The COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, it is a novel and serious global health threat that is spreading rapidly across the globe, with confirmed infections and death. The number of infections is growing, with around 500 million confirmed cases worldwide and more than 6 million deaths. Most patients have mild symptoms, but some may develop severe complications, including ARDS, multiple organ failure, septic shock and hypercoagulability, which may eventually result in death (1–3). While large-scale vaccine production has provided a glimmer of hope for humanity for now, the absence of global vaccination and the continued mutation of the virus make eradication of SARS-CoV-2 challenging. Among them, the largest COVID-19 study in the United States found that among 5,700 hospitalized patients with COVID-19, diabetes was one of the most common comorbidities (33.8%), and chronic disease comorbidities had a significant impact on the clinical outcomes of patients with COVID-19 (4). Studies have shown that people with underlying comorbidities of diabetes are more likely to experience adverse outcomes from COVID-19. The COVID-19 pandemic has placed a huge burden on healthcare facilities, especially for the patients who are with them. Most studies report that diabetes is associated with a higher risk of serious events and mortality (5, 6), while others have no clear association (7, 8), so whether diabetes is associated with adverse outcomes in COVID-19 patients controversy remains. This inconsistency may be related to different sample sizes, different populations, and varying levels of confounding adjustment. Numerous articles show the clinical features of COVID-19 patients in various countries (9, 10), but few studies specifically compare the clinical features of COVID-19 in diabetic and non-diabetic patients. This study can provide information on risk factors by correlative analysis of data on essential laboratory parameters and drug treatment for COVID-19 patients with and without diabetes, while helping inform the development of tailored treatment strategies for diabetic COVID-19 patients.

The rapid global spread of COVID-19 suggests that SARS-CoV-2 has a strong transmission potential in humans. In this systematic review and meta-analysis of 32 studies and 192,693 patients, we systematically reviewed and analyzed numerous clinical and laboratory signatures of predisposition leading to COVID-19 related mortality. Multiple lines of evidence suggest that diabetes is one of the major risks of death in COVID-19 patients, and is considered to be the underlying mechanism of microvascular disease, endothelial dysfunction, severe pneumonia, inflammatory storm, which underlie the adverse outcomes of COVID-19 (12, 13). To the best of our knowledge, this meta-analysis leverages the largest number of studies and largest sample size to date to assess the association between disease severity and mortality risk in COVID-19. Our findings suggest that diabetes in COVID-19 patients is associated with an increased risk of serious infection and mortality compared to non-diabetic patients. Our study provides evidence of how diabetes mediates outcomes in hospitalized adults with COVID-19.

Upon analysis, it was found that the infected patients in the DM group were older, had a higher BMI and were mostly male compared to those without DM, suggesting that they were at higher risk of SARS-CoV-2 infection, with more males than females. This may be due to the fact that females produce extra strong immune response, as estrogen and progesterone can help increase innate and adaptive immune responses, estrogen also promotes B-cell activation, maturation (14, 15). Hypertension is commonly reported as the most common disease associated with COVID-19 patients. It is also an independent risk factor for higher mortality and morbidity in patients with coronavirus infection (16), persistent hyperglycemia and metabolic changes in patients with diabetes and coexisting risk factors. Hypertension causes microvascular changes as well as macrovascular changes, creating a vicious cycle that also leads to cardiovascular events. Therefore, additional attention should be paid to diabetics with underlying comorbidities, especially hypertension. The analysis found that the prevalence of high blood pressure, cerebrovascular disease, chronic kidney disease was significantly higher in the large number of diabetic patients infected with SARS-CoV-2, who were also older than the non-diabetic patients. Diabetes-related comorbidities and uncontrolled hyperglycemia increase the risk of composite endpoints and mortality in COVID-19 patients, especially the increased cardiovascular risk associated with diabetes and hypertension, which additionally contribute to poor outcomes in COVID-19. Common early symptoms of COVID-19 patients include fever, cough, sputum production and additional symptoms of lower respiratory tract infection. As the most common symptom, more than 80% of patients had a fever, but about 40% had a fever on admission, indicating that many patients had intermittent fevers. However, in this meta-analysis there can be no differences in fever between the two groups with cough and dyspnea (Supplementary Table 2). Radiographic findings hinted that bilateral pneumonia obtained on chest CT was more prevalent in diabetic patients, suggesting that these patients had more severe pneumonia.

