key: cord-0842362-0j5828ah
authors: Stafford, Emma G.; Riviere, Jim; Xu, Xuan; Kawakami, Jessica; Wyckoff, Gerald J.; Jaberi-Douraki, Majid
title: 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
date: 2020-06-01
journal: J Am Pharm Assoc (2003)
DOI: 10.1016/j.japh.2020.05.018
sha: 2cfbd9106c09a8ff151de338a0ec23a6677c14ad
doc_id: 842362
cord_uid: 0j5828ah

ABSTRACT OBJECTIVES Current demographic information from China reports that 10-19% of patients hospitalized with COVID-19 were diabetic. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin-II receptor blockers (ARBs) are considered first-line agents in diabetics due to their nephroprotective effects but administration of these drugs leads to upregulation of angiotensin-converting-enzyme-2 (ACE2), responsible for viral entry of severe-acute-respiratory-distress-syndrome, coronavirus-2 (SARS-CoV-2). Data is lacking to determine what pulmonary effects ACEIs/ARBs may have in patients with diabetes, which could be relevant in the management of patients infected with SARS-CoV-2. In this study, the aim was to assess the prevalence of pulmonary adverse drug effects (ADEs) in diabetic patients taking ACEI or ARBs to help provide guidance as to how these medications could affect outcomes in acute respiratory illness, such as SARS-CoV-2 infection. METHODS 1DATA, a unique data platform resulting from collaboration across veterinary and human healthcare, utilized an intelligent medicine recommender system (1DrugAssist) developed using several national and international databases, to evaluate all ADEs reported to the FDA for patients with diabetes taking ACEIs or ARBs. RESULTS Mining of this data elucidated the proportion of a cluster of pulmonary ADEs associated with specific medications in these classes, which may aid healthcare professionals in understanding how these medications could worsen or predispose patients with diabetes to infections affecting the respiratory system specifically, COVID-19. Based on this data mining, Captopril was found to have a statistically significantly higher incidence of pulmonary ADEs compared to other ACEIs (P = 0.005) as well as ARBs (P = 0.012), though other specific drugs also had important pulmonary ADEs associated with their use. CONCLUSION These analyses suggest that pharmacists and clinicians will need to consider specific medication’s adverse event profile, particularly captopril, and how this profile may affect infections and other acute disease states that alter pulmonary function, such as COVID-19.

blockers (ARBs) are considered first-line agents in diabetics due to their nephroprotective effects but 20 administration of these drugs leads to upregulation of angiotensin-converting-enzyme-2 (ACE2), 21

responsible for viral entry of severe-acute-respiratory-distress-syndrome, coronavirus-2 (SARS-CoV-2). 22

Data is lacking to determine what pulmonary effects ACEIs/ARBs may have in patients with diabetes, 23 which could be relevant in the management of patients infected with SARS-CoV-2. In this study, the aim 24 was to assess the prevalence of pulmonary adverse drug effects (ADEs) in diabetic patients taking ACEI 25 or ARBs to help provide guidance as to how these medications could affect outcomes in acute respiratory 26 illness, such as SARS-CoV-2 infection. 27

1DATA, a unique data platform resulting from collaboration across veterinary and human healthcare, 29 utilized an intelligent medicine recommender system (1DrugAssist) developed using several national and 30 international databases, to evaluate all ADEs reported to the FDA for patients with diabetes taking ACEIs 31 or ARBs. 32 significantly higher incidence of pulmonary ADEs compared to other ACEIs (P = 0.005) as well as ARBs 38 (P = 0.012), though other specific drugs also had important pulmonary ADEs associated with their use. 39

These analyses suggest that pharmacists and clinicians will need to consider specific medication's adverse 41 event profile, particularly captopril, and how this profile may affect infections and other acute disease 42 states that alter pulmonary function, such as COVID-19. 43

In late 2019 an outbreak of pneumonia, later found to be caused by severe acute respiratory syndrome, coronavirus 2 (SARS-CoV-2), occurred in Wuhan, China. COVID-19 patient symptomatology includes 48 fever, dyspnea, myalgia, and pneumonia but can also progress to acute respiratory distress syndrome 49 (ARDS), acute cardiac injury, as well as acute kidney injury and death 1 . A study evaluating 191 patients 50 with COVID-19 found that 48% of patients had comorbid conditions including 19% with diabetes 2 . 51

There was a statistically significant difference (P value = 0.0010) in mortality between patients with 52 comorbid conditions, including diabetes, compared to those without 2 . It is known that long term 53 hyperglycemia has deleterious effects on many organ systems-most notably the eyes, kidneys, nerves, 54 and heart. However, less research has described the pathophysiologic effects diabetes may have on the 55 respiratory system. In light of the recent COVID-19 outbreak, more research is needed to understand the 56 effects diabetes, including medications prescribed to patients with diabetes, may have on the respiratory 57 system and how that could impact the management of diseases such as COVID-19. 58

