Diabetes Metab J.  2020 Apr;44(2):213-221. 10.4093/dmj.2020.0001.

Fibrates Revisited: Potential Role in Cardiovascular Risk Reduction

Affiliations
  • 1Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea

Abstract

Fibrates, peroxisome proliferator-activated receptor-α agonists, are potent lipid-modifying drugs. Their main effects are reduction of triglycerides and increase in high-density lipoprotein levels. Several randomized controlled trials have not demonstrated their benefits on cardiovascular risk reduction, especially as an “add on” to statin therapy. However, subsequent analyses by major clinical trials, meta-analyses, and real-world evidence have proposed their potential in specific patient populations with atherogenic dyslipidemia and metabolic syndrome. Here, we have reviewed and discussed the accumulated data on fibrates to understand their current status in cardiovascular risk management.

Keyword

Cardiovascular diseases; Dyslipidemias; Hydroxymethylglutaryl-CoA reductase inhibitors; Metabolic syndrome; Peroxisome proliferator-activated receptors; PPAR alpha

Figure

  • Fig. 1 Summary of primary outcomes in the Effectiveness of Fenofibrate Therapy in Residual Cardiovascular Risk Reduction in the Real World Setting (ECLIPSE-REAL) study. PS, propensity score; LDL-C, low density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; MACE, major adverse cardiovascular events; HR, hazard ratio; CI, confidence interval.


Cited by  3 articles

Lipoprotein Lipase: Is It a Magic Target for the Treatment of Hypertriglyceridemia
Joon Ho Moon, Kyuho Kim, Sung Hee Choi
Endocrinol Metab. 2022;37(4):575-586.    doi: 10.3803/EnM.2022.402.

Current Trends of Big Data Research Using the Korean National Health Information Database
Mee Kyoung Kim, Kyungdo Han, Seung-Hwan Lee
Diabetes Metab J. 2022;46(4):552-563.    doi: 10.4093/dmj.2022.0193.

New, Novel Lipid-Lowering Agents for Reducing Cardiovascular Risk: Beyond Statins
Kyuho Kim, Henry N. Ginsberg, Sung Hee Choi
Diabetes Metab J. 2022;46(4):517-532.    doi: 10.4093/dmj.2022.0198.


