key: cord-0712474-n186ajzo authors: Sutter, Willy; Duceau, Baptiste; Vignac, Maxime; Bonnet, Guillaume; Carlier, Aurélie; Roussel, Ronan; Trimaille, Antonin; Pommier, Thibaut; Guilleminot, Pierre; Sagnard, Audrey; Pastier, Julie; Weizman, Orianne; Giordano, Gauthier; Cellier, Joffrey; Geneste, Laura; Panagides, Vassili; Marsou, Wassima; Deney, Antoine; Karsenty, Clément; Attou, Sabir; Delmotte, Thomas; Ribeyrolles, Sophie; Chemaly, Pascale; Gautier, Alexandre; Fauvel, Charles; Chaumont, Corentin; Mika, Delphine; Pezel, Théo; Cohen, Ariel; Potier, Louis title: Association of diabetes and outcomes in patients with COVID-19: Propensity score-matched analyses from a French retrospective cohort date: 2020-12-31 journal: Diabetes Metab DOI: 10.1016/j.diabet.2020.101222 sha: d0980869d400465dbccb26330d630e3755c16006 doc_id: 712474 cord_uid: n186ajzo Background Our study aimed to compare the clinical outcomes of patients with and without diabetes admitted to hospital with COVID-19. Methods This retrospective multicentre cohort study comprised 24 tertiary medical centres in France, and included 2851 patients (675 with diabetes) hospitalized for COVID-19 between 26 February and 20 April 2020. A propensity score-matching (PSM) method (1:1 matching including patients’ characteristics, medical history, vital statistics and laboratory results) was used to compare patients with and without diabetes (n = 603 per group). The primary outcome was admission to an intensive care unit (ICU) and/or in-hospital death. Results After PSM, all baseline characteristics were well balanced between those with and without diabetes: mean age was 71.2 years; 61.8% were male; and mean BMI was 29 kg/m2. A history of cardiovascular, chronic kidney and chronic obstructive pulmonary diseases were found in 32.8%, 22.1% and 6.4% of participants, respectively. The risk of experiencing the primary outcome was similar in patients with or without diabetes [hazard ratio (HR): 1.16, 95% confidence interval (CI): 0.95–1.41; P = 0.14], and was 1.29 (95% CI: 0.97–1.69) for in-hospital death, 1.26 (95% CI: 0.9–1.72) for death with no transfer to an ICU and 1.14 (95% CI: 0.88–1.47) with transfer to an ICU. Conclusion In this retrospective study cohort of patients hospitalized for COVID-19, diabetes was not significantly associated with a higher risk of severe outcomes after PSM. Trial registration number : NCT04344327. The authors compare the clinical outcomes between patients with and without diabetes admitted to hospital with COVID-19 by using the data from a retrospective multicentre cohort in France. The originality of this study is that it used a propensity score matching (based on clinical characteristics, especially the presence of comorbidities, and some biological characteristics at admission) for the comparison between patients with and without diabetes. The primary outcome was admission to intensive care unit or in-hospital death. The conclusion was that diabetes per se was not significantly associated with a higher risk of severe outcomes after propensity score matching which took into account the presence of comorbidities (more frequent in the diabetic population) and some biological findings at admission. From my side, the review process raised one major remarks and several minor remarks. The manuscript has been also analysed by another independent reviewer who expressed additional remarks (I also fully agree with these remarks). The Authors made their best to take into account the majority of these remarks. Especially, the analysis is now focusing on PSM data only and the conclusions have been made less strong, considering several limitations of the study, especially the absence of clear information regarding the type of diabetes, the glucose-lowering medications used and the level of glucose control (both HbA1c and glucose at admission).Thus, the manuscript is now markedly improved. I have only one final major remark and two remaining minor remarks. If the results are adjusted not only for previous complications (cardiovascular disease, renal impairment, …) but also for criteria of severity at admission (for instance biological characteristics), it is not surprising that diabetes per se does not emerge as a risk factor. One may hypothesize that diabetes was associated with risk factors of severity at admission but that the PSM adjustment vanishes the difference. Perhaps add a sentence in the limitation section or at the end of the manuscript to answer this point. Thanks for this comment. We fully agree with it. That is why, as sensitivity analysis, we tried to address this limitation by building two other propensity score including either previous complications or admission findings. For both PS matching, we did not find any difference between patients with or without diabetes for the primary outcomes (page 9 and J o u r n a l P r e -p r o