key: cord-0945505-1l7ispkc
authors: Barrera, Francisco J; Shekhar, Skand; Wurth, Rachel; Moreno-Pena, Pablo J; Ponce, Oscar J; Hajdenberg, Michelle; Alvarez-Villalobos, Neri A; Hall, Janet E; Schiffrin, Ernesto L; Eisenhofer, Graeme; Porter, Forbes; Brito, Juan P; Bornstein, Stefan R; Stratakis, Constantine A; González-González, José Gerardo; Rodíguez-Gutiérrez, René; Hannah-Shmouni, Fady
title: Prevalence of Diabetes and Hypertension and their Associated Risks for Poor Outcomes in Covid-19 Patients
date: 2020-07-21
journal: J Endocr Soc
DOI: 10.1210/jendso/bvaa102
sha: dcbef387e1541c4db6cf06a09813e2c1a3a75f80
doc_id: 945505
cord_uid: 1l7ispkc

Covid-19 has impacted millions of people and may disproportionately affect those with hypertension and diabetes. Due to inadequate methods in published systematic reviews, the prevalence of diabetes and hypertension and associated risks of poor outcomes in Covid-19 patients are unknown. We searched, databases from December 1, 2019 to April 6, 2020 and selected observational peer-reviewed studies in English language of patients with Covid-19. Independent reviewers extracted data on study participants, interventions, and outcomes and assessed risk of bias, and the certainty of evidence using the. We included 65 (15,794 participants) observational studies at moderate-to-high risk of bias. Overall prevalence of diabetes and hypertension was 12% (95% CI 10-15%, n=12870, I(2): 89%), and 17% (95% CI 13-22%, n=12709, I(2): 95%), respectively. In severe Covid-19, the prevalence of diabetes and hypertension were 18% (95% CI 16-20%, n=1099, I(2): 0%) and 32% (95% CI 16-54%, n=1078, I(2): 63%), respectively. Unadjusted relative risk for ICU admission and mortality were 1.96 (95% CI 1.19-3.22, n=8,890, I(2): 80%, p=.008) and 2.78 (95% CI 1.39-5.58, n=2058, I(2): 75%, p=.0004) for diabetics; and 2.95 (95% CI 2.18-3.99, n=1737, I(2): 0%, p<.001) and 2.39 (95% CI 1.54-3.73, n=3107, I(2): 66%, p<.001) for hypertensives. Neither diabetes (1.50, 95% CI 0.90-2.50, n=1991, I(2): 74%, p=.119) nor hypertension (1.48, 95% CI 0.99-2.23, n=2023, I(2): 69%, p=.058) was associated with severe Covid-19. In conclusion, the risk of ICU admission and mortality for patients with diabetes or hypertension who developed Covid-19 is increased compared to those without these comorbidities.

Coronavirus disease 2019 is the worst pandemic in the last 100 years spanning more than 200 countries 1 and affecting millions of individuals worldwide. 2 The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) was identified as the causative agent of Covid- 19 , with angiotensin converting enzyme 2 (ACE2) as one of its cellular receptor. 3 Covid-19 has a spectrum of clinical manifestations ranging from asymptomatic or mildly symptomatic in about 80% of those affected according to community surveys to an approximate 2% case fatality rate in the hospitalized populations. [4] [5] [6] [7] Although the statistical estimations are changing daily, more than 11 million people have been affected by Covid-19 resulting in more than half a million deaths across the world by July 7, 2020. 1, 6 A great risk of severe Covid-19 has been reported in patients with diabetes and hypertension. 8 One study of 191 patients reported a mortality risk of 2.85-fold and 3.05-fold for those with diabetes and hypertension, respectively. 9 Furthermore, the Chinese Center for Disease Control reported a higher case fatality rate for persons with diabetes compared to those without (7.3%. vs. 2.3%, respectively). 7 This risk may be explained by a dysregulated immune response, a higher comorbidity burden, and alterations of ACE2 cellular expression. 6, [10] [11] [12] The latter has been the subject of intense scrutiny, given the lack of evidence against the use of renin-angiotensin system blocking agents and their known benefits in diabetes and hypertension, [12] [13] [14] as well as other cardiovascular conditions that have been shown to enhance ACE2 expression. 15 Previous systematic reviews reported a prevalence of diabetes and hypertension in patients with Covid-19 ranging from 9.7-11.9% and 17.1-20%, respectively. [16] [17] [18] [19] The risks of severe Covid-A c c e p t e d M a n u s c r i p t 7 19 in patients with diabetes and hypertension were ~3 and ~2-fold, respectively. [16] [17] [18] 20 However, these reports failed to address the high probability of including repeated information and patient duplicates in the analysis and thus may lead to inaccurate effect sizes and misleading results. 16, [18] [19] [20] [21] This has been listed by authors as a major limitation, 20 and has raised major editorial concerns. [22] [23] [24] Ultimately, risk estimates remain uncertain. Therefore, we systematically assessed the prevalence of diabetes and hypertension in patients with Covid-19 after excluding repeated patients across studies and analyzed the associated risks for Covid-19 severity, intensive care unit (ICU) admission and mortality.

