Department of Community Medicine and Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan 3

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1 J Atheroscler Thromb, 218; 25: Origial Article Efficacy ad Safety of Pemafibrate Versus Feofibrate i Patiets with High Triglyceride ad Low HDL Cholesterol Levels: A Multiceter, Placebo-Cotrolled, Double-Blid, Radomized Trial Hideori Arai 1, Shizuya Yamashita 2, 3, Koutaro Yokote 4, 5, Eiichi Araki 6, Hideki Sugaami 7 ad Shu Ishibashi 8, o behalf of the K-877 Study Group 1 Natioal Ceter for Geriatrics ad Gerotology, Aichi, Japa 2 Departmet of Commuity Medicie ad Departmet of Cardiovascular Medicie, Osaka Uiversity Graduate School of Medicie, Osaka, Japa 3 Riku Geeral Medical Ceter, Osaka, Japa 4 Departmet of Diabetes, Metabolism ad Edocriology, Chiba Uiversity Graduate School of Medicie, Chiba, Japa 5 Departmet of Cliical Cell Biology ad Medicie, Chiba Uiversity Graduate School of Medicie, Chiba, Japa 6 Departmet of Metabolic Medicie, Faculty of Life Scieces, Kumamoto Uiversity, Kumamoto, Japa 7 Cliical Data Sciece Departmet, Kowa Compay, Ltd., Tokyo, Japa 8 Divisio of Edocriology ad Metabolism, Departmet of Medicie, Jichi Medical Uiversity, Tochigi, Japa Aim: To verify the superiority of pemafibrate over placebo ad the o-iferiority of pemafibrate to the maximum dose of feofibrate for determiig the percet chage i fastig serum triglyceride (TG) levels ad to ivestigate safety by assessig the icidece of adverse evets (AEs) ad adverse drug reactios (ADRs). Methods: This phase, placebo/active drug-cotrolled, radomized, double-blid, parallel group compariso study erolled patiets with high TG ad low high-desity lipoprotei cholesterol levels. Patiets were radomly assiged to receive placebo; pemafibrate.1 mg/day,.2 mg/day, or.4 mg/ day; or feofibrate 1 mg/day or 2 mg/day for 12 weeks. Results: Amog 526 radomized patiets, 489 completed the study, with drop-out rates of %, 6.7%, 5.5%, 5.9%, 8.2%, ad 1.7% i the placebo; pemafibrate.1 mg/day,.2 mg/day, ad.4 mg/day; ad feofibrate 1 mg/day ad 2 mg/day groups. The study showed the o-iferiority of pemafibrate.4 mg/day ad.2 mg/day to feofibrate 2 mg/day as well the o-iferiority ad superiority of all pemafibrate doses to feofibrate 1 mg/day for reducig TG levels. No dose-depedet icrease i the icidece of AEs or ADRs was observed amog the pemafibrate dose groups. The icidece of AEs ad ADRs for all pemafibrate doses was similar to that for placebo ad feofibrate 1 mg/day ad sigificatly lower tha that for feofibrate 2 mg/day (P.5). Coclusios: The favorable safety profile of pemafibrate, with fewer adverse effects o kidey/liverrelated laboratory tests ad fewer AEs/ADRs, icludig those leadig to treatmet discotiuatio, over feofibrate 2 mg/day may justify the use of this ovel ad potet treatmet optio for reducig TG levels i a broader rage of patiets. Key words: Selective PPAR modulator, Fibrate, Triglycerides, Safety, Residual risk Copyright 218 Japa Atherosclerosis Society This article is distributed uder the terms of the latest versio of CC BY-NC-SA defied by the Creative Commos Attributio Licese. Address for correspodece: Hideori Arai, Natioal Ceter for Geriatrics ad Gerotology, 7-43 Morioka-cho, Obu, Aichi , Japa harai@cgg.go.jp Received: February 6, 218 Accepted for publicatio: March 11, 218 Itroductio Reductio i low-desity lipoprotei cholesterol (LDL-C) levels is a cliical priority for prevetig cardiovascular disease. Eve whe LDL-C levels are reduced by drug therapy, the residual risk of cardiovascular disease still persists 1). Although further reductio 521

2 i LDL-C levels may help decrease this residual risk 2), growig evidece suggests that the pharmaceutical maagemet of other lipid abormalities also have cliical beefits. Oe coditio for which such maagemet ca be applied is atherogeic dyslipidemia, which is characterized by high levels of triglyceride (TG)-rich lipoproteis that are commoly accompaied by low levels of high-desity lipoprotei cholesterol (HDL- C) 3). Patiets with this type of dyslipidemia ofte have comorbidities that make them highly vulerable to cardiovascular evets, ad effective therapeutic strategies must maage TG ad HDL-C levels i additio to LDL-C levels 3, 4). Fibrates, which activate peroxisome proliferatoractivated receptor alpha (PPAR ), ca improve TG ad HDL-C levels 5). Feofibrate, i particular, has bee commoly used worldwide for this purpose. Cliical trials of feofibrate ad other fibrates have show that TG levels decreased by about 25% to 5% ad that HDL-C levels icreased by 5% to 2% 6-8), ad some data suggest that fibrates ca reduce the risk of cardiovascular evets 8, 9). For feofibrate, the greatest risk reductio occurs i patiets who have high TG ( 2 mg/dl) ad low HDL-C ( 35 mg/dl) levels at the start of treatmet 8, 1, 11). However, fibrates, icludig feofibrate, have bee associated with icreased risk of liver damage 12) ad icreased levels of serum creatiie, which is a idicator of kidey damage 13). Most fibrates are excreted through the kideys, ad excretio is reduced i patiets with compromised kidey fuctio 8, 13). Accordig to the Natioal Kidey Foudatio, feofibrate ad several other fibrates are cotraidicated i patiets with abormal kidey fuctio test results 13, 14). Fibrates ca also affect the liver drug-metabolizig ezyme activity ad therefore iteract with other drugs such as gemfibrozil ad statis 8, 15). Pemafibrate (K-877) is a ovel selective PPAR modulator (SPPARM ) with higher potecy ad selectivity for PPAR activatio tha feofibrate 3, 16, 17). Pemafibrate was idetified from several cadidate compouds with excellet potecy ad selectivity for PPAR as exertig more TG-reducig ad HDL-C-icreasig effects, but fewer adverse effects of icreasig liver weight, tha feofibrate i aimal studies 18). Phase ad studies have also show promisig safety ad efficacy results 19, 2). Pemafibrate was well tolerated, with o otable adverse effects o liver or real fuctio 3, 19, 2). The icidece of liver- ad kidey-related adverse evets (AEs) was less i the pemafibrate groups tha i the feofibrate groups i these trials 19). I additio, it has bee reported that pemafibrate atteuated postpradial hypertriglyceridemia i laboratory aimals (mice) 21). A recet study has suggested that postpradial hypertriglyceridemia is related to the accumulatio of TG-rich lipoproteis ad their remats, which have atherogeic effects 22). Available precliical ad cliical data o pemafibrate suggest that this ew drug, with its favorable beefit risk balace, is more effective tha covetioal PPAR agoists. The curret study was desiged to further evaluate the effects of pemafibrate o TG levels i patiets with high TG ad low HDL-C levels. I particular, this trial compared the efficacy ad safety of pemafibrate to the maximum dose of feofibrate (2 mg/day). Aim The objectives of this phase study were to verify 1) the superiority of three doses of pemafibrate over placebo ad 2) the o-iferiority of pemafibrate to the maximum dose of feofibrate (2 mg/day) for reducig TG levels. The icidece of AEs ad adverse drug reactios (ADRs) was ivestigated as the primary safety edpoit. Methods Trial Desig This phase, placebo/active drug-cotrolled, radomized, double-blid, parallel group compariso study was coducted i Japa i accordace with the Declaratio of Helsiki ad i compliace with the study protocol ad Good Cliical Practice. Ethical approval was obtaied from the Istitutioal Review Board at each trial ceter. Patiets Patiets with dyslipidemia, high TG levels, ad low HDL-C levels were erolled. All patiets provided writte iformed coset before participatio. After providig writte coset to participate, they uderwet laboratory testig twice durig the screeig period (withi 8 weeks) to determie eligibility. Me or postmeopausal wome age 2 to 74 years who had received dietary ad exercise couselig for 12 weeks were eligible if two cosecutive tests showed a serum TG level of 2 mg/dl ad serum HDL-C level of 5 mg/dl for me ad 55 mg/dl for wome. Patiets with serum TG level of 1 mg/dl were excluded, alog with patiets requirig other lipid-lowerig medicatios durig the trial; patiets with type 1 diabetes, poorly cotrolled type 2 diabetes (HbA1c 8.4%), poorly cotrolled thyroid disease, poorly cotrolled hypertesio (systolic blood pressure 16 mmhg or diastolic blood pressure 1 mmhg), real dysfuctio (serum creatiie level 1.5 mg/ 522

