Effects of pemafibrate, a novel selective PPARa modulator, on lipid and glucose metabolism in patients with type 2 diabetes and hypertriglyceridemia: A randomized, double-blind, placebo-controlled, phase 3 trial

Diabetes Care

Volumn 41, Issue 3, 2018, Pages 538-546

  Araki, Eiichi ^a   Yamashita, Shizuya ^b,c   Arai, Hidenori ^d   Yokote, Koutaro ^e   Satoh, Jo ^f   Inoguchi, Toyoshi ^g   Nakamura, Jiro ^h   Maegawa, Hiroshi ⁱ   Yoshioka, Narihito ^j   Tanizawa, Yukio ^k   Watada, Hirotaka ^l   Suganami, Hideki ^m   Ishibashi, Shun ⁿ  

^a KUMAMOTO UNIVERSITY   (Japan)

^b OSAKA UNIVERSITY   (Japan)

^c Rinku General Medical Center   (Japan)

^d NATIONAL CENTER FOR GERIATRICS AND GERONTOLOGY   (Japan)

^e CHIBA UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^f NTT East Tohoku Hospital   (Japan)

^g Fukuoka Health Promotion Center   (Japan)

^h AICHI MEDICAL UNIVERSITY   (Japan)

ⁱ SHIGA UNIVERSITY OF MEDICAL SCIENCE   (Japan)

^j Sapporo Medical Center   (Japan)

^k YAMAGUCHI UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^l JUNTENDO UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^m KOWA COMPANY LTD   (Japan)

ⁿ JICHI MEDICAL UNIVERSITY   (Japan)

more..

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; APOLIPOPROTEIN A1; APOLIPOPROTEIN B100; APOLIPOPROTEIN B48; APOLIPOPROTEIN C3; ASPARTATE AMINOTRANSFERASE; ATORVASTATIN; CHOLESTEROL; DIPEPTIDYL PEPTIDASE IV INHIBITOR; FIBROBLAST GROWTH FACTOR 21; GAMMA GLUTAMYLTRANSFERASE; GLUCOSE; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; LOW DENSITY LIPOPROTEIN CHOLESTEROL; PEMAFIBRATE; PITAVASTATIN; PLACEBO; ROSUVASTATIN; (R)-2-(3-((BENZOXAZOL-2-YL-D4 (3-(4-METHOXYPHENOXY-D7)PROPYL)AMINO)METHYL)PHENOXY) BUTANOIC ACID; BENZOXAZOLE DERIVATIVE; BUTYRIC ACID DERIVATIVE; LIPID; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA;

AGED; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; CONTROLLED STUDY; CREATININE BLOOD LEVEL; DIABETES MELLITUS; DISEASE DURATION; DRUG EFFICACY; DRUG RESPONSE; DRUG SAFETY; DRUG WITHDRAWAL; FEMALE; GAMMA GLUTAMYL TRANSFERASE BLOOD LEVEL; GLUCOSE BLOOD LEVEL; GLUCOSE METABOLISM; HOMEOSTASIS MODEL ASSESSMENT; HUMAN; HYPERTRIGLYCERIDEMIA; LIPID METABOLISM; MAJOR CLINICAL STUDY; MALE; NON INSULIN DEPENDENT DIABETES MELLITUS; OUTCOME ASSESSMENT; RANDOMIZED CONTROLLED TRIAL; SIDE EFFECT; TREATMENT DURATION; TREATMENT OUTCOME; TRIACYLGLYCEROL BLOOD LEVEL; BLOOD; CLINICAL TRIAL; COMPLICATION; DOUBLE BLIND PROCEDURE; DRUG EFFECT; METABOLISM; MIDDLE AGED; MULTICENTER STUDY; PHASE 3 CLINICAL TRIAL;

AGED; BENZOXAZOLES; BLOOD GLUCOSE; BUTYRATES; DIABETES MELLITUS, TYPE 2; DOUBLE-BLIND METHOD; FEMALE; HUMANS; HYPERTRIGLYCERIDEMIA; LIPID METABOLISM; LIPIDS; MALE; MIDDLE AGED; PLACEBOS; PPAR ALPHA;

EID: 85042585571     PISSN: 01495992     EISSN: 19355548     Source Type: Journal    
DOI: 10.2337/dc17-1589     Document Type: Article

References (40)