This systematic review adheres to the standards set in the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reported Items for Systematic Reviews and Meta-Analysis (PRISMA). 25, 26 Registration ID: CRD42020176582, available at:

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=176582.

For our first aim, we included observational and interventional studies that reported the frequency of diabetes and/or hypertension in adult population with Covid- 19 

Search results were uploaded into an online software program (DistillerSR; Evidence Partners, Ottawa, ON, Canada). Reviewers, working independently and in duplicate, screened studies for eligibility using standardized and pre-piloted instructions in a round of title-and-abstract and one of full-text screening. In round one, disagreements were included; and in round two, disagreements were resolved by consensus or arbitration by a third investigator (FHS). To identify articles with high probability of patient repetition, studies that were included after full-text screening followed a preliminary data extraction conducted by two pairs of investigators. We extracted the timeframes of each study, hospital(s), location(s), country of origin, and the list of authors. Next, the enrollment timeframes from the studies were plotted with the information of the hospital(s). Studies without overlap in the plot were included for all outcomes. If studies overlapped, we analyzed outcomes reported by each study. If outcomes were repeated in overlapping studies, we included the data for outcomes (or frequency of comorbidities) from the M a n u s c r i p t 9 study with the largest sample. 27 Data extraction was also performed in an independent and duplicated manner using a standardized and pre-piloted.

For case series, we modified two tools and analyzed: selection, ascertainment of outcomes and exposures, causality, and reporting. 28, 29 For case control studies, the Newcastle-Ottawa Scale was used. 30 The quality of evidence for each outcome was determined using the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation). 31 Both risk of bias and overall quality of evidence assessment were performed independently and in duplicate.

Disagreements were resolved by consensus between the two reviewers, or by arbitration by a third author (RRG). 27 Full details are listed elsewhere. 27

We estimated the full-text screening inter-rater reliability with the Cohen's kappa statistic.

To estimate the prevalence we used a binomial-normal model for meta-analysis of proportions (i.e. generalized linear mixed model -GLMM). 32, 33 We calculated the relative risk (RR) for each outcome and performed a meta-analysis results using a random-effect models and the restricted maximum-likelihood estimator. 34 Meta-analysis of unadjusted and adjusted estimates were not combined. We were unable to calculate adjusted estimates due to scarcity of data. Inconsistency for each outcome, not attributable to chance, was assessed visually using forest plots and estimated using the percentage of variance in a meta-analysis that is attributable to study heterogeneity (I 2 ) statistic: I 2 <25% and >75% reflects low and high inconsistency, respectively. 35 All statistical analyses were performed in R (R Foundation for Statistical Computing, Vienna, Austria). 36

A c c e p t e d M a n u s c r i p t 10

Details on all predefined and non-predefined subgroup and sensitivity analyses are listed separately. 27 To identify confounders, we designed a directed acyclic graph (DAG) in R. 27 ,37-41

Search strategy yielded 5,484 studies. After deduplication and screening, 122 studies fulfilled our selection criteria (Figure 1 ). Full-text screening inter-observer agreements were substantial (k=0.77, 0.80, and 0.84, for each pair of reviewers). We identified 93 articles at high probability of repeating patients. From those, we fully excluded 57 (47%), and partially (some outcomes included) excluded some outcomes in 36 (30%). 27 Ultimately, 65 (15,794 patients) were included in our analysis. Overall, 18 (28%) studies had low risk of bias, 3 (4%) had some concerns, and 44 (68%) had high risk. For prevalence, 40 (62%) studies resulted at low risk of bias, 1 (1%) at some concerns, and 24 (37%) at high risk. Overall confidence in the body of evidence is graded as low. 27 We did not assess risk of publication bias through the funnel plot due to the limited number of studies. 22

Most studies were retrospective case series (97%) performed at a single center (63%) in reported in most studies (75%; 9-65 days). Percentage of males varied between 0 and 88, and the mean age ranged from 33-75 years. A total of five studies (8%) reported ethnicity.

