, with the amount of change being- 1.46 ± 0.16 kg/m2. Subcutaneous fat areareduced by- 14.84% ± 1.53%, with the amountof change being-33.47 ± 3.82 cm2. These reduc-

Table 1 Participant characteristics at baseline

Characteristic at thestart of administration

n = 120

Age (years)a 47.3 ± 6.7 (29–61)

Gender

Maleb 93 (77.5)

Femaleb 27 (22.5)

Visceral fat area (cm2)a 130.90 ± 40.13

(65.4–322.5)

Waist circumference (cm)a 96.86 ± 6.03 (85.0–115.5)

Body weight (kg)a 78.25 ± 8.75 (61.6–108.0)

Height (cm)a 169.76 ± 7.34

(149.8–185.8)

BMI (kg/m2)a 27.16 ± 2.64 (22.5–33.8)

BMI body mass index, SD standard deviationa Mean ± SD (min–max)b n (%)

Fig. 3 Percent change in waist circumference comparedwith baseline. Mean ± SE. n (week 52): 108. *Paired t-test, p\ 0.05 compared with baseline. Waist circumfer-ence reduced significantly at whole term compared withbaseline. SE standard error

Fig. 2 Percent change in visceral fat area compared withbaseline. Mean ± SE. n (week 52): 108. *Paired t-test,p\ 0.05 compared with baseline. Visceral fat area reducedsignificantly at whole term compared with baseline. SEstandard error

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tions at week 52 were significant compared withbaseline (p\0.001 for all parameters; Table 2).Moreover, these parameters demonstrated signif-icant reductions at each term compared withbaseline.

At week 52 of the treatment term, theachievement rates of 3% and 5% reductions inbody weight from baseline were observed in 67of the 114 participants [58.8% (95% CI:49.7–67.8%)] and in 54 of the 114 participants[47.4% (95% CI: 38.2–56.5%)], respectively. Theachievement rates of 3% and 5% reductions inwaist circumference were observed in 68 of the114 participants [59.6% (95% CI: 50.6–68.7%)]

and 47 of the 114 participants [41.2% (95% CI:32.2–50.3%)], respectively.

Clinical Laboratory TestsThe changes in lipid parameters related to thedevelopment of metabolic diseases (totalcholesterol, LDL cholesterol, HDL cholesterol,and triglycerides) during the treatment term areshown in Fig. 5. The change from baseline toweek 52 was - 11.0 ± 2.0 mg/dl (mean ± SE)for total cholesterol, - 13.8 ± 1.8 mg/dl for LDLcholesterol, 3.1 ± 0.7 mg/dl for HDL choles-terol, and - 4.3 ± 4.3 mg/dl for triglycerides,and all parameters except triglycerides demon-strated significant changes from baseline(p\ 0.001). Total cholesterol and LDL choles-terol demonstrated a trend of reductionthroughout the treatment term, with significantreductions at each term compared with base-line. Other parameters associated with meta-bolic diseases (blood glucose, HbA1c, systolicblood pressure, and diastolic blood pressure)fluctuated within their normal ranges withoutnotable changes (Supplemental Fig. S1).

Other Analyses of EfficacyThe change in the number of metabolic diseaserisk factors was assessed in 114 participants; sixparticipants who withdrew from the study dur-ing the treatment term were excluded fromanalysis because of a lack of clinical data at week52 (total cholesterol, LDL cholesterol, HDL

Table 2 Changes in parameters from baseline to week 52

Parameter Mean – SE Parameter Mean – SE

Amount of change in visceral fat area

(cm2)

-28.05 ± 2.71a Amount of change in waist

circumference (cm)

-4.73 ± 0.45a

Amount of change in body weight (kg) -4.22 ± 0.45a Percent change in BMI (%) -5.35 ± 0.56a

Amount of change in BMI (kg/m2) -1.46 ± 0.16a Percent change in subcutaneous fat area

(%)

