Sex disparities in COVID-19 outcomes of inpatients with diabetes: insights from the CORONADO study

Abstract

Objective: Male sex is one of the determinants of severe coronavirus diseas-e-2019 (COVID-19). We aimed to characterize sex differences in severe outcomes in adults with diabetes hospitalized for COVID-19.

Methods: We performed a sex-stratified analysis of clinical and biological features and outcomes (i.e. invasive mechanical ventilation (IMV), death, intensive care unit (ICU) admission and home discharge at day 7 (D7) or day 28 (D28)) in 2380 patients with diabetes hospitalized for COVID-19 and included in the nationwide CORONADO observational study (NCT04324736).

Results: The study population was predominantly male (63.5%). After multiple adjustments, female sex was negatively associated with the primary outcome (IMV and/or death, OR: 0.66 (0.49-0.88)), death (OR: 0.49 (0.30-0.79)) and ICU admission (OR: 0.57 (0.43-0.77)) at D7 but only with ICU admission (OR: 0.58 (0.43-0.77)) at D28. Older age and a history of microvascular complications were predictors of death at D28 in both sexes, while chronic obstructive pulmonary disease (COPD) was predictive of death in women only. At admission, C-reactive protein (CRP), aspartate amino transferase (AST) and estimated glomerular filtration rate (eGFR), according to the CKD-EPI formula predicted death in both sexes. Lymphocytopenia was an independent predictor of death in women only, while thrombocytopenia and elevated plasma glucose concentration were predictors of death in men only.

Conclusions: In patients with diabetes admitted for COVID-19, female sex was associated with lower incidence of early severe outcomes, but did not influence the overall in-hospital mortality, suggesting that diabetes mitigates the female protection from COVID-19 severity. Sex-associated biological determinants may be useful to optimize COVID-19 prevention and management in women and men.

Figure 1

Sex-associated predictive factors of COVID-19-related death at day 28 (D28). Multivariable analysis of death at D28: covariates prior to (Model A) and at admission (Model B). Model A was applied to 541 women and 891 men yielding respectively 80 and 164 deaths at 28 days. Model B was applied to 533 women and 911 men yielding respectively 79 and 175 deaths at 28 days. Regarding quantitative variables: all were natural-log transformed, except for age, and the ORs correspond to an increase of 1 s.d. after standardization. Microvascular complications correspond to severe diabetic retinopathy, diabetic kidney disease and/or history of diabetic foot ulcer; macrovascular complications correspond to ischemic heart disease, cerebrovascular disease and/or peripheral artery disease; COPD, chronic obstructive pulmonary disease; OSA, obstructive sleep apnea; eGFR, estimated glomerular filtration rate was determined by the CKD-EPI formula; AST, aspartate amino transferase; ULN, upper limit of normal; OR, odds ratio.

Figure 2

Association of biological markers on admission with COVID-19-related death at day 28 (D28) according to sex. Values are stratified according to cut-off values previously shown to correlate with increased disease severity or mortality in COVID-19 or clinically relevant (lymphocytes < 1000/mm³; platelets < 150 × 10³/μL; CRP > 41.2 mg/L; LDH > 365 IU/L; eGFR < 60 mL/min/1.73m²; AST > 3ULN). OR, odds ratio; Nm, number of men included in the model; Nw, number of women included in the model; LDH, lactate dehydrogenase; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate, according to the CKD-EPI formula; AST, aspartate amino transferase; ULN: upper limit of normal. Multi-adjustment on age, BMI, smoking, microvascular complications, macrovascular complications, hypertension, chronic obstructive pulmonary disease (COPD) and treated obstructive sleep apnea (OSA).