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First Line Hypertensive Medication and Pulmonary Events in COVID-19 Patients with Diabetes

Mar 16, 2021
Editor: Steve Freed, R.PH., CDE

Author: Zahra Hashemy, PharmD. Candidate, USF Taneja College of Pharmacy 

Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin II receptor blockers (ARBs) can allow coronavirus (COVID-19) entry, leading to pulmonary adverse effects.  

The coronavirus (COVID-19) disease has affected millions of people around the world. In 2019, a study observed 191 patients with COVID-19; nearly half of them had comorbidities. Current reports from China state that 10%-19% of individuals who have COVID-19 and are hospitalized have diabetes. There is a lack of data on the pathophysiological effects of diabetes on the respiratory system. The renin-angiotensin system (RAS) is a primary pathophysiological system that plays a role in disease states like hypertension and diabetic nephropathy. Data has shown that angiotensin-converting enzyme 2 (ACE2), a membrane-bound receptor in the RAS, allows entry of the virus known as severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2).  


ACEIs and ARBs are two different hypertensive classes of medication that affect the RAS and are recommended to manage nephropathy for patients with diabetes. ACEIs are separated into three groups: the dicarboxyl-, phosphorous- and sulfhydryl- class. Both ACEIs and ARBs have similar adverse effect profiles, but minor differences are present. There is conflicting data on these hypertensive medications’ effects on mortality and morbidity of patients with COVID-19. An animal model showed that when ACE concentrations increased, it led to asthma, pulmonary fibrosis, and ARDS, but was also protective for the lungs by causing vasodilation by converting angiotensin II to angiotensin (1-7). A new hypothesis states that “ACEIs and ARBs may be detrimental in early SARS-CoV2 infection but paradoxically protective in later stages.” The authors of the study from Stafford et al. in JAPhA, published in May 2020, set out to find the role of ACEIs and ARBS on pulmonary adverse effects and their effects on morbidity and mortality in COVID-19 patients with diabetes.  

The 1DATA database, which includes health care information on both humans and animals, was utilized to analyze ACEIs’ and ARBs’ adverse effects incidents among patients with diabetes. The Food and Drug Administration (FDA) Adverse Event Reporting System (FARES) was also used to collect the medication’s adverse effects and other information like demographics and disease and drug information. Medical Dictionary for Regulatory Activates (MedDRA), where adverse reaction terminologies are reported globally, was also used. Proportional reporting ratio (PRR) compared all the data against diabetes datasets and determined how often the particular drug had an adverse effect. Data mining algorithms found postmarketing adverse events that were more frequently reported than projected. Adverse effects due to ACEI and ARB classes given to patients with diabetes were obtained. Adverse events such as aspiration, bronchitis, cough, dysphonia, dyspnea, emphysema, oropharyngeal pain, pneumonia aspiration, pleurisy, and pulmonary edema were recorded for frequency and medications responsible.  Most adverse effects were not affected by age, sex, and weight except for pleural effusion, oropharyngeal pain, sinusitis, nasopharyngitis, pneumonia aspiration, which were affected by sex, emphysema, and pneumonia which was affected by age. Multiple comparison tests (4 pairwise tests) were performed by using the Friedman test. The comparisons were captopril versus ACE-1, captopril versus ARBs, ACEI-1 versus ARBs, and captopril versus all ACE-1 drugs versus ARB drugs. All statistical analysis was performed by the Statistical Analysis Software University Edition v9.4.  

Thirteen pulmonary adverse effects’ frequency was compared across the ACEIs and ARBs. Captopril had a significantly higher pulmonary adverse event profile in patients with diabetes than ARBs (P=0.012) and other ACEIs (P=0.005). Captopril contains a sulfhydryl group, which may contribute to the higher adverse events seen. This study provides a strong rationale for why all drugs in a class should not be judged. Because this study was a retrospective analysis, data collected from different databases may differ in what they included and excluded. The study explains that future evaluation of the structure-activity and binding affinity relationship of captopril can explain why captopril had a higher incidence of pulmonary adverse events in patients with diabetes than other ACEIs ARBs.  

Practice Pearls 

  • Pharmacokinetics and pharmacodynamics of medication belonging to one class are not identical. 
  • Acute pulmonary diseases like COVID-19 can be affected by adverse events of medications. Physicians and pharmacists alike play a crucial role in the possible prevention or progression of these diseases. 
  • Captopril is linked to a higher incidence of pulmonary adverse events in patients with diabetes than other ACEIs and ARBs, although all can impact pulmonary adverse events. 


Stafford, Emma G. et al. “Pharmacovigilance In Patients With Diabetes: A Data-Driven Analysis Identifying Specific RAS Antagonists With Adverse Pulmonary Safety Profiles That Have Implications For COVID-19 Morbidity And Mortality.”  Journal Of The American Pharmacists Association, 2020. Elsevier BV, doi:10.1016/j.japh.2020.05.018. Accessed July 11, 2020. 


Zahra Hashemy, PharmD. Candidate, USF Taneja College of Pharmacy 



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