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

Figures & data

Figure 1. ACE2 as a key component of the RAAS and as the cell surface receptor for SARS-CoV-2 infection. The RAAS comprises two ‘arms’ or pathways that are opposing or counter-regulating in their actions and it is their relative balance that determines the physiological/pathological consequences. This simplified schematic shows that upon conversion of Angiotensinogen into Angiotensin 1 by renin, the octapeptide Angiotensin II (Ang II) is produced by the action of angiotensin-converting enzyme (ACE) on Angiotensin I that can exert its actions via the AT1 receptor (AT1R). Ang II can also be converted by ACE2 to Angiotensin-(1-7) (Ang-1-7) that can act via it Mas receptor (MasR). The predominance of the ACE-Ang II- AT1 receptor ‘arm’ or pathway leads to actions such as vasoconstriction, cell proliferation, pro-inflammatory and pro-fibrotic signals whereas the activation of the ACE2-Ang-(1-7)-MasR pathway leads to opposing actions of vasodilation, anti-proliferative, anti-inflammatory and anti-fibrotic signals. In addition to its role in RAAS, ACE2 is the receptor by which SARS-CoV-2 gains entry into human cells. Endocytosis of the complex between ACE2 and SARS-CoV-2 viral particles may lead to a reduction in membrane-bound ACE2 levels. Membrane-bound ACE2 can be shed as a soluble form of ACE2 (ACE2s) following cleavage by a disintegrin and metalloprotease 17 (ADAM-17). ACE2s retains it biological activity and might also act as a ‘decoy’ receptor to inhibit SARS-CoV-2 binding to the intended membrane-bound ACE2 receptor. The sites of action for ACE inhibitors and Angiotensin Receptor Blockers (ARBs)-routinely used for treating hypertension and cardiovascular diseases- are shown and these drugs are known to raise ACE2 levels in various fluids/tissues in vivo. Overall balance of ACE2 levels on cells or in body fluids will be dependent on the balance of its synthesis, shedding and/or degradation. The potential interplay of SARS-CoV-2 and the impact of ACE2-rasing medications in COVID-19 patients and the potential implications for shifting the balance between the different ‘arms’ of RAAS is further discussed in the main text.

Table 1. Examples of experimental studies providing evidence of raised ACE2 mRNA expression, protein levels and/or activity with clinically used medications.

