In terms of safety outcomes, Chen et al found that ACEi have a higher risk of adverse effects such as pancreatitis, angioedema, cough, and gastrointestinal bleeding.5
The authors conclude that while current guidelines place ARBs and ACEi on equal footing as first-line therapies, their study provides robust evidence for the superiority of ARBs. They suggest that initiating treatment with ARBs, rather than ACEi, should be the preferred approach to target hypertension through renin-angiotensin-aldosterone-system (RAAS) inhibition.5
How do ARBs and ACEi inhibit RAAS?
RAAS is an endocrine function that regulates long-term blood pressure (BP) by increasing sodium reabsorption, water reabsorption (retention) and vascular tone (the degree to which blood vessels constrict, or narrow). RAAS also regulates electrolyte balance and inapposite activation can lead to hypertension. BP elevation as a result of RAAS activation may also damage other target organs such as the brain, lungs, and the kidneys.1,6,7
RAAS consists of three significant compounds: Renin (a peptide produced primarily by the renal juxtaglomerular cells), angiotensin II (ANGII), and aldosterone (both hormones).7
When BP drops, or when sympathetic signals reach the kidney, renin is released and cleaves off two amino acids forming ANGI, which does not have any known biological activity, but is cleaved into ANGII.7,8,9
ANGII causes vasoconstriction by acting on the smooth muscles of arterioles, thus increasing BP. The effects of ANGII are mediated by two types of receptors: type 1 (ANGI-R) and type 2 (ANGII-R). These receptors have different and often opposing physiological responses.7,9
ANGI-R are found in many cell types, including the heart, vasculature, kidney, adrenal glands, pituitary, and central nervous system. ANGII mediates its physiological effects of vasoconstriction and sodium and water reabsorption through ANGI-R.7,9
In pathogenic states, the activation of the ANGI-R leads to inflammation, fibrosis, oxidative stress, tissue remodeling, and increased BP. The dysregulation of this receptor is central to the pathophysiology of cardiac and renal diseases.7,9
ANGII-R is expressed in foetal tissues, and expression decreases in adulthood. In adults, it is distributed in the heart, kidney, adrenal glands, and brain. ANGII-R mediates the opposing and protective effects of ANGII via ANGI-R. These actions inhibit inflammation, fibrosis, and central sympathetic outflow and cause vasodilation. Stimulation of the ANGII-R by ANGII leads to vasodilation and natriuresis, opposite to the vasoconstriction and anti-natriuresis caused by ANGII via the ANGI-R.7
ANGII also triggers the release of aldosterone from the adrenal glands, which leads to increased concentrations of epithelial sodium channels, resulting in increased sodium reabsorption and BP levels.7,8,9
Mechanisms of action
ARBs and ACEi block RAAS through different mechanisms. ACE inhibition impairs ANGII production, reduces levels of pro-inflammatory markers and endothelial dysfunction, prevents atherogenesis, and inhibits fibrosis as well as thrombosis. Although ANGII reduction by ACE inhibition is beneficial, its long-term benefits may be compromised due to the ‘escape’ effects related to aldosterone, which increases the risk of CV events (ventricular arrhythmias and sudden cardiac death).10,11,12,13,14
ARBs, on the other hand, prevent the selective binding of ANGII to ANGI-R, resulting in the reduction of vasoconstriction, sympathetic stimulation, oxidative stress, release of inflammatory factors, and aldosterone release. 11,15
Compared with ACE inhibition, selective ANGI-R blockade has certain distinct advantages, like the absence of ANGII escape and pronounced inhibition of deleterious effects regulated via ATI-R stimulation and blockade of all ATII, independently from the site of production.15
According to Yusuf et al, this distinction is crucial because this mechanism of ARBs bypasses potential side effects associated with ACEi, such as increased bradykinin levels, which could lead to cough or angioedema. By exclusively blocking ANGII-R activation, ARBs effectively lower BP without affecting bradykinin metabolism.15
When should anti-hypertensives be initiated and when should they be taken?