3 Fig.1. Study desig Patiets were radomly assiged to oe of six groups (placebo, three doses of pemafibrate, ad two doses of feofibrate). Edpoits The primary efficacy edpoit was the percet chage i fastig serum TG levels from baselie to week 8, 1, ad 12 after the start of treatmet. The secodary efficacy edpoits were chages ad percet chages i other parameters from baselie to the ed of treatmet, icludig HDL-C, TC, LDL-C, o-hdl- C, very-low-desity lipoprotei cholesterol (VLDL-C), remat lipoprotei cholesterol (RemL-C), apolipoprotei, glucose, ad isuli levels ad the homeostadl), or gallbladder disease or history of gallstoes; patiets with elevated liver ezyme levels (twice the upper limit of the ormal rage [ULN]), low hemoglobi levels (below 12 g/dl for me ad 11 g/dl for wome), or low fibrioge levels (below the lower limit of the ormal rage [LLN]); patiets with a recet history of myocardial ifarctio (withi 3 moths prior to coset) or heart failure; or those with a maligat tumor. Study Drug Admiistratio Eligible patiets were radomly assiged to oe of six groups at a assigmet ratio of 1:1:3:2:2:3: placebo, pemafibrate.1 mg/day (5 µg bid), pemafibrate.2 mg/day (1 µg bid), pemafibrate.4 mg/ day (2 µg bid), feofibrate 1 mg/day (1 mg qd), or feofibrate 2 mg/day (2 mg qd) (Fig. 1). This study used microized feofibrate capsules. The 1-mg microized feofibrate capsule was bioequivalet to a 8-mg feofibrate tablet. Pemafibrate was admiistered i tablet form. The double-dummy desig was used for blidig of the ivestigatioal product: patiets i all groups took the same umber of preparatios with the same appearace usig idistiguishable pemafibrate ad placebo tablets ad idistiguishable feofibrate ad placebo capsules. The drug admiistratio period was 12 weeks with 4-week follow-up period. Sample Collectio ad Assessmet Blood ad urie were collected for edpoit aa- lysis at the two screeig visits ad at weeks, 4, 8, 1, ad 12 of treatmet. Mea baselie values were obtaied usig the results from two screeig tests ad measuremets at week for fastig serum TG, HDL-C (direct method), total cholesterol (TC), LDL-C (direct method), ad o-hdl-c (direct method). Other parameters used measuremets at treatmet week as baselie. Radomizatio ad Blidig Radomizatio was performed by a third party resposible for allocatio. Patiet allocatio was performed by the Patiet Registratio Ceter based o the provisioal/fial registratio iformatio ad test results, ad the trial drugs were prescribed accordig to the drug umbers idicated by the Patiet Registratio Ceter. Double blidig was implemeted as follows: the perso resposible for drug allocatio prepared a key code ad stored it util the key was opeed. The key was opeed after database lockig. 523

4 Fig.2. Dispositio of patiets sis model assessmet for isuli resistace (HOMA-R). The primary safety edpoit was the icidece of AEs ad ADRs. Secodary edpoits icluded (1) the percetages of patiets who had aspartate amiotrasferase (AST), alaie amiotrasferase (ALT), creatie kiase (CK), or serum creatiie levels exceedig the cut-off levels ( 3 ad 5 ULN for AST ad ALT; 2.5 ad 5 ULN for CK; 1.5 ad 2. mg/dl for serum creatiie) or those who had fibrioge or hemoglobi levels below the cut-off levels (1,.75, ad.5 LLN for fibrioge ad 1., 8., ad 6.5 g/dl for hemoglobi) durig treatmet ad (2) chages from week i physiological ad cliical test levels (AST, ALT, gamma-glutamyl traspeptidase [ -GT], CK, ad serum creatiie levels ad (i posthoc aalysis) estimated glomerular filtratio rate [egfr]). Sample Size The sample size was determied usig the results of a previous phase study 2). To reproduce the previous fidigs, the study desig called for at least 29 patiets per group, which is the same umber as that i the phase study. Uder these circumstaces, to achieve at least 9% power i the primary aalysis, the required umber of patiets was determied to be 29 i the placebo ad pemafibrate.1 mg/day groups, 97 i the pemafibrate.2 mg/day group, 68 i the pemafibrate.4 mg/day group, ad 97 i the feofibrate 2 mg/day group. The target umber of patiets i the feofibrate 1 mg/day group was set to the same umber as that i the pemafibrate.4 mg/ day group to clearly defie the effects of pemafibrate. Fially, to accommodate potetial discotiuatios/ drop-outs ad the pre-established allocatio ratio (1:1: 3:2:2:3), the followig umbers were targeted: 4 i the placebo group, 4 i the pemafibrate.1 mg/day group, 12 i the pemafibrate.2 mg/day group, 8 i the pemafibrate.4 mg/day group, 8 i the feofibrate 1 mg/day group, ad 12 i the feofibrate 2 mg/day group. Statistical Aalysis Statistical aalysis used a sigificace level of 5% ad a cofidece coefficiet of 95% o both sides. 524