Only 69% of studies reported their definition of severity. Among those that did report severity definitions, 78% of their definitions were derived from established guidelines. 27 Moreover, only 6 of the studies (9%) described the subtype of diabetes (type 2 diabetes), and 1 study (2%) defined the subtype of hypertension (primary hypertension). Finally, none of the included studies provided a definition for diabetes or hypertension.

The overall prevalence was 12% (95% CI 10-15%; n=12870; I 2 : 89%) for diabetes, 17%

(95% CI 13-22%; n=12709; I 2 : 95%) for hypertension, and 12% (95% CI 6-22%; n=54; I 2 : 0%)

for coexisting diabetes and hypertension (Figure 2 Figure 3 .

After excluding studies at high risk of bias, the overall prevalence of diabetes ( 

According to our DAG, conditioning age and obesity is necessary to analyze the effect of diabetes on mortality; while for hypertension, age, diabetes, and obesity. 27

Our results suggest an overall prevalence of 12% and 17% for diabetes and hypertension (respectively) among non-pregnant, adult patients with Covid-19, respectively. Additionally, these comorbidities were associated with an increased risk for ICU admission and mortality. We found an overwhelming proportion of studies at high risk of data repetition, which indicates a high risk of misrepresentation of estimates in previous systematic reviews that did not address this issue. 16,18- A c c e p t e d M a n u s c r i p t 14 20 The body of evidence is comprised of observational studies at moderate-to-high risk of bias yielding low confidence in the estimates.

We developed a methodology to identify publications at high risk of patient repetition, which compared to previous systematic reviews, provides a major strength to the current analysis. 16, [18] [19] [20] Moreover, we also analyzed and grouped the various definitions used for severe Other meta-analyses did not report ICU admission or mortality risk estimates. 16, 49 Comparatively, the severe acute respiratory syndrome (SARS) epidemic in 2003, also caused by a betacoronavirus, was associated with a 3-fold risk of poor outcomes in the presence of diabetes, the highest among all comorbidities. 50 A c c e p t e d M a n u s c r i p t 16 The heightened Covid-19 risks in diabetes are multifactorial. Diabetes may facilitate the entry of SARS-CoV-2 by increased expression of ACE2 surface receptors due to the disease itself and the employed treatment strategies. 10, 11, [51] [52] [53] Furthermore, diabetes leads to dysregulation of immune responses by cytokines such as IL-6 and attenuating anti-inflammatory signaling leading to increased end organ injury. 10, 11, [54] [55] [56] Given that obesity and diabetes often coexist, 57 

Initial reports indicated a 26-30% prevalence of hypertension in Covid-19 patients. 9, 59 Published data from systematic reviews reported a 17.1-20% prevalence of hypertension in Covid-19, comparable to our estimates of 17% in our analysis of 12,709 patients. 16, 17 In the inpatient setting, our results suggest that hypertension prevalence could be up to 26%, which is still lower compared to recent data from the United States of ~50%. 60, 61 Moreover, our estimates were lower than the 31.1% global prevalence of hypertension, which could suggest an average (or belowaverage) risk of Covid-19. 62 We found a non-conclusive risk of severe Covid-19 in hypertension. Other reports suggest a higher risk of severe Covid-19 in hypertensives, of approximately 2.3-fold. 17, 49 However, after analyzing the important variation in the parameters used to define severity, we conclude that these A c c e p t e d M a n u s c r i p t 17 estimates, are non-interpretable. In contrast, the risk of ICU admission, which we consider a more reliable proxy of Covid-19 severity, was elevated in our analysis. Finally, we found an elevated risk of Covid-19 mortality associated with hypertension that was not described in other metaanalyses but is comparable to 2.4-3.0 fold risk reported in primary studies. 9, 63 The observed risk of Covid-19 in patients with hypertension is likely multifactorial. The underlying immune dysregulation, with a higher propensity for an exaggerated immune response to viral exposure, resulting in a cytokine storm and end organ injury could be a major contributor to this risk. 64,65 Additional contributors may include a higher sympathetic drive, hyperactivity of T-helper cells, increased ACE2 expression and an enhanced angiotensin II/angiotensin 1-7 ratio reducing anti-inflammatory effects of the latter, and increased pro-inflammatory action of angiotensin II. 66-70

Future studies of Covid-19 patients with diabetes or hypertension should report on patient characteristics, subtype of hypertension or diabetes, duration of disease, medications used and disease control markers. This information would not only be valuable for future systematic reviews but also assist frontline clinicians in individualizing the Covid-19 risks faced by their patients.