The COVID-19 virus spreads through the respiratory mucosa and induces a cytokine storm in the body, producing a series of immune responses that alter peripheral white blood cells and lymphocytes, thus increasing inflammation levels. Cell counts increased but lymphocyte counts were significantly lower. The findings may suggest that people with diabetes are more susceptible to viral infections and more susceptible to bacterial infections. Hyperglycemia inhibits neutrophil chemotaxis, reduces phagocytosis of neutrophils, macrophages, monocytes, and impairs cell-mediated immunity (17). The reduction in lymphocyte counts indicates that SARS-CoV-2 depletes immune cells and suppresses the body’s immune function. In addition, severe patients had significantly fewer lymphocytes than non-severe patients, suggesting that the degree of lymphocyte decline can be used to assess the severity of the disease. The continued decline of lymphocytes in the cells is also an indicator of disease progression. The levels of inflammatory markers including CRP, erythrocyte sedimentation rate (ESR), TNF-α, Procalcitonin, IL-6, and IL-8 in diabetic patients were significantly higher than those in non-diabetic patients, while CD4+ and CD8+ were lower than in the control group (Supplementary Table 3). CRP is simply an inflammatory biochemical marker, elevated levels of CRP hint the introduction of a cytokine storm by 2019-nCoV, which is critical for the progression of 2019-nCoV. A higher PCT indicates an increased risk of systemic infection and sepsis among diabetic patients infected with COVID-19. Elevated glucose levels directly induce viral replication and pro-inflammatory cytokine expression, which primarily affect lymphocytes, especially T cells, with an increased proportion of pro-inflammatory Th17 CD4+ T cells and cytokine levels. CD4+ and CD8+ peripheral counts of T cells decreased. Meanwhile, viral infection promotes T cell programmed cell death protein 1 (PD-1) expression. Thus, hyperglycemic patients may exhibit impaired antiviral interferon responses and delayed Th1/Th17 activation, which lead to hyperinflammatory responses (18, 19), it may explain why blood glucose levels are elevated during SARS-CoV-2 infection cause T cell dysfunction and lymphopenia. Studies have shown that hyperglycemia plays a deleterious role in the overproduction of IL-6, which is associated with increased lung infiltration and severity of COVID-19, for elevated IL-6, anti-IL-6 therapeutic strategies (Tocilizumab or Janus kinase inhibitors) may be particularly effective in DM patients with severe COVID-19 (12, 20). One study pointed out that inflammatory markers such as CRP levels, serum ferritin and ESR in COVID-19 cases were positively correlated with glycated hemoglobin, while SaO2 was negatively correlated with glycated hemoglobin (21), therefore, low and elevated HbA1c levels may have a positive correlation. Identification of risk of death and adverse outcomes in hospitalized COVID-19 patients. A recent study showed that even patients with diabetes who had properly-controlled HbA1c (6–7%) had a risk of serious infections compared with patients without diabetes, and that this risk increased with increased HbA1c (22). At the same time, hypoglycemia or hyperglycemia is associated with poor prognosis and poor clinical outcomes. Some studies on the management of hospitalized patients with hyperglycemia (especially in the ICU setting) suggest that blood glucose levels should be maintained between 7.8-10 mmol/L to avoid excessive hyperglycemia or moderate/severe hypoglycemia, preventing multiple organ failure and fatal consequences. Second, DM may induce clotting in COVID-19 patients, especially D-dimer produced from fibrin degradation, reflecting the severity of the clotting condition. In addition to deep vein thrombosis, elevated D-dimer can be the expression of capillary microthrombi, which leads to an increased risk of death due to pulmonary capillary endothelial damage (23), some preventive regimens should be taken in clinical work. In addition, indicators of kidney injury, including serum creatinine and blood urea nitrogen are associated with higher mortality in patients with COVID-19, plenty of patients with diabetes have significantly lower eGFR on admission compared with non-diabetic patients, which is due to the incidence of acute kidney injury in patients with diabetes higher than non-diabetic patients. Diabetics commonly develop a chronic inflammatory condition. It makes these patients more vulnerable to the devastating effects of the so-called COVID-19 cytokine storm, causing multiple organ damage and secondary pathophysiological changes in tissues (24), leading to severe complications such as ARDS, shock, acute heart and kidney damage in novel coronavirus pneumonia. Respiratory support for patients with RSV is critical to reducing mortality because the disease is so severe. It is essential to note that most patients require hyperbaric oxygen therapy. Some patients require mechanical ventilation, both invasive and noninvasive. As can be seen from the data, infected patients in the diabetes group required more mechanical ventilation. We found that patients with diabetes were more likely to be transferred to the ICU and were treated most frequently with antibiotics, antivirals, corticosteroids, and especially advanced life support including ECMO, mechanical ventilation, and continuous renal replacement therapy. Intravenous corticosteroids are indicated primarily for acute respiratory distress syndrome in mechanically ventilated patients with novel coronavirus pneumonia. They are administered in the shortest amount of time to reduce side effects. In terms of hypoglycemia treatment, current recommendations for hypoglycemia medication for diabetics with COVID-19 mainly contain the use of metformin and DPP-4 inhibitors for mild cases and the addition of insulin for severe cases. In terms of antihypertensive therapy, angiotensin converting enzyme 2 (ACE2) may genuinely protect against severe respiratory infections by converting angiotensin II to angiotensin with significant anti-inflammatory properties, so an angiotensin converting enzyme inhibitors (ACEI) that results in increased ACE2 expression may really be beneficial, using ACEI or angiotensin II receptor blockers (ARBs) may benefit COVID-19 outcomes and positively modulate its outcomes, the recent meta-analyses further support the role of ACEIs and ARBs in disease progression beneficial effect (25). Studies have suggested that another significant factor contributing to poor outcomes is the use of beta-blockers in hospitalized COVID-19 patients, although controversial, β-blockers may be beneficial because they reduce pulmonary vascular flow, ultimately reducing additional damage to the lungs of patients with suspected ARDS (26).

In summary, this is the largest meta-analysis to date of the clinical characteristics and outcomes of diabetic patients infected with SARS-CoV-2. A large global multicenter study of data showed that patients with diabetes who were hospitalized with COVID-19 had an increased risk of death, lower hospital discharge rates and higher ICU admission rates than patients without diabetes. Hypertension, cerebrovascular disease, CKD, higher levels of inflammatory markers, and multiple complications in COVID-19 patients with diabetes are all predictors of poor outcomes in people with diabetes. Our findings will help identify elevated risk factors in diabetes patients, which will aid in early prediction, accurate diagnosis and treatment of COVID-19 patients.