-14.84 ± 1.53a

Amount of change in subcutaneous fat

area (cm2)

-33.47 ± 3.82a

The amount of change in visceral fat area, waist circumference, and body weight as well as percent change and amount ofchange in BMI and subcutaneous fat area were significantly reduced at week 52 compared with baseline. n (week 52): 108BMI body mass index, SE standard errora Paired t-test, p\ 0.05 compared with baseline

Fig. 4 Percent change in body weight compared withbaseline. Mean ± SE. n (week 52): 108. *Paired t-test,p\ 0.05 compared with baseline. Body weight reducedsignificantly at whole term compared with baseline. SEstandard error

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cholesterol, triglycerides, blood glucose, HbA1c,systolic blood pressure, or diastolic blood pres-sure). Results showed that a significantimprovement was observed (p = 0.004), and 26of the 64 participants (40.6%) who had one ormore risk factors at baseline had zero risk factorsat week 52 of the treatment term (Table 3).Moreover, all seven participants with two riskfactors at baseline had fewer risk factors at week52.

With respect to the compliance rate fordietary improvement, more than 90% of par-ticipants had a rate of 100% throughout thetreatment term. In the remaining participants,none had a compliance rate\ 80%.

Safety and Tolerability

The incidence of adverse reactions is shown inTable 4. There were 142 adverse reactionsobserved in 73 of the 120 participants (60.8%).Of these, 133 were episodes of defecation-re-lated symptoms such as oily spotting and flatuswith discharge due to the pharmacologic effectsof the lipase inhibitor, observed in 70 partici-pants (58.3%). Additionally, there were twoincidences of hepatic function abnormal in twoparticipants (1.7%), two incidences of hyper-uricemia in one participant (0.8%), and a singleincidence of hyperbilirubinemia, dysuria,

Fig. 5 Changes in lipid parameters. Mean ± SE. n (week52): a 114, b 114, c 114, d 113. *Paired Wilcoxon test,p\ 0.05 compared with baseline. a Total cholesterol;b LDL cholesterol; c HDL cholesterol; d triglycerides.Total cholesterol and LDL cholesterol reduced throughout

the treatment term with significant reductions comparedwith baseline at whole term until week 52 of treatment.HDL high-density lipoprotein, LDL low-density lipopro-tein, SE standard error

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cough, skin erosion, and liver function testabnormal in one participant (0.8%). The sever-ity of these adverse reactions was categorized asfollows: 140 mild episodes in 73 participants(60.8%) and two moderate episodes in oneparticipant (0.8%). No serious or severe adversereactions were observed. Only two adversereactions required medical treatment (gastritisand skin erosion), which resolved with phar-macologic intervention. There were noremarkable differences in the frequency ofadverse reactions with respect to participantbaseline characteristics (age, gender, BMI, etc.).

The incidence of adverse reactions by time isshown in Fig. 6. Of the 142 adverse reactionsthat occurred during the treatment term, 92(64.8%) occurred during the first 4 weeks(0–35 days) of the treatment term. Subse-quently, there were one (0.7%) to 10 (7.0%)adverse reactions per assessment interval(Fig. 6a). Similar results were observed for defe-cation-related symptoms, with 90 of the 133adverse reaction episodes (67.7%) occurring inthe first 4 weeks of the treatment term andsubsequently one (0.8%) to 10 (7.5%) adversereactions per assessment interval (Fig. 6b).

As mentioned above, defecation-relatedsymptoms were the most common adversereactions. Specifically, those symptoms thatoccurred in C 5% of participants included oily

spotting [46 episodes in 41 participants(34.2%)], flatus with discharge [37 episodes in28 participants (23.3%)], fatty/oily stool [11episodes in 11 participants (9.2%)], fecalincontinence [nine episodes in eight partici-pants (6.7%)], and liquid stool [six episodes insix participants (5.0%)]. These symptoms weremostly mild, reversible, and recognizable by theparticipants; none were serious or severe. Noparticipants were advised by the physician towithdraw from treatment.

