Authors

• Ljiljana Banfić — University of Zagreb School of Medicine, University Hospital Centre Zagreb, Zagreb, Croatia — ORCID: 0000-0002-4538-8980

Abstract

The application of angiotensin receptor blockers (AT1) in cardiovascular prevention is based on the treatment of arterial hypertension. Telmisartan, a medication from the sartan group, has not only an antihypertensive effect but proven pleiotropic, metabolic, biohumoral, antiproliferative, and vascular effects – the basic processes of vascular aging as well as the progression of atherosclerosis, a disease with a high mortality that requires early risk recognition and comprehensive primary and secondary cardiovascular prevention. Based on scientific evidence, telmisartan has been proven to provide a well tolerated antihypertensive effect over 24 hours, and is indicated in the prevention of cardiovascular diseases.

Keywords

angiotensin receptor blockers, cardiovascular prevention, telmisartan

DOI

Full Text

Preventing cardiovascular diseases (CVD) and their often fatal effects is one of the top medical and scientific priorities. Coronary heart disease and CVD in general are the leading cause of premature mortality worldwide. The early onset of this often asymptomatic disease necessitates prevention from a very early age. (1) It is especially important to identify at-risk individuals. These are primarily patients with diabetes, arterial hypertension, metabolic syndrome, dyslipidemia, carotid and peripheral vascular asymptomatic disease, and those with a clear positive family history. On the other hand, we are witnessing new demographic trends such as an increase in the older population, in which cardiovascular (CV) changes are most common. In this age group comorbidities are more common and more complex and often lead to adverse side-effects, which may lead to the cessation of treatment with that medication. Changes in the CV system that comes with aging are similar to atherosclerosis, although they differ in some important characteristics. Atherosclerosis is a systematic disease with focal, non-homogenous changes in the vascular wall, as opposed to the diffuse process that universally comes with old age. These two processes intertwine and support each other. Atherosclerosis and vascular aging are layered processes that are based on both material fatigue and genetic predispositions. The aging process is the result of cumulative episodes of oxidative stress, exposure to acute and chronic inflammatory and metabolic diseases, lifestyle choices, and a number of risk factors that cause changes in the arterial wall, elastin fragmentation, and an increase in the collagen ratio, primarily in the large blood vessels of the aortic arch and its branches. This is one of the basic events in the CV pathophysiology of aging. The aorta and the large elastic arteries of the aortic arch gradually lose the role of a vascular reservoir that attenuates the pulse wave during systolic ventricular ejection, which also causes deforming stress in small blood vessels, especially in the brain and kidneys. Changes in the stiffness of peripheral arteries correlate with the increase in pulse wave velocity and the augmentation index, leading to arterial hypertension, hypertensive heart disease, and all the well-known elements of CV scenarios with all too common fatal events such as myocardial infarction, stroke, and cardiovascular death. (2) Well-known risk factors lead to the development of atherosclerosis, which further contributes to the loss of endothelial function and associated cardiometabolic consequences. Loss of endothelial function is connected with endothelial repair, which largely depends on the potential of endothelial progenitor cells. (3) Atherosclerosis, arterial hypertension, and diabetes onset accelerate the abovementioned process of the CV continuum in which heart failure, coronary heart disease, acute myocardial infarction, and vascular diseases of the aorta as well as the peripheral, carotid, cerebral, and renal arteries, leading to high comorbidity and mortality, are an unwanted scenario. How and when to stop this unfortunate cascade? The solution is a timely personalized approach and prevention, which in addition to primarily preventive sociocultural initiatives also requires objectivization and pharmacotherapy, primarily in at-risk groups. In both basic and clinical studies on most of these events, the rennin-angiotensin system and angiotensin II play key roles, especially in the changes we call vascular “aging” but also in the onset and progression of atherosclerosis. Angiotensin II encourages cellular growth by activating growth hormones, inflammation, fibrosis, vasoconstriction due to increased endothelin levels, and oxidative stress. It is also responsible for the dysfunction of the repair potential of endothelial progenitor cells, stimulates the release of aldosterone, and stimulates fibrosis and water and salt retention through the same mechanism. (4, 5) Most effects of angiotensin II are related to the activation of the AT1 receptor. (6) Angiotensin converting enzyme (ACE) blockers and ACE receptor blockers are crucial for preserving the endothelial function, as well as in preserving central pressure in the aorta. There is extensive experimental evidence on prevention of metabolic syndrome and reduction in body weight from the application of AT1 receptor blockers. (7, 8) The importance of angiotensin-converting enzyme and angiotensin II receptor blockers in the treatment of arterial hypertension is indubitable. Their use also is fully justified in the treatment of heart failure, in post-infarction periods due to the effect on cardiac remodeling, in preventing nephropathy in diabetics, in patients with peripheral arterial disease, and in diseases