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Hypertension and Hypercholesterolemia: is it Time for Anti-«Lipitensive» Therapy?

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Despite the widespread awareness that hypertension and dyslipidemia are risk factors of prime importance for cardiovascular disease, the prevalence of these risk factors is still high, and the success of their control can hardly be considered satisfactory. The latest European guidelines for the management of hypertension strengthened the position of fixed-dose combinations, the main advantage of which is increased adherence to treatment. The purpose of this review was to discuss the background and the possibility of using fixed-dose combinations containing antihypertensive drugs and a statin in the treatment of patients with hypertension and dyslipidemia. We outlined the theoretical concepts that substantiate the possibility of using such therapy and discussed the results of randomized clinical trials investigating the efficacy of combined administration of antihypertensive and lipidlowering drugs. Illustrated by single pill combination of indapamide, perindopril and rosuvastatin, the requirements for fixed drug combinations are discussed, as well as clinical scenarios when their use is considered justified.

About the Authors

Z. D. Kobalava
Peoples' Friendship University of Russia (RUDN University)
Russian Federation

Zhanna D. Kobalava – MD, PhD, Professor, Corresponding Member of the Russian Academy of Sciences, Head of Chair of Internal Medicine with the Subspecialty of Cardiology and Functional Diagnostics named after Academician V.S. Moiseev

Miklukho-Maklaya ul. 6, Moscow, 117198

E. V. Kokhan
Peoples' Friendship University of Russia (RUDN University)
Russian Federation

Elizaveta V. Kokhan – MD, Resident, Chair of Internal Medicine with the Subspecialty of Cardiology and Functional Diagnostics named after Academician V.S. Moiseev

Miklukho-Maklaya ul. 6, Moscow, 117198


1. Yusuf P.S., Hawken S., Ôunpuu S., et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study. Lancet. 2004;364(9438):937-52. DOI:10.1016/S0140-6736(04)17018-9.

2. O’Donnell M.J., Chin S.L., Rangarajan S., et al. Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study. Lancet. 2016;388(10046):761-75. DOI:10.1016/S0140-6736(16)30506-2.

3. Muromtseva G.A., Kontsevaya A.V., Konstantinov V.V., et al. Prevalence of risk factors for non-communicable diseases in the Russian population in 2012-2013. ESSE-RF study results. Cardiovascular Therapy and Prevention. 2014;1(6):4-11 (In Russ.) DOI:10.15829/1728-8800-2014-6-4-11.

4. Mach F., Baigent C., Catapano A.L., et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111-88. DOI:10.1093/eurheartj/ehz455.

5. Grundy S.M., Stone N.J., Bailey A.L., et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/ APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):E1082-E1143. DOI:10.1161/CIR.0000000000000625.

6. Williams B., Mancia G., Spiering W., et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021-104. DOI:10.1093/eurheartj/ehy339.

7. Whelton P.K., Carey R.M., Aronow W.S., et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71(19):e127-e248. DOI:10.1016/j.jacc.2017.11.006.

8. Kannel W.B. Fifty years of Framingham Study contributions to understanding hypertension. J Hum Hypertens. 2000;14(2):83-90. DOI:10.1038/sj.jhh.1000949.

9. Egan B.M., Li J., Qanungo S., Wolfman T.E. Blood pressure and cholesterol control in hypertensive hypercholesterolemic patients: National health and nutrition examination surveys 1988-2010. Circulation. 2013;128(1):29-41. DOI:10.1161/CIRCULATIONAHA.112.000500.

10. Chobanian A.V., Bakris G.L., Black H.R., et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. J Am Med Assoc. 2003;289(19):2560-72. DOI:10.1001/jama.289.19.2560.

11. Eaton B., Feldman A., Assaf R., et al. Prevalence of hypertension, dyslipidemia, and dyslipidemic hypertension. J Fam Pract. 1994;38:17-23.

12. Johnson M.L., Pietz K., Battleman D.S., Beyth R.J. Prevalence of co-morbidity hypertension and dyslipidemia and associated cardiovascular disease. Am J Manag Care. 2004;10:926-32.

13. Williams R.R. Familial dyslipidemic hypertension. Evidence from 58 Utah families for a syndrome present in approximately 12% of patients with essential hypertension. JAMA J Am Med Assoc. 1988;259(24):3579-86. DOI:10.1001/jama.259.24.3579.

14. Gulati A., Dalal J., Padmanabhan T.N.C., et al. Lipitension: Interplay between dyslipidemia and hypertension. Indian J Endocrinol Metab. 2012;16(2):240. DOI:10.4103/2230-8210.93742.