No adverse reactions related to fat-solublevitamin deficiencies were observed, and noparticipants required treatment or vitaminsupplementation. Changes in vitamin A (reti-nol), vitamin D (25-OH vitamin D), and vitaminE (tocopherol) during the treatment term areshown in Fig. 7. Significant differences wereobserved, with a change from baseline to week52 of the treatment term of 34.8 ± 87.1 ng/ml(mean ± SD) for vitamin A, 2.36 ± 5.11 ng/mlfor vitamin D, and - 0.081 ± 0.197 mg/dl forvitamin E (p\ 0.001 for all parameters). Nota-bly, only vitamin E showed a reduction.Although vitamin E levels at whole term afterweek 4 were lower than those at baseline, thelevels did not continue to reduce. Further, theobserved changes were within the normal ran-ges, and no other remarkable changes wereobserved. All other laboratory tests showed

Table 3 Changes in metabolic disease risk factors

Term Baseline Wilcoxon signed-rank testa

0 1 2 Total (%)

Week 52 of treatment

0 40 24 2 66 (57.9) S = - 205.5

1 9 30 5 44 (38.6) p = 0.004

2 1 2 0 3 (2.6)

Undeterminable 0 1 0 1 (0.9)

Total (%) 50 (43.9) 57 (50.0) 7 (6.1) 114

A significant reduction in the number of metabolic disease risk factors was observed (p = 0.004), and 26 of the 64participants who had one or more risk factors at baseline (40.6%) had zero risk factors at week 52 of the treatment term.Moreover, all seven participants with two risk factors at baseline had fewer risk factors at week 52a Undeterminable is excluded

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changes within their normal ranges, with nonotable changes or safety concerns.

DISCUSSION

This study was the first to evaluate the efficacyand safety of 52-week administration of orlistat(60 mg, administered three times daily) inJapanese participants with excessive visceral fataccumulation and without metabolic diseases.

In terms of efficacy, 52-week administrationof orlistat 60 mg reduced the visceral fat area inJapanese participants with excessive visceral fataccumulation and without metabolic diseases;these effects continued after 24 weeks, which isa new finding. At week 52 of the treatmentterm, the change from baseline in visceral fatarea was - 21.52% ± 1.89% (mean ± SE). Thevisceral fat area reduced during the 12-weekobservation term as a result of improvement indiet and maintenance of exercise habits, and itcontinued to reduce gradually throughout theentire 52-week treatment term without return-ing to baseline levels. Significant reductions invisceral fat area were observed at whole termcompared with baseline. Additionally, the sub-cutaneous fat area reduced, and waist circum-ference, which consists of visceral fat andsubcutaneous fat, also decreased. These resultssuggest that the use of orlistat reduces the risk ofdeveloping metabolic diseases resulting fromexcessive visceral fat accumulation by

Table 4 Incidence of adverse reactions

Number of participantsincluded in the analysis

n = 120

Event Number ofepisodes

Numberof cases(%)

Total 142 73 (60.8)

Defecation-related symptoms

Subtotal 133 70 (58.3)

Fecal incontinence 9 8 (6.7)

Oily spotting 46 41 (34.2)

Flatus with discharge 37 28 (23.3)

Fecal urgency 5 5 (4.2)

Oily evacuation 4 4 (3.3)

Fatty/oily stool 11 11 (9.2)

Liquid stool 6 6 (5.0)

Increased defecation 3 3 (2.5)

Soft stool 3 3 (2.5)

Decreased defecation 3 3 (2.5)

Abdominal distension 1 1 (0.8)

Abdominal pain 3 3 (2.5)

Flatulence 1 1 (0.8)

Gastritis 1 1 (0.8)

Hepatobiliary disorders

Subtotal 3 2 (1.7)

Hepatic function abnormal 2 2 (1.7)

Hyperbilirubinemia 1 1 (0.8)

Metabolism and nutrition disorders

Subtotal 2 1 (0.8)