5 Table 1. Patiet Characteristics Age, year Male, (%) BMI, kg/m 2 Type 2 diabetes, (%) Hypertesio, (%) Fatty liver, (%) TG, mg/dl HDL-C, mg/dl LDL-C, mg/dl No-HDL-C, mg/dl HbA1c, % Placebo Pemafibrate Feofibrate (N 43) (88.4) (16.3) 15 (34.9) 13 (3.2) mg/day (N ) (97.8) (8.9) 12 (26.7) 11 (24.4) mg/day (N 128) (89.1) (18.8) 44 (34.4) 35 (27.3) mg/day (N 84) (97.6) (17.9) 17 (2.2) 2 (23.8) mg/day (89.4) (12.9) 23 (27.1) 21 (24.7) mg/day (N 14) (89.3) (13.6) 43 (3.7) 29 (2.7) Data are preseted as mea SD for cotiuous parameters ad the umber of patiets (%) for categorical parameters. : Direct method-metabo Lead : Direct method BMI, body mass idex; TG, triglyceride; HDL-C, high-desity lipoprotei cholesterol; LDL-C, low-desity lipoprotei cholesterol; HbA1c, hemoglobi A1c; SD, stadard deviatio Efficacy aalysis set icluded all patiets who were radomized, had at least oe dose of the trial drug, ad had baselie ad post-baselie efficacy measuremets. The safety aalysis set icluded all patiets who were radomized ad had at least oe dose of the trial drug. For primary aalysis of the primary efficacy edpoit, the cofirmatio of a dose respose relatioship ad assessmet of o-iferiority were coducted with the closed testig procedure. To examie the dose respose relatioship ad superiority over the placebo group, each pemafibrate dose group was compared to the placebo group. I each examiatio, homogeeity of variace betwee the placebo ad active drug groups was ot assumed. The o-iferiority margi was set at 1%. There were four steps i this closed procedure. First, to test whether there was a dose respose relatioship usig the maximum cotrast method, repeated measures aalysis of covariace (ANCOVA) was performed o the percet chage i fastig serum TG level with baselie as the covariate ad weeks 8, 1, ad 12 as repeated time poits. If those results were sigificat, the secod step was Duett s test to compare the three pemafibrate groups with the placebo group. If those results were sigificat, the third step was to assess the o-iferiority of pemafibrate.4 mg/day to feofibrate 2 mg/day. Fourth, the o-iferiority of pemafibrate.2 mg/day was compared with feofibrate 2 mg/day. Secodary assessmets were implemeted to test the superiority of pemafibrate.2 mg/day ad pemafibrate.4 mg/day over feofibrate 2 mg/day ad to test the o-iferiority (ad superiority, if o-iferiority was established) for each pemafibrate dose to feofibrate 1 mg/day. For the secodary efficacy edpoits, the levels of the other parameters at the completio of the treatmet period were compared to baselie levels. For each group, oe-sample t -test was used for determiig the chage or percet chage from baselie ad two-sample t -test was used to compare those chages betwee each pemafibrate group ad placebo or each feofibrate group. For the aalysis of the primary safety edpoits, Fisher s exact test was performed to compare the icidece of AEs ad ADRs i each pemafibrate group ad placebo or each feofibrate group ad the 95% cofidece itervals (CIs) of the differeces i icidece were calculated. The dose respose relatioship for icidece was examied usig the Cochra Armitage test. For the secodary safety edpoits, the percetage of patiets whose AST, ALT, CK, or serum creatiie levels exceeded the cut-off value or whose fibrioge ad hemoglobi levels fell below the cut-off value were calculated. The Wilcoxo siged-rak test was performed to assess chages at each time poit. Results Patiets Patiets were erolled from May 14 to December 27, 212, i a total of 32 medical istitutios i Japa. Iformed coset was obtaied from 854 pa- 525

6 Fig.3. Percet chage i TG levels I repeated measures aalysis of covariace (baselie as the covariate ad weeks 8, 1, ad 12 as repetitio poits). Data are preseted as LS mea (SE). : P.1 vs. baselie. LS, least squares; SE, stadard error tiets, 526 were radomized to the treatmet group, ad 489 completed the study (Fig. 2). Most patiets who provided iformed coset but were ot radomized did ot meet the iclusio criteria or satisfied the exclusio criteria based o laboratory test results durig the screeig period. The drop-out rate was highest i the feofibrate groups. The trial was discotiued i patiets i the placebo group, 3 of (6.7%) patiets i the pemafibrate.1 mg/day group, 7 of 128 (5.5%) patiets i the pemafibrate.2 mg/day group, 5 of 85 (5.9%) patiets i the pemafibrate.4 mg/day group, 7 of 85 (8.2%) patiets i the feofibrate 1 mg/day group, ad 15 of 14 (1.7%) patiets i the feofibrate 2 mg/day group. demographics were similar i all treatmet groups (Table 1). The mea (stadard deviatio [SD]) age was 5.3 (1.2) years. Most patiets were me (91.2%; 479/525). The mea (SD) body mass idex was 26.7 (3.7) kg/m 2. Type 2 diabetes was preset i 15.2% (8 of 525) of the patiets. The mea (SD) level for TG was (138.3) mg/dl, for HDL-C was 38.9 (5.2) mg/dl, ad for LDL-C was (35.4) mg/dl. Efficacy For primary edpoit assessmet, repeated measures ANCOVA was performed for fastig serum TG levels usig baselie as the covariate ad weeks 8, 1, ad 12 as repetitio poits. Fastig serum TG levels decreased i all pemafibrate ad feofibrate treatmet groups. The percet chage i TG levels was aalyzed usig the aforemetioed closed procedure. Whe the dose respose relatioship was aalyzed i the placebo ad pemafibrate dose groups, all cotrasts were sigificat (P.1) (Supplemetary Table 1). The cotrast coefficiet matrix of ( 5, 1, 3, 3) was selected by the maximum cotrast method ad cofirmed a dose respose relatioship. The superiority of all pemafibrate dose groups over the placebo group was also cofirmed (Duett s test, P.1) (Supplemetary Table 2). The percet chage i TG levels raged from 46% to 52% i pemafibrate groups (Fig. 3). The chage i the pemafibrate.4 mg/day group was cofirmed to be o-iferior to that i the feofibrate 2 mg/day group, with the upper limit of the 95% CI of the betwee-group differece less tha 1%, the o-iferiority margi (.3% [95% CI: 5.3%, 4.7%], P.96). Similarly, the o-iferiority of pemafibrate.2 mg/day to feofibrate 2 mg/day was cofirmed (4.8% [95% CI:.4%, 9.3%], P.33). No superiority was cofirmed i the pemafibrate.2 mg/ day or.4 mg/day groups compared with the feofibrate 2 mg/day group. The pemafibrate.1,.2 ad.4 mg/day groups were cofirmed to be o-iferior ad superior ( 8.% [95% CI: 14.7%, 1.3%], P.2; 8.4% [95% CI: 13.5%, 3.3%], P.1; ad 13.6% [95% CI: 19.2%, 8.%], P.1, respectively) to the feofibrate 1 mg/day group. The results of the secodary efficacy edpoits 526

