Correction of hypertriglyceridemia in order to reduce the residual risk in atherosclerosis-related diseases. Expert Council Opinion

In opinion the Expert council provides management tactics for patients with hypertriglyceridemia (HTG). It is demonstrated that HTG is a common condition in overweight patients and is an important component of residual risk. HTG creates additional conditions for the progression of atherosclerosis, so the level of triglycerides (TG) is recommended to be measured in patients with a high, very high and extremely high risk level. An indication for the appointment of drugs that reduce the concentration of TG is its level of more than 2,3 mmol/L. Statins are the agents of choice to reduce the risk of cardiovascular disease in high-risk patients with hypercholesterolemia and HTG. Fenofibrate is used to correct HTG, and in case of intolerance to it or when the target level of TG is not reached, omega-3 ethers of polyunsaturated fatty acids in a dose of 2-4 g/day are recommended. In patients with HTG with a TG level >5,6 mmol/L, fenofibrate is the agent of choice.

1. WHO newsletter. Cardiovascular diseases [cited by Apr 20, 2019]. Available from: https:// www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds).

2. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356(15):1503-16. doi:10.1056/NEJMoa070829.

3. Chung SC, Hlatky MA, Faxon D, et al. The effect of age on clinical outcomes and health status BARI 2D (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes). J Am Coll Cardiol. 2011;58(8):810-9. doi:10.1016/j.jacc.2011.05.020.

4. Frye RL, August P, Brooks MM, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009;360(24):2503-15. doi:10.1056/NEJMoa0805796.

5. Henderson RA, Pocock SJ, Clayton TC, et al. Seven-year outcome in the RITA-2 trial: coronary angioplasty versus medical therapy. J Am Coll Cardiol. 2003;42(7):1161-70. doi:10.1016/S0735-1097(03)00951-3.

6. Poole-Wilson PA, Lubsen J, Kirwan BA, et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet. 2004;364(9437):849-57. doi:10.1016/S01406736(04)16980-8.

7. Steg PG, Greenlaw N, Tardif JC, et al. Women and men with stable coronary artery disease have similar clinical outcomes: insights from the international prospective CLARIFY registry. Eur Heart J. 2012;33(22):2831-40. doi:10.1093/eurheartj/ehs289.

8. Daly CA, De Stavola B, Sendon JL, et al. Predicting prognosis in stable angina-results from the Euroheart survey of stable angina: prospective observational study. BMJ. 2006;332(7536):262-7. doi:10.1136/bmj.38695.605440.AE.

9. Steg PG, Bhatt DL, Wilson PW, et al. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA. 2007;297(11):1197-206. doi:10.1001/jama.297.11.1197.

10. Taylor J. SWEDEHEART: Sweden’s new online cardiac registry, the first of its kind. Eur Heart J. 2009;30:2165-73.

11. Castelli WP. Epidemiology of triglycerides: a view from Framingham. Am J Cardiol. 1992;70(19):3H-9H. doi:10.1016/0002-9149(92)91083-G.

12. Barter P, Gotto AM, LaRosa JC, et al. HDL Cholesterol, Very Low Levels of LDL Cholesterol, and Cardiovascular Events. N Engl J Med. 2007;357:1301-10. doi:10.1056/NEJMoa064278.

13. Carey VJ, Bishop L, Laranjo N, at al. Contribution of high plasma triglycerides and low high-density lipoprotein cholesterol to residual risk of coronary heart disease after establishment of low-density lipoprotein cholesterol control. Am J Cardiol. 2010;106(6):757-63. doi:10.1016/j.amjcard.2010.05.002.

14. Aguiar C, Alegria E, Bonadonna RC, et al. A review of the evidence on reducing macrovascular risk in patients with atherogenic dyslipidaemia: A report from an expert consensus meeting on the role of fenofibrate-statin combination therapy. Atheroscler Suppl. 2015;19:1-12. doi:10.1016/S1567-5688(15)30001-5.

15. Grundy SM, Becker D, Clark LT, et al. National Cholesterol Education Program. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. September 2002. NIH Publication No. 02-5215.

16. Yezhov MV, Sergienko IV, Aronov DM, et al. Diagnosis and correction of lipid metabolism disorders for the prevention and treatment of atherosclerosis, Atherosclerosis and Dyslipidemia. 2017;3:5-22 (In Russ.)

17. Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J. 2016;37(39):2999-3058. doi:10.1093/eurheartj/ehw272.

18. Hegele RA, Ginsberg HN, Chapman MJ, et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinology. 2013;2(8):655-66. doi:10.1016/S2213-8587(13)70191-8.

19. Ghandehari H, Kamal-Bahl S, Wong ND. Prevalence and extent of dyslipidemia and recommended lipid levels in US adults with and without cardiovascular comorbidities: The National Health and Nutrition Examination Survey 2003-2004. Am Heart J. 2008;156 (1):112-9. doi:10.1016/j.ahj.2008.03.005.

20. Gitt AK, Drexel H, Feely J, et al. DYSIS Investigators. Persistent lipid abnormalities in statin-treated patients and predictors of LDL-cholesterol goal achievement in clinical practice in Europe and Canada. Eur J Prev Cardiol. 2012;19(2):221-30. doi:10.1177/1741826711400545.

21. Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ. 2007;176 (8):1113-20. doi:10.1503/cmaj.060963

22. Aguiar C. Atherogenic dyslipidaemia: the importance of its management in high risk patients. Clin Invest Arterioscl. 2017;29(Supl 2):2-8.

23. Reaven GM, Chen YDL, Jeppesen J, et al. Insulin resistance and hypertriglyceridemia in an individuals with small, dense low density lipoprotein particles. J Clin Invest 1993;92:141.

24. Sarwar N, Sandhu MS, Ricketts SL, et al. Triglyceride Coronary Disease Genetics, Consortium and Emerging Risk Factors Collaboration. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet. 2010;375:1634-9. doi:10.1016/S0140-6736(10)60545-4.

25. Ridker P.M., Rifai N., Cook N.R., et al. Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. JAMA. 2005;294(3):326-33. doi:10.1001/jama.294.3.326.

26. International Atherosclerosis Society. An International Atherosclerosis Society position paper: global recommendations for the management of dyslipidaemia. J Clin Lipidol. 2014;8(1):29-60.

27. The ACCORD Study Group. Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus. N Engl J Med. 2010;362:1563-74. doi:10.1056/NEJMoa1001282.

28. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019;380:11-22. doi:10.1056/NEJMoa1812792.

29. Franssen R, Vergeer M, Stroes ES, Kastelein JJ. Combination statin-fibrate therapy: safety aspects. Diabetes Obes Metab. 2009;11(2):89-94. doi:10.1111/j.1463-1326.2008.00917.x.

30. Fruchart JC, Duriez P. Mode of action of fibrates in the regulation of triglyceride and HDL-cholesterol metabolism. Drugs Today (Barc). 2006;42(1):39-64. doi:10.1358/dot.2006.42.1.963528.

31. Keating GM, Croom KF. Fenofibrate: a review of its use in primary dyslipidaemia, the metabolic syndrome and type 2 diabetes mellitus. Drugs. 2007;67(1);121-53. doi:10.2165/00003495-200767010-00013.

32. Feher MD, Caslake M, Foxton J, et al. Atherogenic lipoprotein phenotype in type 2 diabetes: reversal with micronised fenofibrate. Diabetes Metab Res Rev. 1999;15:395. doi:10.1002/(SICI)1520-7560(199911/12)15:6<395::AID-DMRR65>3.0.CO;2-N.

33. Baigent C, Blackwell L, Emberson J, et al. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a metaanalysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:167081. doi:10.1016/S0140-6736(10)61350-5.

34. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-97. doi:10.1056/NEJMoa1410489.

35. Mark L, Dani G, Fazekas O, et al. Effects of ezetimibe on lipids and lipoproteins in patients with hypercholesterolemia and different apolipoprotein E genotypes. Curr Med Res Opin. 2007;23(7):1541-8. doi:10.1185/030079907X199817.

36. DAIS investigators. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet. 2001;357:905-10. doi:10.1016/S0140-6736(00)04209-4.

37. The 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(9500):1849-61. doi:10.1016/S0140-6736(05)67667-2.

38. Wierzbicki AS. FIELD of dreams, fields of tears: a perspective on the fibrate trials. Int J Clin Pract. 2006;60(4):442-9. doi:10.1111/j.1368-5031.2006.00882.x.

39. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113:2363-72. doi:10.1161/CIRCULATIONAHA.106.174516.

40. Ballantyne CM, Jones PH, Kelly MT, et al. Long-term efficacy of adding fenofibric acid to moderate-dose statin therapy in patients with persistent elevated triglycerides. Cardiovasc Drugs Ther. 2011;25:59-67. doi:10.1007/s10557-011-6280-1.

41. Roth EM, McKenney JM, Kelly MT, et al. Efficacy and safety of rosuvastatin and fenofibric acid combination therapy versus simvastatin monotherapy in patients with hypercholesterolemia and hypertriglyceridemia: a randomized, double-blind study. Am J Cardiovasc Drugs. 2010;10(3):175-86. doi:10.2165/11533430-000000000-00000.

42. Farnier M, Ducobu J, Bryniarski L. Efficacy and safety of adding fenofibrate 160 mg in high-risk patients with mixed hyperlipidemia not controlled by pravastatin 40 mg monotherapy. Am J Cardiol. 2010;106:787-92. doi:10.1016/j.amjcard.2010.05.005.

43. Farnier M, Steinmetz A, Retterstol K, et al. Fixed-dose combination fenofibrate/ pravastatin 160/40 mg versus simvastatin 20 mg monotherapy in adults with type 2 diabetes and mixed hyperlipidemia uncontrolled with simvastatin 20 mg: a double-blind, randomized comparative study. Clin Ther. 2011;33(1):1-12. doi:10.1016/j.clinthera.2011.02.006.

44. Jones PH, Cusi K, Davidson MH, et al. Efficacy and safety of fenofibric acid co-administered with lowor moderate-dose statin in patients with mixed dyslipidemia and type 2 diabetes mellitus. Am J Cardiovasc Drugs. 2010;10(2):73-84. doi:10.2165/10061630000000000-00000.