The ESH guidelines recommend initiation of therapy in patients 18- to 79-years with an office threshold of 140mmHg for systolic BP (SBP) and/or 90mmHg diastolic BP (DBP). In patients ≥80-years, the recommended office SBP threshold for initiation of drug treatment is 160mmHg. However, in patients ≥80 years a lower SBP threshold in the range 140mmHg-160mmHg may be considered. In adult patients with a history of CVD, predominantly coronary artery disease, treatment should be initiated in the high-normal BP range (SBP ≥130mmHg or DBP ≥80mmHg).1
Studies show that CV events occur at different times during the day with peak occurrences in the early morning soon after waking. In their study involving >66 000 patients, Cohen et al showed that the risk of for example myocardial infarction increases by 40% between 6h00-12h00 as a result of BP surges.17,18
Two European studies showed that patients treated with anti-hypertensives can still have hypertension in the morning. The Spanish study showed that >50% of patients with well-controlled hypertension had elevated morning BP, while the study conducted in Portugal, showed that ∼35% of patients with well-controlled hypertension failed to achieve morning ambulatory BP (<133/85mmHg).19,20
According to Parati et al, it is possible that the low control rates achieved in these treated patients were, in part, due to the use of short-acting agents that could not sustain BP control throughout the 24-hour period.21
Therefore, states Gosse, it is important to prescribe a long-acting agent to ensure sustained control of BP at the time of heightened risk. The importance of 24-hour BP control is emphasised by several international medical societies.17
Telmisartan offers extended BP control
Among the ARBs available for commercial use, telmisartan stands out with its extended half-life of ~24-hours. This extended half-life strongly implies that telmisartan is equipped with a prolonged efficacy, thereby ensuring effective control of BP over the course of a single daily dose.17
Furthermore, telmisartan boasts a unique attribute that sets it apart from its ARB counterparts: Its notably high lipophilicity. This quality enhances its ability to permeate tissues, facilitate intracellular absorption, and optimise bioavailability. This heightened lipophilicity is mirrored in its substantial volume of distribution, measuring around 500 liters. Notably, this elevated lipophilicity, particularly when compared to compounds like losartan, may confer advantageous vascular protection.17
A distinguishing characteristic that sets telmisartan apart from other ARBs is its status as a non-prodrug. This distinction implies that the compound's anti-hypertensive potency is directly associated with the activity of the parent compound, without requiring any conversion or activation steps.17
The efficacy of telmisartan as monotherapy has been extensively studied. Various studies used ambulatory BP monitoring (ABPM) to examine if telmisartan’s prolonged half-life results in sustained BP control throughout the day.17
In a study comparing telmisartan with a long-acting CCB, both treatments yielded similar reductions in clinical BP in patients living with mild-to-moderate hypertension. However, telmisartan demonstrated a greater reduction in mean DBP during the nighttime and the last four hours of the dosing interval compared to the CCB. In studies involving ramipril (an ACEi) and losartan, telmisartan exhibited superior reductions in mean SBP and DBP during the last six hours of the dosing interval.17
Studies investigating fixed-dose combination therapy with telmisartan, and hydrochlorothiazide (HCTZ) resulted in significant reductions in SBP and DBP compared to losartan/HCTZ.17
Telmisartan's effectiveness was also highlighted in specific patient populations. In overweight patients with hypertension, telmisartan-based treatment demonstrated significant reductions in daytime and nighttime mean BP, helping to mitigate the risks associated with metabolic syndrome.17
In elderly patients with systolic hypertension, telmisartan/HCTZ was at least as effective as amlodipine/HCTZ in reducing SBP, with fewer drug-related adverse events reported in the telmisartan group.17
Hypertension affects a substantial global population, necessitating effective management through lifestyle changes and pharmacotherapy. International guidelines recommend ARBs, ACEi, CCBs, beta-blockers, and diuretics as first-line treatments. Recent large-scale evidence supports ARBs' superior safety profile compared to ACEi. The importance of 24-hour BP control is underscored by studies indicating peak CV events in the early morning. Among ARBs, telmisartan's extended half-life and high lipophilicity offer advantages in achieving sustained and comprehensive BP control.
- Mancia G, et al, Authors/Task Force Members: 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 European Renal Association (ERA) and the International Society of Hypertension (ISH). J Hypertens, 2023.
- Unger T, et al. 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension, 2020.
- Whelton PK, et al. 2017 ACC/AHA/APA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults. Hypertension, 2018.
- Seedat YK, et al, Hypertension guideline working group. South African hypertension practice guideline 2014. Cardiovasc J Afr, 2014.
- Chen RJ, et al. Comparative First-Line Effectiveness and Safety of ACE (Angiotensin-Converting Enzyme) Inhibitors and Angiotensin Receptor Blockers: A Multinational Cohort Study. Hypertension, 2021.
- Jia G, et al. Role of Renin-Angiotensin-Aldosterone System Activation in Promoting Cardiovascular Fibrosis and Stiffness. Hypertension, 2018.
- Fountain JH, et al. Physiology, Renin Angiotensin System. [Updated 2023 Mar 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470410/
- Patel P, Sanghavi DK, Morris DL, et al. Angiotensin II. [Updated 2023 May 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499912/
- Edmunds C. Hypertension and Clinical trial Training. Accord, 2023.
- Ferrari R, Fox K. Insight into the mode of action of ACE inhibition in coronary artery disease: The ultimate ‘EUROPA’ story. Drugs, 2009.
- Probstfield JL, O'Brien KD. Progression of cardiovascular damage: the role of renin-angiotensin system blockade. Am J Cardiol, 2010.
- Athyros VG, Mikhailidis DP, Kakafika AI, et al. Angiotensin II reactivation and aldosterone escape phenomena in renin-angiotensin-aldosterone system blockade: is oral renin inhibition the solution? Expert Opin Pharmacother, 2007.
- Lopez-Sendon J, et al. Expert consensus document on angiotensin converting enzyme inhibitors in cardiovascular disease: The Task Force on ACE-inhibitors of the European Society of Cardiology. European Heart Journal, 2004.
- Struthers AD. The clinical implications of aldosterone escape in congestive heart failure. European Journal of Heart Failure, 2004.
- Unger T, Stoppelhaar M. Rationale for double renin-angiotensin-aldosterone system blockade. Am J Cardiol, 2007.
- Yusuf S, et al on behalf of the ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med, 2008.
- Gosse P. A review of telmisartan in the treatment of hypertension: blood pressure control in the early morning hours. Vasc Health Risk Manag, 2006.
- Cohen MC. Meta-analysis of the morning excess of acute myocardial infarction and sudden cardiac death. Am J Cardiol, 1997.
- Redon J, et al. Uncontrolled early morning blood pressure in medicated patients: the ACAMPA study. Analysis of the Control of Blood Pressure using Abulatory Blood Pressure Monitoring. Blood Press Monit, 2002.
- Polonia J, et al. Lack of adequate blood pressure control in the morning and evening periods in medicated hypertensive patients considered to be controlled in the office. Rev Port Cardiol, 2005.
- Parati G, et al. The effects of telmisartan alone or with hydrochlorothiazide on morning and 24-h ambulatory BP control: results from a practice-based study (SURGE 2). Hypertens Res, 2013.