key: cord-0980579-rhojc8hx authors: Mantovani, Alessandro; Byrne, Christopher D.; Zheng, Ming-Hua; Targher, Giovanni title: Diabetes as a risk factor for greater COVID-19 severity and in-hospital death: a meta-analysis of observational studies date: 2020-05-29 journal: Nutr Metab Cardiovasc Dis DOI: 10.1016/j.numecd.2020.05.014 sha: 18e9e45659afeb7facbabe5107454fd292be32a9 doc_id: 980579 cord_uid: rhojc8hx Abstract Aims To estimate the prevalence of established diabetes and its association with the clinical severity and in-hospital mortality associated with COVID-19. Data synthesis We systematically searched PubMed, Scopus and Web of Science, from 1st January 2020 to 15th May 2020, for observational studies of patients admitted to hospital with COVID-19. Meta-analysis was performed using random-effects modeling. A total of 83 eligible studies with 78,874 hospitalized patients with laboratory-confirmed COVID-19 were included. The pooled prevalence of established diabetes was 14.34% (95% CI 12.62-16.06%). However, the prevalence of diabetes was higher in non-Asian vs. Asian countries (23.34% [95% CI 16.40-30.28] vs. 11.06% [95% CI 9.73-12.39]), and in patients aged ≥60 years vs. those aged <60 years (23.30% [95% CI 19.65-26.94] vs. 8.79% [95% CI 7.56-10.02]). Pre-existing diabetes was associated with an approximate twofold higher risk of having severe/critical COVID-19 illness (n=22 studies; random-effects odds ratio 2.10, 95% CI 1.71-2.57; I 2 =41.5%) and ∼threefold increased risk of in-hospital mortality (n=15 studies; random-effects odds ratio 2.68, 95% CI 2.09-3.44; I 2 =46.7%). Funnel plots and Egger’s tests did not reveal any significant publication bias. Conclusions Pre-existing diabetes is significantly associated with greater risk of severe/critical illness and in-hospital mortality in patients admitted to hospital with COVID-19. The outbreak of coronavirus disease 2019 , caused by the severe acute 68 respiratory syndrome coronavirus 2 (SARS-CoV-2), has been recently declared a 69 pandemic by the World Health Organization, and the disease has spread to nearly all 70 countries worldwide [1] . It is known that people with diabetes have a higher overall 71 risk of infection(s) resulting from multiple perturbations of innate immunity [2] [3] [4] . 72 Whether people with diabetes are also at greater susceptibility to COVID-19 is 73 currently uncertain, but there is a perception that the risk is higher; both of infection, 74 and of greater severity of illness [5, 6] . Quality assessment of eligible studies was also performed by two investigators (AM 127 and GT), using the Newcastle-Ottawa Quality Assessment Scale (NOS), which is a 128 validated scale for non-randomized observational studies in meta-analyses [8] . A NOS 129 scale adapted for cross-sectional studies was specifically used [9] . The NOS scale uses 130 a star system to assess the quality of a study in three domains: selection, 131 comparability and outcome/exposure. The NOS assigns a maximum of five stars for 132 selection, two stars for comparability, and three stars for outcome/exposure. Studies 133 7 achieving a score of at least eight stars were classified as being at low risk of bias (i.e., 134 thus reflecting the highest quality). Data extraction and quality assessment 137 For all eligible studies, we extracted information on study country, study size, The pooled prevalence of established diabetes and the odds of having severe/critical 153 COVID-19 illness or in-hospital mortality were considered as the effect size for all 154 eligible studies, and an overall estimate of effect size was calculated using a 155 8 random-effects model, as this methodology takes into account any differences 156 between studies even if there is no statistically significant heterogeneity [8, 11] . The 157 95% confidence intervals for the eligible studies that were used for estimating the 158 pooled prevalence of established diabetes amongst hospitalized patients with 159 COVID-19 were computed by the Wilson's score method [12] . The possibility of publication bias was evaluated using the funnel plot and the Egger's 170 regression asymmetry test [14] . To examine the possible sources of (expected) high heterogeneity among the pooled 173 studies and to test the robustness of the associations, we conducted some subgroup 174 analyses. In particular, based on the data from eligible studies, the pooled prevalence 175 of established diabetes was assessed stratifying the studies according to study 176 country (Asian vs. non-Asian countries), age (<60 vs. ≥60 years), COVID-19 severity of 177 9 illness (non-severe vs. severe/critical), or discharge vital status (dead or alive). Additionally, we tested for possibly excessive influence of individual studies using a 179 meta-analysis influence test that eliminated each of the included studies at a time. 180 We also performed univariable meta-regression analyses in order to examine the 181 effect of age and sex on the association between established diabetes and risk of 182 both COVID-19 severity and in-hospital mortality in the eligible studies. <0.10 was used to determine statistical significance considered for heterogeneity. The proportion of heterogeneity accounted for by between-study variability was also 187 estimated using the I 2 -statistics and adjudicated to be significant if I 2 value was >50%. 188 We used STATA® 14.2 (StataCorp, College Station, Texas) for all statistical analyses. Specifically, the STATA metaprop command was used for statistical analyses. between diabetes and risk of in-hospital mortality associated with Pre-existing diabetes was significantly associated with a ~three-fold greater risk of 245 in-hospital mortality associated with COVID-19 (n=15 studies included; 246 random-effects odds ratio 2.68, 95%CI 2.09-3.44; I 2 =46.7%). the association between established diabetes and risk of these two clinical outcomes 286 (especially for in-hospital mortality) appeared to be independent of age and sex. Our results corroborate and extend the recent findings of some smaller 289 meta-analyses performed in Chinese patients with laboratory-confirmed COVID-19. In a meta-analysis of 12 studies including 2,108 Chinese hospitalized patients with relevant comorbidities showed that pre-existing diabetes was independently 344 associated with poorer in-hospital outcomes, and that diabetic patients with better 345 controlled blood glucose had a less severe COVID-19 illness and lower mortality rate 346 compared to those with poorly controlled blood glucose during hospitalization 347 [95, 96] . Third, the majority of patients (i.e., ~85% of total) included in the 348 meta-analysis were of Asian ancestry (mostly Chinese population), and it was not 349 possible to test for ethnic-specific differences in risk of COVID-19 severity and of seven methods. Stat Med. 1998; 17: 857-872. 423 13. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 424 2002; 21: 1539 -1558 14. Egger M, Smith GD, Phillips AN. Meta-analysis: principles and procedures. BMJ. 1997; 426 315: 1533 -1537 15. Xu T, Chen C, Zhu Z, Cui M, Chen C, Dai 40. 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Zhang H, Penninger JM, Li Y For more information, visit www.prisma-statement.org. Records identified through electronic databases searching (published up to May 15th, 2020) 1448) • Little is known about the association of diabetes with the clinical severity and in-hospital mortality associated with COVID-19. • We meta-analyzed 83 observational studies for a total of 78,874 in-patients with COVID-19. • Pre-existing diabetes was associated with a two to three times greater risk of severe/critical illness and in-hospital mortality associated with COVID-19. 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