European Journal of Cardiovascular Medicine

COVID-19, caused by SARS-CoV-2, has emerged as a rapidly spreading communicable disease, affecting more than 100 countries across the globe. India has reported the highest number of new cases and deaths in Southeast Asia.(1) The burden of COVID-19 is further exacerbated by its association with chronic diseases, including DM, which increases the risk of infection severity and mortality.(2) Interestingly, there is evidence suggesting a bidirectional relationship between COVID-19 and DM. Not only does DM increase the risk and severity of COVID-19, but there is also an increased risk for new-onset DM following SARS-CoV-2 infection. (3) This interconnection is supported by clinical and epidemiological studies, although experimental evidence is still emerging. The global health burden of both conditions is thus intertwined, with COVID-19 potentially contributing to the prevalence of DM through new-onset cases. (4) It reflect a dual burden where DM is prevalent and associated with poorer outcomes in COVID-19, and COVID-19 may contribute to the incidence of DM. This complex interplay highlights the need for integrated healthcare strategies to manage both conditions effectively.(5)

Understanding the mechanisms by which diabetes impacts COVID-19 severity, such as compromised immunity and proinflammatory cytokine responses, is crucial for improving treatment strategies.(6) Contradictorily, one study suggests that diabetes is not the leading cause of comorbidity or mortality in COVID-19, indicating that the relationship may not be as straightforward as previously thought.(7)Moreover, the pandemic has affected diabetes management due to changes in lifestyle and healthcare access, which could indirectly influence

COVID-19 outcomes in diabetic patients. The contradictory findings and the potential for

COVID-19 to affect diabetes control necessitate further research to clarify these associations and to inform clinical practice for better outcomes in diabetic patients during the pandemic.(6) Hence this study was planned to further fill the knowledge gap in understanding the clinical relationship between T2DM and COVID-19.

This retrospective cohort study included a total of 180 COVID-19 patients admitted to SCB Medical College and Hospital, Cuttack, between September 2020 and September 2021. The study population comprised 90 patients with type 2 diabetes mellitus (T2DM) and 90 non- diabetic patients. Following the application of inclusion and exclusion criteria, demographic data, clinical and laboratory findings were collected and compared based on diabetes status. Complications and clinical outcomes were also observed and compared between the two groups.

Inclusion criteria were patients with a confirmed case of COVID-19 through RT-PCR or RAT, patients older than 14 years, and those who provided informed consent. Diabetic patients were those on oral hypoglycaemic agents (OHA) or insulin, while non-diabetic patients had no history of taking OHA or insulin and presented with normal random blood glucose and HbA1c levels. Exclusion criteria included pregnant patients, those who did not consent to participate, patients with type 1 diabetes mellitus, and patients with comorbidities such as COPD, CHF, PVD, CVA, CLD, CKD, malignancies, or AIDS.

The study involved recording clinical, radiological (chest X-ray and/or CT chest), and laboratory data, including complete blood count (CBC), differential white blood cell (WBC) count, and C-reactive protein (CRP) levels at admission and discharge. Additionally, durations of hospitalization, ICU admission, mechanical ventilation, oxygen supplementation, and complications developed were calculated. WHO guidelines were used to categorize the severity of COVID-19 cases.

Statistical analysis was performed using SPSS software (version 26). Nominal data were described as counts and percentages, continuous data as means and standard deviations, and correlations were analysed using the Chi-Square Test for categorical data and Spearman’s Correlation Coefficient for continuous data. Ethical clearance for the study was obtained from the Institutional Ethics Committee (IEC) of SCB Medical College, Cuttack.

The mean age was 52.2 years in diabetics and 49.67 years in non-diabetics. Most common gender in both the groups were male (68.9% in diabetics vs 73.3% non-diabetics). In the diabetic group, 5 patients (5.6%) exhibited mild disease severity, 14 patients (15.6%) exhibited moderate severity, and 71 patients (78.9%) exhibited severe disease. In contrast, in the non- diabetic group, 16 patients (17.8%) exhibited mild severity, 16 patients (17.8%) exhibited

moderate severity, and 58 patients (64.4%) exhibited severe disease. The association between disease severity and diabetes mellitus was statistically significant (Χ² = 7.2053, p = 0.0273).

