Phenotype of a patient with arterial hypertension for therapy with candesartan and its combinations with a diuretic or calcium antagonist

The article provides a review on the efficacy and safety of the use of candesartan in hypertension through the lens of current clinical guidelines, and considers updated data on the efficacy and metabolic effects of different candesartan-based combinations. A clear phenotype of a patient with hypertension who can be selected for the prescription of candesartan has been built-up, and the principles of differentiated approach to prescribing candesartan-based combinations for the treatment of hypertension have been outlined, taking into account metabolic effects and impact on the end points. It has been shown  that candesartan is more effective than irbesartan, valsartan and losartan in lowering blood pressure, can reduce the risk of hypertension in people with normal high blood pressure or in young people with familial risks, and has the largest and most diverse evidence in the treatment of chronic heart failure, and significantly reduces the risk of cardiovascular complications as well as restrains the progression rates of diabetic retinopathy. The patient’s phenotype for the candesartan and amlodipine combination suggests that the presence of one or more of the following conditions: metabolic syndrome (particularly with impaired glucose tolerance and hypertriglyceridemia), the need for targeted angioprotection, hyperuricemia, hypokalemia tendency, or the necessity to replace other angiotensin II receptor blockers with candesartan-based combinations. The candesartan and hydrochlorothiazide combination is preferable for HOPE-3-like patients, patients with a history of strokes or transient ischemic attacks, as well as recurrent strokes, the presence of hypervolemia (obesity, perimenopause), the need for treatment or prevention of chronic heart failure, replacement of other angiotensin II receptor blockers with candesartan-based combinations. The prescription of the candesartan and hydrochlorothiazide combination using the 24-hour blood pressure monitoring in a patient requires to exclude the 24-hour night-picker or non-dipper profile and the morning blood pressure surge, as the effect of hydrochlorothiazide does not exceed 12 hours. Both combinations have also been shown to improve cognitive function.

1. Nedogoda SV, Sabanov AV, Salasyuk AS, Lutova VO, Popova EA, Bychkova OI, Rubtsova MV. Quantitative assessment of options for the use of single-component antihypertensive drugs at various stages of the intensification of hypertension therapy. Journal of Volgograd State Medical University. 2021;18(2):141–145. (In Russ.) https://doi.org/10.19163/1994-9480-2021-2(78)-141-145.

2. Mancia G, Kreutz R, Brunström M, Burnier M, Grassi G, Januszewicz A et al. 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA). J Hypertens. 2023;41(12):1874–2071. https://doi.org/10.1097/HJH.0000000000003480.

3. Kobalava ZhD, Konradi AO, Nedogoda SV, Shlyakhto EV, Arutyunov GP, Baranova EI et al. Arterial hypertension in adults. Clinical guidelines 2020. Russian Journal of Cardiology. 2020;25(3):3786. (In Russ.) https://doi.org/10.15829/1560-4071-2020-3-3786.

4. Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D et al. 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension. 2020;75(6):1334–1357. https://doi.org/10.1161/HYPERTENSIONAHA.120.15026.

5. Evdokimova AG, Lozhkina MV, Kovalenko EV. Key features of candesartan application in clinical practice. Consilium Medicum. 2016;18(1):54–59. (In Russ.) Available at: https://consilium.orscience.ru/2075-1753/article/view/94388.

6. Gilyarevsky SR, Golshmid MV, Kuzmina IM. Evidence-based history of candesartan: past, future and present. Serdechnaya Nedostatochnost. 2015;16(5):303–310. (In Russ.) Available at: https://elibrary.ru/vhcyzf.

7. Sirenko YuN, Donchenko NV. Symposium “The place of candesartan in modern therapy of cardiovascular diseases: a review of the evidence.” Arterial Hypertension and Cardiovascular Disease. 2011;(4):141–153. (In Russ.) Available at: http://www.mif-ua.com/archive/article/21168.

8. Hansson L. The relationship between dose and antihypertensive effect for different AT1-receptor blockers. Blood Press Suppl. 2001;(3):33–39. https://doi.org/10.1080/08037050152518348.

9. Coca A, Kreutz R, Manolis AJ, Mancia G. A practical approach to switch from a multiple pill therapeutic strategy to a polypill-based strategy for cardiovascular prevention in patients with hypertension. J Hypertens. 2020;38(10):1890–1898. https://doi.org/10.1097/HJH.0000000000002464.

10. Burnier M, Brunner HR. Comparative antihypertensive effects of angiotensin II receptor antagonists. J Am Soc Nephrol. 1999;10(12 Suppl.):S278–282. Available at: https://pubmed.ncbi.nlm.nih.gov/10201883/.

11. Elmfeldt D, Olofsson B, Meredith P. The relationships between dose and antihypertensive effect of four AT1-receptor blockers. Differences in potency and efficacy. Blood Press. 2002;11(5):293–301. https://doi.org/10.1080/080370502320779502.