7 Table 2. Chages i Lipid ad Glucose Metabolism Durig the 12-Week Treatmet Period (LOCF) Placebo Pemafibrate Feofibrate (N 43).1 mg/day (N ).2 mg/day (N 128).4 mg/day (N 84) 1 mg/day 2 mg/day (N 14) HDL-C, mg/dl %Chage P vs. feofibrate 1 mg/day P vs. feofibrate 2 mg/day TC, mg/dl %Chage P vs. feofibrate 1 mg/day P vs. feofibrate 2 mg/day..1.1 LDL-C, mg/dl %Chage P vs. feofibrate 1 mg/day P vs. feofibrate 2 mg/day No-HDL-C, mg/dl %Chage P vs. feofibrate 1 mg/day P vs. feofibrate 2 mg/day VLDL-C, mg/dl %Chage P vs. feofibrate 1 mg/day P vs. feofibrate 2 mg/day RemL-C, mg/dl %Chage P vs. feofibrate 1 mg/day P vs. feofibrate 2 mg/day

8 (Cot. Table 2) Placebo Pemafibrate Feofibrate (N 43).1 mg/day (N ).2 mg/day (N 128).4 mg/day (N 84) 1 mg/day 2 mg/day (N 14) ApoA-I, mg/dl %Chage P vs. feofibrate 1 mg/day P vs. feofibrate 2 mg/day ApoA-, mg/dl %Chage P vs. feofibrate 1 mg/day P vs. feofibrate 2 mg/day ApoB, mg/dl %Chage P vs. feofibrate 1 mg/day P vs. feofibrate 2 mg/day ApoB48, µg/ml %Chage P vs. feofibrate 1 mg/day P vs. feofibrate 2 mg/day ApoB1, mg/dl %Chage P vs. feofibrate 1 mg/day P vs. feofibrate 2 mg/day ApoC-, mg/dl %Chage P vs. feofibrate 1 mg/day P vs. feofibrate 2 mg/day

9 (Cot. Table 2) Placebo Pemafibrate Feofibrate (N 43).1 mg/day (N ).2 mg/day (N 128).4 mg/day (N 84) 1 mg/day 2 mg/day (N 14) ApoC-, mg/dl %Chage P vs. feofibrate 1 mg/day P vs. feofibrate 2 mg/day ApoC- /C %Chage P vs. feofibrate 1 mg/day P vs. feofibrate 2 mg/day Glucose, mg/dl Chage P vs. feofibrate 1 mg/day P vs. feofibrate 2 mg/day Isuli, µu/ml Chage P vs. feofibrate 1 mg/day P vs. feofibrate 2 mg/day HOMA-R Chage * P vs. feofibrate 1 mg/day P vs. feofibrate 2 mg/day P value vs. placebo ad agaist feofibrate 1 mg/day ad 2 mg/day were calculated usig the 2-sample t-test. Data are preseted as mea SD for cotiuous parameters. Here, is the umber of subjects who had both baselie ad post baselie measuremets. : P.5, : P.1, : P.1 vs. baselie (1-sample t-test). : Direct method- Metabo Lead : Ultracetrifugatio HDL-C, high-desity lipoprotei cholesterol; TC, total cholesterol; LDL-C, low-desity lipoprotei cholesterol; VLDL-C, very-low-desity lipoprotei cholesterol; RemL-C, remat lipoprotei cholesterol; Apo, apolipoprotei; HOMA-R, homeostasis model assessmet for isuli resistace; SD, stadard deviatio 529

10 Table 3. Icidece of Adverse Evets ad Adverse Drug Reactios (A) Adverse Evets Placebo Pemafibrate Feofibrate Number of subjects with adverse evets, (%) 95%CI P P vs. feofibrate 1 mg/day P vs. feofibrate 2 mg/day Serious, (%) Discotiuatio, (%) (B) Adverse Drug Reactios Number of subjects with adverse evets, (Icidece, %) 95%CI P P vs. feofibrate 1 mg/day P vs. feofibrate 2 mg/day Serious, (%) Discotiuatio, (%) (N 43) 18 (41.9) 27., mg/day (N ) 15 (33.3) 2., (2.2) 2 (4.4).2 mg/day (N 128) 49 (38.3) 29.8, (1.6) 2 (1.6).4 mg/day 34 (4.) 29.5, mg/day 36 (.4) 31.7, (3.5) Placebo Pemafibrate Feofibrate (N 43) 3 (7.) 1.5, mg/day (N ) 2 (4.4).5, (2.2).2 mg/day (N 128) 1 (7.8) 3.8, (.8).4 mg/day 1 (11.8) 5.8, mg/day 12 (14.1) 7.5, (2.4) 2 mg/day (N 14) 79 (56.4) 47.8, (2.1) 14 (1.) 2 mg/day (N 14) 37 (26.4) 19.3, (8.6) : Cochra-Armitage test (placebo, pemafibrate) : Fisher s exact test CI, cofidece iterval are summarized i Table 2. HDL-C, apolipoprotei A- (ApoA- ), ApoA-, ad LDL-C levels icreased ad VLDL-C, RemL-C, ApoB48, ApoC-, ApoC-, ad ApoC- /ApoC- levels decreased i all pemafibrate ad feofibrate groups. No-HDL-C levels decreased i all groups other tha the pemafibrate.4 mg/ day group, ad TC, ApoB, ad ApoB1 levels decreased i the feofibrate 2 mg/day group. Fastig plasma glucose levels decreased i the pemafibrate.4 mg/day ad feofibrate 2 mg/day groups, fastig isuli levels decreased i the pemafibrate.2 ad.4 mg/day groups, ad HOMA-R decreased i the pemafibrate.2 mg/day group. Safety The icidece of AEs (Table 3) was 41.9% (18/ 43) i the placebo group, 33.3% (15/) i the pemafibrate.1 mg/day group, 38.3% (49/128) i the pemafibrate.2 mg/day group, 4.% (34/85) i the pemafibrate.4 mg/day group,.4% (36/85) i the feofibrate 1 mg/day group, ad 56.4% (79/14) i the feofibrate 2 mg/day group. The icidece of ADRs was 7.% (3/43) i the placebo group, 4.4% (2/) i the pemafibrate.1 mg/day group, 7.8% (1/128) i the pemafibrate.2 mg/day group, 11.8% (1/85) i the pemafibrate.4 mg/day group, 14.1% (12/85) i the feofibrate 1 mg/day group, ad 26.4% (37/ 14) i the feofibrate 2 mg/day group. No dosedepedet icrease i the icidece of AEs or ADRs was observed amog the pemafibrate dose groups (P.931 or.219, respectively). Whe compared with the placebo ad feofibrate groups by Fisher s exact test, the icidece of AEs ad ADRs i the pemafibrate dose groups showed o marked differece compared with that i the feofibrate 1 mg/day group, but were sigificatly less frequet tha that i the feofibrate 2 mg/day group (P.5). There was oly oe serious AE leadig to death i the study: pulmoary embolism i oe patiet i the pemafibrate.4 mg/day group (Table 3). This evet ad all other serious AEs were judged by ivestigators to have o relatioship with the ivestigatioal 53