Hyperuricemia 2 1 (0.8)

Renal and urinary disorders

Subtotal 1 1 (0.8)

Dysuria 1 1 (0.8)

Respiratory, thoracic, and mediastinal disorders

Subtotal 1 1 (0.8)

Cough 1 1 (0.8)

Table 4 continued

Number of participantsincluded in the analysis

n = 120

Event Number ofepisodes

Numberof cases(%)

Skin and subcutaneous tissue disorders

Subtotal 1 1 (0.8)

Skin erosion 1 1 (0.8)

Investigations

Subtotal 1 1 (0.8)

Liver function test abnormal 1 1 (0.8)

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enhancing the effects of lifestyle improvementin Japanese participants with excessive visceralfat accumulation and without metabolic dis-eases. Orlistat, therefore, may be a useful optionfor early intervention in obesity. Moreover,based on orlistat’s mechanism of action, it isconceivable that the suppression of dietary fatabsorption enhances the utilization of lipids inthe body, which may further lead to reductionsin visceral fat and body weight. Reduction inwaist circumference can be attributed to subse-quent abdominal fat reduction.

In Europe and the US, a 60-mg formulationof orlistat for administration three times daily isavailable without a prescription. Multiplereports have confirmed the safety and efficacyof orlistat in individuals with severe obesity inthese countries, and significant body weightchanges were observed as well in a previousstudy (orlistat was administered three timesdaily for 104 weeks at a dose of 60 mg toseverely obese patients with BMIs between 30and 44 kg/m2 [18]).

Central appetite suppressants, such as lor-caserin and the combination of bupropion andnaltrexone, are used as anti-obesity drugs inEurope and the USA. Significant body weightreductions have been demonstrated in clinicalstudies for lorcaserin (in obese patients withBMI 30–45 kg/m2 or those with BMI C 27 kg/m2

with hypertension and/or dyslipidemia) [19]

and the combination of bupropion and nal-trexone (in obese patients with BMI C 30 kg/m2 or those with BMI C 27 kg/m2 with hyper-tension and/or dyslipidemia) [20]. Furthermore,the frequency of headache, nausea, and dizzi-ness was higher in the lorcaserin group com-pared with placebo; the combination ofbupropion and naltrexone caused nausea,headache, constipation, dizziness, and drymouth [21]. However, because orlistat has verylittle absorption in the body, these symptomswere not observed in individuals taking orlistat(with the exception of constipation).

Waist circumference was used to select par-ticipants for this study, and, as a result, partic-ipants with a visceral fat area \ 100 cm2 wereincluded in this study (19.2%) (as in anotherstudy [6]). Notably, not only was the visceral fatarea reduced in these participants, but waistcircumference, which serves as a surrogateindex for visceral fat, was also reduced.

Orlistat inhibits the absorption of dietary fatby 25%–30% [15] and is therefore presumed toreduce the concentration of lipids in the blood.In this study, all lipid parameters (total choles-terol, LDL cholesterol, HDL cholesterol, andtriglycerides) showed significant differencescompared with baseline at some terms. How-ever, only total cholesterol and LDL cholesterollevels showed a reducing trend throughout the52-week treatment term with significant

Fig. 6 Incidence of adverse reactions by time. Percentagesare calculated as the number of adverse reactions perassessment interval over the total number of adversereactions during the entire treatment term. a Incidence ofall adverse reactions; b incidence of defecation-related

adverse reactions. In both a and b, the majority of adversereactions occurred within the first 4 weeks (0–35 days) oftreatment; frequency of adverse reactions did not increasewith longer administration time

Adv Ther (2019) 36:217–231 227

reductions from baseline at whole term. In ameta-analysis by Tian Hu et al., participantsreceiving a low-carbohydrate diet showed agreater increase in HDL cholesterol and areduction in triglycerides compared with thosereceiving a low-fat diet, but experienced lessreduction in total cholesterol and LDL choles-terol compared with those receiving a low-fatdiet [22]. Orlistat, then, likely did not affectHDL cholesterol or triglycerides, which aremore likely to be affected by carbohydrateintake than fat intake, as orlistat’s mechanismof action inhibits the absorption of food-derived fat.

