Analysis of risk factors for COVID-19-related fatal outcome in 337991 patients with type 1 and type 2 diabetes mellitus in 2020–2022 years: Russian nationwide retrospective study

BACKGROUND: The coronavirus pandemic has had an extremely negative impact on the patients with diabetes mellitus (DM both in terms of a more severe course of COVID -19 and an increased risk of death.

AIM: Analysis of risk factors for death due to COVID -19 in patients with DM type 1 and type 2 (DM1 and DM2).

MATERIALS AND METHODS: Retrospective analysis of the database of the national diabetes register (NDR), which included DM patients with COVID-19 and reported virus infection outcome (recovery/or death) in 15 712 DM1 and 322 279 DM2 patients during a 2-year follow-up period (01/02/2020 to 03/04/2022) (discharge date)).

RESULTS: Case fatality rate in patients with DM, who underwent COVID -19 was 17.1% (DM1–8.8%; DM2–17.5%). As a result of multivariate regression analysis of seven significant factors in DM1 and thirteen in DM2 (evaluated by univariate anlisys), a number of the most important predictors of risk for fatal outcome were identified: in DM1 these were age ≥65 years (OR =4.01, 95% CI: 1.42–11.36), presence of arterial hypertension (AH) (OR =2.72, 95% CI: 1.03 -7.16) and diabetic foot syndrome (DFS) (OR = 7.22, 95% CI: 1.98–26.29); for T2DM: age ≥ 65 years (OR =2.53, 95% CI: 1.96–3.27), male (OR =1.51, 95% CI: 1.23–1.84), duration DM ≥10 years (OR =2.01, 95% CI: 1.61–2.51), BMI ≥ 30 kg/m² (OR =1.26, 95% CI: 1.02–1.55), ASCVD/CKD (OR =1.49, 95% CI: 1.01–2.04), history of diabetic coma (OR =12.97, 95% CI: 1.89–88.99) and presence of disability ( OR =1.40, 95% CI: 1.14–1.73). In T2DM, the type of antidiabetic therapy (ADT) prior to COVID -19 (last visit before the development of infection) had a significant impact: Insulin therapy (OR = 1.64, 95% CI: 1.30–2.07), sulfonylureas (SU) (OR =1.51, 95% CI: 1.23–1.84)); dipeptidyl peptidase-4 inhibitor (iDPP-4) therapy (OR =0.57, 95% CI: 0.39–0.83) and sodium-glucose cotransporter-2 inhibitor (iSGLT2) therapy (OR =0.64, 95% CI: 0.46–0.88). Vaccination was the most important protective factor in both types of DM: DM1 OR =0.19, 95% CI: 0.06–0.59; SD2 OR =0.20, 95% CI: 0.16–0.26.

CONCLUSION: The common risk factor for fatal outcome in both DM1 and DM2 was age ≥65 years; in DM1 — history of hypertension and DFS, in DM2 — male sex, diabetes duration ≥10 years, BMI ≥30 kg/m², history of ASCVD/CKD and diabetic coma, disability. In T2DM, significant differences in risk were observed depending on the type of ADT: insulin and SU therapy were factors that increased the risk of death, whereas therapy with iDPP-4 and iSGLT2 reduced the risk of death. Vaccination reduced the risk of death in DM1 and DM2 by 5.2 and 5-fold, respectively.

1. Huang I, Lim MA, Pranata R. Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia – A systematic review, meta-analysis, and meta-regression. Diabetes Metab Syndr Clin Res Rev. 2020;14(4):395-403. doi: https://doi.org/10.1016/j.dsx.2020.04.018

2. Wu J, Li W, Shi X, et al. Early antiviral treatment contributes to alleviate the severity and improve the prognosis of patients with novel coronavirus disease (COVID‐19). J Intern Med. 2020;288(1):128-138. doi: https://doi.org/10.1111/joim.13063

3. COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU) [Internet]. Available from: https://coronavirus.jhu.edu/map.html