11 Table 4. Types of Adverse Evets (Liver-related ad Rhabdomyolysis/Myopathy-related) Liver-related AEs Hepatobiliary disorders Hepatic fuctio abormal Laboratory test abormalities Abormal liver fuctio tests AST icreased ALT icreased -GT icreased Blood bilirubi icreased Blood fibrioge decreased Rhabdomyolysis-/myopathy-related AEs Laboratory test abormalities Serum CK icreased Serum Cr icreased Musculoskeletal ad coective tissue disorders Myalgia Placebo Pemafibrate Feofibrate (N 43) 4 (9.3) 4 (9.3) 1 (2.3) 1 (2.3) 1 (2.3) 1 (2.3) 3 (7.) 3 (7.) 3 (7.).1 mg/day (N ) 2 (4.4) 2 (4.4) 2 (4.4) 1 (2.2) 1 (2.2) 1 (2.2).2 mg/day (N 128) 3 (2.3) 3 (2.3) 2 (1.6) 1 (.8) 2 (1.6) 2 (1.6) 1 (.8) 1 (.8).4 mg/day 7 (8.2) 7 (8.2) 4 (4.7) 2 (2.4) 1 mg/day 13 (15.3) 12 (14.1) 11 (12.9) 3 (3.5) 2 (2.4) 2 (2.4) 2 mg/day (N 14) 34 (24.3) 3 (2.1) 3 (2.1) 31 (22.1) 22 (15.7) 2 (1.4) 4 (2.9) 2 (1.4) 2 (1.4) 7 (5.) 7 (5.) 3 (2.1) 4 (2.9) AST, aspartate amiotrasferase; ALT, alaie amiotrasferase; -GT, gamma glutamyl traspeptidase; CK, creatie kiase; Cr, creatiie; AE, adverse evet product. No serious ADRs were observed. AEs that led to the discotiuatio of the study drug occurred i 4.4% (2/) of the patiets i the pemafibrate.1 mg/day group, 1.6% (2/128) of the patiets i the.2 mg/day group, 1.2% (1/85) of the patiets i the.4 mg/day group, 3.5% (3/85) of the patiets i the feofibrate 1 mg/day group, ad 1.% (14/14) of the patiets i the feofibrate 2 mg/day group (P values vs feofibrate 2 mg/day were estimated as.365,.4 ad.11 for pemafibrate.1,.2 ad.4 mg/ day, respectively, by post-hoc Fisher s exact test). ADRs required discotiuatio of the study drug i 2.2% (1/) of the patiets i the pemafibrate.1 mg/day group,.8% (1/128) of the patiets i the.2 mg/day group, % (/85) of the patiets i the.4 mg/day group, 2.4% (2/85) of the patiets i the feofibrate 1 mg/day group, ad 8.6% (12/14) of the patiets i the feofibrate 2 mg/day group (P values vs feofibrate 2 mg/day were estimated as.193,.3 ad.4 for pemafibrate.1,.2 ad.4 mg/day, respectively, by post-hoc Fisher s exact test). The icidece of liver-related AEs was 8.2% (7/85) i the pemafibrate.4 mg/day dose group, but this icidece was similar to that i the placebo group (9.3%). I cotrast, 13 of 85 (15.3%) patiets treated with feofibrate 1 mg/day ad 34 of 14 (24.3%) patiets treated with feofibrate 2 mg/day had liverrelated AEs (Table 4). The icidece of rhabdomyoly- sis-/myopathy-related AEs was low ad similar to placebo i all pemafibrate ad feofibrate dose groups (Table 4). The icidece of asopharygitis was 5% i some pemafibrate dose groups, but the icidece did ot markedly differ from the icidece i the placebo group. I the aalysis of liver fuctio test results, AST, ALT, ad -GT levels markedly icreased i the feofibrate groups compared with those i the placebo ad pemafibrate groups. ALT ad -GT levels sigificatly decreased i the pemafibrate dose groups from baselie to weeks 4 to 12 (Fig. 4). I kidey fuctio tests, serum creatiie ad egfr levels dramatically icreased ad decreased, respectively, i the feofibrate groups, particularly i the 2 mg/day group, compared with those i the placebo ad pemafibrate groups (Fig. 4). CK levels were early uchaged. Table 5 shows the umber of patiets with laboratory test results exceedig the cut-off values or goig below the cut-off values. Four patiets (4.7%) i the feofibrate 1 mg/day group ad seve (5.%) i the feofibrate 2 mg/day group had ALT levels that rose to 3 ULN. No patiets i the placebo or pemafibrate groups had ALT levels this high. Results were similar for AST levels. CK level chages exceeded 2.5 or 5 ULN i some patiets i the pemafibrate groups, but the percetage of patiets with such chages 531

12 Fig.4. Safety edpoits (liver ezymes, CK, kidey fuctio) Data are preseted as mea levels. (A) AST, (B) ALT, (C) -GT, (D) CK, (E) Creatiie, (F) egfr. The error bar idicates stadard deviatio. : P.5, : P.1, : P.1 vs. baselie (Wilcoxo siged-rak test). AST, aspartate amiotrasferase; ALT, alaie amiotrasferase; -GT, gamma-glutamyl traspeptidase; CK, creatie kiase; egfr, estimated glomerular filtratio rate 532

