key: cord-1004184-02vwdfy0
authors: Al‐Salameh, Abdallah; Lanoix, Jean‐Philippe; Bennis, Youssef; Andrejak, Claire; Brochot, Etienne; Deschasse, Guillaume; Dupont, Hervé; Goeb, Vincent; Jaureguy, Maité; Lion, Sylvie; Maizel, Julien; Moyet, Julien; Vaysse, Benoit; Desailloud, Rachel; Ganry, Olivier; Schmit, Jean‐Luc; Lalau, Jean‐Daniel
title: Characteristics and outcomes of COVID‐19 in hospitalized patients with and without diabetes
date: 2020-07-19
journal: Diabetes Metab Res Rev
DOI: 10.1002/dmrr.3388
sha: d2599df20c1fcf8058807c56c37609dae435f8e6
doc_id: 1004184
cord_uid: 02vwdfy0

AIMS: Coronavirus disease 2019 (COVID‐19) is a rapidly progressing pandemic, with four million confirmed cases and 280,000 deaths at the time of writing. Some studies have suggested that diabetes is associated with a greater risk of developing severe forms of COVID‐19. The primary objective of the present study was to compare the clinical features and outcomes in hospitalized COVID‐19 patients with vs. without diabetes. METHODS: All consecutive adult patients admitted to Amiens University Hospital (Amiens, France) with confirmed COVID‐19 up until April 21(st), 2020, were included. The composite primary endpoint comprised admission to the intensive care unit (ICU) and death. Both components were also analyzed separately in a logistic regression analysis and a Cox proportional hazards model. RESULTS: A total of 433 patients (median age: 72; 238 (55%) men; diabetes: 115 (26.6%)) were included. Most of the deaths occurred in non‐ICU units and among older adults. Multivariate analyses showed that diabetes was associated neither with the primary endpoint (odds ratio (OR): 1.12; 95% confidence interval (CI): 0.66‐1.90) nor with mortality (hazard ratio: 0.73; 95%CI: 0.40‐1.34) but was associated with ICU admission (OR: 2.06; 95%CI 1.09‐3.92, p=0.027) and a longer length of hospital stay. Age was negatively associated with ICU admission and positively associated with death. DISCUSSION: Diabetes was prevalent in a quarter of the patients hospitalized with COVID‐19; it was associated with a greater risk of ICU admission but not with a significant elevation in mortality. Further investigation of the relationship between COVID‐19 severity and diabetes is warranted. This article is protected by copyright. All rights reserved.

Since December 2019, more than 4 million persons have been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and more than 280,000 have been killed by the resulting coronavirus disease 2019 .

Extrapolating these figures to the total number of people with diabetes worldwide (463 million in 2019 1 ) gives a conservative global estimate of 230,000 SARS-CoV-2 infections and 15,000 deaths due to COVID-19 in this population. The actual numbers are probably higher because diabetes is generally reported in about 20% (7.4%-33.8%) of hospitalized patients with COVID-19 [2] [3] [4] . In some studies in China and the USA, diabetes appears to be associated with more severe course of the COVID-19 2,5 , including poor survival 6 . However, people with diabetes have higher prevalence of hypertension and obesity, and a greater burden of cardiovascular disease than non-diabetic people. Indeed, hypertension and obesity are frequent among COVID-19 patients (50% and 40%, respectively) 7, 8 and are associated with more severe course of COVID-19 [8] [9] [10] . Cardiovascular disease is also associated with an elevated risk of inpatient death among inpatients with COVID-19 11 . Therefore, in order to characterize the probably complex associations between diabetes, co-existing conditions, and COVID-19, we decided to directly compare people with vs. without diabetes within the same general population and same hospital context. In a rather small study from China, a comparison of 137 COVID-19 patients without diabetes with 37 COVID-19 patients with diabetes found that the disease was more severe in the diabetic group 12 . However, the characteristics and This article is protected by copyright. All rights reserved.

outcomes of patients in China might not apply to patients from other countries because of differences in ethnicity, genetic backgrounds, lifestyles and demographics. The goal of the present study was therefore to assess the characteristics and outcomes of consecutive hospitalized patients with COVID-19 as a function of the presence or absence of diabetes.

We constituted an observational cohort in order to gather information about the possible impact of pretreatment with metformin on the clinical course of COVID-19.

The cohort included all consecutive hospitalized adult patients with laboratoryconfirmed COVID-19 at Amiens University Hospital (Amiens, France). Confirmed COVID-19 was defined as a nasopharyngeal swab specimen that tested positive in a reverse-transcriptase polymerase-chain-reaction assay. We included all confirmed COVID-19 cases up until April 21 st , 2020. Hence, the main inclusion criteria were a confirmed diagnosis of COVID-19 and inpatient admission to Amiens University Hospital. The main exclusion criteria were past or present opposition to data collection by the patient or his/her legal guardian, outpatient admission (even in confirmed cases of COVID-19), and age under 18.

