Risk of mortality among inpatients with COVID‐19 and type 2 diabetes: National data from Kuwait

Abstract Introduction To investigate type 2 diabetes as a risk factor for COVID‐19 death following hospital admission in Kuwait. Methods A retrospective cohort study using data from a central hospital that cared for all hospitalized COVID‐19 patients in Kuwait. We investigated the association between type 2 diabetes, with COVID‐19 mortality using multiply imputed logistic regression and calculated the population attributable fraction. Results A total of 5333 patients were admitted with COVID‐19, of whom 244 died (4.6%). Diabetes prevalence was 24.8%, but 53.7% of those who died had diabetes. After adjusting for age, sex, ethnicity and other comorbidities, diabetes was associated with death (OR 1.70 [95% CI 1.23, 2.34]) and admission to the intensive care unit more than 3 days after initial admission (OR 1.78 [95% CI 1.17, 2.70]). Assuming causality, the population attributable fraction for type 2 diabetes in COVID‐19 death was 19.6% (95% CI 10.8, 35.6). Conclusion Type 2 diabetes is a strong risk factor for COVID‐19 death in the Middle East. Given the high prevalence of type 2 diabetes in the Middle East, as well as many Western countries, the public health implications are considerable.


| INTRODUC TI ON
The COVID-19 pandemic 1 has led to efforts to identify people at greatest risk including older age groups, those with comorbidities such as type 2 diabetes and cardiovascular disease (CVD), poor oxygen saturation and elevated markers of inflammation. [2][3][4] The association of type 2 diabetes with poor outcomes is of particular interest, 5 since it is a risk factor that is potentially amenable to public health interventions.
Kuwait faces specific challenges in terms of health care, due to the high burden of obesity, poor lifestyle and type 2 diabetes.
Specifically, prevalence of type 2 diabetes in older adults is around 25% and obesity 40%-50%. 6,7 Previous studies and a systematic review have shown that the issue of incidence and clinical management of type 2 diabetes in Kuwait and the Middle East in general is complicated by several lifestyle and cultural circumstances including low levels of habitual physical activity, peer and family pressure to consume a poor diet and poor medication adherence. 8 For instance, a hot climate, as well as lack of facilities and infrastructure to promote physical activity (such as pavements and walking routes), high traffic volume and cultural expectations surrounding PA behaviour among women are highly impactful. 9 This raises the question of whether diabetes is a particular risk factor for poor COVID-19 outcomes in the Middle East, since the severity and prevalence of type 2 diabetes is distinct in this area of the world. One recent study specifically in people with type 2 diabetes in Kuwait suggests that diabetes patients with COVID-19 have poor clinical prognosis. 10 We have previously reported demographic and clinical data on the first consecutive 1096 patient to be admitted to hospital with COVID-19 in Kuwait, 11 and here, we expand to make use of this resource. Specifically, our objective was to investigate the importance of type 2 diabetes as a risk factors for COVID-19 death in Kuwait, compared with the general population and report the population attributable fraction (PAF) for type 2 diabetes.

| Study population
This retrospective cohort study included a single cohort of adult and paediatric inpatients admitted to Jaber Al Ahmad Al Sabah hospital, the largest tertiary hospital with 1240 bed capacity, and swabs, in accordance with WHO interim guidance. The data are derived from in-hospital databases used during routine care as previously described. 11 Ethical approval for use of the data was obtained by the standing committee for coordination of health and medical research in the ministry of health in Kuwait (IRB 2020/1400).

| Outcome of interest
The primary outcome was death from COVID-19, from the death certificate, which was matched to patients' hospital file numbers and study numbers using the Kuwaiti national Civil ID number, a unique number given to all residents. A secondary outcome was transfer to the intensive care unit (ICU) during COVID-related hospitalization; this secondary outcome was only explored in patients who were not admitted to intensive care in the first 3 days following general admission.

| Exposures of interest
Exposures of interest included age, sex, nationality and ethnicity, smoking status and clinical comorbidities, including type 2 diabetes.
Vitals taken on admission included temperature, pulse, respiratory rate and oxygen saturation, systolic and diastolic blood pressure and body mass index. Laboratory biomarkers variables considered in the present study included routinely measured (as standard of care) platelet count, white blood cell count, estimated glomerular filtration rate

| Statistical analyses
Associations between exposures and outcomes of interest were first explored using a complete case analysis. All tests were performed in R using version 4.0.2. We then implemented and reported an as part of the 'mice' R package. 12 The imputation methods were predictive mean matching for continuous variables and proportional odds models for ordered factor variables. The number of iterations for each permutation was 10, with 10 permutations performed.
Convergence was checked using plots. Pooled confidence intervals were derived using Wald method with pooled estimates and SEs. We reported two models, the first including age, sex, ethnicity and baseline comorbidities. The second model also included clinical vitals and admission and biomarkers of interest. Logistic regression using the multiple imputation data sets was implemented, using model development as detailed above. Additionally, for the first, simpler, model for the mortality outcome, analyses were stratified by median age (43 years) and sex. PAFs were derived for comorbidities using model 1, as above, using the 'AF' R package. 13

| DISCUSS ION
Although Kuwait has a population with a high prevalence of type 2 diabetes and obesity, death rates from COVID-19 were comparable to or lower than those reported in other parts of the world. 14,15 Despite this, type 2 diabetes appears to be an important risk factor for COVID-19 death. Type 2 diabetes was associated with 70% increased odds of in-hospital COVID-19 death, and assuming causality, the PAF for COVID-19 death caused by type 2 diabetes was 19.6%. Our data suggest that type 2 diabetes is an important, and potentially modifiable, driver of COVID-19 deaths, and is of particular concern in countries with high prevalence of the condition.

AUTH O R CO NTR I B UTI O N S
EA-O, YH, LA, NV, JAK, DA-S, AAO, AH and FAM contributed to conception and data acquisition as well as interpretation of the data and critically revised the manuscript for important intellectual content.
YH and NV cleaned the clinical data prior to statistical analysis. SVK, SRG, JMRG, CAC-M and NS contributed to study design, analysis and interpretation of the data and critically revised the manuscript for important intellectual content. RB conducted statistical analyses and with PW contributed to conception and interpretation of the data and wrote the first draft. EA-O is the guarantor and accepts full responsibility for the work and/or the conduct of the study, had access to the data and controlled the decision to publish.

E TH I C A L A PPROVA L
Ethical approval for use of the data was obtained by the standing committee for coordination of health and medical research in the ministry of health in Kuwait (IRB 2020/1400).

DATA AVA I L A B I L I T Y S TAT E M E N T
The raw data of the study can be provided upon request with maintenance of confidentiality, privacy and anonymity of the participants and abiding to ethical board regulations.