1. Tancredi M, Rosengren A, Svensson AM, et al. Excess mortality among persons with type 2 diabetes. N Engl J Med 2015;373:1720-1732.
2. Haffner SM, Lehto S, Ronnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229-234.
3. Mulnier HE, Seaman HE, Raleigh VS, et al. Risk of myocardial infarction in men and women with type 2 diabetes in the UK: A cohort study using the General Practice Research Database. Diabetologia 2008;51:1639-1645.
4. Vergès B. Pathophysiology of diabetic dyslipidaemia: Where are we? Diabetologia 2015;58: 886-899.
5. Colhoun HM, Betteridge DJ, Durrington PN, et al.; CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebocontrolled trial. Lancet 2004;364:685-696.
6. Kearney PM, Blackwell L, Collins R, et al.; Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy of cholesterol-lowering therapy in 18, 686 people with diabetes in 14 randomised trials of statins: A meta-Analysis. Lancet 2008; 371:117-125.
7. Sone H, Tanaka S, Tanaka S, et al.; Japan Diabetes Complications Study Group. Serumlevel of triglycerides is a potent risk factor comparable to LDL cholesterol for coronary heart disease in Japanese patients with type 2 diabetes: subanalysis of the Japan Diabetes Complications Study (JDCS). J Clin Endocrinol Metab 2011;96:3448-3456.
8. Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ 1998;316:823-828.
9. Ginsberg HN, Elam MB, Lovato LC, et al.; ACCORDStudy Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-1574.
10. Scott R, O'Brien R, Fulcher G, et al.; Fenofibrate Intervention and Event Lowering inDiabetes (FIELD) Study Investigators. Effects of fenofibrate treatment on cardiovascular disease risk in 9, 795 individuals with type 2 diabetes and various components of themetabolic syndrome: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care 2009;32:493-498.
11. Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT). Arch Intern Med 2002;162:2597-2604.
12. Ishibashi S, Yamashita S, Arai H, et al.; K-877-04 Study Group. Effects of K-877, a novel selective PPARa modulator (SPPARMa), in dyslipidaemic patients: A randomized, double blind, activeand placebo-controlled, phase 2 trial. Atherosclerosis 2016;249:36-43.
13. Arai H, Yamashita S, Yokote K, Araki E, Suganami H, Ishibashi S; K-877 Study Group. Efficacy and safety of K-877, a novel selective peroxisome proliferator-Activated receptor a modulator (SPPARMa), in combinationwith statin treatment: Two randomised, double-blind, placebo-controlled clinical trials in patients with dyslipidaemia. Atherosclerosis 2017;261:144-152.
14. Lally S, Tan CY, Owens D, Tomkin GH. Messenger RNA levels of genes involved in dysregulation of postprandial lipoproteins in type 2 diabetes: The role of Niemann-Pick C1-like 1, ATP-binding cassette, transporters G5 and G8, and of microsomal triglyceride transfer protein. Diabetologia 2006;49:1008-1016.
15. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC.Mechanismof action of fibrates on lipid and lipoprotein metabolism. Circulation 1998;98:2088-2093.
16. Raza-Iqbal S, Tanaka T, Anai M, et al. Transcriptome analysis of K-877 (a novel selective PPARa modulator (SPPARMa))-regulated genes in primary human hepatocytes and the mouse liver. J Atheroscler Thromb 2015;22:754-772.
17. Takei K, Han SI, Murayama Y, et al. The selective PPARalpha modulator K-877 efficiently activates the PPARalpha pathway and improves lipid metabolism in mice. J Diabetes Investig 2017;8: 446-452.
18. Takizawa T, Inokuchi Y, Goto S, et al. The mechanismof K-877, a highly potent and selective pparalpha modulator, on regulation of synthesis, secretion and metabolism of triglycerides and cholesterol (Abstract). Circulation 2013;128: A12867.
19. Jia L, Betters JL, Yu L. Niemann-pick C1-like 1 (NPC1L1) protein in intestinal and hepatic cholesterol transport. Annu Rev Physiol 2011;73:239- 259.
20. Sandoval JC, Nakagawa-Toyama Y, Masuda D, et al. Fenofibrate reduces postprandial hypertriglyceridemia in CD36 knockout mice. J Atheroscler Thromb 2010;17:610-618.
21. Takei K, Nakagawa Y, Wang Y, et al. Effects of K-877, a novel selective PPARa modulator, on small intestine contribute to the amelioration of hyperlipidemia in low-density lipoprotein receptor knockoutmice. J Pharmacol Sci 2017;133:214-222.
22. Hennuyer N, Duplan I, Paquet C, et al. The novel selective PPARa modulator (SPPARMa) pemafibrate improves dyslipidemia, enhances reverse cholesterol transport and decreases inflammation and atherosclerosis. Atherosclerosis 2016;249:200-208.