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Specifically trained physicians extracted data on demographics, risk factors, personal medical history, history of diabetes, antidiabetic drug use (including daily doses of metformin and dipeptidyl peptidase 4 inhibitors), medications of special concern (such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) 13 ), the main clinical data, routine laboratory results, and outcomes from the hospital's electronic medical records. All data were doublechecked by the first and last authors, who vouch for the accuracy of the data. The study was conducted in compliance with good clinical practice guidelines and the French legislation on clinical research and data protection. Furthermore, the study was approved by the local institutional review board (IRB) and registered with the French National Data Protection Commission (Commission nationale de l'informatique et des libertés (Paris, France); reference: PI2020_843_0051).

Although the requirement for written informed consent was waived by the IRB, patients who expressed their opposition to data collection were excluded. Patient confidentiality was protected by the assignment of an anonymous identifier to each enrolled participant. The identifier was attributed when the data were extracted, and only anonymized data were analyzed. It should be noted that due to the study's retrospective, observational design and the inclusion of the entire cohort of consecutive adult patients admitted to Amiens University Hospital, it is probable that some patients had also been included in other studies -especially the CORONADO study (Coronavirus SARS-CoV2 and Diabetes Outcomes; ClinicalTrials.gov identifier This article is protected by copyright. All rights reserved.

Hospitalized Adults; ClinicalTrials.gov identifier NCT04315948).

In order to compare outcomes between the study groups (namely COVID-19 patients The threshold for statistical significance was set to p<0.05. All statistical tests were two-sided and were performed with R software (version 4.0.0, R Core Team, R Foundation for Statistical Computing, Vienna, Austria). The survival package was used to fit the Cox model and the forestmodel package was used to generate forest plots from the logistic regression and Cox models.

From the start of the COVID-19 epidemic until April 21 st , 2020, 433 patients were admitted to Amiens University Hospital with COVID-19. The patients' baseline characteristics are summarized according to the presence or absence of diabetes in Table 1 . There were 115 patients with diabetes (26.6%), 317 patients without diabetes; and 1 patient whose diabetes status was unknown. The proportion of males was 63% in the diabetic group and 52% the non-diabetic group. The mean ± standard deviation (SD) age was 72 ± 14.3 years in the diabetic group (median: 72 years) and 70.6 ± 16.4 years in the non-diabetic group (median: 73 years). Patients with diabetes had a significantly higher body mass index (BMI) than patients without diabetes. Furthermore, patients with diabetes were more likely to have hypertension, hyperlipidaemia, cardiovascular disease and chronic kidney disease and more likely to be treated with ARBs than those without diabetes. On admission, median glycaemia in the diabetic group (8.3 mmol/l) was higher than in the non-diabetic group (6.3 mmol/l; p<0.001), and the median GFR was lower (71.5 vs. 85 ml/min/1.73m², respectively; p<0.001). The two groups did not differ with regard to the other laboratory results (WBC count, lymphocyte count, and CRP).

The diabetic group was composed of 111 patients (96.5%) with type 2 diabetes, three patients with type 1 diabetes, and one patient with gestational diabetes. The mean duration of diabetes was 8 ± 9.4 years (median: 5 years) and mean HbA1c level was 7.5% ± 1.67 (median: 7.1%). Metformin was the most widely prescribed antidiabetic medication (used by 71 patients (61.7%)), followed by insulin (33 patients (28.7%)) and dipeptidyl peptidase 4 inhibitors (27 patients (23.5%)).

Glinides, sulphonylureas, and glucagon-like peptide-1 analogues were employed much less frequently (by 17, 15, and 9 patients, respectively). Forty-four patients were taking one antidiabetic medication (monotherapy), 32 were taking two medications, 16 Table 2 . Patients with diabetes had higher risk of developing ARDS and acute renal injury, whereas the groups did not differ in terms of the incidence of cardiac injury and a documented secondary infection. The mean length of stay was 17.1 ± 11.7 days in the diabetic group and 13.5 ± 9.1 days in the non-diabetic group. Table 1 ).

The main findings of our study are as follows. Firstly, diabetes was present in 26.6% of patients hospitalized with COVID-19; this proportion is considerably higher than the prevalence of diabetes in Amiens University Hospital's referral area (5.53% in 2013 and ≈6% in 2016). Secondly, COVID-19 with diabetes was significantly associated with a greater likelihood of admission to the ICU (relative to COVID-19 without diabetes) but was not associated with increased mortality. Thirdly, COVID-19

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with diabetes was also associated with a higher risk of developing ARDS and acute renal injury, relative to COVID-19 without diabetes. Lastly, the median length of stay was longer in COVID-19 patients with diabetes than in COVID-19 patients without diabetes.