15. Freiberg J.J., Tybjærg-Hansen A., Jensen J.S., Nordestgaard B.G. Nonfasting triglycerides and risk of ischemic stroke in the general population. JAMA. 2008;300(18):2142-52. DOI:10.1001/jama.2008.621.

16. Elias P.K., Elias M.F., D’Agostino R.B., et al. Serum cholesterol and cognitive performance in the Framingham Heart Study. Psychosom Med. 2005;67(1):24-30. DOI:10.1097/01.psy.0000151745.67285.c2.

17. Ebrahim S., Sung J., Song Y.M., et al. Serum cholesterol, haemorrhagic stroke, ischaemic stroke, and myocardial infarction: Korean national health system prospective cohort study. Br Med J. 2006;333(7557):22-5. DOI:10.1136/bmj.38855.610324.80.

18. Haffner S.M, Miettinen H., Gaskill S.P., Stern M.P. Metabolic precursors of hypertension. The San Antonio Heart Study. Arch Intern Med. 1996;156(17):1994-2001.

19. Sesso H.D., Buring J.E., Chown M.J., et al. A prospective study of plasma lipid levels and hypertension in women. Arch Intern Med. 2005;165(20):2420-7. DOI:10.1001/archinte.165.20.2420.

20. Laaksonen D.E., Niskanen L., Nyyssönen K., et al. Dyslipidaemia as a predictor of hypertension in middle-aged men. Eur Heart J. 2008;29(20):2561-8. DOI:10.1093/eurheartj/ehn061.

21. Borghi C., Veronesi M., Bacchelli S., et al. Serum cholesterol levels, blood pressure response to stress and incidence of stable hypertension in young subjects with high normal blood pressure. J Hypertens. 2004;22(2):265-72. DOI:10.1097/00004872-200402000-00009.

22. Otsuka T., Takada H., Nishiyama Y., et al. Dyslipidemia and the risk of developing hypertension in a working-age male population. J Am Heart Assoc. 2015;5(3):e003053. DOI:10.1161/JAHA.115.003053.

23. Creager M.A., Cooke J.P., Mendelsohn M.E., et al. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990;86(1):228-34. DOI:10.1172/JCI114688.

24. Piccirillo G., Giuseppe V.D., Marialuce Nocco M.L., et al. Influence of aging and other cardiovascular risk factors on baroreflex sensitivity. J Am Geriatr Soc. 2001;49(8):1059-65. DOI:10.1046/j.1532-5415.2001.49209.x.

25. Wilkinson I.B., Prasad K., Hall I.R., et al. Increased central pulse pressure and augmentation index in subjects with hypercholesterolemia. J Am Coll Cardiol. 2002;39(6):1005-11. DOI:10.1016/S0735-1097(02)01723-0.

26. Ivanovic B., Tadic M. Hypercholesterolemia and Hypertension: Two Sides of the Same Coin. Am J Cardiovasc Drugs. 2015;15(6):403-14. DOI:10.1007/s40256-015-0128-1.

27. Neaton J.D., Wentworth D. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Overall findings and differences by age for 316,099 white men. Multiple Risk Factor Intervention Trial Research Group. Arch Intern Med. 1992;152(1):56-64.

28. Liao D., Mo J., Duan Y., et al. The joint effect of hypertension and elevated LDL-cholesterol on CHD is beyond additive. Eur Heart J. 2004;25(abstract suppl):235[abstract #1377].

29. Navar-Boggan A.M., Peterson E.D., D’Agostino R.B., et al. Hyperlipidemia in early adulthood increases long-term risk of coronary heart disease. Circulation. 2015;131(5):451-8. DOI:10.1161/CIRCULATIONAHA.114.012477.

30. Gray L., Lee I.M., Sesso H.D., Batty G.D. Blood pressure in early adulthood, hypertension in middle age, and future cardiovascular disease mortality: HAHS (Harvard Alumni Health Study). J Am Coll Cardiol. 2011;58(23):2396-403. DOI:10.1016/j.jacc.2011.07.045.

31. Zhang Y., Vittinghoff E., Pletcher M.J., et al. Associations of Blood Pressure and Cholesterol Levels During Young Adulthood With Later Cardiovascular Events. J Am Coll Cardiol. 2019;74(3):330-41. DOI:10.1016/j.jacc.2019.03.529.

32. Domanski M.J., Fuster V., Diaz-Mitoma F., et al. Next steps in primary prevention of coronary heart disease rationale for and design of the ECAD Trial. J Am Coll Cardiol. 2015;66(16):1828-36. DOI:10.1016/j.jacc.2015.08.857.