The renin-angiotensin system (RAS) is implicated in the pathophysiology of numerous disease states 59 including diabetic nephropathy and hypertension. Drugs affecting this system have been explored to 60 manage nephropathy occurring in patients with diabetes and angiotensin-converting enzyme inhibitors 61 (ACEIs) and angiotensin-II receptor blockers (ARBs) are currently recommended for use in patients with 62 diabetes 3,4 . Currently available ACEIs differ based on potency, pharmacokinetics (especially tissue 63 distribution), and whether the molecule is a prodrug. ACEIs are also delineated into three structural 64 classes based on the functional group responsible for binding to ACE 5,6 . Although ACEIs and ARBs are 65 generally considered to have similar adverse event profiles, evaluation of post-marketing adverse drug 66 events (ADEs) may shed light on minute differences that could have important clinical impacts. membrane-bound receptor involved in RAS, has been found to be the host-cell receptor responsible for 69 viral entry. This was also true for SARS-CoV, which lead to an outbreak in 2002. Administration of 70

ACEIs and ARBs, as well as thiazolidinediones and ibuprofen, leads to upregulated expression of ACE2 7 . 71

The upregulation of ACE2 receptors theoretically puts patients at higher risk of infection with SARS-72

CoV-2 because more target host receptors would be available for cellular virus entry. Conversely, ACE2 73 presence was found to be protective in lung tissue of animal models due to the conversion of angiotensin 74 II to angiotensin (1-7), which has vasodilatory properties. Animal models have shown an increase in ACE 75 concentration can result in pulmonary fibrosis, asthma, and ARDS. The effects of ACE inhibiting 76 medications, which will lower the activity of ACE and therefore the concentration of angiotensin II, 77 would theoretically be protective against patients developing ARDS 7 . This has led to the hypothesis that 78

ACEIs/ARBs may be detrimental in early SARS-CoV-2 infection but paradoxically protective in later 79 stages. RAS is exceedingly complex and conflicting data is available regarding the contribution of ACEIs 80

and ARBs on the mortality and morbidity of COVID-19 patients 8 . 81

In this study, we aimed to assess if individual ACEIs/ARBs had particularly serious pulmonary adverse 83 event profiles, which could either place diabetics at increased risk of SARS-CoV-2 infection due to 84 diminished lung function or may affect with the management of such patients. 85

The 1DATA partnership between the University of Missouri-Kansas City and Kansas State University 88 has led to the development of a platform to share human and animal healthcare data 9 . In this partnership, public databases were integrated in the 1DATA database (www.1DATA.life), and in this study, were used 90 to assess the incidence of ADEs related to ACEIs and ARBs in patients with diabetes. 91

The data used in this study were curated from multiple publicly available data sources for patients with 92 includes other pertinent data such as disease information, drug information, adverse drug event data, 97 demographic information, as well as outcome data. 98

Internationally, ADEs terminologies are reported by a similar process to the MedDRA. In this database, 99

ADEs terminologies are hierarchically structured to regulate information for medical products on a global 100 level. The data structure of these terms is organized in accordance with MedDRA terminology as well as the use of quantitative signal detection methods such as PRR. For this purpose, we were able to correct 129 the analysis after applying logistic regression for the known covariates of age, weight, and gender, and 130 combine this approach with PRR to improve analyses of drug effects using the diabetes data sets. We 131 found that these factors do not play a significant role in the analysis of the data. Significantly, we found 132 that the most important ADEs (pulmonary edema, dyspnea, dysphonia, cough, bronchitis, and pleurisy), Therefore, we proceeded with some specific, pairwise analysis of Captopril to see if any other distinctions 163 were found. Thirteen different pulmonary ADEs were selected to assess the related variation due to 164 adverse event differences. Percent incidence of reported pulmonary ADEs for each drug can be found in 165 Table 1 ). Friedman tests also shows that 170

Captopril had statistically significant increases in pulmonary ADEs in patients with diabetes as compared 171 to other ACEIs (P = 0.005) as well as compared to ARBs (P = 0.012). For a multiple comparison among 172 all the groups using this test, Captopril vs all ACEi-1 drugs vs ARB drugs, a P value of 0.004 was seen 173 indicating significant differences in pulmonary ADEs occurrences for the two drug groups compared to 174 the lower confidence interval itself being over 1. After applying these criteria, Captopril had reportable 180 incidences for a majority of reported pulmonary ADEs in patients with diabetes. Other drugs, including 181

ARBs, met criteria for some pulmonary ADEs (Supplementary Table 1 ) but did not show the same 182 trends across multiple ADEs as depicted with Captopril. 183

Evaluation of the collated databases revealed that Captopril, the first ACEi approved back in 1981, has a 185 higher incidence of pulmonary ADEs in patients with diabetes as compared to other ACEi drugs (P = 186 0.005) as well as a statistically significant difference in pulmonary events compared to ARBs (P = 0.012) 187 (Table 1) . 188

Captopril's high incidence of pulmonary ADEs highlights the fact that all drugs in a class are not identical Figure 1 . Relative percentages of reported pulmonary adverse events of ACEis and ARBs from FAERS and MedDRA databases organized by drug.

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