13 Table 5. Number of Patiets with Laboratory Test Values Exceedig or Decreasig below the Cut-off Values AST ULN 3 AST ULN 5 ALT ULN 3 ALT ULN 5 CK ULN 2.5 CK ULN 5 Serum Cr 1.5 mg/dl Serum Cr 2. mg/dl Fibrioge LLN 1 Fibrioge LLN.75 Fibrioge LLN.5 Hemoglobi 1. g/dl Hemoglobi 8. g/dl Hemoglobi 6.5 g/dl Number of patiets (%) Placebo Pemafibrate Feofibrate (N 43) 1 (2.3) 1 (2.3).1 mg/day (N ) 1 (2.2) 3 (6.7).2 mg/day (N 128) 3 (2.3) 1 (.8) 1 (.8) 3 (2.3).4 mg/day (N 84) 4 (4.8) 1 mg/day 4 (4.7) 2 (2.4) 2 mg/day (N 14) 3 (2.1) 1 (.7) 7 (5.) 1 (.7) 1 (.7) 7 (5.) ULN of AST: 4 IU/L/37, ALT: IU/L/37, CK: 27 (Male) or 15 (Female) IU/L/37, LLN of Fibrioge: 155 mg/dl AST, aspartate amiotrasferase; ULN, upper limit of the ormal rage; ALT, alaie amiotrasferase; CK, creatie kiase; Cr, creatiie; LLN, lower limit of the ormal rage. was similar to that i the placebo group. The serum creatiie level exceeded 2. mg/dl i 1 patiet i the pemafibrate.2 mg/day group. This icrease was cosidered to be a AE (icreased blood creatiie level) but was judged to be ot related to the trial drug. Discussio I this multiceter, radomized study, pemafibrate treatmet demostrated potet ad dose-depedet reductio i TG levels at.1,.2 ad.4 mg/ day i patiets with high TG ad low HDL-C levels. This is the first study to compare the safety ad efficacy of pemafibrate with the maximum dose of feofibrate (2 mg/day). Pemafibrate.2 mg/day ad.4 mg/day were cofirmed to be o-iferior to feofibrate 2 mg/day, ad pemafibrate.1 to.4 mg/day was cofirmed to be superior to feofibrate 1 mg/ day for reducig TG levels. The icidece of AEs/ ADRs i all pemafibrate groups was cofirmed to be comparable to that of placebo ad less frequet tha that of feofibrate 2 mg/day. Overall, pemafibrate.4 mg/day was superior to feofibrate 2 mg/day. The efficacy results i the curret study were cosistet with aother phase study that foud that pemafibrate.2 mg/day ad.4 mg/day provided sigificatly better reductio i TG levels tha feofibrate tablets (16.6 mg/day, equivalet to microized feofibrate capsules with 134 mg/day) 19). I a earlier phase study, TG reductios were at least 1% greater i pemafibrate-treated patiets (.2 mg/day or.4 mg/day) tha i feofibrate patiets (1 mg/ day), but the differece was ot sigificat 2). The statistical sigificace i the curret study was likely due to the higher patiet umbers ad greater statistical power. Similar treds were observed i the preset study for other TG-related idicators, icludig VLDL-C, RemL-C, ad ApoC-. At all doses, pemafibrate provided more potet improvemet i TG-rich lipoprotei levels tha feofibrate 1 mg/day, ad the effects of pemafibrate.2 mg/day ad.4 mg/day were equivalet to those of feofibrate 2 mg/day. Pemafibrate groups teded to show decreased fastig serum glucose levels ad decreased fastig isuli levels. Treatmet with pemafibrate may thus help reduce isuli resistace. This poit requires further ivestigatio. I the preset study, LDL-C levels icreased i the pemafibrate ad feofibrate groups. May erolled patiets had hyperlipidemia Type, which is ofte associated with icreases i LDL-C levels after treatmet with feofibrate or bezafibrate. With feofibrate, LDL-C levels may icrease, eve whe these levels are iitially low 23). I patiets with high TG levels but low LDL-C levels, VLDLs accout for a relatively high proportio of apob-cotaiig lipoproteis, ad LDL-C 533

14 levels may icrease as a result of TG-rich lipoprotei catabolism ehaced by treatmet with those agets. Ofte, i cliical practice, LDL-C levels are iitially elevated after fibrate treatmet but the gradually decrease with cotiued fibrate treatmet i combiatio with diet therapy. I the study metioed above 23), LDL-C levels icreased after feofibrate treatmet compared to placebo, but the differece i LDL-C levels betwee the groups gradually dimiished durig the 14-week treatmet period. No further details are available, but there might be itegrated effects o slightly differet baselie characteristics of patiets, such as mea baselie levels ad/or distributio of TG ad LDL-C levels. I additio to demostratig efficacy, this study also cofirmed the safety of pemafibrate. The icidece of AEs ad ADRs i all pemafibrate groups was similar to that i the placebo group ad less frequet tha that i the feofibrate groups; these differeces betwee each of the pemafibrate groups ad the feofibrate 2 mg/day group were sigificat. More specifically, pemafibrate was associated with a low risk of AEs related to liver fuctio. Eve at the highest dose (.4 mg/day) i the preset study, pemafibrate was associated with reduced ALT ad -GT levels. I cotrast, feofibrate, particularly at a high dose (2 mg/day), caused further elevatio i ALT ad -GT levels. These observatios are cosistet with previous precliical ad cliical fidigs 19, 2, 24-26). Ulike feofibrate, pemafibrate is primarily excreted ito the bile 27). I rats, pemafibrate provided more potet reductio i TG levels tha feofibrate with less icrease i liver weight 18). I aother double-blid comparative study, liver-related AEs occurred i 6.8% of patiets i the pemafibrate.2 mg/day group, % of those i the pemafibrate.4 mg/day group, ad 39.5% of those i the feofibrate 16.6 mg/day group 19). The ability of pemafibrate to potetly reduce TG levels without affectig liver fuctio clearly distiguishes it from feofibrate. The preset study also cofirmed the safety profile of pemafibrate related to real fuctio over feofibrate. The greatest reductio i egfr was oted at the maximum dose of feofibrate (2 mg/day), which was eve more extesive tha that for feofibrate 1 mg/day; egfr was miimally affected by the maximum dose of pemafibrate (.4 mg/day). I aother phase study, feofibrate was associated with icreases i serum creatiie levels ad decreases i egfr, but these chages were miimal i the pemafibrate group 19). I the same study, the icidece of kideyrelated AEs was % i the pemafibrate.2 mg/day ad.4 mg/day groups ad 3.9% i the feofibrate 16.6 mg/day group 19). Drug effectiveess i real-world cliical practice is clearly affected by the umber of treatmet discotiuatios due to AEs. To maximize the effectiveess of a drug, it is ecessary to miimize treatmet discotiuatios. I the preset study, the discotiuatio rate was 1% for feofibrate 2 mg/day (14 of 14 patiets). The primary reaso was cocer for patiet safety followig worseig of liver fuctio (11 patiets). The pemafibrate groups showed oe treatmet discotiuatio due to ALT level elevatio i the.2 mg/day group ad o discotiuatios due to worseig liver fuctio i the.4 mg/day (high dose) group. The low level of discotiuatio suggests that patiets ca beefit from the highly potet reductio i TG levels at a high dose without compromisig safety. Additioally, the ACCORD study prespecified rules for discotiuatio or dose reductio based o laboratory values, icludig egfr 11). A compariso of feofibrate ad placebo i the same study foud greater egfr reductio (2.4% vs. 1.1%) ad a higher rate of dose reductio with feofibrate 11). These results suggest that some patiets are uable to beefit from the maximum feofibrate dose. I cotrast, pemafibrate appears to cause very little reductio i egfr, eve at the maximum dose. For this reaso, we ca aticipate few istaces of drug withdrawal. These favorable efficacy ad safety results compared to feofibrate may also be related to fidigs that pemafibrate qualifies as a SPPARM, which permits the separatio of desirable effects from adverse effects 16, 17). This study has some limitatios. First, the treatmet period was short (12 weeks), ad the sample size was moderate. Correlatig the preset fidigs to cliical outcomes, such as the prevetio of cardiovascular evets or acute pacreatitis, will require a larger study coducted over a loger duratio. The ogoig PROMINENT study (NCT371692), expected to have about four years of follow-up, should provide additioal data o these kids of cliical evets 3). Particularly, the risk of pulmoary embolism was slightly higher i the feofibrate group tha i the placebo group i the FIELD study 28). Pulmoary embolism may be of iterest i cliical practice, although it was ot observed i the ACCORD study, ad the istace observed i the pemafibrate.4 mg/day group was reported to have o relatioship with pemafibrate by the ivestigator 11). Secod, i compariso with other cliical studies of pemafibrate, the upper limit of baselie TG levels i the preset study was high (1 mg/dl). Therefore, it may be possible that various baselie patiet characteristics were ot sufficietly homogeized by radomizatio, which may have made it difficult to iterpret the results. Third, patiets receivig cocomitat stati therapy or those with 534

