key: cord-0833163-zmii965v
authors: Shukla, Alpana P.; Tchang, Beverly G.; Lam, Tiffany; Steller, Ian; Samir Touhamy, I.I.; Askin, Gulce; Mendelsohn Curanaj, Felicia A.; Seley, Jane J.; Lorber, Daniel; Safford, Monika M.; Aronne, Louis J.; Alonso, Laura C.
title: Preadmission Predictors of Severe COVID-19 in Patients with Diabetes Mellitus
date: 2021-05-28
journal: J Diabetes Complications
DOI: 10.1016/j.jdiacomp.2021.107967
sha: 6e11fa4f8f24d4da3ac9ae4b4c65024718be8695
doc_id: 833163
cord_uid: zmii965v

OBJECTIVE: To explore predictors of severe COVID-19 disease in patients with diabetes hospitalized for COVID-19. METHODS: This is a retrospective observational study of adults with diabetes admitted for COVID-19. Bivariate tests and multivariable Cox regression were used to identify risk factors for severe COVID-19, defined as a composite endpoint of intensive care unit admission/ intubation or in-hospital death. RESULTS: In 1134 patients with diabetes admitted for COVID-19, more severe disease was associated with older age (HR 1.02, p<0.001), male sex (HR 1.28, p=0.017), Asian race (HR 1.34, p=0.029 [reference: white]), and greater obesity (moderate obesity HR 1.59, p=0.015; severe obesity HR 2.07, p=0.002 [reference: normal body mass index]). Outpatient diabetes medications were not associated with outcomes. CONCLUSIONS: Age, male sex, Asian race, and obesity were associated with increased risk of severe COVID-19 disease in adults with type 2 diabetes hospitalized for COVID-19. SUMMARY: In patients with type 2 diabetes hospitalized for COVID-19 disease, we observed that age, male sex, Asian race, and obesity predicted severe COVID-19 outcomes of intensive care unit admission, intubation, or in-hospital death. The risk conferred by obesity increased with worsening obesity. Outpatient diabetes medications were not observed to be significant predictors of study outcomes.

Diabetes has been identified as an independent risk factor for COVID-19 severity in multiple studies; however, data regarding predictors of poor clinical outcome among patients with diabetes are mixed (1) (2) (3) . Initial findings from Wuhan suggested age and pre-admission insulin therapy were associated with increased risk of mortality or poor prognosis (1) . The multicenter CORONADO study of admitted patients with diabetes and COVID-19 found that only body mass index (BMI) was associated with the composite outcome of tracheal intubation for mechanical ventilation and/or death within 7 days of admission. Age, treated obstructive sleep apnea, and microvascular and macrovascular complications of diabetes were found to be predictors of 7-day mortality, while outpatient insulin usage was not (2) . A recent analysis of pre-admission diabetes-specific risk factors in a predominantly Black population showed that obesity and outpatient insulin treatment predicted mortality (3).

To further clarify risk factors associated with COVID-19 severity in patients with diabetes, we conducted a retrospective cohort study in a large, racially diverse population of (4, 5) . Clinical courses were followed for all patients admitted during the study period until the occurrence of an event, discharge or until date last observed.

Data on demographics, medical history, and outpatient diabetes medications were queried and abstracted from electronic health records and manually verified. All inpatients with COVID-19 confirmed by reverse transcriptase-polymerase chain reaction were eligible for inclusion.

Diabetes status was defined by documentation of type 1 or type 2 diabetes or by hemoglobin A1c (HbA1c) ≥ 6.5% within 90 days prior to or 10 days following the date of admission. BMI categories were defined according to the World Health Organization, including race-specific thresholds for Asian populations: (BMI [kg/m 2 ], overweight: 23.0-27.4; mild obesity: 27.5-32.4; moderate obesity: 32.5-37.4; severe obesity: ≥37.5) (6).

Bivariate tests (i.e., Wilcoxon rank-sum, chi-square and Fisher's exact) were used to explore associations between clinical and demographic variables and COVID-19 outcomes.

Multivariable Cox regression adjusting for covariates selected by bivariate testing or clinical relevancy (i.e., age, sex, race, body mass index, coronary artery disease, congestive heart failure, cerebrovascular accident, hypertension, pulmonary disease, chronic kidney disease, smoking, and individualized outpatient diabetes medications) was used to assess independent risk factors for the composite outcome and mortality, separately. All analyses were based on non-missing data. The study was approved by the Institutional Review Board.

