Both high and low pre-infection glucose levels associated with increased risk for severe COVID-19: New insights from a population-based study

Importance Patients with diabetes are known to be at increased risk for infections including severe coronavirus disease 2019 (COVID-19) but the relationship between COVID-19 severity and specific pre-infection glucose levels is not known. Objective To assess the differential effects of pre-infection glucose levels on the risk for severe COVID-19 amongst patients with and without diabetes. Design Population based historical cohort study. Setting National state-mandated HMO. Patients All adult patients with a positive SARS-COV2 test between March-October 2020. Exposure Recent fasting blood glucose (FBG) and glycated hemoglobin (HBA1C), age, gender, body mass index (BMI) and diagnoses of diabetes, hypertension, ischemic heart disease. Outcome Risk for severe COVID-19, defined as resulting in >= 10 hospitalization days, ICU admission or death. Results 37,121 patients with a positive SARS-COV2 test were identified; 707 defined as severe (1.9%). Unadjusted risk factors for severe disease were age (OR = 1.1 for every year increase; 95% CI 1.09-1.11, p < 0.001), male gender (OR = 1.34, 95% CI 1.06-1.68, p = 0.012); BMI (OR = 1.02 for 1 kg/m(2) increase, 95% CI 1.00-1.04, p = 0.025). Controlling for these factors, we found an association between pre-infection FBG and the risk of severe COVID-19, with a differential effect in patients with and without a diagnosis of diabetes. For patients without diabetes, elevated FBG in the pre-diabetes range (106-125 mg/dl) was associated with severe COVID-19 (OR 1.55 95% CI 1.04-2.26 p = 0.027). For patients with a diagnosis of diabetes, we found a J-shaped association between pre-infection glucose control and the risk for severe COVID-19 where the lowest risk for was for patients with FBG 106-125 mg/dl; the risk increased with higher pre-infection glucose levels but strikingly also for patients with a low pre-infection FBG (<100mg/dl) or HbA1C (<5.7%). Conclusions and relevance Elevated pre-infection blood glucose is a risk factor for severe COVID-19 even in non-diabetics. For patients with a diagnosis of diabetes both high as well as low pre-infection glucose levels are risk factors for severe COVID-19. Further research is required to assess whether these associations are causal, but we believe these findings can already have clinical implications for COVID-19 risk assessment and stratification.

Automated summary

This study indicates that elevated pre-infection blood glucose is a risk factor for severe COVID-19, even in non-diabetic individuals. For patients with diabetes, both high and low pre-infection glucose levels are risk factors for severe COVID-19. Further research is needed to determine if these associations are causal, but these findings can already have clinical implications for COVID-19 risk assessment and stratification.