Reference

1. Kim HC. Epidemiology of dyslipidemia in Korea. J Korean Med Assoc. 2016; 59:352–357.
Article
2. Rhee EJ, Kim HC, Kim JH, Lee EY, Kim BJ, Kim EM, Song Y, Lim JH, Kim HJ, Choi S, Moon MK, Na JO, Park KY, Oh MS, Han SY, Noh J, Yi KH, Lee SH, Hong SC, Jeong IK. 2018 Guidelines for the management of dyslipidemia. Korean J Intern Med. 2019; 34:723–771. PMID: 31272142.
Article
3. Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009; 29:431–438. PMID: 19299327.
4. Pedersen TR. The success story of LDL cholesterol lowering. Circ Res. 2016; 118:721–731. PMID: 26892969.
Article
5. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014; 63:2889–2934. PMID: 24239923.
6. Fruchart JC, Sacks FM, Hermans MP, Assmann G, Brown WV, Ceska R, Chapman MJ, Dodson PM, Fioretto P, Ginsberg HN, Kadowaki T, Lablanche JM, Marx N, Plutzky J, Reiner Z, Rosenson RS, Staels B, Stock JK, Sy R, Wanner C, Zambon A, Zimmet P. Residual Risk Reduction Initiative (R3I). The residual risk reduction initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab Vasc Dis Res. 2008; 5:319–335. PMID: 18958843.
7. Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD Jr, DePalma SM, Minissian MB, Orringer CE, Smith SC Jr. 2017 Focused update of the 2016 ACC expert consensus decision pathway on the role of non-statin therapies for ldl-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology task force on expert consensus decision pathways. J Am Coll Cardiol. 2017; 70:1785–1822. PMID: 28886926.
8. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol. 2019; 73:3168–3209. PMID: 30423391.
9. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Tokgozoglu L, Wiklund O. ESC Scientific Document Group. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020; 41:111–188. PMID: 31504418.
10. Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ. Nuclear receptors and lipid physiology: opening the X-files. Science. 2001; 294:1866–1870. PMID: 11729302.
Article
11. Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med. 2002; 53:409–435. PMID: 11818483.
Article
12. Heller F, Harvengt C. Effects of clofibrate, bezafibrate, fenofibrate and probucol on plasma lipolytic enzymes in normolipaemic subjects. Eur J Clin Pharmacol. 1983; 25:57–63. PMID: 6617725.
Article
13. Malmendier CL, Lontie JF, Delcroix C, Dubois DY, Magot T, De Roy L. Apolipoproteins C-II and C-III metabolism in hypertriglyceridemic patients. Effect of a drastic triglyceride reduction by combined diet restriction and fenofibrate administration. Atherosclerosis. 1989; 77:139–149. PMID: 2751746.
Article
14. Martin G, Schoonjans K, Lefebvre AM, Staels B, Auwerx J. Coordinate regulation of the expression of the fatty acid transport protein and acyl-CoA synthetase genes by PPARalpha and PPARgamma activators. J Biol Chem. 1997; 272:28210–28217. PMID: 9353271.
15. Schoonjans K, Watanabe M, Suzuki H, Mahfoudi A, Krey G, Wahli W, Grimaldi P, Staels B, Yamamoto T, Auwerx J. Induction of the acyl-coenzyme A synthetase gene by fibrates and fatty acids is mediated by a peroxisome proliferator response element in the C promoter. J Biol Chem. 1995; 270:19269–19276. PMID: 7642600.
Article
16. Staels B, Auwerx J. Regulation of apo A-I gene expression by fibrates. Atherosclerosis. 1998; 137:S19–S23. PMID: 9694537.
Article
17. Marx N, Sukhova GK, Collins T, Libby P, Plutzky J. PPARalpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation. 1999; 99:3125–3131. PMID: 10377075.
18. Delerive P, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol. 2001; 169:453–459. PMID: 11375115.
Article
19. Sampson UK, Fazio S, Linton MF. Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges. Curr Atheroscler Rep. 2012; 14:1–10. PMID: 22102062.
Article
20. Boekholdt SM, Arsenault BJ, Mora S, Pedersen TR, LaRosa JC, Nestel PJ, Simes RJ, Durrington P, Hitman GA, Welch KM, DeMicco DA, Zwinderman AH, Clearfield MB, Downs JR, Tonkin AM, Colhoun HM, Gotto AM Jr, Ridker PM, Kastelein JJ. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA. 2012; 307:1302–1309. PMID: 22453571.
21. Miller M, Cannon CP, Murphy SA, Qin J, Ray KK, Braunwald E. PROVE IT-TIMI 22 Investigators. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2008; 51:724–730. PMID: 18279736.
Article
22. Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJ, Bittner V, Fruchart JC. Treating to New Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007; 357:1301–1310. PMID: 17898099.
Article
23. Lawler PR, Akinkuolie AO, Chu AY, Shah SH, Kraus WE, Craig D, Padmanabhan L, Glynn RJ, Ridker PM, Chasman DI, Mora S. Atherogenic lipoprotein determinants of cardiovascular disease and residual risk among individuals with low low-density lipoprotein cholesterol. J Am Heart Assoc. 2017; 6:e005549. PMID: 28733430.
Article
24. Ray KK, Cannon CP, Cairns R, Morrow DA, Ridker PM, Braunwald E. Prognostic utility of apoB/AI, total cholesterol/HDL, non-HDL cholesterol, or hs-CRP as predictors of clinical risk in patients receiving statin therapy after acute coronary syndromes: results from PROVE IT-TIMI 22. Arterioscler Thromb Vasc Biol. 2009; 29:424–430. PMID: 19122170.
25. Tenenbaum A, Fisman EZ, Motro M, Adler Y. Atherogenic dyslipidemia in metabolic syndrome and type 2 diabetes: therapeutic options beyond statins. Cardiovasc Diabetol. 2006; 5:20. PMID: 17002798.
26. Sirimarco G, Labreuche J, Bruckert E, Goldstein LB, Fox KM, Rothwell PM, Amarenco P. PERFORM and SPARCL Investigators and Committees. Atherogenic dyslipidemia and residual cardiovascular risk in statin-treated patients. Stroke. 2014; 45:1429–1436. PMID: 24736236.
Article
27. Jafri H, Alsheikh-Ali AA, Karas RH. Baseline and on-treatment high-density lipoprotein cholesterol and the risk of cancer in randomized controlled trials of lipid-altering therapy. J Am Coll Cardiol. 2010; 55:2846–2854. PMID: 20579542.
Article
28. Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF, Visseren FL, Sijbrands EJ, Trip MD, Stein EA, Gaudet D, Duivenvoorden R, Veltri EP, Marais AD, de Groot E. ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008; 358:1431–1443. PMID: 18376000.
Article
29. ORIGIN Trial Investigators. Bosch J, Gerstein HC, Dagenais GR, Diaz R, Dyal L, Jung H, Maggiono AP, Probstfield J, Ramachandran A, Riddle MC, Ryden LE, Yusuf S. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012; 367:309–318. PMID: 22686415.
30. AIM-HIGH Investigators. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011; 365:2255–2267. PMID: 22085343.
Article
31. HPS2-THRIVE Collaborative Group. Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J, Wallendszus K, Craig M, Jiang L, Collins R, Armitage J. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014; 371:203–212. PMID: 25014686.
32. Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, Chaitman BR, Holme IM, Kallend D, Leiter LA, Leitersdorf E, McMurray JJ, Mundl H, Nicholls SJ, Shah PK, Tardif JC, Wright RS. dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012; 367:2089–2099. PMID: 23126252.
Article
33. ACCORD Study Group. Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC Jr, Cushman WC, Simons-Morton DG, Byington RP. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010; 362:1563–1574. PMID: 20228404.
34. Ray KK, Corral P, Morales E, Nicholls SJ. Pharmacological lipid-modification therapies for prevention of ischaemic heart disease: current and future options. Lancet. 2019; 394:697–708. PMID: 31448741.
Article
35. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, Maenpaa H, Malkonen M, Manttari M, Norola S, Pasternack A, Pikkarainen J, Romo M, Sjoblom T, Nikkila EA. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987; 317:1237–1245. PMID: 3313041.
36. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999; 341:410–418. PMID: 10438259.
37. Bezafibrate Infarction Prevention (BIP) study. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation. 2000; 102:21–27. PMID: 10880410.
38. Meade T, Zuhrie R, Cook C, Cooper J. Bezafibrate in men with lower extremity arterial disease: randomised controlled trial. BMJ. 2002; 325:1139. PMID: 12433762.
Article
39. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesaniemi YA, Sullivan D, Hunt D, Colman P, d'Emden M, Whiting M, Ehnholm C, Laakso M. 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. PMID: 16310551.