15 serious liver or kidey damage were excluded. Further research will be required to determie the drug s effects i a real-world settig. Lastly, this study was limited to Japaese patiets, ad the results may ot be applicable to other racial or ethic populatios. Coclusio I patiets with high TG ad low HDL-C levels, pemafibrate treatmet at.1,.2, ad.4 mg/day demostrated potet ad dose-depedet reductio i TG levels i compariso with placebo ad feofibrate at 1 ad 2 mg/day; the results also suggested a favorable beefit risk balace compared with feofibrate. The favorable safety profile of pemafibrate, icludig fewer adverse effects o kidey/liverrelated laboratory tests ad fewer AEs/ADRs, icludig those leadig to treatmet discotiuatio, may provide a broader rage of patiets with this ovel ad potet treatmet optio for reducig TG levels. Ackowledgemets The authors ackowledge the ivestigators ad patiets who participated i this study. This study was coducted at OCROM Cliic (Satoshi Ioue), ToCROM Cliic (Osamu Matsuoka), Nada Cliic (Masaharu Murakami), PS Cliic (Masaari Shiramoto), Sumida Hospital (Ippei Ikushima), Nishi-Kumamoto Hospital (Makoto Yoo), Tokyo-Eki Ceter-Buildig Cliic (Arihiro Kiyosue), Yaagibashi Aex, Eiju Geeral Hospital (Hirotaka Nagashima), Shiagawa East Oe Medical Cliic (Hiroshige Itakura), Kaauchi Medical Cliic (Naohisa Hoshio), New Medical Research System Cliic (Atsuko Abe), P-Oe Cliic (Keichi Furihata), Akasaka Chuo Cliic (Yuji Hidaka), Suidoubashi Medical Cliic (Satoshi Suayama), Fuamoto Cliic (Masaobu Fuamoto), Tokyo Ekimae Cliic (Yoshio Ohashi), Soe Cliic (Masayoshi Soe), Asahi Cliic (Tetsu Aoki), Gakketoshi Cliic (Hiroaki Yamamoto), Tomo Cliic (Tomofumi Murakami), Niwa Family Cliic (Kiyoshi Niwa), Fukuoka Rehabilitatio Hospital (Toru Kihara), Kobari Geeral Cliic (Fumihiko Hojo), Yoshimura Iteral Medicie (Ryuuji Yoshimura), Fukuhama Chuo Cliic (Naofumi Tomita), Yotsuya Iteral Medicie (Takahiro Yokoyama), Nako Cliic (Shoichi Kitao), Abe Heart Cliic (Jiro Abe), Ogio Cliic (Kazuori Ogio), Pedi Shiodome Medical Cliic (Hideki Kaizuka), Shiozaki Ekimae Cliic (Yoshihiro Okada), Nihobashi Eomoto Iteral Medicie (Yasuyuki Eomoto). This work was supported by Kowa Compay, Ltd. The fuder had a role i the study desig, data collectio, data aalysis, ad data iterpretatio. EDIT, Ic. (Tokyo, Japa) pro- vided medical writig ad editig. Coflict of Iterest H.A. reports persoal fees from Kowa durig the coduct of the study as well as grats from Daiichi Sakyo ad persoal fees from Daiichi Sakyo, MSD, ad Otsuka Pharmaceutical outside the submitted work. S.Y. reports grats ad persoal fees from Kowa durig the coduct of the study as well as grats from Nippo Boehriger Igelheim, Otsuka Pharmaceutical, Shioogi, Bayer Yakuhi, Natioal Istitute of Biomedical Iovatio, MSD, Japa Tobacco, Kyowa Medex, Takeda Pharmaceutical, Sawa Kagaku Kekyusho, Astellas Pharma, Daiichi Sakyo, Mochida Pharmaceutical, AstraZeeca, Izumisao City, Kaizuka City, Hayashibara, Teiji Pharma, Kake Pharmaceutical, Kissei Pharmaceutical ad persoal fees from Otsuka Pharmaceutical, Shioogi, Bayer Yakuhi, MSD, Takeda Pharmaceutical, Sawa Kagaku Kekyusho, Oo Pharmaceutical, Astellas Pharma, Daiichi Sakyo, Astra- Zeeca, Medical Review, Skylight Biotech, Kake Pharmaceutical, Pfizer Japa, Bristol-Myers Squibb, Amge Astellas BioPharma, Saofi, ad Toa Eiyo outside the submitted work; i additio, S.Y. has a patet Fujirebio pedig. K.Y. reports persoal fees from Kowa durig the coduct of the study as well as grats from Astellas Pharma, Otsuka Pharmaceutical, Daiichi Sakyo, Takeda Pharmaceutical, Mitsubishi Taabe Pharma, ad Bristol-Myers Squibb ad persoal fees from Astellas Pharma, AstraZeeca, Eisai, MSD, Oo Pharmaceutical, Kyowa Hakko Kiri, Kowa Pharmaceutical, Shioogi, Daiichi Sakyo, Takeda Pharmaceutical, Mitsubishi Taabe Pharma, Pfizer Japa, ad Mochida Pharmaceutical outside the submitted work. E.A. reports persoal fees from Kowa durig the coduct of the study as well as grats from Nippo Boehriger Igelheim, Novo Nordisk Pharma, Oo Pharmaceutical, Saofi, Daiichi Sakyo, Mitsubishi Taabe Pharma, Novartis Pharma, Kowa Pharmaceutical, Astellas Pharma, AstraZeeca, Takeda Pharmaceutical, Taisho Toyama Pharmaceutical, ad Pfizer Japa ad persoal fees from MSD, Nippo Boehriger Igelheim, Novo Nordisk Pharma, Oo Pharmaceutical, Saofi, Daiichi Sakyo, Mitsubishi Taabe Pharma, Novartis Pharma, Kowa Pharmaceutical, Astellas Pharma, AstraZeeca, Takeda Pharmaceutical, Taisho Toyama Pharmaceutical ad Eli Lilly Japa outside the submitted work. H.S. is a employee of Kowa. S.I. reports persoal fees from Kowa durig the coduct of the study as well as grats from Astellas Pharma, Daiichi Sakyo, Teiji Pharma, Takeda Pharmaceutical, Oo Pharmaceutical, Taisho Toyama Pharmaceutical, ad Nippo Boehriger Igelheim ad persoal fees from MSD, AstraZeeca, Sawa Kagaku 535