Figure 1-Distribution of presence of diabetes and COVID -19 severity

Table-1A: Association between of laboratory parameters and Diabetes:

We compared various clinical parameters between diabetic and non-diabetic patients. Diabetic patients had significantly higher Random Blood Sugar (RBS) levels (316.30 ± 136.67) compared to non-diabetic patients (125.85 ± 23.63), with a t-value of 13.026 and p-value <0.0001. Serum Glutamic-Pyruvic Transaminase (SGPT) levels were significantly lower in diabetic patients (53.45 ± 47.40) than in non-diabetic patients (92.97 ± 137.18), with a t-value of 2.584 and p-value of 0.010. C-Reactive Protein (CRP) levels were also higher in diabetic

patients (59.84 ± 43.86) compared to non-diabetic patients (40.72 ± 2.10), with a t-value of 2.065 and p-value of 0.040. No significant differences were observed in haemoglobin (Hb), Serum Glutamic-Oxaloacetic Transaminase (SGOT), and Sedimentation Rate (SR) between the groups.(Table- 1A)

Table 1B: Association between of laboratory parameters and Diabetes:

Our study compared laboratory parameters between diabetic and non-diabetic patients. Lymphopenia was observed exclusively in diabetics (100%, p = 0.073). Diabetics showed slightly higher neutrophilia (53.2%) and significantly higher raised LDH (53.5%, p = 0.017), D-dimer (63.0%, p = 0.0003), and ferritin levels (59.3%, p = 0.002). Thrombocytosis was more common in diabetics (75.0%, p = 0.121), while thrombocytopenia was found only in diabetics (100%).Raised interleukin-6 levels were slightly higher in diabetics (57.7%, p = 0.093). Procalcitonin levels were significantly elevated in diabetics (64.8%, p = 0.001). These findings suggest that diabetics have higher levels of certain inflammatory and coagulation markers compared to non-diabetics, highlighting differences in their clinical profiles.(Table 1B)

Table 2:Risk of complication among diabetics and Non-diabetics

In our study, we compared the occurrence of various complications between diabetic and non- diabetic patients through binary logistic regression. Diabetics had a significantly higher risk of developing acute kidney injury (AKI) (OR=2.42, 95% CI=1.24-4.74, p = 0.009) and sepsis (OR=2.87, 95% CI=1.54-5.36, p < 0.001) compared to non-diabetics. Additionally, the risk of multiple organ dysfunction syndrome (MODS) was markedly higher in diabetics (OR=6.76, 95% CI=1.46-31.18, p = 0.014).Although diabetics showed higher odds of acute respiratory distress syndrome (ARDS) (OR=1.87, 95% CI=0.92-3.81, p = 0.084) and cytokine storm (OR=1.67, 95% CI=0.91-3.05, p = 0.094), these differences were not statistically significant. There was no significant difference in the occurrence of transaminitis between diabetics and non-diabetics (OR=0.79, 95% CI=0.41-1.54, p = 0.5). The risk of death was found to be higher among diabetic as compared to non-diabetic(OR=2.55, 95% CI=1.27-5.09, p = 0.007).These findings suggest that diabetics are at a higher risk for certain severe complications compared to non-diabetics.(Table-2)

Our study reveals that diabetic patients exhibit a higher prevalence of severe complications and elevated inflammatory markers compared to non-diabetic patients. As per current literature,The association between diabetes and COVID-19 with respect to age and gender is multifaceted. A study by Razaq and Alkufi indicates that genetic predisposition, specifically the allele locus 3p21.31 at rs11342, is associated with severe COVID-19 in patients with diabetes who require oxygen supplementation, with a higher incidence in males and a notable impact on C-reactive protein levels in the age group 55-65.(8) Shi et al. also supports the finding that male patients with diabetes have a higher proportion of severe lung infections and worse prognoses.(9)

Our study results showed that diabetes is a significant risk factor for the severity of COVID-

Garg et al. reported that diabetes alone or in conjunction with other comorbidities increases the odds of death in COVID-19 patients. Similarly, Kubjane et al. supports these findings, indicating that individuals with diabetes are more likely to develop a severe clinical course if hospitalized for COVID-19.(10,11) Chen and El-Hashash also highlights the relationship between diabetes and severe acute respiratory distress in COVID-19 patients, emphasizing the importance of early and aggressive diabetes management. Wang et al. further confirms the association between diabetes and increased severity and fatality of COVID-19, suggesting that intensive monitoring and antidiabetic therapy should be considered for patients with diabetes infected with SARS-CoV-2.(12,13)