o f 10) . Moreover, it is noteworthy that in PSM cohort in which patients with and without diabetes were matched based only on their personal characteristics and comorbidities, no difference was found for vital signs, laboratory and radiological findings between both groups (Supplemental Table S5 ). These results suggest that diabetes was not associated with a higher risk of severity at admission. We hope these findings can address this remark. MINOR REMARKS 1) Page 8, Results N° 34-37 : : "whereas most of the laboratory findings at admission were in the normal range" : may appear strange, especially 22.4 % of patients had already severe abnormalities on chest computed tomography. I would suggest to slightly modify this sentence and to give somewhat more information or justification. Thanks for this comment. By laboratory findings, we meant biological findings. We added precision regarding which findings were in the normal ranges in the revised version of the manuscript. "Regarding biological findings, levels of C -reactive protein were elevated whereas most of other laboratory findings at admission (such as hemoglobin, platelets, white cell count, liver enzymes and eGFR) were in the normal range." 2) Page 13, Discussion, N° 29-30 : "but no related diabetes pattern" : I would suggest to be more cautious (or informative) because some important information data regarding diabetes were missing in the initial CORONADO report (for instance the degree of glucose control during hospitalization and which glucose-lowering agents were used). Furthermore, previous glucose-lowering medication use might have a positive impact, such as metformin therapy with was associated with a better outcome according to CORONADO findings. We agree. We changed this sentence accordingly by adding more information on the patterns available in the CORONADO study (ie. those concerning diabetes before admission). Regarding glucose control during hospitalization, we discussed this point in the second point of the limitation section. Regarding positive impact of metformin therapy in Coronado, this finding is not yet published to the best of our knowledge. J o u r n a l P r e -p r o o f ☐ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☒The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LP reports grants, personal fees and non-financial support from Novo Nordisk, MSD and Sanofi, personal fees and non-financial support from Eli Lilly and non-financial support from Servier. AC acknowledges the following without any relationship to the current manuscript: research grant from cases, and a dramatic increase in mortality in patients with diabetes [1] [2] [3] [4] . Other comorbidities frequently associated with diabetes, such as obesity, hypertension, chronic kidney disease and cardiovascular disease, have also been shown to be associated with a higher risk of severe outcomes for COVID-19 [5] [6] [7] [8] [9] . However, whether diabetes is associated with poorer COVID-19 outcomes independently of diabetes-related comorbidities has remained unclear. Thus far, only a few published studies have directly compared patients with and without diabetes to address this issue [10] [11] [12] [13] . Moreover, despite multiple adjustments, comparisons between patients with and without diabetes have remained potentially biased by important differences in terms of clinical characteristics and medical history, but also by their varied clinical and biological presentations at admission. The aim of the present study, therefore, is to investigate the potential association between diabetes and clinical outcomes in patients hospitalized for COVID-19 by using a propensity score-matching (PSM) approach to account for a wide range of comorbidities. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 The present Critical COVID-19 France (CCF) study is a retrospective, observational, multicentre study initiated by the French Society of Cardiology that includes all consecutive adult patients admitted to hospital with a diagnosis of SARS-CoV-2 infection between 26 February and 20 April 2020 at 24 clinical centres across France (NCT04344327). Its overall protocol has been partially described in a previous report [14] . All data were collected by local investigators using an electronic case-report form available on However, no information regarding type of diabetes was available for our cohort. The primary study outcome was a composite of transfer to an ICU or in-hospital death. Secondary outcomes were each component of the primary outcome on its own, death in an ICU and death with no transfer to an ICU. The date of the final follow-up for patients who remained hospitalized was 21 April 2020. The present report was prepared in compliance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist [15] . As most patients' characteristics-whether covariates prior to admission