4. Kung S, Doppen M, Black M, et al. Underestimation of COVID-19 mortality during the pandemic. ERJ Open Res. 2021;7(1):00766-02020. doi: https://doi.org/10.1183/23120541.00766-2020

5. Official information about COVID-19 in Russia [Internet]. 2022. Доступ по ссылке: https://стопкоронавирус.рф

6. Shestakova MV, Vikulova OK, Elfimova AR, et al. Risk factors for COVID-19 case fatality rate in people with type 1 and type 2 diabetes mellitus: A nationwide retrospective cohort study of 235,248 patients in the Russian Federation. Front Endocrinol (Lausanne). 2022;13:100105. doi: https://doi.org/10.3389/fendo.2022.909874

7. Shestakova MV, Vikulova OK, Isakov MА, Dedov II. Diabetes and COVID-19: analysis of the clinical outcomes according to the data of the russian diabetes registry. Problems of Endocrinology. 2020;66(1):35-46. (In Russ.). doi: https://doi.org/10.14341/probl12458

8. Rawshani A, Kjölhede EA, Rawshani A, et al. Severe COVID-19 in people with type 1 and type 2 diabetes in Sweden: A nationwide retrospective cohort study. Lancet Reg Heal - Eur. 2021;4:100105. doi: https://doi.org/10.1016/j.lanepe.2021.100105

9. Barron E, Bakhai C, Kar P, et al. Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study. Lancet Diabetes Endocrinol. 2020;8(10):813-822. doi: https://doi.org/10.1016/S2213-8587(20)30272-2

10. Holman N, Knighton P, Kar P, et al. Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study. Lancet Diabetes Endocrinol. 2020;8(10):823-833. doi: https://doi.org/10.1016/S2213-8587(20)30271-0

11. Ando W, Horii T, Uematsu T, et al. Impact of overlapping risks of type 2 diabetes and obesity on coronavirus disease severity in the United States. Sci Rep. 2021;11(1):17968. doi: https://doi.org/10.1038/s41598-021-96720-x

12. Kazakou P, Lambadiari V, Ikonomidis I, et al. Diabetes and COVID-19; A Bidirectional Interplay. Front Endocrinol (Lausanne). 2022;13:780663. doi: https://doi.org/10.3389/fendo.2022.780663

13. Khunti K, Knighton P, Zaccardi F, et al. Prescription of glucose-lowering therapies and risk of COVID-19 mortality in people with type 2 diabetes: a nationwide observational study in England. Lancet Diabetes Endocrinol. 2021;9(5):293-303. doi: https://doi.org/10.1016/S2213-8587(21)00050-4

14. Mali SN, Thorat BR, Chopade AR. A Viewpoint on Angiotensin-Converting Enzyme 2, Anti-Hypertensives and Coronavirus Disease 2019 (COVID-19). Infect Disord - Drug Targets. 2021;21(3):311-313. doi: https://doi.org/10.2174/1871526520666200511005546

15. Dedov II, Shestakova MV, Vikulova OK, et al. Epidemiological characteristics of diabetes mellitus in the Russian Federation: clinical and statistical analysis according to the Federal diabetes register data of 01.01.2021. Diabetes mellitus. 2021;24(3):204-221. (In Russ.). doi: https://doi.org/10.14341/DM12759

16. Dedov II, Shestakova MV, Mayorov AYu et al. Standards of specialized diabetes care. Diabetes Mellitus. 2021;24(S1):1-235 (In Russ.). doi: https://doi.org/10.14341/DM12802

17. de Miguel-Yanes JM, Jimenez-Garcia R, de Miguel-Diez J, et al. Impact of Type 2 Diabetes Mellitus on the Incidence and Outcomes of COVID-19 Needing Hospital Admission According to Sex: Retrospective Cohort Study Using Hospital Discharge Data in Spain, Year 2020. J Clin Med. 2022;11(9):2654. doi: https://doi.org/10.3390/jcm11092654

18. Crouse AB, Grimes T, Li P, et al. Metformin use is associated with reduced mortality in a diverse population with COVID-19 and diabetes. Front Endocrinol (Lausanne). 2021;11:600439. doi: https://doi.org/10.3389/fendo.2020.600439