Furthermore, future studies reporting multivariate analyses should consider our proposed minimal sufficient adjustment sets to avoid unnecessary or over-adjustment of prognosticators. A c c e p t e d M a n u s c r i p t 26   Tables Legends   Table 1 . Characteristics of the included studies. General selection criteria included hospitalized due to pneumonia caused by SARS-CoV-2. 

Barrera: figures, study design, data collection, data analysis, data interpretation, writing

Skand Shekhar: figures, study design, data collection, data analysis, data interpretation, writing. Rachel Wurth: figures, data collection, data interpretation, writing

Moreno-Pena: figures, data collection, data interpretation

Ponce: figures, study design, data collection, data analysis, data interpretation

Michelle Hajdenberg: data collection, data interpretation

Alvarez-Villalobos: literature search

Hall: study design, data interpretation, approval of final manuscript

Ernesto Schiffrin: study design, data interpretation, approval of final manuscript

Graeme Eisenhofer: study design, data interpretation, approval of final manuscript

Forbes Porter: study design, data interpretation, approval of final manuscript

Brito: figures, study design, data collection, data analysis, data interpretation, approval of final manuscript

Bornstein: study design, data interpretation, approval of final manuscript

Stratakis: study design, data interpretation, approval of final manuscript

González: study design, data interpretation, approval of final manuscript

René Rodríguez Gutiérrez: study design, data collection, data analysis, data interpretation, approval of final manuscript

data analysis, data interpretation, approval of final manuscript. References 1. Organization WH. Coronavirus disease (COVID-2019) situation reports

Structure of SARS Coronavirus Spike Receptor-Binding Domain Complexed with Receptor

Comorbidity and its impact on 1590 patients with Covid-19 in China: A Nationwide Analysis

Covid-19 -Navigating the Uncharted

Whipple Triad Its Limitations in Diagnosis and Management of Hypoglycemia as a Co-morbidity in Covid-19 Diabetics and Diabetes Mellitus in General-A Review

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Coronavirus infections and type 2 diabetes-shared pathways with therapeutic implications

Endocrine and metabolic link to coronavirus infection

Endocrine Conditions and COVID-19

Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19

Practical recommendations for the management of diabetes in patients with COVID-19

Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2

Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis

Prevalence of comorbidities and its effects in coronavirus disease 2019 patients: A systematic review and meta-analysis

Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China

Population-level COVID-19 mortality risk for non-elderly individuals overall and for non-elderly individuals without underlying diseases in pandemic epicenters

Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia -A systematic review, meta-analysis, and meta-regression

Coronavirus disease 2019: the harms of exaggerated information and non-evidence-based measures

Cochrane Handbook for Systematic Reviews of Interventions version 6

Editorial Concern-Possible Reporting of the Same Patients With COVID-19 in Different Reports

Duplicate Publication

Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group

Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement

Prevalence and Impact of Diabetes and Hypertension on Patients with Covid-19

Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9<sup>th</sup> edition

Diabetic patients with COVID-19 infection are at higher risk of ICU admission and poor short-term outcome

Effects of hypertension, diabetes and coronary heart disease on COVID-19 diseases severity: a systematic review and meta-analysis. medRxiv

Clinical Features and Short-term Outcomes of 144 Patients With SARS in the Greater Toronto Area

Characterization of ACE and ACE2 Expression within Different Organs of the NOD Mouse

Pioglitazone upregulates angiotensin converting enzyme 2 expression in insulin-sensitive tissues in rats with high-fat diet-induced nonalcoholic steatohepatitis

Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus

Immune dysfunction in patients with diabetes mellitus (DM)

INFECTIONS IN DIABETES

An update on immune dysregulation in obesityrelated insulin resistance

Prevalence of hypertension and obesity in patients with type 2 diabetes mellitus in observational studies: a systematic literature review

Obesity in patients younger than 60 years is a risk factor for Covid-19 hospital admission

Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease

Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the

Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease

MMWR Morb Mortal Wkly Rep

Global Disparities of Hypertension Prevalence and Control: A Systematic Analysis of Population-Based Studies From 90 Countries

Hypertension and its severity or mortality in Coronavirus Disease 2019 (COVID-19): a pooled analysis

A c c e p t e d M a n u s c r i p t 28