33. Downs J.R., Clearfield M., Weis S., et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: Results of AFCAPS/TexCAPS. J Am Med Assoc. 1998;279(20):1615-22. DOI:10.1001/jama.279.20.1615.

34. Ridker P.M., Danielson E., Fonseca F.A..H, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-207. DOI:10.1056/NEJMoa0807646.

35. Yusuf S., Bosch J., Dagenais G., et al. Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med. 2016;374(21):2021-31. DOI:10.1056/NEJMoa1600176.

36. Shepherd J., Blauw G.J., Murphy M.B., et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): A randomised controlled trial. Lancet. 2002;360(9346):1623-30. DOI:10.1016/S0140-6736(02)11600-X.

37. Collins R., Armitage J., Parish S., et al. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: A randomised placebo-controlled trial. Lancet. 2002;360(9326):7-22. DOI:10.1016/S0140-6736(02)09327-3.

38. Athyros V.G., Papageorgiou A.A., Mercouris B.R., et al. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus “usual” care in secondary coronary heart disease prevention: The Greek atorvastatin and coronary-heart-disease evaluation (GREACE) study. Curr Med Res Opin. 2002;18(4):220-8. DOI:10.1185/030079902125000787.

39. Sacks F.M., Pfeffer M.A., Moye L.A., et al. The Effect of Pravastatin on Coronary Events after Myocardial Infarction in Patients with Average Cholesterol Levels. N Engl J Med. 1996;335(14):1001-9. DOI:10.1056/NEJM199610033351401.

40. Furberg C.D., Wright J.T., Davis B.R., et al. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT-LLT). J Am Med Assoc. 2002;288(23):2998-3007. DOI:10.1001/jama.288.23.2998.

41. Furberg C.D., Wright J.T., Davis B.R., et al. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). J Am Med Assoc. 2002;288(23):2981-97. DOI:10.1001/jama.288.23.2981.

42. Dahlöf B., Sever P.S., Poulter N.R., et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOTBPLA): A multicenter randomised controlled trial. Lancet. 2005;366(9489):895-906. DOI:10.1016/S0140-6736(05)67185-1.

43. Sever P.S., Dahlöf B., Poulter N.R., et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm (ASCOT-LLA): A multicentrerandomised controlled trial. Lancet. 2003;361(9364):1149-58. DOI:10.1016/S0140-6736(03)12948-0.

44. Gupta A., Mackay J., Whitehouse A., et al. Long-term mortality after blood pressure-lowering and lipid-lowering treatment in patients with hypertension in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy study: 16-year follow-up results of a randomised factorial trial. Lancet. 2018;392(10153):1127-37. DOI:10.1016/S0140-6736(18)31776-8.

45. Yusuf S., Lonn E., Pais P., et al. Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease. N Engl J Med. 2016;374(21):2032-43. DOI:10.1056/NEJMoa1600177.

46. Lonn E.M., Bosch J., López-Jaramillo P., et al. Blood-Pressure Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med. 2016;374(21):2009-20. DOI:10.1056/NEJMoa1600175.

47. World Health Organization. Secondary prevention of noncommunicable disease in low and middle income countries through community based and health service interventions. WHO - Wellcome Trust Meeting report 1-3. Geneva: World Health Organization; 2002.

48. Wald N.J., Law M.R. A strategy to reduce cardiovascular disease by more than 80%. Br Med J. 2003;326(7404):1419-23. DOI:10.1136/bmj.326.7404.1419.

49. Ridker P.M. Is Statin Monotherapy the Perfect Polypill? Circulation. 2016;134(2):91-3. DOI:10.1161/CIRCULATIONAHA.116.023166.

50. Gaziano J.M., Brotons C., Coppolecchia R., et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebocontrolled trial. Lancet. 2018;392(10152):1036-46. DOI:10.1016/S0140-6736(18)31924-X.

51. McNeil J.J., Wolfe R., Woods R.L., et al. Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly. N Engl J Med. 2018;379(16):1509-18. DOI:10.1056/NEJMoa1805819.

52. Philipp T., Anlauf M., Distler A., et al. Randomised, double blind, multicentre comparison of hydrochlorothiazide, atenolol, nitrendipine, and enalapril in antihypertensive treatment: Results of the HANE study. Br Med J. 1997;315(7101):154-9. DOI:10.1136/bmj.315.7101.154.

53. Ruzicka M., Leenen F.H.H. Monotherapy versus combination therapy as first line treatment of uncomplicated arterial hypertension. Drugs. 2001;61(7):943-54. DOI:10.2165/00003495-200161070-00004.

54. Hansson L., Zanchetti A., Carruthers S.G., et al. Effects of intensive blood-pressure lowering and lowdose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351(9118):1755-62. DOI:10.1016/S0140-6736(98)04311-6.