19. Agarwal S, Schechter C, Southern W, et al. Preadmission diabetes-specific risk factors for mortality in hospitalized patients with diabetes and coronavirus disease 2019. Diabetes Care. 2020;43(10):2339-2344. doi: https://doi.org/10.2337/dc20-1543

20. Kastora S, Patel M, Carter B, et al. Impact of diabetes on COVID‐19 mortality and hospital outcomes from a global perspective: An umbrella systematic review and meta‐analysis. Endocrinol Diabetes Metab. 2022;5(3):221-230. doi: https://doi.org/10.1002/edm2.338

21. Bechmann N, Barthel A, Schedl A, et al. Sexual dimorphism in COVID-19: potential clinical and public health implications. Lancet Diabetes Endocrinol. 2022;10(3):221-230. doi: https://doi.org/10.1016/S2213-8587(21)00346-6

22. Perazzo H, Cardoso SW, Ribeiro MPD, et al. In-hospital mortality and severe outcomes after hospital discharge due to COVID-19: A prospective multicenter study from Brazil. Lancet Reg Heal - Am. 2022;11:100244. doi: https://doi.org/10.1016/j.lana.2022.100244

23. Jin J-M, Bai P, He W, et al. Gender differences in patients with COVID-19: Focus on severity and mortality. Front Public Heal. 2020;8. doi: https://doi.org/10.3389/fpubh.2020.00152

24. Zhu L, She Z-G, Cheng X, et al. Association of blood glucose control and outcomes in patients with COVID-19 and Pre-existing type 2 diabetes. Cell Metab. 2020;31(6):1068-1077.e3. doi: https://doi.org/10.1016/j.cmet.2020.04.021

25. Raoufi M, Khalili S, Mansouri M, et al. Well-controlled vs poorly-controlled diabetes in patients with COVID-19: Are there any differences in outcomes and imaging findings? Diabetes Res Clin Pract. 2020;166:108286. doi: https://doi.org/10.1016/j.diabres.2020.108286

26. Cariou B, Hadjadj S, Wargny M, et al. Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study. Diabetologia. 2020;63(8):1500-1515. doi: https://doi.org/10.1007/s00125-020-05180-x

27. Alhakak A, Butt JH, Gerds TA, et al. Glycated haemoglobin levels among 3295 hospitalized COVID‐19 patients, with and without diabetes, and risk of severe infection, admission to an intensive care unit and all‐cause mortality. Diabetes, Obes Metab. 2022;24(3):499-510. doi: https://doi.org/10.1111/dom.14604

28. Gregory JM, Slaughter JC, Duffus SH, et al. COVID-19 severity is tripled in the diabetes community: A prospective analysis of the pandemic’s impact in type 1 and type 2 diabetes. Diabetes Care. 2021;44(2):526-532. doi: https://doi.org/10.2337/dc20-2260

29. McGurnaghan SJ, Weir A, Bishop J, et al. Risks of and risk factors for COVID-19 disease in people with diabetes: a cohort study of the total population of Scotland. Lancet Diabetes Endocrinol. 2021;9(2):82-93. doi: https://doi.org/10.1016/S2213-8587(20)30405-8

30. Wang W, Sun Y, Wang S, Sun Y. The relationship between insulin use and increased mortality in patients with COVID-19 and diabetes: A meta-analysis. Endocr Res. 2022;47(1):32-38. doi: https://doi.org/10.1080/07435800.2021.1967376

31. Nguyen NN, Ho DS, Nguyen HS, et al. Preadmission use of antidiabetic medications and mortality among patients with COVID-19 having type 2 diabetes: A meta-analysis. Metabolism. 2022;131(2):155196. doi: https://doi.org/10.1016/j.metabol.2022.155196

32. Smati S, Tramunt B, Wargny M, et al. COVID-19 and Diabetes Outcomes: Rationale for and Updates from the CORONADO Study. Curr Diab Rep. 2022;22(2):53-63. doi: https://doi.org/10.1007/s11892-022-01452-5