or those related to medical presentation at admission-were dramatically different between those with and without diabetes, a PSM approach was used to better account for such differences. This involved 1:1 matching based on 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f without diabetes at hospital admission were plotted and compared by log-rank test. A two-tailed P value < 0.05 was considered statistically significant. All data were analyzed using R software, version 3.6.3 (R Project for Statistical Computing, Vienna, Austria). Overall, 2878 patients hospitalized for COVID-19 at 24 French clinical centres were included between 26 February and 20 April 2020 (all participating centres are listed in Table S1 ; see supplementary materials associated with this article online). Of these patients, 27 were excluded from analysis because of missing data for outcomes or diabetes status (Fig. 1) . Baseline characteristics and outcomes for the 2851 unmatched patients are presented in Table S2 and Table S3 (see supplementary materials associated with this article online). After PSM, 603 patients in each group (with and without diabetes) were compared for outcomes ( Fig. 1) ; their baseline characteristics according to diabetes status are presented in Table I (Table I and Table II) . Antibiotic drugs were the most prescribed therapy (75.9%) while in hospital. 14] or any of the secondary outcomes (Table III) . In these analyses, the incidence of outcomes in the diabetes and non-diabetes groups were compared with two other PSM cohorts (one including personal characteristics and comorbidities, the other including admission vital statistics and laboratory findings) to better assess the impact of each type of covariate on the association between diabetes and outcome events. In the first PSM cohort wherein patients with and without diabetes were matched according to their personal characteristics and comorbidities, no differences were found in either vital statistics or laboratory or radiological findings between the two groups (Table S5; see supplementary materials associated with this article online). In the second PSM cohort, which included only those with matching vital statistics and biological findings, patients with diabetes were older, more frequently male, had higher BMI scores and a greater prevalence of comorbidities than noted in the unmatched cohort. Cox's regression analysis revealed that, in both PSM cohorts, any associations between diabetes status and risk of severe outcomes were non-significant (Table S6 ; see supplementary materials associated with this article online). In this cohort of 1206 PSM patients hospitalized for COVID-19, no greater risk for worse outcomes was observed in patients with vs without diabetes. Yet, from the beginning of the COVID-19 pandemic in January 2020, there had been growing evidence from both descriptive 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 and epidemiological studies of a greater prevalence of diabetes in severe COVID-19 patients. Indeed, diabetes prevalence varied from 17% to 37% in the most recent case series of hospitalized patients in the US and Europe [2, 3, [17] [18] [19] . In the present study, a similar rate of 23.6% patients with diabetes was reported among patients hospitalized for COVID-19. Likewise, a high rate of associated comorbidities, with hypertension being the most frequent one, followed by cardiovascular diseases, chronic respiratory disease and chronic kidney disease, was also observed. Most of these comorbidities (hypertension, cardiovascular diseases, chronic kidney disease) are known to be commonly found in those living with diabetes [20] . It was also revealed that, in the unmatched cohort, patients with diabetes were more prone to receive invasive mechanical ventilation and intensive care, and to face greater mortality, than those without diabetes [10] [11] [12] [13] . Despite several case series of patients hospitalized with COVID-19 worldwide, only a few studies have been specifically focused on the prognosis of patients with and without diabetes. In contrast to our present findings, those studies found that diabetes was associated with a higher risk of severe outcomes. Zhu et al. [12] reported a significant 1.49-fold higher risk of all-cause mortality between subgroups in a retrospective study of 7337 patients [952 with type 2 diabetes (T2D)] hospitalized in China for COVID-19. However, the authors failed to adjust for comorbidities closely related to T2D, such as hypertension, cardiovascular disease and chronic kidney disease, all of which have proved to be major risk factors in COVID-19 prognoses [17] . Another Chinese retrospective study of a small number of subjects (193 patients, 48 with diabetes) found that patients with diabetes had lower survival rates than those without diabetes, with an HR of 1.53 (P = 0.041) after