It is well established that body weight lossinhibits the progression of metabolic diseasesresulting from insulin resistance in individualswith obesity [2]. In this study, the effects oforlistat on blood glucose levels and blood pres-sure were not clear, partly because most of theparticipants had both normal blood glucose andnormal blood pressure at baseline. However, itmay be reasonable to expect that orlistat pre-vents the aggravation of blood glucose andblood pressure imbalances in the long term.Moreover, in this study, 26 of the 64 partici-pants with one or more risk factors at baseline(40.6%) had no risk factors at week 52 of treat-ment, and all seven participants who had two or

Fig. 7 Changes in fat-soluble vitamin concentrations.Mean ± SD. n (week 52): a 114, b 114, c 114. *PairedWilcoxon test, p\ 0.05 compared with baseline. a VitaminA (retinol); b vitamin D (25-OH vitamin D); c vitamin E(tocopherol). Although all parameters showed significant

differences compared with baseline at a certain term, allchanges were within their normal ranges. Nonotable changes in terms of safety were observed. SDstandard deviation

228 Adv Ther (2019) 36:217–231

more risk factors at baseline had fewer risk fac-tors at week 52.

By demonstrating reductions in totalcholesterol, LDL cholesterol, visceral fat area,waist circumference, and the number of meta-bolic disease risk factors, the clinical signifi-cance of orlistat as a potential benefit forJapanese participants with excessive visceral fataccumulation and without metabolic diseaseswas confirmed. Furthermore, a study suggestinghigh blood pressure, high blood glucose, andabnormal lipid metabolism to be cardiovascularrisk factors [6] showed reductions in the num-ber of metabolic disease risk factors as well asvisceral fat area with the use of orlistat, whichmay ultimately lead to a reduced risk of car-diovascular diseases.

In terms of safety, 142 adverse reactions in73 of the 120 participants (60.8%) wereobserved. However, most of these [133 episodesin 70 participants (58.3%)] were defecation-re-lated symptoms such as oily spotting and flatuswith discharge due to the pharmacologic effectsof the lipase inhibitor. The majority of thesesymptoms were mild, reversible, and recogniz-able by the participant; none were serious orsevere. Few adverse reactions required medicaltreatment, and no participants were advised bythe investigator to withdraw from treatment.The frequency of adverse reactions observed inthis study does not exceed that observed inprevious studies of orlistat 60 mg conducted inother countries as an over-the-counter drug(including defecation-related adverse reactions)[23]; therefore, it is reasonable to assume thatorlistat is also sufficiently tolerable with self-management in the Japanese population.Moreover, among the 133 defecation-relatedadverse reactions that occurred during thetreatment term, the majority (90 episodes,67.7%) occurred during the first 4 weeks of thetreatment term, and most of these participantswere able to continue the 52-week term (a fewparticipants withdrew from the study at theirrequest).

Because orlistat inhibits the absorption ofdietary fat by inactivating lipase, a lipolyticenzyme, the absorption of fat-soluble vitaminssuch as A, D, and E could also be inhibited. Noadverse reactions related to fat-soluble vitamin

deficiencies were observed, and no participantsrequired treatment or vitamin supplementa-tion. In this study, levels of vitamin A andvitamin D at week 52 were higher than those atbaseline; levels of vitamin E, however,decreased by - 0.081 ± 0.197 mg/dl (mean ±SD). Although there was a statistically signifi-cant reduction in vitamin E at week 52 of thetreatment term, levels did not subsequentlycontinue to reduce. Therefore, it is doubtfulthat this change is clinically meaningful. Fur-ther, the observed changes in this study werewithin the normal ranges, and no otherremarkable changes were observed. All otherlaboratory tests showed changes within theirnormal ranges, and no notable changes wereobserved with regard to safety.