A total of 1134 patients with diabetes were included in the analyses. Median age was 69 years (interquartile range [IQR] 60, 79) and 59% were male. Nearly all patients (96%) had J o u r n a l P r e -p r o o f Journal Pre-proof documented type 2 diabetes. The race distribution was 26% white, 23% Asian, 16% Black and 35% other (patient-selected category). The median HbA1c (n=689) was 7.6% (IQR 6.7, 9.3) . The composite outcome occurred in 476 (42%) patients, and in-hospital mortality occurred in 339 (30%).

Multivariable Cox regression analysis showed that, age, male sex, Asian race, underweight and obesity were independently associated with greater risk of the composite outcome (Table 1) .

Age, male sex, and underweight were also associated with higher mortality.

In a separate multivariable model containing extended BMI classes, accounting for age, sex, race, comorbidities and outpatient diabetes medications, we observed a J-shaped curve for the risk of the composite outcome, with both lowest and highest BMI categories conferring greater risk compared to normal BMI and increasing risk with greater severity of overweight/obesity: underweight (HR 1.65; 95% CI 1.05, 2.60), overweight (HR 1.14; 0.88, 1.46), mild obesity (HR 1.22; 0.92, 1.62), moderate obesity (HR 1.59; 1.09, 2.32) and severe obesity (HR 2.07; 1.29, 3.30). In addition to age, male sex, and underweight, another independent risk factor for mortality was severe obesity (HR 1.76; 1.02, 3.03).

To our knowledge, this study is the first to assess risk factors utilizing race-specific BMI cut-offs in a diverse U.S. cohort of patients with diabetes. Our study corroborated previous reports highlighting the increased risk of COVID-19 severity conferred by age, male sex, and obesity in patients with diabetes, but outpatient diabetes medications were not found to be independent predictors of increased COVID-19 severity. Metformin demonstrated a protective effect in unadjusted bivariate analysis that was not confirmed after adjustment for multiple J o u r n a l P r e -p r o o f Journal Pre-proof covariates. The association of diabetes medications with COVID-19 severity has been inconsistent in the literature with some observing a reduced risk of mortality with outpatient metformin usage (7-9), while others finding no effect (4). One explanation for this difference in observations may be the dose of metformin (7), which requires a level of granularity that is often absent in retrospective studies. Prospective studies are needed to better understand the effect of antihyperglycemic therapies and risk of severe COVID-19 disease.

Study limitations included incomplete data on glycemic outcomes and lack of information regarding diabetes duration, diabetes-related complications, and socioeconomic status. Additionally, certain covariates (e.g., ethnicity, Asian subgroups, dose or strength of diabetes medication) were not included in our multivariable model due to lack of granularity in the dataset, while other potential covariates (e.g., cirrhosis, hepatitis, human immunodeficiency virus, active cancer, transplant status, inflammatory bowel disease, rheumatologic disorder) were excluded due to the small proportion of individuals with these characteristics. Finally, given that our cohort predominantly had type 2 diabetes, our findings cannot be applied to populations with type 1 diabetes.

The strengths of our study included a racially diverse population with a significant Asian proportion, utilization of race-specific BMI thresholds for obesity classification, and delineation of a graded risk with increasing BMI above normal that was statistically significant for moderate and severe obesity. The increased risk of COVID-19 severity in Asian patients is not unexpected 

Clinical Characteristics and Outcomes of Patients With Diabetes and COVID-19 in Association With Glucose-Lowering Medication

Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study

Preadmission Diabetes-Specific Risk Factors for Mortality in Hospitalized Patients With Diabetes and Coronavirus Disease

Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: a nationwide cohort study

Conceptualization, Methodology, Supervision, Writing-Original Draft, Writing-Review & Editing

Visualization, Writing-Original Draft, Writing-Review & Editing Tiffany Lam

Formal Analysis, Methodology, Writing-Review & Editing Felicia A. Mendelsohn Curanaj, M.D.: Methodology, Writing-Review & Editing Jane J. Seley, D.N.P.: Methodology, Writing-Review & Editing Daniel Lorber, M.D.: Resources, Writing-Review & Editing

Resources, Writing-Review & Editing

Methodology, Funding Acquisition, Writing-Review & Editing Laura C. Alonso, M.D.: Conceptualization, Methodology, Writing-Review & Editing J o u r n a l P r e