The effect of angiotensin converting enzyme inhibitors and angiotensin receptor blockers on death and severity of disease in patients with coronavirus disease 2019 (COVID-19): A meta-analysis

Ghosal, Samit; Mukherjee, J. J.; Sinha, Binayak; Gangopadhyay, Kalyan Kumar

doi:10.1101/2020.04.23.20076661

Cited by 32 publications

(49 citation statements)

References 24 publications

(28 reference statements)

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“…Based on nonhuman animal models, RAAS inhibitors were predicted to increase ACE2 levels thereby elevating COVID-19 morbidity and mortality. 31,54,55 However, our findings in this DKD cohort counter such predictions by providing evidence for an absence of RAAS inhibition-associated ACE2 expression induction in PTECs. Meanwhile, a series of case-control, database, and electronic health record studies also did not find any association of RAAS inhibitors with poor outcomes in 3 independent cohorts of patients with COVID-19 and RAAS exposures.…”

Section: Q11supporting

confidence: 48%

SARS-CoV-2 receptor networks in diabetic and COVID-19–associated kidney disease

Menon

Otto

Sealfon

et al. 2020

Kidney International

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COVID-19 morbidity and mortality are increased via unknown mechanisms in patients with diabetes and kidney disease. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for entry into host cells. Because ACE2 is a susceptibility factor for infection, we investigated how diabetic kidney disease and medications alter ACE2 receptor expression in kidneys. Single cell RNA profiling of kidney biopsies from healthy living donors and patients with diabetic kidney disease revealed ACE2 expression primarily in proximal tubular epithelial cells. This cellspecific localization was confirmed by in situ hybridization. ACE2 expression levels were unaltered by exposures to renin-angiotensin-aldosterone system inhibitors in diabetic kidney disease. Bayesian integrative analysis of a large compendium of public-omics datasets identified molecular network modules induced in ACE2-expressing proximal tubular epithelial cells in diabetic kidney disease (searchable at hb.flatironinstitute.org/covid-kidney) that were linked to viral entry, immune activation, endomembrane reorganization, and RNA processing. The diabetic kidney disease ACE2-positive proximal tubular epithelial cell module overlapped with expression patterns seen in SARS-CoV-2-infected cells. Similar cellular programs were seen in ACE2-positive proximal tubular epithelial cells obtained from urine samples of 13 hospitalized patients with COVID-19, suggesting a consistent ACE2-coregulated proximal tubular epithelial cell expression program that may interact with the SARS-CoV-2 infection processes. Thus SARS-CoV-2 receptor networks can seed further research into risk stratification and therapeutic strategies for COVID-19-related kidney damage.

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Section: Q11supporting

confidence: 48%

SARS-CoV-2 receptor networks in diabetic and COVID-19–associated kidney disease

Menon

Otto

Sealfon

et al. 2020

Kidney International

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“…Interestingly, ACE inhibitors and ARBs were associated with reduced odds for inpatient mortality and a critical or fatal outcome (OR = 0.33, 95% CI 0.22-0.49, I 2 = 0%, and OR = 0.32, 95% CI 0.22-0.46, I 2 = 32%, respectively) [50]. Similarly, Ghosal et al found a significant decrease in the odds for death with the use of ACE inhibitors/ARBs (OR = 0.57, 95% CI 0.37-0.88, I 2 = 0%), while non-significant benefits were also observed in terms of developing severe disease or hospitalization (OR = 0.62, 95% CI 0.31-1.23, I 2 = 70.36%, and OR = 0.81, 95% CI 0.42-1.55, I 2 = 0%, respectively) [51]. Nevertheless, the former meta-analysis included five and the latter six studies, most of which were located in China.…”

Section: Discussionmentioning

confidence: 98%

Renin-Angiotensin System Inhibitors and COVID-19: a Systematic Review and Meta-Analysis. Evidence for Significant Geographical Disparities

