key: cord-0776972-o5tppc1w
authors: Harris, Sophie; Ruan, Yue; Wild, Sarah H.; Wargny, Matthieu; Hadjadj, Samy; Delasalle, Béatrice; Saignes, Maëva; Ryder, Robert EJ.; Field, Benjamin C.T.; Narendran, Parth; Zaccardi, Francesco; Wilmot, Emma G.; Vlacho, Bogdan; Llauradó, Gemma; Mauricio, Didac; Nagi, Dinesh; Patel, Dipesh; Várnai, Kinga A.; Davies, Jim; Gourdy, Pierre; Cariou, Bertrand; Rea, Rustam; Khunti, Kamlesh
title: Association of statin and/or renin-angiotensin-aldosterone system modulating therapy with mortality in adults with diabetes admitted to hospital with COVID-19: A retrospective multicentre European study
date: 2022-04-11
journal: Diabetes Metab Syndr
DOI: 10.1016/j.dsx.2022.102484
sha: 91afd9cf801edee518f9d40d63bb810f3cfa83ed
doc_id: 776972
cord_uid: o5tppc1w

Background & aims To assess the impact of pre-admission renin-angiotensin-aldosterone system inhibitor (RAASi) and statin use on mortality following COVID-19 hospitalization in adults with pre-existing diabetes. Methods Retrospective cohort study of adults with diabetes admitted to ninety-nine participating hospitals in the United Kingdom, France and Spain during the first wave of the COVID-19 pandemic. Logistic regression models adjusted for demographic factors and comorbidity were used to describe associations with mortality in hospital or within 28 days of admission and individual or combined RAASi and statin therapy prescription followed by a country level meta-analysis. Results Complete data were available for 3474 (42.6%) individuals. Prescribing patterns varied by country: 25–50% neither RAASi nor statin therapy, 14–36% both RAASi and statin therapy, 9–24% RAASi therapy alone, 12–36% statin alone. Overall, 20–37% of patients died within 28 days. Meta-analysis found no evidence of an association between mortality and prescription of RAASi therapy (OR 1.09, CI 0.78–1.52 (I2 22.2%)), statin (OR 0.97, CI 0.59–1.61 (I2 72.9%)) or both (OR 1.14, CI 0.67–1.92 (I2 78.3%)) compared to those prescribed neither drug class. Conclusions This large multicentre, multinational study found no evidence of an association between mortality from COVID-19 infection in people with diabetes and use of either RAASi, statin or combination therapy. This provides reassurance that clinicians should not change their RAASi and statin therapy prescribing practice in people with diabetes during the COVID-19 pandemic.

Tables: 1 Supplemental online material: Table 1 Details of study contributors can be found in the supplementary material.

J o u r n a l P r e -p r o o f Structured abstract:

To assess the impact of pre-admission renin-angiotensin-aldosterone system inhibitor (RAASi) and statin use on mortality following COVID-19 hospitalization in adults with preexisting diabetes.

Retrospective cohort study of adults with diabetes admitted to ninety-nine participating hospitals in the United Kingdom, France and Spain during the first wave of the COVID-19

pandemic. Logistic regression models adjusted for demographic factors and comorbidity were used to describe associations with mortality in hospital or within 28 days of admission and individual or combined RAASi and statin therapy prescription followed by a country level meta-analysis.

Complete data were available for 3474 (42.6%) individuals. Prescribing patterns varied by country: 25-50% neither RAASi nor statin therapy, 14-36% both RAASi and statin therapy, Research Highlights:

1. No association between COVID-19 related mortality and use of renin-angiotensinaldosterone system inhibitor or statin therapy in people with diabetes

The COVID-19 pandemic has been one of the biggest human catastrophes of the modern age;

killing almost 5 million people in 2 years and being one of the leading causes of death in the 

Retrospective data from hospitalized adults with pre-existing diabetes and concomitant The CORONADO study set out to describe the phenotypic characteristics and prognosis of people with diabetes admitted with COVID-19 between March 10 and April 10, 2020 10,11 .

CORONADO is a retrospective study from French hospitals volunteering to share data on hospitalized COVID-19 patients with diabetes. The study was sponsored by Nantes University Hospital and designed in accordance with the Declaration of Helsinki. It obtained all regulatory approvals.

The six hospitals in the HM Hospitales group collected anonymized observational data for people infected with COVID-19 during the first wave. This dataset is made available to researchers via "Covid Data Save Lives" 9 . The electronic hospital health records were collected for admitted persons including pre-existing disease status, medication use, demographic and outcome. A subset of people with pre-existing diabetes from this crosssectional database was used in this study. Before access was granted, a formal petition, specific study protocol, and ethics committee approval were obtained. The study was approved by the Ethics Committee of the Primary Health Care University Research Institute (IDIAP) Jordi Gol, Barcelona (approval number: 20/089-PCV).

J o u r n a l P r e -p r o o f The primary outcome was death. French data was collected to day 28 of admission, Spanish and UK data included outcome to conclusion of hospital episode.

We conducted complete-case analyses and reported descriptive statistics comparing the complete dataset to those excluded due to missing variables. Clinical characteristics were reported as frequency and percentages for categorical variables, and as mean and standard deviation for continuous variables. Multivariable logistic regression models were used to obtain odds ratios for the outcome variable, death. The main exposure was RAASi use, statin use, or both, and associations were estimated using as a reference category neither RAASi nor Statin. Potential confounders were ethnicity, CKD, macrovascular complications, hypertension, gender and type of diabetes (categorical) and age (continuous). Logistic regressions were performed using R in each contributing country; country-specific odds ratios were then pooled in a random-effects DerSimonian and Laird meta-analysis, with estimates stratified by model adjustment. Heterogeneity across studies was evaluated using the statistic I 2 . Results are reported with 95% confidence interval (CI) and P-values of less than 0.05 were considered statistically significant.