adjusting for age, gender, hypertension, cardiovascular disease and cerebrovascular disease [11] . Similarly, in a preprint version of a 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f nationwide study of 23,804 COVID-19-related deaths in England, the odds ratio (OR) for dying in hospital with COVID-19 in patients with T2D was 1.81-fold higher than in the population not known to have diabetes [21] . However, despite the large number of participants in that study, some important potential confounding comorbidities, such as hypertension and chronic kidney disease, were ignored. Moreover, time-to-event data were also not available in this preprint, which could negatively impact the robustness of their results. Unlike the above-mentioned studies, our present study used PSM analysis to avoid the confounding effects of the comorbidities frequently associated with both diabetes and poorer outcomes with COVID-19, and also failed to find that diabetes was associated with a higher risk of severe outcomes. In accordance with our results, a recent study of 20,133 UK patients in hospital for COVID-19 found that, even though diabetes was commonly seen (28.1%) in this population, the association of diabetes with mortality risk was attenuated to the point of nonsignificance after multiple adjustments on Cox's analysis (HR: 1.06) [22] . Similarly, in a US study of 5279 subjects in New York City, Petrilli et al. [23] found a 3.6-fold greater prevalence of diabetes in patients with COVID-19 admitted to hospital compared with those not admitted. However, after multiple adjustments, the risk of critical illness among inpatients with diabetes was similar to that of those without diabetes. Taken together, these findings suggest that the increased risk of severe outcomes reported in patients with diabetes is ameliorated after adjusting for diabetes-related comorbidities. Indeed, the diabetes-associated risk of severe outcomes with COVID-19 could be more driven by the associated comorbidities than by the diabetes itself. In sensitivity analyses where only vital statistics and laboratory findings were used to construct the propensity scores for matching, the risk of negative outcomes in both diabetes and non -1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f diabetes groups proved to be similar, even though diabetes patients were older, had higher BMI scores and higher rates of associated comorbidities. The interpretation of these findings, however, is not obvious and subject to biases. Nevertheless, it could be argued that the differential risk between patients with and without diabetes might be driven by vital signs and biological findings rather than clinical characteristics and comorbidities. In two previous studies comparing patients with and without diabetes, Cox's regression analyses found a higher rate of outcomes in patients with diabetes after adjusting for age, gender, hypertension, cardiovascular disease and cerebrovascular disease, although no adjustments were made for biochemical values despite a significant difference in inflammatory markers between groups [10, 11] . Moreover, in the study by Petrilli et al. [23] , the risk of severe outcomes was significantly greater when adjusted only for clinical characteristics and medical history, but no longer significant after adjusting for both previous comorbidities and biological findings at admission. Taken together, these data suggest that the severity of infection at admission (based on, for example, clinical presentation or expression of inflammatory markers) instead of previous comorbidities might better for assessing risk for worse outcomes. Our study has some limitations. Unfortunately, detailed data for diabetes characteristics that might influence outcomes, such as type of diabetes, HbA1c levels, diabetes duration, diabetic therapies and microvascular complications, were not available for the present cohort. Such a lack of information is a clear study limitation as it diminishes any confidence in our results. However, in the Coronavirus SARS-CoV-2 and Diabetes Outcomes (CORONADO) study, involving a well-documented French cohort of 1317 diabetes patients hospitalized for COVID -1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 19, Cariou et al. [24] found that BMI scores, but not diabetes-related patterns before admission, were positively and independently associated with tracheal intubation and/or death within 7 days. Nevertheless, another obvious limitation is the lack of data on glycaemic control at admission or during hospitalization. Indeed, Wang et al. [25] observed that, in 605 patients with no previous diagnosis of diabetes, fasting blood glucose at admission was an independent predictor of 28-day mortality in patients with COVID-19. Furthermore, Zhu et al. [12] demonstrated that, in patients with T2D, those with well-controlled blood