12. Meredith PA. Clinical comparative trials of angiotensin II type 1 (AT1)-receptor blockers. Blood Press Suppl. 2001;(3):11–17. https://doi.org/10.1080/08037050152518311.

13. Lacourcière Y, Asmar R. A comparison of the efficacy and duration of action of candesartan cilexetil and losartan as assessed by clinic and ambulatory blood pressure after a missed dose, in truly hypertensive patients: a placebo-controlled, forced titration study. Candesartan/Losartan study investigators. Am J Hypertens. 1999;12(12):1181–1187. https://doi.org/10.1016/s0895-7061(99)00142-9.

14. Kjeldsen SE, Stålhammar J, Hasvold P, Bodegard J, Olsson U, Russell D. Effects of losartan vs candesartan in reducing cardiovascular events in the primary treatment of hypertension. J Hum Hypertens. 2010;24(4):263–273. https://doi.org/10.1038/jhh.2009.77.

15. Bakris G, Gradman A, Reif M, Wofford M, Munger M, Harris S et al. Antihypertensive efficacy of candesartan in comparison to losartan: the CLAIM study. J Clin Hypertens (Greenwich). 2001;3(1):16–21. https://doi.org/10.1111/j.1524-6175.2001.00826.x.

16. Vidt DG, White WB, Ridley E, Rahman M, Harris S, Vendetti J et al. A forced titration study of antihypertensive efficacy of candesartan cilexetil in comparison to losartan: CLAIM Study II. J Hum Hypertens. 2001;15(7):475–480. https://doi.org/10.1038/sj.jhh.1001205.

17. Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Kaciroti N et al. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med. 2006;354(16):1685–1697. https://doi.org/10.1056/NEJMoa060838.

18. Williams SA, Michelson EL, Cain VA, Yang M, Nesbitt SD, Egan BM, Julius S. An evaluation of the effects of an angiotensin receptor blocker on health-related quality of life in patients with high-normal blood pressure (prehypertension) in the Trial of Preventing Hypertension (TROPHY). J Clin Hypertens (Greenwich). 2008;10(6):436–442. https://doi.org/10.1111/j.1751-7176.2008.07837.x.

19. Ndumele CE, Rangaswami J, Chow SL, Neeland IJ, Tuttle KR, Khan SS et al. Cardiovascular-Kidney-Metabolic Health: A Presidential Advisory From the American Heart Association. Circulation. 2023;148(20):1606–1635. https://doi.org/10.1161/CIR.0000000000001184.

20. Pothen L, Balligand JL. Legacy in Cardiovascular Risk Factors Control: From Theory to Future Therapeutic Strategies? Antioxidants (Basel). 2021;10(11):1849. https://doi.org/10.3390/antiox10111849.

21. Itoh H, Kurihara I, Miyashita K, Tanaka M. Clinical significance of ‘cardiometabolic memory’: a systematic review of randomized controlled trials. Hypertens Res. 2017;40(6):526–534. https://doi.org/10.1038/hr.2016.192.

22. Skov K, Eiskjaer H, Hansen HE, Madsen JK, Kvist S, Mulvany MJ. Treatment of young subjects at high familial risk of future hypertension with an angiotensin-receptor blocker. Hypertension. 2007;50(1):89–95. https://doi.org/10.1161/HYPERTENSIONAHA.107.089532.

23. Lonn E, Bosch J, Pogue J, Avezum A, Chazova I, Dans A et al. Novel Approaches in Primary Cardiovascular Disease Prevention: The HOPE-3 Trial Rationale, Design, and Participants’ Baseline Characteristics. Can J Cardiol. 2016;32(3):311–318. https://doi.org/10.1016/j.cjca.2015.07.001.

24. Yusuf S, Bosch J, Dagenais G, Zhu J, Xavier D, Liu L et al. Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med. 2016;374(21):2021–2031. https://doi.org/10.1056/NEJMoa1600176.

25. Lonn EM, Bosch J, López-Jaramillo P, Zhu J, Liu L, Pais P et al. Blood-Pressure Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med. 2016;374(21):2009–2020. https://doi.org/10.1056/NEJMoa1600175.

26. Yusuf S, Lonn E, Pais P, Bosch J, López-Jaramillo P, Zhu J et al. Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease. N Engl J Med. 2016;374(21):2032–2043. https://doi.org/10.1056/NEJMoa1600177.

27. Bosch J, Lonn EM, Jung H, Zhu J, Liu L, Lopez-Jaramillo P et al. Lowering cholesterol, blood pressure, or both to prevent cardiovascular events: results of 8.7 years of follow-up of Heart Outcomes Evaluation Prevention (HOPE)-3 study participants. Eur Heart J. 2021;42(31):2995–3007. https://doi.org/10.1093/eurheartj/ehab225.