23. Hoogeveen RC, Gaubatz JW, Sun W, et al. Small dense low-density lipoprotein-cholesterol concentrations predict risk for coronary heart disease: The Atherosclerosis Risk In Communities (ARIC) study. Arterioscler Thromb Vasc Biol 2014;34:1069-1077.
24. Nissen SE, Nicholls SJ, Wolski K, et al. Effects of a potent and selective PPAR-Alpha agonist in patients with atherogenic dyslipidemia or hypercholesterolemia: Two randomized controlled trials. JAMA 2007;297:1362-1373.
25. Millar JS, Duffy D, Gadi R, et al. Potent and selective PPAR-Alpha agonist LY518674 upregulates both ApoA-I production and catabolism in human subjectswith themetabolic syndrome. Arterioscler Thromb Vasc Biol 2009;29:140-146.
26. Blair HA. Pemafibrate: first global approval. Drugs 2017;77:1805-1810.
27. Singh JP, Kauffman R, Bensch W, et al. Identification of a novel selective peroxisome proliferator-Activated receptor alpha agonist, 2-methyl-2-(4-3-[1-(4-methylbenzyl)-5-oxo-4, 5- dihydro-1H-1, 2, 4-Triazol-3-yl]propylphenoxy)- propanoic acid (LY518674), that produces marked changes in serum lipids and apolipoprotein A-1 expression. Mol Pharmacol 2005;68:763-768.
28. Wiggins BS, Saseen JJ, Page RL 2nd, et al,; American Heart Association Clinical Pharmacology Committee of the Council on Clinical Cardiology; Council on Hypertension; Council on Quality of Care and Outcomes Research; and Council on Functional Genomics and Translational Biology. Recommendations for management of clinically significant drug-drug interactions with statins and select agents used in patients with cardiovascular disease: A scientific statement from the American Heart Association. Circulation 2016;134:e468-e495.
29. Ishibashi S, Arai H, Yokote K, Araki E, Suganami H, Yamashita S. Efficacy and safety of pemafibrate (K-877), a selective peroxisome proliferator-Activated receptor a modulator (SPPARMa), in patients with dyslipidemia: Results from a 24-week, randomized, double blind, active-controlled, phase 3 trial. J Clin Lipidol. 27 October 2017 [Epub ahead of print]. https://doi.org/10.1016/j.jacl.2017.10.006.
30. Catapano AL, Graham I, De Backer G, et al.; Authors/Task Force Members. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for theManagement of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis 2016;253:281-344.
31. Bajaj M, Suraamornkul S, Hardies LJ, Glass L, Musi N, DeFronzo RA. Effects of peroxisome proliferator-Activated receptor (PPAR)-Alpha and PPAR-gamma agonists on glucose and lipid metabolismin patientswith type 2 diabetesmellitus. Diabetologia 2007;50:1723-1731.
32. Cariou B, Hanf R, Lambert-Porcheron S, et al. Dual peroxisome proliferator-Activated receptor a/d agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care 2013;36:2923-2930.
33. Black RN, Ennis CN, Young IS, Hunter SJ, Atkinson AB, Bell PM. The peroxisome proliferatoractivated receptor alpha agonist fenofibrate has no effect on insulin sensitivity compared to atorvastatin in type 2 diabetesmellitus; a randomised, double-blind controlled trial. J Diabetes Complications 2014;28:323-327.
34. Shiochi H, Ohkura T, Fujioka Y, et al. Bezafibrate improves insulin resistance evaluated using the glucose clamp technique in patients with type 2 diabetes mellitus: A small-scale clinical study. Diabetol Metab Syndr 2014;6:113.
35. Taniguchi A, Fukushima M, Sakai M, et al. Effects of bezafibrate on insulin sensitivity and insulin secretion in non-obese Japanese type 2 diabetic patients. Metabolism 2001;50:477-480.
36. Matsuba I, Matsuba R, Ishibashi S, et al. The effects of selective PPAR alpha modulator, K-877, on the insulin sensitivity evaluated by glucose clamp test (Abstract). J-Stage 2016;59:S462 [in Japanese].
37. Araki E, Ishibashi S, Yamashita S, et al. A highly potent and specific PPAR alpha agonist, K-877, improves lipid profiles and insulin sensitivity in dyslipidaemia subjects; an integrated analysis of 3 phase 2/3 trials (Abstract). Diabetologia 2014; 57:S272.
38. Gaich G, Chien JY, Fu H, et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab 2013; 18:333-340.
39. Digenio A, Dunbar RL, Alexander VJ, et al. Antisense-mediated lowering of plasma apolipoprotein C-III by volanesorsen improves dyslipidemia and insulin sensitivity in type 2 diabetes. Diabetes Care 2016;39:1408-1415.
40. Keech A, Simes RJ, Barter P, et al.; FIELD study investigators. Effects of long-Term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): Randomised controlled trial. Lancet 2005;366: 1849-1861.