40. Elam MB, Ginsberg HN, Lovato LC, Corson M, Largay J, Leiter LA, Lopez C, O'Connor PJ, Sweeney ME, Weiss D, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm R, Ismail-Beigi F, Goff DC Jr, Fleg JL, Rosenberg Y, Byington RP. ACCORDION Study Investigators. Association of fenofibrate therapy with long-term cardiovascular risk in statin-treated patients with type 2 diabetes. JAMA Cardiol. 2017; 2:370–380. PMID: 28030716.
Article
41. Jun M, Foote C, Lv J, Neal B, Patel A, Nicholls SJ, Grobbee DE, Cass A, Chalmers J, Perkovic V. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet. 2010; 375:1875–1884. PMID: 20462635.
Article
42. Lee M, Saver JL, Towfighi A, Chow J, Ovbiagele B. Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. Atherosclerosis. 2011; 217:492–498. PMID: 21592479.
Article
43. Bruckert E, Labreuche J, Deplanque D, Touboul PJ, Amarenco P. Fibrates effect on cardiovascular risk is greater in patients with high triglyceride levels or atherogenic dyslipidemia profile: a systematic review and meta-analysis. J Cardiovasc Pharmacol. 2011; 57:267–272. PMID: 21052016.
Article
44. American Diabetes Association. 9. Cardiovascular disease and risk management: standards of medical care in diabetes-2018. Diabetes Care. 2018; 41:S86–S104. PMID: 29222380.
45. Kim MK, Ko SH, Kim BY, Kang ES, Noh J, Kim SK, Park SO, Hur KY, Chon S, Moon MK, Kim NH, Kim SY, Rhee SY, Lee KW, Kim JH, Rhee EJ, Chun S, Yu SH, Kim DJ, Kwon HS, Park KS. Committee of Clinical Practice Guidelines, Korean Diabetes Association. 2019 Clinical practice guidelines for type 2 diabetes mellitus in Korea. Diabetes Metab J. 2019; 43:398–406. PMID: 31441247.
Article
46. Alperovitch A, Kurth T, Bertrand M, Ancelin ML, Helmer C, Debette S, Tzourio C. Primary prevention with lipid lowering drugs and long term risk of vascular events in older people: population based cohort study. BMJ. 2015; 350:h2335. PMID: 25989805.
Article
47. Kim NH, Han KH, Choi J, Lee J, Kim SG. Use of fenofibrate on cardiovascular outcomes in statin users with metabolic syndrome: propensity matched cohort study. BMJ. 2019; 366:l5125. PMID: 31562117.
Article
48. Suissa S. Lower risk of death with SGLT2 inhibitors in observational studies: real or bias? Diabetes Care. 2018; 41:6–10. PMID: 29263192.
Article
49. Pradhan AD, Paynter NP, Everett BM, Glynn RJ, Amarenco P, Elam M, Ginsberg H, Hiatt WR, Ishibashi S, Koenig W, Nordestgaard BG, Fruchart JC, Libby P, Ridker PM. Rationale and design of the pemafibrate to reduce cardiovascular outcomes by reducing triglycerides in patients with diabetes (PROMINENT) study. Am Heart J. 2018; 206:80–93. PMID: 30342298.
Article
50. Mellies MJ, Stein EA, Khoury P, Lamkin G, Glueck CJ. Effects of fenofibrate on lipids, lipoproteins, and apolipoproteins in 33 subjects with primary hypercholesterolemia. Atherosclerosis. 1987; 63:57–64. PMID: 3548734.
Article
51. Rizos E, Bairaktari E, Ganotakis E, Tsimihodimos V, Mikhailidis DP, Elisaf M. Effect of ciprofibrate on lipoproteins, fibrinogen, renal function, and hepatic enzymes. J Cardiovasc Pharmacol Ther. 2002; 7:219–226. PMID: 12490967.
Article
52. Miller M, Bachorik PS, McCrindle BW, Kwiterovich PO Jr. Effect of gemfibrozil in men with primary isolated low high-density lipoprotein cholesterol: a randomized, double-blind, placebo-controlled, crossover study. Am J Med. 1993; 94:7–12. PMID: 8420303.
Article
53. Watts GF, Barrett PH, Ji J, Serone AP, Chan DC, Croft KD, Loehrer F, Johnson AG. Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome. Diabetes. 2003; 52:803–811. PMID: 12606523.
Article
54. Vega GL, Ma PT, Cater NB, Filipchuk N, Meguro S, Garcia-Garcia AB, Grundy SM. Effects of adding fenofibrate (200 mg/day) to simvastatin (10 mg/day) in patients with combined hyperlipidemia and metabolic syndrome. Am J Cardiol. 2003; 91:956–960. PMID: 12686335.
Article
55. Belfort R, Berria R, Cornell J, Cusi K. Fenofibrate reduces systemic inflammation markers independent of its effects on lipid and glucose metabolism in patients with the metabolic syndrome. J Clin Endocrinol Metab. 2010; 95:829–836. PMID: 20061429.
Article
56. Krysiak R, Gdula-Dymek A, Bachowski R, Okopien B. Pleiotropic effects of atorvastatin and fenofibrate in metabolic syndrome and different types of pre-diabetes. Diabetes Care. 2010; 33:2266–2270. PMID: 20587704.
Article
Full Text Links
  • DMJ
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr