Can the use of sartans reduce mortality and severity of COVID-19 in hypertensives?

RAAS in the pathogenesis of COVID-19

The coronavirus enters human cells through binding to angiotensin-converting enzyme 2 (ACE2). This enzyme catalyzes the conversion of angiotensin II to angiotensin 1–7, which has vasodilatory and anti-inflammatory effects. During infection, there is a partial reduction or complete loss of its enzymatic function in alveolar cells, leading to a deviation of homeostatic balance in the RAAS in favor of the AT₁ receptor axis for angiotensin II. Angiotensin II binds to AT₁ receptors, has vasoconstrictive and pro-inflammatory effects, induces apoptosis and fibrosis. This creates a self-perpetuating cascade leading to acute respiratory distress syndrome (ARDS). The emerging inflammatory process, during which pro-inflammatory and pyrogenic cytokines are released systemically, therefore requires rapid and effective intervention.

Possibilities of using sartans

AT₁ receptor antagonists for angiotensin II (ARBs, sartans) are among the first-choice antihypertensive agents. They are well tolerated – clinical studies evaluating the safety of the treatment did not find a difference in the frequency and intensity of adverse events between certain sartans and placebo.

From comparative analysis, it was found that telmisartan has the most favorable pharmacological properties as an antagonist of the pro-inflammatory effects of angiotensin II in patients with COVID-19. Its high lipophilicity leads to rapid absorption and penetration into tissues after oral administration. It is characterized by a high affinity for the AT₁ receptor and 10 times greater antagonistic ability compared to losartan.

Studies that examined the dissociation rate of ARBs have shown their slow dissociation from receptors. Telmisartan has the longest dissociation half-life and also induces a reduction in the number of AT₁ receptors.

From the existing findings, it has been concluded that:

• Telmisartan is well absorbed after oral administration.
• Compared to other ARBs, it has the longest plasma half-life (24 hours).
• Due to its high lipophilicity and high distribution volume, it reaches the highest tissue concentrations.
• It dissociates from the AT₁ receptor very slowly, approaching almost irreversible blockade.

Results of clinical research

Based on the above findings, a randomized open controlled multicentric study was conducted at Hospital de Clínicas José de San Martín in Buenos Aires, evaluating the effects of telmisartan compared to standard care in patients with a positive PCR test for SARS-CoV-2. The results confirmed the involvement of RAAS in the inflammatory process in hospitalized patients infected with SARS-CoV-2. They also suggested that telmisartan (at a dose of 80 mg) could reduce morbidity and mortality in these patients. However, the study had significant methodological limitations, such as the absence of blinding, exclusion of patients hospitalized in the ICU at the time of randomization, restriction to individuals with a relatively short time from symptom onset to randomization, and a low number of participants (n = 158) due to early termination of the study.

During the second year of the pandemic, analyses also confirmed that drugs targeting the RAAS do not worsen the course of COVID-19 and the mortality of those infected, as initially speculated. In some studies, a benefit of their use even emerged. For example, a meta-analysis of 7 randomized controlled trials involving 1321 patients with COVID-19 showed that the use of ACE inhibitors (ACEi) or ARBs was not associated with a higher risk of mortality and severity of the disease. Moreover, subgroup analysis indicated that the use of ARBs was associated with a significant reduction in mortality and severity of the disease compared to the non-use of ACEi/ARBs.

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Sources:
1. Rothlin R. D., Vetulli H. M., Duarte M., Pelorosso F. G. Telmisartan as tentative angiotensin receptor blocker therapeutic for COVID-19. Drug Development Research 2020; 81 (7): 768–770, doi: 10.1002/ddr.21679.
2. Duarte M., Pelorosso F. K., Rothlin R. D. Telmisartan for treatment of Covid-19 patients: an open multicenter randomized clinical trial. EClinicalMedicine 2021 Jun 18, doi: 10.1016/j.eclinm.2021.100962.
3. Yin J., Wang Ch, Song X. et al. Effects of renin-angiotensin system inhibitors on mortality and disease severity of COVID-19 patients: a meta-analysis of randomized controlled trials. Am J Hypertens 2022 May 5; 35 (5): 462–469, doi: 10.1093/ajh/hpac001.