Drug	Tissue or Fluid	Animal model or Human patients	Main Findings	References
A) Angiotensin receptor blockers (ARBs)/Angiotensin receptor antagonists/Sartans
Losartan and Olmesartan	Plasma	Lewis rats	Increased plasma ACE2 mRNA	Ishiyama et al. [41]
Losartan	Heart and plasma	Lewis rats	Increased plasma ACE2 mRNA and cardiac ACE2 activity	Ferrario et al. [49]
Losartan	Heart and Kidney	Transgenic Ren2 rats	Increased cardiac and renal ACE2 mRNA and ACE2 activity	Jessup et al. [50]
Irbesartan	Heart	C57BL/6 mice	Increased cardiac ACE2 mRNA, and attenuated Ang II-mediated reduction in ACE2 protein	Patel et al. [51]
Irbesartan	Aorta	C57BL/6 mice	Increased aortic ACE2 mRNA and protein expression	Jin et al. [52]
Telmisartan	Kidney	C57BLKS/J mice	Increased renal ACE2 protein levels, and ACE2 mRNA expression	Soler et al. [53]
Olmesartan	Aorta	SHR rats	Increased thoracic aortic ACE2 mRNA expression and ACE2 protein levels	Igase et al. [54]
Olmesartan	Urine	Hypertensive human patients	Increased urinary ACE2 levels	Furuhashi et al. [55]
B) Angiotensin converting enzyme Inhibitors (ACEI)
Enalapril	Heart and plasma	Sprague Dawley rats	Increased plasma and cardiac ACE2 activity	Ocaranza et al. [56]
Lisinopril	Heart and Kidney	Transgenic Ren2 rats	Increased cardiac and renal ACE2 mRNA and activity	Jessup et al. [50]
Lisinopril	Heart and plasma	Lewis rats, Transgenic Ren2 rats	Increased plasma ACE2 mRNA, but not cardiac ACE2 activity	Ferrario et al. [49]
Lisinopril	Kidney	Lewis rats	increased renal ACE2 activity	Ferrario et al. [57]
Various ACEIs (not specified)	intestine	Human patients	Increased intestinal ACE2 mRNA expression	Vuille-dit-Bille et al. [58]
C) Mineralocorticoid receptor Inhibitors (MCRIs)/ Aldosterone antagonists
Spironolactone	Monocyte-derived Macrophages	Human patients with Heart failure	Increase in ACE2 activity and ACE2 mRNA expression one-month post therapy	Keidar et al. [59]
Eplerenone	Heart	Balb/C mice	Increased cardiac ACE2 mRNA and protein activity but not in kidneys	Keidar et al. [59]
D) HMG-CoA reductase inhibitors/Statins
Atorvastatin	Heart/kidney	Atherosclerotic New Zealand White rabbits	Increase cardiac and renal ACE2 protein	Tikoo et al. [60]
Fluvastatin	Heart	Streptozotocin-induced diabetic Male Wistar rats	Synergistically increased cardiac ACE2 protein expression with insulin	Shin et al. [61]
E) PPAR-gamma agonists / Thiazolidinediones (TZDs) / Glitazones
Rosiglitazone	Aorta	Male Wistar rats made hypertensive by aortic coarctation	Increased aortic ACE2 protein	Sánchez-Aguilar et al. [62]
Pioglitazone	Liver, adipose tissue, skeletal muscle	Sprague-Dawley rats with high-fat diet-induced non-alcoholic steatohepatitis	Increased ACE2 protein expression in liver, adipose tissue, and skeletal muscle after 24 week treatment	Zhang et al. [63]
Rosuvastatin	Aorta	Wistar rats with vascular balloon injury	Increased ACE mRNA and protein levels	Li et al. [64]
F) Glucagon-like peptide 1 receptor agonists (GLP-1-agonists)/ Incretin mimetics
Liraglutide	Lung	Streptozotocin-induced diabetic male Sprague-Dawley rats	Increased ACE2 mRNA expression and protein activity in the lungs of both diabetic and control rats	Romaní-Pérez et al. [65]
Liraglutide	Lung	Pups from Food-restricted pregnant Sprague-Dawley rats	Increased ACE2 mRNA expression in the lungs of male pups	Fandiño et al. [66]
Liraglutide	Heart	Ang II infused Sprague-Dawley rats	Increased ACE2 activity	Zhang et al. [67]
G) DPP4 Inhibitors/ Gliptins
Linagliptin	Heart	Ang II infused Sprague-Dawley rats	Increased ACE2 activity (corrected Ang II-induced reduction in ACE2 activity)	Zhang et al. [67]
H) Thiazide and thiazide-like diuretics
Hydrochlorothiazide	Heart	Normotensive Wistar Kyoto rat	Increased cardiac ACE2 mRNA and activity	Jessup et al. [68]
I) Beta Blockers
Nebivolol	Heart	SHR	Increased cardiac ACE2 mRNA	Varagic et al. [69]
J) Calcium channel blockers
Nimodipine	Brain	Cerebral ischemia/reperfusion induced by bilateral carotid artery occlusion in Wistar Rats	Increased cerebral ACE2 mRNA	Abdel-Fetah et al. [70]
K) GABA analogues
Pregabalin	Heart	Cardiotoxicity Male Sprague-Dawley rats	Prevented reduction in ACE2 protein expression when co-treated with Telmisartan or Captopril	Awwad et al. [71]
L) Non-steroidal Anti-inflammatory agents (NSAIDS)
Ibuprofen	Heart	Streptozotocin-induced diabetic male Sprague-Dawley rats	Increased ACE2 protein levels in diabetic hearts (corrected diabetes-induced reduction in ACE2)	Qiao et al. [72]
M) Oestrogen Hormones
Oestrogen	Heart	Heart Surgery Human patients	Increased ACE2 mRNA in atrial myocardium	Bukowska et al. [73]
N) Arterial Vasodilators
Hydralazine	Heart	Cardiac hypertrophy in Ren-Tg mice (over expressing renin in the liver)	Increased cardiac ACE2 mRNA (shown in data but not mentioned in text by authors)	Tanno et al. [74]
O) Vitamin D analogues
Calcitriol	Kidney	Streptozotocin-induced diabetic Wistar rats	Increased renal ACE2 protein levels and activity	Lin et al. [75]

Table 2. Examples of clinical studies showing that COVID-19 patients taking ACEIs/ARBs are not associated with increased risk of either a) infection, b) severity of COVID-19 disease, c) risk of admission to hospital or d) mortality.