Throughout the treatment term of this study,[90% of participants had a compliance rate of100% for dietary improvement. Among theremaining participants, none had a compliancerate \ 80%. Therefore, orlistat can also be auseful option when used as a complement todiet and maintenance of exercise habits in thelong term.

The open-label design and lack of a controlgroup are limitations of this study and mayhave contributed to observational bias of theinvestigators and high expectations ofparticipants.

In this study, we selected participants andmeasured the efficacy based on waist circum-ference. Thus, it is conceivable that users oforlistat can monitor feasibility of drug use andits effects by using their waist circumference asan indicator. Considering the fact that orlistat60 mg is already available as an over-the-coun-ter drug in several countries, for Japanese par-ticipants with excessive visceral fataccumulation and without metabolic diseases,orlistat is expected to provide significantpotential benefits.

CONCLUSIONS

It was confirmed that the 52-week administra-tion of orlistat 60 mg three times daily waseffective in reducing the visceral fat area andwaist circumference and was sufficiently

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tolerated by Japanese participants with exces-sive visceral fat accumulation and withoutmetabolic diseases when their diet wasimproved and exercise habits were maintained.The longer orlistat is administered, the morevisceral fat is expected to decrease; moreover, itmay lead to reductions in risk factors for meta-bolic diseases caused by obesity.

ACKNOWLEDGEMENTS

The authors would like to thank the partici-pants, investigators, and other staff membersfor their invaluable contributions to the study.We would like to thank Dr. Ichiro Tatsuno(Sakura Medical Center, Toho University) andDr. Yutaka Kimura (Kansai Medical University)for support and implementation of this study.We would like to acknowledge Dr. Norio Tada(Jikei University Kashiwa Hospital) for theinterpretation of results.

Funding. Funding for this study, articleprocessing charges, and open access was pro-vided by Taisho Pharmaceutical Co., Ltd.,Tokyo, Japan. All authors have sufficient accessto all data of this study and are responsible forthe integrity of the data and accuracy of thedata analysis.

Editorial Assistance. Editorial assistance inthe preparation of this article was provided byPearl Gomes, Cactus Communications, Tokyo,Japan. Support for this assistance was funded byTaisho Pharmaceutical Co., Ltd., Tokyo, Japan.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship of thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Dr. Kohji Shirai has receivedcompensation for his contribution to manu-script preparation and submission from TaishoPharmaceutical Co., Ltd., Tokyo, Japan. Michi-taka Tanaka, Toru Fujita, Yuka Fujii, Masatsugu

Shimomasuda, Soichi Sakai, and YoshishigeSamukawa are employees of Taisho Pharma-ceutical Co., Ltd., Tokyo, Japan.

Compliance with Ethics Guidelines. Thestudy was implemented in accordance withGood Clinical Practice guidelines and the ethi-cal principles of the Helsinki Declaration of1964, as revised in 2013, concerning humanand animal rights. Springer’s policy concerninginformed consent has been followed. This studywas approved by the Institutional Review Boardof each participating institution. After receivinga sufficient explanation and achieving a fullunderstanding of the study, all potential par-ticipants provided written consent to voluntar-ily participate in the study.

Data Availability. The data sets generatedduring and/or analyzed during the currentstudy are not publicly available because ofconfidentiality reasons but are available fromthe corresponding author on reasonablerequest.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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Reduction of Excessive Visceral Fat and Safety with 52-Week Administration of Lipase Inhibitor Orlistat in Japanese: Long-Term Clinical StudyAbstractIntroductionMethodsResultsConclusionTrial RegistrationFunding

IntroductionMethodsParticipantsStudy DesignAssessmentsStatistical Analysis

ResultsParticipantsEfficacyEfficacy End PointsClinical Laboratory TestsOther Analyses of Efficacy

Safety and Tolerability

DiscussionConclusionsAcknowledgementsReferences