55. Materson B.J., Reda D.J., Cushman W.C., et al. Single-Drug Therapy for Hypertension in Men - A Comparison of Six Antihypertensive Agents with Placebo. N Engl J Med. 1993;328(13):914-21. DOI:10.1056/NEJM199304013281303.

56. Bangalore S., Kamalakkannan G., Parkar S., Messerli F.H. Fixed-Dose Combinations Improve Medication Compliance: A Meta-Analysis. Am J Med. 2007;120(8):713-9. DOI:10.1016/j.amjmed.2006.08.033.

57. Tomaszewski M., White C., Patel P., et al. High rates of non-adherence to antihypertensive treatment revealed by high-performance liquid chromatography-tandem mass spectrometry (HP LC-MS/MS) urine analysis. Heart. 2014;100(11):855-61. DOI:10.1136/heartjnl-2013-305063.

58. Chapman R.H., Benner J.S., Petrilla A.A., et al. Predictors of adherence with antihypertensive and lipidlowering therapy. Arch Intern Med. 2005;165(10):1147-52. DOI:10.1001/archinte.165.10.1147.

59. Dresser G.K., Nelson S.A.E., Mahon J.L., et al. Simplified therapeutic intervention to control hypertension and hypercholesterolemia: A cluster randomized controlled trial (STITCH2). J Hypertens. 2013;31(8):1702-13. DOI:10.1097/HJH.0b013e3283619d6a.

60. Baigent C., Blackwell L., Emberson J., et al. Efficacy and safety of more intensive lowering of LDL cholesterol: A meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-81. DOI:10.1016/S0140-6736(10)61350-5.

61. Collins R., Reith C., Emberson J., et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388(10059):2532-61. DOI:10.1016/S0140-6736(16)31357-5.

62. Ettehad D., Emdin C.A., Kiran A., et al. Blood pressure lowering for prevention of cardiovascular disease and death: A systematic review and meta-analysis. Lancet. 2016;387(10022):957-67. DOI:10.1016/S0140-6736(15)01225-8.

63. Committee for Human Medicinal Products (CHMP). Guideline on Clinical Development of Fixed Combination Medicinal Products.; 2017 [cited by August 12, 2020]. Available from:

64. FDA. Hypertension: Developing Fixed-Combination Drug Products for Treatment Guidance for Industry.; 2018 [cited by August 12, 2020]. Available from:

65. Napalkov D.A. Russian Trial ALGORITHM: Implementation of Combined Antihypertensive and Hypolipidemic Treatment for Clinical Efficacy Achievement in Routine Clinical Practice. Rational Pharmacotherapy in Cardiology. 2019;15(6):779-88 (In Russ.) DOI: 10.20996/1819-6446-2019-15-6-779-788

66. Gosse P., Sheridan D.J., Zannad F., et al. Regression of left ventricular hypertrophy in hypertensive patients treated with indapamide SR 1.5 mg versus enalapril 20 mg: The LIVE study. J Hypertens. 2000;18(10):1465-75. DOI:10.1097/00004872-200018100-00015.

67. Marre M., Puig J.G., Kokot F., et al. Equivalence of indapamide SR and enalapril on microalbuminuria reduction in hypertensive patients with type 2 diabetes: The NESTOR study. J Hypertens. 2004;22(8):1613-22. DOI:10.1097/01.hjh.0000133733.32125.09.

68. London G., Schmieder R., Calvo C., Asmar R. Indapamide SR versus candesartan and amlodipine in hypertension: The X-CELLENT study. Am J Hypertens. 2006;19(1):113-21. DOI:10.1016/j.amjhyper.2005.06.027.

69. Fox K.M., Bertrand M., Ferrari R., et al. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362(9386):782-8. DOI:10.1016/S0140-6736(03)14286-9.

70. MacMahon S., Neal B., Tzourio C., et al. Randomised trial of a perindopril-based blood-pressurelowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358(9287):1033-41. DOI:10.1016/S0140-6736(01)06178-5.

71. Patel A. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370(9590):829-40. DOI:10.1016/S0140-6736(07)61303-8.

72. Beckett N.S., Peters R., Fletcher A.E., et al. Treatment of Hypertension in Patients 80 Years of Age or Older. N Engl J Med. 2008;358(18):1887-98. DOI:10.1056/NEJMoa0801369.

For citation:

Kobalava Z.D., Kokhan E.V. Hypertension and Hypercholesterolemia: is it Time for Anti-«Lipitensive» Therapy? Rational Pharmacotherapy in Cardiology. 2020;16(5):842-851. (In Russ.)

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