Current study also highlighted the relationship between diabetes and various laboratory parameters. A study by El-Meligui et al. indicates that the presence of hypertension and/or diabetes was found to be a significant risk factor for disease severity and poor outcome in COVID-19 patients. This suggests that diabetes influence laboratory parameters associated with disease severity, such as highly sensitive C-reactive protein (HS-CRP), D-dimer, neutrophil lymphocyte ratio (NLR), and lactate dehydrogenase (LDH), which were excellent predictors for both disease severity and death. (12) While diabetes is not directly linked to specific changes in serum glutamic-oxaloacetic transaminase (SGOT, also known as aspartate aminotransferase or AST), serum glutamic-pyruvic transaminase (SGPT, also known as alanine aminotransferase or ALT), sedimentation rate (SR), C-reactive protein (CRP), platelet count, LDH, D-dimer, interleukin-6 (IL-6), and procalcitonin (PCT) in the provided papers, it is reasonable to infer that diabetes, as a comorbidity, could exacerbate the alterations in these parameters that are associated with COVID-19 severity. For instance, elevated levels of CRP, LDH, D-dimer, and IL-6 are indicative of more severe disease and diabetes could potentially intensify these responses due to its impact on immune function and inflammation.(14,15)

Diabetes has been recognized as a risk factor for severe complications in COVID-19 patients, including acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), cytokine storm, multiple organ dysfunction syndrome (MODS) and transaminitis. This is also reported by the present study. Compared to non-diabetic group, more number of diabetic patients developed AKI, ARDS, sepsis, cytokine storm and MODS, most common being sepsis, followed by cytokine storm and AKI. We compared our findings with other studies. Zhang et al and Akbariqomi et al found that the most common complications in diabetic patients were ARDS, septic shock, AKI and secondary infections. (16,17) This can be explained by the fact that the presence of diabetes may exacerbate the inflammatory response to COVID-19, leading to a higher propensity for these complications.(18) It is also implied that endothelial dysfunction, which is a common feature in diabetes, may contribute to the severity of COVID- 19 by exacerbating conditions like ARDS and MODS. Additionally, the hypercoagulable state and immune dysregulation associated with diabetes could potentially worsen the cytokine storm and lead to further organ damage.(19)

The preponderance of evidence from original studies supports our finding that diabetes is a significant risk factor for increased mortality in COVID-19 patients. Gregg et al. reported the substantial increase in mortality rates among the population with diabetes during the pandemic, with diabetes being a central contributor to severe COVID-19 morbidity.(20)The hyperglycaemic environment may promote the entry of SARS-CoV-2 into host cells, and COVID-19 infection can modulate immune and inflammatory responses, potentially leading to a cytokine storm and acute respiratory distress syndrome (ARDS), which are lethal outcomes in diabetics.(21)

Diabetes has been identified as a significant factor influencing the severity and outcomes of COVID-19. Unmanaged diabetes and acute glycemia have been associated with increased severity and length of hospital stay for COVID-19 patients, emphasizing the importance of diabetes management in the treatment of COVID-19. Interestingly, while diabetes management can mitigate some risks, the presence of diabetes itself, especially when newly diagnosed, is

associated with a higher likelihood of progression to critical conditions and higher average plasma blood glucose levels, suggesting that diabetes is a critical factor in COVID-19 prognosis. Additionally, diabetes is linked to compromised innate immunity and an excessive proinflammatory cytokine response, which can exacerbate COVID-19 severity. The presence of diabetes has also been correlated with higher mortality rates among COVID-19 patients. In conclusion, diabetes is a crucial comorbidity in COVID-19 patients due to its impact on disease severity, hospitalization duration, and mortality rates. The bidirectional relationship between diabetes and COVID-19, along with the compromised immune response and heightened inflammatory state in diabetic patients, underscores the need for diligent management and monitoring of diabetes among those infected with COVID-19.