Study Aim	Setting and Study design	Number of cases on ACEIs /ARBs	Number of controls		Total Number of patients in study	% Patients on ACEI/ARBs	Study period	Age	Female%	Main findings	Author
			COVID-19 Positive NOT on ACEI /ARBs	COVID-19 Negative on ACEI /ARBs
A) Risk of infection	Population-based case-control. Italy (Lombardy region)	2896	0	6,569 ACEI 5,910 ARBs 12,479	15375	18.84	Feb 21 to Mar 11 2020	68 (±13)	37%	No significant increase in likelihood of having COVID-19 infections if on ACEIs/ ARBs.	Mancia et al. [108]
	Population-based cohort. USA (New York	1019	986	NA	2005	52.52	Mar 1 to Apr 15 2020	64 (54–75)	50%	No significant increase in likelihood of having COVID-19 infections if on ACEIs/ARBs. Similar results were reported for beta-blockers, Ca2+ Channel Blockers and Thiazide diuretics	Reynolds et al. [109]
	Single-center retrospective cohort. China (Wuhan)	43	83	NA	126	34.13	Jan 5 to Feb 22 2020	66 (57−75)	51%	No increase in risk of COVID-19 infection if on ACEIs/ARBs.	Yang et al. [110]
B) Severity of disease	Multi-center retrospective case-control. China (Wuhan, Shanghai, Anhui)	33	80	NA	113	29.20	Jan 1 to Feb 15 2020	53 (40−64)	43%	Patients on ACEIs/ARBs are less likely to have severe disease. The proportion of patients taking ACEIs/ARBs therapy was higher in the moderate disease group when compared to those patients severely affected or in critical conditions.	Feng et al. [111]
	Retrospective, single-center case series. China (Wuhan)	115	247	NA	362	31.76	Jan 15 to Mar 15 2020	66 (59−73)	48%	ACEIs/ARBs therapy was not associated with increased severity of COVID-19.	Li et al. [112]
	Single-center retrospective cohort. China (Shenzheng)	17	25	NA	42	40.48	Jan 11 to Feb 23 2020	64 (56−69)	43%	No increase in risk of severe COVID-19 disease with ACEIs/ARBs therapy. ACEIs/ARBs increased CD3 and CD8 T cell counts and prevented neutrophil depletion.	Meng et al. [113]
	Population-based cohort. USA (New York)	1091	986	NA	2077	52.52	Mar 1 to Apr 15 2020	64 (54–75)	50%	ACEIs/ARBs therapy was not associated with increased severity of COVID-19.	Reynolds et al. [109]
	Retrospective case-control. China (Wuhan)	42	503	NA	545	7.71	Jan 26 to Feb 5 2020	60 (48−69)	49.10%	ACEIs/ARBs therapy was not associated with increased severity of COVID-19.	Li et al. [112]
C) Hospitalisations	Single-centre retrospective cohort. China (Wuhan)	43	83	NA	126	34.13	Jan 5 to Feb 22 2020	66 (57−75)	51%	No significant increase in likelihood of being admitted to hospital if on ACEIs/ARBs therapy.	Yang et al. [110]
	Case population study. Spain (Madrid)	484	0	2192 ACEI 1616 ARBs 3808	4292	11.28	Mar 1 to Mar 24 2020	69.1 (±15.4)	39%	No significant increase in likelihood of being admitted to hospital if on ACEIs/ARBs therapy.	de Abajo et al. [114]
D) Mortality	Retrospective, single-centre case series. China (Wuhan)	42	503	NA	545	7.71	Jan 15 to Mar 15 2020	60 (48−69)	49.10%	ACEIs/ARBs therapy was not associated with increase mortality in COVID-19 infected patients.	Li et al. [112]
	Prospective cohort. Italy (Bologna)	165	136	NA	301	54.82	Feb 1 to Apr 4 2020	76 (67−83)	28%	ACEIs/ARBs therapy was not associated with Charlson Comorbidity Index in COVID-19 infected patients.	Tedeschi et al. [115]
	Retrospective, multi-centre cohort study. China (Wuhan)	188	940	NA	1128	16.67	Dec 31 2019 to Feb 20 2020	64 (55−69)	47%	ACEIs/ARBs therapy was associated with reduced risk of all-cause of mortality in COVID-19 infected patients.	Zhang et al. [116]
	Retrospective observational study. (Wuhan	174	527	N/A	2877	33.01	Feb 5 to Mar 15, 2020	64.27 (11.17)	47.9%	No increased of mortality with ACEIs or ARBS in own study. Meta-analysis of 4 studies reported reduced risk of mortality in hypertensive patients on ACEIs/ARBs	Guo et al. [101]

ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blockers.

Figure 2. Re-analysis of data from the meta-analysis of Zhang X et al [119] on the association between ACEIs/ARBs use, irrespective of clinical indication, and all-cause mortality in COVID-19 patients using a robust model. Forest plots of the meta-analysis with (A) and without (B) Mehra et al [121] data sets. Doi plots with Luis Furuya-Kanamori (LFK) index values are also shown for re-analysed data with (C) and without (D) Mehra et al [121] data sets. Note that LFK index of greater than 2 suggests major asymmetry.

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