16 Kekyusho, ad Nippo Boehriger Igelheim outside the submitted work. Registratio Idetifier JapicCTI Refereces 1) Fulcher J, O Coell R, Voysey M, Emberso J, Blackwell L, Mihaylova B, Simes J, Collis R, Kirby A, Colhou H, Brauwald E, La Rosa J, Pederse TR, Toki A, Davis B, Sleight P, Frazosi MG, Baiget C ad Keech A: Efficacy ad safety of LDL-lowerig therapy amog me ad wome: meta-aalysis of idividual data from 174, participats i 27 radomised trials. Lacet, 215; 385: ) Sabatie MS, Giugliao RP, Keech AC, Hoarpour N, Wiviott SD, Murphy SA, Kuder JF, Wag H, Liu T, Wasserma SM, Sever PS ad Pederse TR: Evolocumab ad Cliical Outcomes i Patiets with Cardiovascular Disease. N Egl J Med, 217; 376: ) Fruchart JC: Pemafibrate (K-877), a ovel selective peroxisome proliferator-activated receptor alpha modulator for maagemet of atherogeic dyslipidaemia. Cardiovasc Diabetol, 217; 16: 124 4) Natioal Cholesterol Educatio Program (NCEP) Expert Pael o Detectio E, ad Treatmet of High Blood Cholesterol i Adults (Adult Treatmet Pael ): Third Report of the Natioal Cholesterol Educatio Program (NCEP) Expert Pael o Detectio, Evaluatio, ad Treatmet of High Blood Cholesterol i Adults (Adult Treatmet Pael ) fial report. Circulatio, 22; 16: ) Staels B, Dallogeville J, Auwerx J, Schoojas K, Leitersdorf E ad Fruchart JC: Mechaism of actio of fibrates o lipid ad lipoprotei metabolism. Circulatio, 1998; 98: ) Loomba RS ad Arora R: Prevetio of cardiovascular disease utilizig fibrates--a pooled meta-aalysis. Am J Ther, 21; 17: e ) Roseso RS: Feofibrate: treatmet of hyperlipidemia ad beyod. Expert Rev Cardiovasc Ther, 28; 6: ) Feigold K ad Grufeld C: Triglyceride Lowerig Drugs. I: Edotext, ed by De Groot LJ, Chrousos G, Duga K, Feigold KR, Grossma A, Hershma JM, Koch C, Korboits M, McLachla R, New M, Purell J, Rebar R, Siger F, ad Viik A, MDText.com, Ic., South Dartmouth (MA), 217 9) Wag D, Liu B, Tao W, Hao Z ad Liu M: Fibrates for secodary prevetio of cardiovascular disease ad stroke. Cochrae Database Syst Rev, 215; Cd958 1) Bruckert E, Labreuche J, Deplaque D, Touboul PJ ad Amareco P: Fibrates effect o cardiovascular risk is greater i patiets with high triglyceride levels or atherogeic dyslipidemia profile: a systematic review ad meta-aalysis. J Cardiovasc Pharmacol, 211; 57: ) Gisberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Liz P, Friedewald WT, Buse JB, Gerstei HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC Jr., Cushma WC, Simos-Morto DG ad Byigto RP: Effects of combiatio lipid therapy i type 2 diabetes mellitus. N Egl J Med, 21; 362: ) Ahmad J, Odi JA, Hayashi PH, Chalasai N, Fotaa RJ, Barhart H, Cirulli ET, Kleier DE ad Hoofagle JH: Idetificatio ad Characterizatio of Feofibrate- Iduced Liver Ijury. Dig Dis Sci, 217; 62: ) Davidso MH, Armai A, McKeey JM ad Jacobso TA: Safety cosideratios with fibrate therapy. Am J Cardiol, 27; 99: 3c-18c 14) Natioal Kidey Foudatio: KDOQI Cliical Practice Guidelie for Diabetes ad CKD: 212 Update. Am J Kidey Dis, 212; 6: ) Ferri N, Corsii A, Sirtori C ad Ruscica M: PPAR-alpha agoists are still o the rise: a update o cliical ad experimetal fidigs. Expert Opi Ivestig Drugs, 217; 26: ) Fruchart JC: Selective peroxisome proliferator-activated receptor modulators (SPPARM ): the ext geeratio of peroxisome proliferator-activated receptor -agoists. Cardiovasc Diabetol, 213; 12: 17) Raza-Iqbal S, Taaka T, Aai M, Iagaki T, Matsumura Y, Ikeda K, Taguchi A, Gozalez FJ, Sakai J ad Kodama T: Trascriptome Aalysis of K-877 (a Novel Selective PPAR Modulator (SPPARM ))-Regulated Gees i Primary Huma Hepatocytes ad the Mouse Liver. J Atheroscler Thromb, 215; 22: ) Yamazaki Y, Abe K, Toma T, Nishikawa M, Ozawa H, Okuda A, Araki T, Oda S, Ioue K, Shibuya K, Staels B ad Fruchart JC: Desig ad sythesis of highly potet ad selective huma peroxisome proliferator-activated receptor alpha agoists. Bioorg Med Chem Lett, 27; 17: ) Ishibashi S, Arai H, Yokote K, Araki E, Sugaami H ad Yamashita S: Efficacy ad safety of pemafibrate (K-877), a selective peroxisome proliferator-activated receptor modulator, i patiets with dyslipidemia: Results from a 24- week, radomized, double blid, active-cotrolled, phase 3 trial. J Cli Lipidol, 218; 12: ) Ishibashi S, Yamashita S, Arai H, Araki E, Yokote K, Sugaami H, Fruchart JC ad Kodama T: Effects of K-877, a ovel selective PPAR modulator (SPPARM ), i dyslipidaemic patiets: A radomized, double blid, active- ad placebo-cotrolled, phase 2 trial. Atherosclerosis, 216; 249: ) Sairyo M, Kobayashi T, Masuda D, Kao K, Zhu Y, Okada T, Koseki M, Ohama T, Nishida M, Sakata Y ad Yamashita S: A Novel Selective PPAR Modulator (SPPARM ), K-877 (Pemafibrate), Atteuates Postpradial Hypertriglyceridemia i Mice. J Atheroscler Thromb, 218; 25: ) Masuda D ad Yamashita S: Postpradial Hyperlipidemia ad Remat Lipoproteis. J Atheroscler Thromb, 217; 24: ) Davidso MH, Roseso RS, Maki KC, Nicholls SJ, Ballatye CM, Mazzoe T, Carlso DM, Williams LA, Kelly MT, Camp HS, Lele A ad Stolzebach JC: Effects of feofibric acid o carotid itima-media thickess i patiets with mixed dyslipidemia o atorvastati therapy: radomized, placebo-cotrolled study (FIRST). Arterio- 536