1. World Health Organization. "COVID-19 Cases | WHO COVID-19 Dashboard." WHO, 19 May 2024, https://data.who.int/dashboards/covid19/cases?n=c.
2. Koneru, G., Sayed, H. H., Abd-Elhamed, N. A., Elsedfy, N., Mohamed, A. H., Abdellatif, H. A., et al. "COVID-19 and Diabetes Mellitus: A Complex Interplay." J Pure Appl Microbiol, vol. 15, no. 2, 11 May 2021, pp. 512–523.
3. Ilic, I., and M. Ilic. "Diabetes Mellitus after SARS-CoV-2 Infection: An Epidemiological Review." Life (Basel), vol. 13, no. 6, 23 May 2023, https://doi.org/10.3390/life13061316.
4. Huang, Q., et al. "Aggravated Pneumonia and Diabetes in SARS-CoV-2 Infected Diabetic Mice." Emerg Microbes Infect, vol. 12, no. 1, 18 Apr. 2023, https://doi.org/10.1038/s41564-023-01171-3.
5. Ahmed, G. M. "Managing Diabetic Patients During the Coronavirus Disease (COVID-19) Pandemic." SVU-International Journal of Medical Sciences, vol. 0, 4 Dec. 2020, pp. 0–0.
6. Bajpai, S., et al. "Coronavirus Disease 2019 in Diabetes: A Pathophysiological Linkage." International Journal of Clinical Biochemistry and Research, vol. 9, no. 2, 15 Jun. 2022, pp. 92–97.
7. Kamani, M., and A. Mohammadi. "Diabetes and the Outbreak of Coronavirus Disease (COVID-19): A Critical Review." Gene Cell Tissue, vol. 10, no. 3, 17 Jan. 2023, https://doi.org/10.22317/gct.2023.129811.
8. Razaq, Z., and S. G. J. Alkufi. "Association between LZTF1 Gene Variation and Risk Infection of COVID-19 in Holy Najaf Province Patients." Int J Health Sci (Qassim), vol. 6, S7, 17 Sep. 2022, pp. 4233–47.
9. Shi, M. Jing, et al. "Trends in Coronavirus Disease 2019 Hospitalization and Prognosis: Gender Effect." Curr Med Sci, vol. 41, no. 2, 1 Apr. 2021, pp. 312–317.
10. Garg, A., Posa, M. K., and A. Kumar. "Diabetes and Deaths of COVID-19 Patients: Systematic Review of Meta-Analyses." Health Sciences Review, vol. 7, 1 Jun. 2023, Article 100099.
11. Kubjane, M., et al. "Association of Diabetes and Severe COVID-19 Outcomes: A Rapid Review and Meta-Analysis." J Endocrinol Metab, vol. 10, no. 5, 16 Oct. 2020, pp. 118–130.
12. Ahmed El-Hashash, F. C. "Balancing Treatment of COVID-19 with Diabetes." 10 2022.
13. Wu, J., et al. "Influence of Diabetes Mellitus on the Severity and Fatality of SARS-CoV-2 (COVID-19) Infection." Diabetes Obes Metab, vol. 22, no. 10, 7 Jul. 2020, pp. 1907–1914.
14. Kadhim, A. S., and Y. J. Abdullah. "Serum Levels of Interleukin-6, Ferritin, C-Reactive Protein, Lactate Dehydrogenase, D-Dimer, and Count of Lymphocytes and Neutrophils in COVID-19 Patients: Its Correlation to the Disease Severity." Biomedical and Biotechnology Research Journal (BBRJ), vol. 5, no. 1, 1 Jan. 2021, pp. 69–73.
15. Fathalla, L. A., et al. "Laboratory Biomarker Predictors for Disease Progression and Outcome Among Egyptian COVID-19 Patients." Int J Immunopathol Pharmacol, vol. 36, 1 Jan. 2022, pp. 1–11.
16. Akbariqomi, M., et al. "Clinical Characteristics and Outcome of Hospitalized COVID-19 Patients with Diabetes: A Single-Center, Retrospective Study in Iran." Diabetes Res Clin Pract, vol. 169, 1 Nov. 2020.
17. Zhang, N., et al. "Risk Factors for Poor Outcomes of Diabetes Patients with COVID-19: A Single-Center, Retrospective Study in Early Outbreak in China." Front Endocrinol (Lausanne), vol. 11, 24 Sept. 2020, Article 571037.
18. Matsuishi, Y., et al. "Severe COVID-19 Infection Associated with Endothelial Dysfunction Induces Multiple Organ Dysfunction: A Review of Therapeutic Interventions." Biomedicines, vol. 9, no. 3, 10 Mar. 2021, https://doi.org/10.3390/biomedicines9030270.
19. Wang, J., et al. "Specific Cytokines in the Inflammatory Cytokine Storm of Patients with COVID-19-Associated Acute Respiratory Distress Syndrome and Extrapulmonary Multiple-Organ Dysfunction." Virol J, vol. 18, no. 1, 4 Jun. 2021, https://doi.org/10.1186/s12985-021-01532-9.
20. Gregg, E. W., Sophiea, M. K., and M. Weldegiorgis. "Diabetes and COVID-19: Population Impact 18 Months into the Pandemic." Diabetes Care, vol. 44, no. 9, 1 Sept. 2021, pp. 1916–1923.
21. Sen, S., et al. "Diabetes Mellitus and COVID-19: Understanding the Association in Light of Current Evidence." World J Clin Cases, vol. 9, no. 28, 10 Oct. 2021, pp. 8327–8338.