et al. 2020

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Purpose of Review While the COVID-19 pandemic is constantly evolving, it remains unclear whether the use of angiotensinconverting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) affects the clinical course of SARS-CoV-2 infection. For this meta-analysis, PubMed, CENTRAL, and grey literature were searched from their inception to 19 May 2020 for randomized, controlled trials or observational studies that evaluate the association between the use of either ACE inhibitors or ARBs and the risk for major clinical endpoints (infection, hospitalization, admission to ICU, death) in adult patients during the COVID-19 pandemic. In addition, a subgroup geographical analysis of outcomes was performed. Studies including less than 100 subjects were excluded from our analysis. Recent Findings In total, 25 observational studies were included. ACE inhibitors and ARBs were not associated with increased odds for SARS-CoV-2 infection, admission to hospital, severe or critical illness, admission to ICU, and SARS-CoV-2-related death. In Asian countries, the use of ACE inhibitors/ARBs decreased the odds for severe or critical illness and death (OR = 0.37, 95% CI 0.16-0.89, I 2 = 83%, and OR = 0.62, 95% CI 0.39-0.99, I 2 = 0%, respectively), whereas they increased the odds for ICU admission in North America and death in Europe (OR = 1.75, 95% CI 1.37-2.23, I 2 = 0%, and OR = 1.68, 95% CI 1.05-2.70, I 2 = 82%, respectively). ACE inhibitors might be marginally protective regarding SARS-CoV-2-related death compared with ARBs (OR = 0.86, 95% CI 0.74-1.00, I 2 = 0%). Summary Randomized controlled trials are needed to confirm the aforementioned associations between ACE inhibitors, ARBs, and SARS-CoV-2.

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“…Recent publications further highlight the use of ACE-I and ARBs in providing cardiovascular and renal benefits to patients with COVID-19 diagnosis [59,60]. In a metaanalysis, patients treated with ACE-I/ARBS had 44% reduction in odds of developing severe disease and death compared with patients not treated with ACE-I/ARBs [61]. These studies provide rationale for investigation into the utility of ACE-I/ARBs in the ethnic population with known prevalence of ACE deletion polymorphisms in an effort to mitigate severity and improve outcomes in response to COVID-19 infections.…”

Section: Ace-2 Inhibition By Covid-19: Increased Ras Activitymentioning

confidence: 99%

Ethnic Prevalence of Angiotensin-Converting Enzyme Deletion (D) Polymorphism and COVID-19 Risk: Rationale for Use of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers

Sarangarajan¹,

Winn

Kiebish³

et al. 2020

J. Racial and Ethnic Health Disparities

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Rationale Hypertension, obesity and diabetes are major risk factors associated with morbidities underlying COVID-19 infections. Regression analysis correlated presence of ACE insertion/deletion (I/D) polymorphism to COVID-19 incidence and mortality. Furthermore, COVID-19 prevalence correlated to allele frequency of angiotensin-converting enzyme (ACE) deletion (D) polymorphism within the European population. Objective Homozygous ACE deletion polymorphism is associated with increase in ACE and angiotensin II (Ang-II), sustained levels can result in inflammation, fibrosis and organ damage. The ACE DD polymorphism is also associated with hypertension, acute respiratory distress and diabetic nephropathy, all considered high risk for COVID-19 infection and outcomes. The study objective was to describe a biological framework associating ethnic prevalence of ACE deletion polymorphism to COVID-19 comorbidities providing rationale for therapeutic utility of ACE-I/ARBs to improve outcomes. Method and Results The Allele Frequency Database (ALFRED) was queried for frequency of rs4646994 representing ACE I/D polymorphism. In a total of 349 worldwide population samples, frequency of ACE D allele was higher in European, Asian, and Africans cohorts. In the USA, the frequency of ACE D allele was higher in non-Hispanic Black compared with non-Hispanic White and Mexican Americans. Conclusion COVID-19 binding mediated reduction/inactivation of ACE-II can increase ACE/Ang-II signalling pathway and related pathologies. The presence of ACE DD polymorphism with COVID-19 infection likely augments ACE/Ang-II activities, increasing severity of COVID-19 morbidities and impacts outcomes. Thus, ethnic prevalence of ACE DD polymorphism can explain in part the severity of COVID-19 morbidity providing rationale for the use of ACE-I/ARBs to improve outcomes.

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The effect of angiotensin converting enzyme inhibitors and angiotensin receptor blockers on death and severity of disease in patients with coronavirus disease 2019 (COVID-19): A meta-analysis

Cited by 32 publications

References 24 publications

SARS-CoV-2 receptor networks in diabetic and COVID-19–associated kidney disease

SARS-CoV-2 receptor networks in diabetic and COVID-19–associated kidney disease

Renin-Angiotensin System Inhibitors and COVID-19: a Systematic Review and Meta-Analysis. Evidence for Significant Geographical Disparities

Ethnic Prevalence of Angiotensin-Converting Enzyme Deletion (D) Polymorphism and COVID-19 Risk: Rationale for Use of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers

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