glucose during their hospital stay had better prognoses than those with poorly controlled glycaemia. Thus, these data suggest it may be glycaemic control at admission and during hospitalization that has an impact on COVID-19 prognoses in diabetes patients instead of their previous glycaemic control or other specific patterns of diabetes [26] . can be claimed, especially as all HRs from Cox's analyses were also > 1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Our present findings suggest that, despite the high prevalence of diabetes in patients hospitalized for COVID-19, the risk of severe outcomes was mainly driven by associated comorbidities or more severe clinical presentations at admission to hospital. These results provide new insights into risk stratification for patients with COVID-19. However, further studies on a larger scale and with better control of confounding biases, especially for glucose control before and during hospitalization, are still warranted to confirm these findings. Supplementary materials (Tables S1-S6, Fig. S1 ) associated with this article can be found at http://www.scincedirect.com at doi . . . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 The CCF study was declared to and authorized by the French Data Protection Committee The datasets used and/or analyzed during the present study are available from the corresponding author upon reasonable request. L.P. reports grants, personal fees and non-financial support from Novo Nordisk, MSD and Sanofi, personal fees and non-financial support from Eli Lilly, and non-financial support from Servier. A.C. acknowledges a research grant from RESICARD (research nurses), and consultancy and lecture fees from Amgen, AstraZeneca, Bayer Pharma, Alliance BMS-Pfizer, Novartis and Sanofi-Aventis, which are not related to the present manuscript. The other authors have nothing to declare This research received no specific grants from funding agencies in either the public, commercial or not-for-profit sectors. 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f Immediab team, F-75006 Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese center for disease control and prevention Prevalence of obesity among adult inpatients with COVID-19 in France Association of hypertension and antihypertensive treatment with COVID-19 mortality: a retrospective observational study Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China Patients with chronic kidney disease have a poorer prognosis of coronavirus disease 2019 (COVID-19): an experience in Body mass index and outcome in patients with COVID-19: A dose-response meta-analysis clinical characteristics and risk factors for mortality of Covid-19 patients with diabetes in Wuhan, China: a two-center, retrospective study Clinical characteristics and outcomes of patients with severe covid-19 with diabetes Association of blood glucose control and outcomes in patients with Covid-19 and pre-existing type 2 diabetes Patients with diabetes are at higher risk for severe illness from COVID-19 Pulmonary embolism in COVID-19 patients: a French multicentre cohort study Strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 aAdmitted to ICUs of the Lombardy Region Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the Prevalence and coprevalence of comorbidities among patients with type 2 diabetes mellitus Type 1 and Type 2 diabetes and COVID-19 related mortality in England: a whole population study Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study Fasting blood glucose at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes: a multi-centre retrospective study Prognostic factors in patients with diabetes hospitalized for COVID-19: Findings from the CORONADO study and other recent reports Laboratory findings at admission, median GFR, mL/min/1.73 Alanine aminotransferase Data are presented as means ± SD unless otherwise specified; a data not normally distributed GFR, glomerular filtration rate; COPD, chronic obstructive pulmonary disease; ACEIs, angiotensin-converting enzyme inhibitors FiO2, fraction of inspired oxygen We are grateful to the medical and paramedical staff involved in the care of patients during the study period as well as all members of the French Society of Cardiology. Authors' contributions L.P. and W.S. had full access to all of the study data, and take full responsibility for the integrity of the data and accuracy of the data analysis. Study concept and design: L.P., W.S.; acquisition, analysis or interpretation of data: all authors. Drafting of the manuscript: L.P., W.S. Critical revision of the manuscript for important intellectual content: all authors. Final approval of the version submitted for publication: all authors. The corresponding author attests that all listed authors have met authorship criteria and that no others meeting the criteria have been omitted. Figure 1