In the present study, we used a comprehensive database containing data collected the clinical outcomes of COVID-19 to study the relationships of type 2 diabetes, CKD, and their interaction with poor outcomes. We found that type 2 diabetes and CKD increase the risk of a poor outcome in patients with COVID-19 and that there is a synergistic interaction between type 2 diabetes and CKD, particularly in terms of in-hospital mortality.
In the present study, we have demonstrated a significant positive association between type 2 diabetes or CKD and a poor outcome in patients with COVID-19 after adjustment for age; sex; coronary atherosclerotic cardiopathy; chronic obstructive pulmonary disease; cerebral infarction; cancer; antiviral drug use; the leukocyte, lymphocyte, and neutrophil counts; the circulating concentrations of CRP, D dimer, albumin, and cholesterol; and the presence of consolidation or ground-glass opacities on imaging. Type 2 diabetes is a progressive chronic disease characterized by hyperglycemia(15), and previous studies have demonstrated that it is a risk factor for severe COVID-19(16). The possible mechanisms of this are that diabetes mellitus is associated with immune dysfunction, greater susceptibility to inflammation, and reduced viral clearance(17, 18, 19, 20). Furthermore, SARS-CoV-2 has glycoprotein spikes on its surface, which can bind to angiotensin-converting enzyme 2 (ACE2) on the target cell membrane(21). The expression of the ACE2 receptor and furin is high in patients with diabetes mellitus, which would facilitate the entry of SARS-CoV-2 and its replication(22, 23). Thus, patients with diabetes may more susceptible to SARS-CoV-2 infection and experience worse clinical outcomes. CKD is a progressive disease characterized by the gradual loss of kidney function(24). Previous studies have shown that patients with CKD are more likely to have a poor outcome of COVID-19 than those without, and CKD is also associated with higher risks of mortality and severe COVID-19(25, 26, 27). This may be because of the impaired activation of both the innate and adaptive immune systems, resulting in greater susceptibility to infection in patients with CKD.(28, 29, 30, 31). Therefore, both type 2 diabetes and CKD increase the risk of a poor outcome in patients with COVID-19.
We next determined whether there is an interaction between type 2 diabetes and CKD to increase the risk of a poor outcome in patients with COVID-19. We found that patients with type 2 diabetes or CKD had 3.302- and 4.703-fold higher risks of a poor outcome, respectively. However, patients with both type 2 diabetes and CKD had a 27.139-fold higher risk. Moreover, type 2 diabetes and CKD also showed significant positive additive interactions, further increasing the risk of a poor outcome. The estimated RERI was 20.134, implying that there is a 20-fold relative excess risk owing to the interaction between type 2 diabetes and CKD. Calculation of the AP value revealed that 74.2% of the total risk of a poor outcome could be attributed to the interaction between type 2 diabetes and CKD. In addition, the SI was calculated to be 4.353, indicating that the risk of a poor outcome in patients with both type 2 diabetes and CKD was 4.353 times higher than the sum of the risks associated with a single comorbidity.
Several mechanisms may explain the additive interaction between type 2 diabetes and CKD with respect to a poor outcome of COVID-19. First, both diabetes and CKD are associated with chronic inflammation and impairments in immune function (32, 33, 34), and their coexistence is associated with a still higher risk of infection. Moreover, when patients with diabetes or CKD are infected with COVID-19, these pre-existing conditions can cause an exacerbation of the inflammatory response to the virus. This may involve a cytokine storm (35, 36), which is a serious immune response in which large amounts of cytokines are released, causing damage to multiple organs, including the lungs, heart, and kidneys; thereby increasing the risk of mortality (37). Second, type 2 diabetes and CKD are key components of the metabolic syndrome (38). Diabetes and CKD involve the dysregulation of glucose and electrolyte homeostasis, which can lead to complications such as diabetic ketoacidosis and hyperkalemia (39, 40). Third, both diabetes and CKD involve endothelial cell dysfunction and are associated with greater platelet activation and aggregation, leading to a hypercoagulable state, which increases the risks of venous thromboembolism and mortality (41, 42). Finally, patients with diabetes or CKD frequently also have other cardiovascular risk factors, and the combination of diabetes and CKD predisposes toward the development of cardiovascular disease. Previous studies have shown that such patients are more likely to die than those who do not have diabetes or CKD (43, 44). Thus, the findings of the present study confirm that there are biological interactions between diabetes and CKD in patients with COVID-19 that lead to worse outcomes. However, the specific mechanisms involved and the significance of the interaction remain unclear, and therefore further studies are warranted.
The subgroup analysis showed a synergistic effect of the combination of type 2 diabetes and CKD on the risk of in-hospital mortality, but not on those of invasive ventilation or ICU admission. This may be because the requirements for invasive ventilation and ICU admission were underestimated, or because if a patient’s prognosis was extremely poor, their family might have refused invasive ventilation and transfer to the ICU for treatment(45). In addition, because the study was conducted during the peak of the COVID-19 pandemic, when a large number of patients were admitted to hospital in a serious condition, a limited number of ICU beds were available. Therefore, it was recommended that clinicians should actively intervene with respect to hyperglycemia during the routine treatment of COVID-19 and attempt to improve the kidney function of their patients.
There were certain limitations to the study that should be noted. First, it was a retrospective study, meaning that there may have been selection bias, and therefore a large prospective study is needed to confirm our findings. Second, even though we performed a multivariable analysis, involving adjustment for multiple potential confounders, the possibility of residual confounding, including by socioeconomic status and polypharmacy, could not be ruled out. Finally, the participants were not representative of patients with COVID-19 in the general population or in other clinical settings, but rather only those attending a Department of Respiratory and Critical Care Medicine.
In conclusion, we have shown that type 2 diabetes and CKD increase the risk of a poor outcome in patients with COVID-19, and that they synergistically interact to worsen the outcome of patients with COVID-19. In addition, in a subgroup analysis, we found a significant synergistic effect on the risk of in-hospital mortality specifically. These findings imply that efforts should also be made to improve the blood glucose concentrations and kidney function of patients with COVID-19, in addition to treating the primary disease. These findings provide epidemiological evidence for the independent associations of type 2 diabetes and CKD with poor outcomes and for a synergistic effect of the two on the outcomes of patients with COVID-19.