Pharmacotherapy in COVID-19 patients: a review of ACE2-raising drugs and their clinical safety

Abstract

The COVID-19 pandemic is caused by the severe acute-respiratory-syndrome-coronavirus-2 that uses ACE2 as its receptor. Drugs that raise serum/tissue ACE2 levels include ACE inhibitors (ACEIs) and angiotensin-II receptor blockers (ARBs) that are commonly used in patients with hypertension, cardiovascular disease and/or diabetes. These comorbidities have adverse outcomes in COVID-19 patients that might result from pharmacotherapy. Increasing ACE2 could potentially increase the risk of infection, severity or mortality in COVID-19 or it might be protective as it forms angiotensin-(1-7) which exhibits anti-inflammatory/anti-oxidative effects and prevents diabetes-and/or hypertension-induced end-organ damage. Thus, there existed clinical uncertainty. Here, we review studies implicating 15 classes of drugs in increasing ACE2 levels in vivo and the available literature on the clinical safety of these drugs in COVID-19 patients. Further, in a re-analysis of clinical data from a meta-analysis of 9 studies, we show that ACEIs/ARBs usage was not associated with an increased risk of all-cause mortality. Literature suggests that ACEIs/ARBs usage generally appears to be clinically safe though their use in severe COVID-19 patients might increase the risk of acute renal injury. For definitive clarity, further clinical and mechanistic studies are needed in assessing the safety of all classes of ACE2 raising medications.

Glucagon‐like peptide‐1 receptor agonists in the era of COVID‐19: Friend or foe?

“…To elaborate, Romaní‐Pérez et al demonstrated that GLP‐1R activation by liraglutide increases the ACE‐2 expression and improves production of SP‐A and SP‐B in the lungs of streptozotocin‐induced diabetes Sprague‐Dawley rats, while Fandiño et al reported that liraglutide enhances the activity of the ACE‐2/Ang(1‐7)/Mas receptor pathway in lungs of male pups from food‐restricted mothers 6,66 . To the best of our knowledge, no human studies demonstrating the respiratory ACE‐2 upregulation due to GLP‐1R agonists have been reported yet 67,68 . Thus, practical significance of potential changes in ACE‐2 levels and associated COVID‐19 susceptibility is another conundrum 69 .…”

“…Thus, practical significance of potential changes in ACE‐2 levels and associated COVID‐19 susceptibility is another conundrum 69 . At this point of time it is definitely worth mentioning that, on the other hand, there are some speculations that ACE‐2 raising drugs might even lead to beneficial outcomes in patients with SARS CoV‐2 infection, since it is thought that increased ACE‐2 activity could result in shifting of the balance within the renin‐angiotensin‐aldosterone system towards ACE‐2/Ang(1‐7)/Mas receptor pathway, which is known to exert anti‐inflammatory, anti‐oxidative, and anti‐fibrotic stress signals 67 . However; in order to draw the final conclusions on the present topic, further well‐conducted clinical and experimental studies are still needed.…”

Coronavirus Disease-2019 Treatment Strategies Targeting Interleukin-6 Signaling and Herbal Medicine

“…There is a potential for high blood glucose levels during dexamethasone treatment (Russell et al, 2020). If dexamethasone is used over a long period of time, conditions such as hypertension and weight gain may be observed (Akhtar et al, 2020). Another corticosteroid, methylprednisolone, is also under clinical trials, together with antibiotics in treating COVID-19 (Alberici et al, 2020;Fan et al, 2020a;Liu et al, 2020b).…”

Three-Dimensional Cell Cultures as a Research Platform in Lung Diseases and COVID-19

“…Increases in the expression or functional activation of sirtuin-1 is associated with an increase in the expression of ACE2. The prevention of COVID-19 by targeting cellular ACE2 receptors has been shown to not be a practically useful treatment strategy and can potentially increase infection, severity, or mortality [19][20][21][22].…”