28. Ariff B, Zambanini A, Vamadeva S, Barratt D, Xu Y, Sever P et al. Candesartanand atenolol-based treatments induce different patterns of carotid artery and left ventricular remodeling in hypertension. Stroke. 2006;37(9):2381–2384. https://doi.org/10.1161/01.STR.0000236839.69658.c5.

29. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362(9386):759–766. https://doi.org/10.1016/s0140-6736(03)14282-1.

30. McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-convertingenzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362(9386):767–771. https://doi.org/10.1016/S0140-6736(03)14283-3.

31. Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362(9386):772–776. https://doi.org/10.1016/S0140-6736(03)14284-5.

32. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362(9386):777–781. https://doi.org/10.1016/S0140-6736(03)14285-7.

33. Burgess E, Muirhead N, Rene de Cotret P, Chiu A, Pichette V, Tobe S. Supramaximal dose of candesartan in proteinuric renal disease. J Am Soc Nephrol. 2009;20(4):893–900. https://doi.org/10.1681/ASN.2008040416.

34. Cuspidi C, Muiesan ML, Valagussa L, Salvetti M, Di Biagio C, Agabiti-Rosei E et al. Comparative effects of candesartan and enalapril on left ventricular hypertrophy in patients with essential hypertension: the candesartan assessment in the treatment of cardiac hypertrophy (CATCH) study. J Hypertens. 2002;20(11):2293–2300. https://doi.org/10.1097/00004872-200211000-00030.

35. Ogihara T, Fujimoto A, Nakao K, Saruta T. ARB candesartan and CCB amlodipine in hypertensive patients: the CASE-J trial. Expert Rev Cardiovasc Ther. 2008;6(9):1195–1201. https://doi.org/10.1586/14779072.6.9.1195.

36. Penicka M, Gregor P, Kerekes R, Marek D, Curila K, Krupicka J. The effects of candesartan on left ventricular hypertrophy and function in nonobstructive hypertrophic cardiomyopathy: a pilot, randomized study. J Mol Diagn. 2009;11(1):35–41. https://doi.org/10.2353/jmoldx.2009.080082.

37. Sakamoto M, Suzuki H, Hayashi T, Iuchi H, Isaka T, Sakamoto N et al. Effects of candesartan in hypertensive patients with type 2 diabetes mellitus on inflammatory parameters and their relationship to pulse pressure. Cardiovasc Diabetol. 2012;11:118. https://doi.org/10.1186/1475-2840-11-118.

38. Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003;21(5):875–886. https://doi.org/10.1097/00004872-200305000-00011.

39. Schrader J, Lüders S, Kulschewski A, Berger J, Zidek W, Treib J et al. The ACCESS Study: evaluation of Acute Candesartan Cilexetil Therapy in Stroke Survivors. Stroke. 2003;34(7):1699–1703. https://doi.org/10.1161/01.STR.0000075777.18006.89.

40. Chaturvedi N, Porta M, Klein R, Orchard T, Fuller J, Parving HH et al. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebocontrolled trials. Lancet. 2008;372(9647):1394–1402. https://doi.org/10.1016/S0140-6736(08)61412-9.

41. Sjølie AK, Porta M, Parving HH, Bilous R, Klein R. The DIabetic REtinopathy Candesartan Trials (DIRECT) Programme: baseline characteristics. J Renin Angiotensin Aldosterone Syst. 2005;6(1):25–32. https://doi.org/10.3317/jraas.2005.003.

42. Bönner G, Landers B, Bramlage P. Candesartan cilexetil/hydrochlorothiazide combination treatment versus high-dose candesartan cilexetil monotherapy in patients with mild to moderate cardiovascular risk (CHILI Triple T). Vasc Health Risk Manag. 2011;7:85–95. https://doi.org/10.2147/VHRM.S17004.

43. Lindholm LH, Persson M, Alaupovic P, Carlberg B, Svensson A, Samuelsson O. Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study). J Hypertens. 2003;21(8):1563–1574. https://doi.org/10.1097/01.hjh.0000084723.53355.76.

44. Escobar C, Barrios V, Calderón A, Barrios S, Echarri R, Navarro-Cid J et al. Electrocardiographic left ventricular hypertrophy regression induced by an angiotensin receptor blocker-based regimen in hypertensive patients with the metabolic syndrome: data from the SARA Study. J Clin Hypertens (Greenwich). 2008;10(3):208–214. https://doi.org/10.1111/j.1751-7176.2008.07596.x.

45. Kloner RA, Weinberger M, Pool JL, Chrysant SG, Prasad R, Harris SM et al. Comparative effects of candesartan cilexetil and amlodipine in patients with mild systemic hypertension. Comparison of Candesartan and Amlodipine for Safety, Tolerability and Efficacy (CASTLE) Study Investigators. Am J Cardiol. 2001;87(6):727–731. https://doi.org/10.1016/s0002-9149(00)01491-0.