of the aorta, for instance Marfan syndrome. The use of angiotensin II receptor blockers (ARB), AT1 in the treatment of Marfan syndrome is based on their beneficial effect on aortic blood pressure. Studies where parallel measurement of blood pressure was performed in the brachial artery and for central aortic blood pressure with the application of losartan and atenolol showed no significant difference in brachial blood pressure values, but the central aortic blood pressure and reflecting wave values were significantly lower after the application of losartan. (9) The coexistence of arterial hypertension and insulin resistance in metabolic syndrome, the scourge of modern medicine, is related to the pathophysiology of the nuclear hormone receptor PPAR-γ which modulates and controls the transcription of genes whose cellular response is associated with lipid and glucose metabolism and vascular processes, primarily through the production of nitric oxide (NO), endothelin-1 (ET1) levels, calcium channel activity, AT1 receptor expression, elevated sympathoadrenal activity, and peripheral vascular resistance. (10) High risk populations, such as diabetics or patients on chronic hemodialysis programs, were shown to have reduced cardiovascular mortality with the use of ACE inhibitors, in particular angiotensin II (AT1) receptor blockers. (11) ## Telmisartan - sartan for the prevention of cardiovascular diseases A revolutionary development in CV prevention in the 21st century came in the form of the HOPE trial which introduced ramipril for the treatment and prevention of CVD. (12) As opposed to angiotensin-converting enzyme inhibitors, angiotensin (AT1) receptor blockers and telmisartan in particular have other pleiotropic, cardiometabolic, and hemodynamic benefits which are not just a result of their antihypertensive effect, and are also better tolerated in comparison with ACE inhibitors. On the basis of the ONTARGET and TRANSCEND trials, telmisartan, a medication with a number of beneficial protective vascular effects over and above its antihypertensive effect, was selected for the category of medication used for cardiovascular prevention. Telmisartan was shown to have an effect on the onset of cardiac hypertrophy caused by arterial hypertension and on the regression and reduction of glomerulosclerosis. (13) The clinical applicability of telmisartan in both prevention and treatment is comparable to the application of ramipril, with a lower incidence of side-effects such as dry cough and angioedema. In the ONTARGET trial, patient compliance when treated with telmisartan was better than that of patients treated with ramipril in the HOPE trial. Effectiveness in the ONTARGET trial was comparable with ramipril, with a significantly lower incidence of dry cough. Telmisartan has been shown to have a superior antihypertensive effect in cases of moderate arterial hypertension in comparison with valsartan, losartan, ramipril, perindopril, and atenolol, both with regard to better tolerability and control of arterial blood pressure over a 24 hour interval. Side-effects under telmisartan were shown to be identical to placebo. In combination with hydrochlorothiazide it had a good effect on blood pressure in the elderly population. (14) The TRANSCEND trial looked at the application of telmisartan in patients that do not tolerate ACE inhibitors and have manifesting CVD, ventricle hypertrophy with heart failure, and other risk factors such as diabetes. Over a period of 56 months, the trial showed a reduction in heart failure, CV mortality, myocardial infarction, and stroke. The effect was detectable six months after the commencement of the treatment. At the start of the treatment, there was no reduction in the progression of cardiac decompensation or rates of hospitalization in comparison with placebo. These data indicate extended use of telmisartan angiotensin (AT1) receptor blockers until the desired clinical targets have been achieved. (15) In comparison with ramipril, the annual incidence of myocardial infarction with telmisartan was lower than in the HOPE trial. (16) The importance of angiotensin receptor blockers in the prevention of significant cardiovascular events and cardiovascular mortality has also been demonstrated in the high risk population of patients with acute limb ischemia in which a reduction in significant cardiovascular events was found. (17) A beneficial effect of telmisartan in CV prevention in at-risk vascular patients with newly developed diabetes was also found in combination with ramipril, and is based on the selective modulation and partial agonism of the nuclear hormone receptor PPAR-γ, which encourages glucose metabolism and improves insulin sensitivity. The beneficial effect on lipoprotein metabolism is also related to the reduction and normalization of triglyceride values in diabetics. (18) Telmisartan has a positive effect on endothelial function, influences the stiffness of peripheral arteries, and reduces oxidative stress caused by free fatty acids. (19) All this indicates that telmisartan, as an angiotensin (AT1) receptor blocker, influences most of the processes in CV pathophysiology, from the initial events that cause changes in vascular structure and function to beneficial therapeutic effects across the whole CV continuum. Evidence-based effects such as central aortic blood pressure normalization, treatment of arterial hypertension, stimulation of a positive biohumoral response and effect on risk factors, inflammation, fibrosis, dyslipidemia, insulin resistance in metabolic syndrome, endothelial function, arterial stiffness, and oxidative stress, along with its good tolerability, have secured a special place for telmisartan among other angiotensin receptor blockers in cardiovascular prevention.

Literature

1. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, et al. European Association for Cardiovascular Prevention & Rehabilitation (EACPR); ESC Committee for Practice Guidelines (CPG). European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J. 2012;33(13):1635–701. https://doi.org/10.1093/eurheartj/ehs092
2. Nichols W, O'Rourke M, Vlachopoulos C, editors. McDonald's Blood Flow in Arteries, Sixth Edition: Theoretical, Experimental and Clinical Principles. London, UK: Hodder Arnold; 2011.
3. De Caterina R, Libby P, editors. Endothelial Dysfunctions and Vascular Disease. Wiley-Blackwell; 2008.
4. Nakano N, Moriguchi A, Morishita R, Kida I, Tomita N, Matsumoto K, et al. Role of angiotensin II in the regulation of a novel vascular modulator, hepatocyte growth factor (HGF), in experimental hypertensive rats. Hypertension. 1997;30(6):1448–54. https://doi.org/10.1161/01.HYP.30.6.1448
5. Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003;348(7):593–600. https://doi.org/10.1056/NEJMoa022287
6. Schuchard J, Winkler M, Stölting I, Schuster F, Vogt FM, Barkhausen J, et al. Prevention of weight gain after AT1 receptor blockade in diet-induced rat obesity is at least partially related to an angiotensin(1-7)/Mas-dependent mechanism. Br J Pharmacol. 2015 Apr 23;•••: [Epub ahead of print]. https://doi.org/10.1111/bph.13172
7. Imanishi T, Hano T, Nishio I. Angiotensin II accelerates endothelial progenitor cell senescence through induction of oxidative stress. J Hypertens. 2005;23(1):97-104. https://pubmed.ncbi.nlm.nih.gov/15643130/
8. Makita S, Abiko A, Naganuma Y, Moriai Y, Nakamura M. Effects of telmisartan on adiponectin levels and body weight in hypertensive patients with glucose intolerance. Metabolism. 2008;57(10):1473–8. https://doi.org/10.1016/j.metabol.2008.05.019
9. Nichols WW, O’Rourke MF. McDonald’s Blood Flow in Arteries. 5th ed. London: Edward Arnold; 2005.
10. Marx N, Duez H, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells. Circ Res. 2004;94(9):1168–78. https://doi.org/10.1161/01.RES.0000127122.22685.0A
11. Wu CK, Yang YH, Juang JM, Wang YC, Tsai CT, Lai LP, et al. Effects of angiotensin converting enzyme inhibition or angiotensin receptor blockade in dialysis patients: a nationwide data survey and propensity analysis. Medicine (Baltimore). 2015;94(3):e424. https://doi.org/10.1097/MD.0000000000000424
12. Sleight P. The HOPE Study (Heart Outcomes Prevention Evaluation). J Renin Angiotensin Aldosterone Syst. 2000;1(1):18-20. https://pubmed.ncbi.nlm.nih.gov/11967789/
13. Sabbah ZA, Mansoor A, Kaul U. Angiotensin receptor blockers - advantages of the new sartans. J Assoc Physicians India. 2013;61(7):464-70. https://pubmed.ncbi.nlm.nih.gov/24772750/
14. Galzerano D, Capogrosso C, Di Michele S, Galzerano A, Paparello P, Lama D, et al. New standards in hypertension and cardiovascular risk management: focus on telmisartan. Vasc Health Risk Manag. 2010;6:113–33. https://doi.org/10.2147/VHRM.S7857
15. Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators, Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, Copland I, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet. 2008;372(9644):1174-83. https://doi.org/10.1016/S0140-6736(08)61242-8
16. Jugdutt BI. Clinical effectiveness of telmisartan alone or in combination therapy for controlling blood pressure and vascular risk in the elderly. Clin Interv Aging. 2010;5:403–16. https://doi.org/10.2147/CIA.S6709
17. Armstrong EJ, Chen DC, Singh GD, Amsterdam EA, Laird JR. Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use is associated with reduced major adverse cardiovascular events among patients with critical limb ischemia. Vasc Med. 2015;20(3):237–44. https://doi.org/10.1177/1358863X15574321
18. Benson SC, Pershadsingh HA, Ho CI, Chittiboyina A, Desai P, Pravenec M, et al. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension. 2004;43(5):993–1002. https://doi.org/10.1161/01.HYP.0000123072.34629.57
19. Jung AD, Kim W, Park SH, Park JS, Cho SC, Hong SB, et al. The effect of telmisartan on endothelial function and arterial stiffness in patients with essential hypertension. Korean Circ J. 2009;39(5):180–4. https://doi.org/10.4070/kcj.2009.39.5.180