The UK ABCD COVID-19 audit collected data on 3007 people with diabetes from twenty- Output from individual logistic regression models for each country were combined in a metaanalysis and showed no significant association between death and use of either RAASi or statin therapy with considerable heterogeneity (Fig. 1) 

This is the first multinational European retrospective study to specifically investigate the outcomes of hospitalized adults with pre-existing diabetes and COVID-19 in relation to prior use of RAASi and statin therapy. We found no significant association between the prior use of RAASi or statin and the primary outcome of death in the meta-analysis, although the findings for statins were highly heterogeneous between the participating countries. The findings remained non-significant after adjusting for age, gender, diabetes type, hypertension, macrovascular disease and CKD. Further adjustment for ethnicity in two of the nations' data had no further impact on the findings.

COVID-19 infection is associated with poorer outcome for those with long-term conditions, such as diabetes, and several potential mechanisms have been proposed 6, 9 . This paper specifically examined medications used by many people with diabetes (type 1 and 2) for the prevention of diabetic complications and, therefore, the potential detrimental or beneficial effect of these medications on outcomes for this specific population. It uses large heterogenous real world datasets to draw clinically relevant conclusions. 

Antecedent statin use with an associated lower lipid profile on admission has been associated with lower 30-day mortality in a general USA population 18 . A meta-analysis of adults with COVID-19 infection found almost 50% mortality risk reduction associated with in-hospital use of statin in a mixed patient population, but no benefit from statin use pre-admission 19 . In a population with high diabetes prevalence (44%), similar beneficial results were found with in-hospital statin use 20 . However, a recent meta-analysis of 25 studies, including 33% people with diabetes, found benefit of statin therapy only in chronic use prior to admission 21 .

Our study did not examine either inflammatory markers or lipid levels, nor collect data on 

RAASi treatment may be interrupted to minimise potential nephrotoxic effects 28 . Further research is required to investigate whether stopping RAASi is appropriate in the face of COVID-19 infection. As with statin therapy, this research is in progress, but it will be important to look at the diabetes-specific population where prescribing indications differ 29 .

This study has clinical relevance to the general practitioner, diabetologist and their patients. It provides reassurance about continued outpatient use of RAASi and statin therapy during the pandemic, with no significant association with increased mortality or disease severity in those prescribed them. The multinational and demographically diverse datasets allow for wider generalisability of findings.

Our study is limited by the heterogeneity of data collection methods across the nations due to use of databases not initially created in collaboration to answer the study question and, therefore, by some missing data. The meta-analysis combines a larger dataset to provide an overall relationship of association, rather than causality, but masks heterogeneity across nations. Markers of inflammation and lipid levels were not collected, as well as other potential confounding factors such as smoking status, body mass index and diabetes duration.

Lastly, drug histories were often collected from health records, rather than being confirmed with individuals, introducing the possibility of error in the context of access to pharmacies being restricted during pandemic lockdowns.

This large multinational study of people with diabetes requiring hospitalisation for COVID- United Kingdom (UK), France and Spain. Abbreviations used: Chronic kidney disease (CKD), renin-angiotensin-aldosterone-system

World Health Organisation. WHO Coronavirus COVID-19 dashboard

COVID-19 as the Leading Cause of Death in the

United States

COVID-19) in the WHO European Region

Relation of Statin Use Prior to Admission to Severity and Recovery Among COVID-19 Inpatients

ESC Guidelines on diabetes, prediabetes, and cardiovascular diseases developed in collaboration with the EASD

Prevalence of co-morbidities and their association with mortality in patients with <scp>COVID</scp> -19: A systematic review and meta-analysis. Diabetes

Prescription of glucose-lowering therapies and risk of COVID-19 mortality in people with type 2 diabetes: a nationwide observational study in England

Risk factors for severe outcomes in people with diabetes hospitalised for COVID-19: a cross-sectional database study

Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial. The Lancet Respiratory Medicine

Statin Use and In-Hospital Mortality in Patients With Diabetes Mellitus and COVID-19

-Hospital Use of Statins Is Associated with a

Reduced Risk of Mortality among Individuals with COVID-19

Routine use of statins and increased COVID-19 related mortality in inpatients with type 2 diabetes: Results from the CORONADO study

Increased mortality risk associated with statins in the CORONADO study

Association between antecedent statin use and decreased mortality in hospitalized patients with COVID-19

-hospital use of statins is associated with a 22

Lipid-Modulating Agents for Prevention or Treatment of COVID-19 in Randomized Trials. medRxiv : the preprint server for health sciences

ACEI/ARB use and risk of infection or severity or mortality of COVID-19: A systematic review and meta-analysis

Association of <scp>angiotensin converting enzyme inhibitors and angiotensin II receptor blockers</scp> with risk of <scp>COVID</scp> -19, inflammation level, severity, and death in patients with <scp>COVID</scp> -19: A rapid systematic review and <scp>meta-analysis</scp>

The use of renin-angiotensin-aldosterone system (RAAS) inhibitors is associated with a lower risk of mortality in hypertensive COVID-19 patients: A systematic review and meta-analysis

Prospective meta-analysis protocol on randomised trials of renin-angiotensin system inhibitors in patients with COVID-19: an initiative of the International Society of Hypertension