Most cases of COVID-19 are mildly symptomatic or even asymptomatic. As such, these cases may not be detected or are managed by a general practitioner or in an outpatient setting. However, pneumonia and severe symptoms occur in about 15% of cases of COVID-19 15 This article is protected by copyright. All rights reserved.

Our results show that diabetes is significantly associated with ICU admission and the development of ARDS and acute renal injury. At the time of ICU admission, diabetic and non-diabetic patients had a similar Simplified Acute Physiology Score II; this suggests that the COVID-19 was not more severe in the diabetic group and does not support the application of a lower threshold for ICU referral among diabetic patients.

Indeed, type 2 diabetes is associated with obesity, insulin resistance, and low grade inflammation; these factors may result in immune dysregulation and more severe COVID-19. In one study, mice were made susceptible to Middle East respiratory syndrome coronavirus (via the expression of human dipeptidyl peptidase-4) and

given a high fat diet to induce diabetes. The mice showed delayed but prolonged, severe inflammation of the lungs upon infection 16 . It remains to be seen whether these observations are of relevance to COVID-19. Interestingly, people with diabetes have elevated urine levels of ACE 2, the SARS-CoV-2's co-receptor for cell entry 17 .

The relationship between diabetes and our present study endpoints was independent of obesity (as a categorical variable) and BMI (as a continuous variable). Indeed, obesity is one of the main underlying conditions in patients with COVID-19, and is associated with an elevated risk of hospital admission 18 and with worse inpatient outcomes 19 (e.g. invasive mechanical ventilation 9 and mortality 20 ).

The mechanisms responsible for the poor prognosis in obese people with COVID-19 include obesity-related respiratory dysfunction, low-grade systemic inflammation, and complement system hyperactivation. Moreover, it has been suggested that adipose tissue accumulation within the lungs has a detrimental local effect 21 .

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Our most striking finding is that diabetes was not associated with greater risk of inpatient death, despite a longer hospital stay. In a small study from China, diabetes was associated with an increased risk of death in a univariable analysis (OR [95%CI]: 2.85 [1.35-6.05]; p=0.0062) but was not selected for multivariable analysis 6 . Notably, the patients' median age was 56 years in the Chinese study and 72 in the present study. Furthermore, a recent meta-analysis and systematic review found that diabetes was associated with an elevated relative risk (RR) [95%CI] of death (2.12 [1.44-3.11] ). The review's authors suggested that the RR was lower in studies with a median age ≥55 years than in studies with a median age <55 22 . It is therefore possible that the RR of death in patients with COVID-19 and diabetes falls with agea phenomenon that is also encountered for diabetes-related cardiovascular disease, cardiovascular death 23 , and overall mortality 24 . In our cohort, patients who died were considerably older than those admitted to the ICU; this suggests that younger patients with co-existing diseases (including diabetes) were more frequently referred to the ICU, whereas elder patients were not. This is supported by the fact that more than 75% of deaths in our study (regardless of diabetes status) occurred outside the ICU. In our multivariable analyses, age was positively associated with death but negatively associated with ICU admission.

The main strength of our study relates to its inclusive nature: the inclusion of consecutive patients gave us a true, precise picture of COVID-19 in our region. The fact that the study was undertaken in only one tertiary hospital is also a strength because the criteria for admission to the hospital in general and to the ICU in This article is protected by copyright. All rights reserved. particular were relatively homogenous. Furthermore, the diabetic group was relatively homogenous, as almost all of the patients had type 2 diabetes.

Our study had the limitations inherently associated with observational studies. Firstly, causality cannot be inferred from an association between variables, and the absence of a statistically significantly association does not rule out clinical relevance.

Secondly, there were some missing data for important variables, such as BMI and smoking status. Other measures of adiposity (such as waist circumference and neck circumference) were not available. In a recent multicentre study performed in Italy, neck circumference was significantly associated with the need for invasive mechanical ventilation in COVID-19 patients 25 . Thirdly, and despite our adjustment for a large number of variables, residual confounding cannot be ruled out. Lastly, the observational design prevented us from prespecifying the statistical power, and so our results should be considered as being indicative only.

In conclusion, our observational study of all consecutive patients hospitalized with COVID-19 in a tertiary referral centre found that diabetes was present in a quarter of admissions and was associated with a greater risk of ICU admission and a longer length of stay but not with mortality (relative to non-diabetic patients). Further investigations of the relationship between COVID-19 and diabetes are now warranted, with a focus on (i) the RR of death in COVID-19 patients with vs. without diabetes, and (ii) the interaction between age and/or diabetes duration on one hand and COVID-19 mortality and other outcomes on the other. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. 

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We are grateful to Edgardo Reyes and Marvin Tchuem Tchuente for their assistance with data extraction.Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

AAS and JDL designed the study and drafted the manuscript which was