33. Yeh H-C, Kraschnewski JL, Kong L, et al. Hospitalization and mortality in patients with COVID-19 with or at risk of type 2 diabetes: data from five health systems in Pennsylvania and Maryland. BMJ Open Diabetes Res Care. 2022;10(3):e002774. doi: https://doi.org/10.1136/bmjdrc-2022-002774

34. Yang Y, Cai Z, Zhang J. Insulin Treatment May Increase Adverse Outcomes in Patients With COVID-19 and Diabetes: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne). 2021;12:696087. doi: https://doi.org/10.3389/fendo.2021.696087

35. Dedov II, Mokrysheva NG, Shestakova MV, et al. Glycemia control and choice of antihyperglycemic therapy in patients with type 2 diabetes mellitus and COVID-19: a consensus decision of the board of experts of the Russian association of endocrinologists. Diabetes mellitus. 2022;25(1):27-49. (In Russ.). doi: https://doi.org/10.14341/DM12873

36. Chee YJ, Tan SK, Yeoh E. Dissecting the interaction between COVID‐19 and diabetes mellitus. J Diabetes Investig. 2020;11(5):1104-1114. doi: https://doi.org/10.1111/jdi.13326

37. Han T, Ma S, Sun C, et al. Association between anti-diabetic agents and clinical outcomes of COVID-19 in patients with diabetes: A systematic review and meta-analysis. Arch Med Res. 2022;53(2):186-195. doi: https://doi.org/10.1016/j.arcmed.2021.08.002

38. Li J, Wei Q, McCowen KC, et al. Inpatient use of metformin and acarbose is associated with reduced mortality of COVID‐19 patients with type 2 diabetes mellitus. Endocrinol Diabetes Metab. 2022;5(1):e00301. doi: https://doi.org/10.1002/edm2.301

39. Chen Y, Lv X, Lin S, et al. The Association Between Antidiabetic Agents and Clinical Outcomes of COVID-19 Patients With Diabetes: A Bayesian Network Meta-Analysis. Front Endocrinol (Lausanne). 2022;13(7):646-651. doi: https://doi.org/10.3389/fendo.2022.895458

40. Mendy A, Gopal R, Alcorn JF, Forno E. Reduced mortality from lower respiratory tract disease in adult diabetic patients treated with metformin. Respirology. 2019;24(7):646-651. doi: https://doi.org/10.1111/resp.13486

41. Ho T-W, Huang C-T, Tsai Y-J, et al. Metformin use mitigates the adverse prognostic effect of diabetes mellitus in chronic obstructive pulmonary disease. Respir Res. 2019;20(1):69. doi: https://doi.org/10.1186/s12931-019-1035-9

42. Sharma S, Ray A, Sadasivam B. Metformin in COVID-19: A possible role beyond diabetes. Diabetes Res Clin Pract. 2020;164:108183. doi: https://doi.org/10.1016/j.diabres.2020.108183

43. Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk. JAMA. 2019;321(1):69. doi: https://doi.org/10.1001/jama.2018.18269

44. Gupta P, White WB. Cardiovascular safety of therapies for type 2 diabetes. Expert Opin Drug Saf. 2017;16(1):13-25. doi: https://doi.org/10.1080/14740338.2017.1239707

45. Anastasiou G, Hatziagelaki E, Liberopoulos E. Could dapagliflozin attenuate COVID-19 progression in high-risk patients with or without diabetes? Behind DARE-19 concept. J Cardiovasc Pharmacol. 2021;78(1):e12-e19. doi: https://doi.org/10.1097/FJC.0000000000001011

46. Zelniker TA, Braunwald E. Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes. J Am Coll Cardiol. 2018;72(15):1845-1855. doi: https://doi.org/10.1016/j.jacc.2018.06.040

47. Kidokoro K, Cherney DZI, Bozovic A, et al. Evaluation of glomerular hemodynamic function by empagliflozin in diabetic mice using in vivo imaging. Circulation. 2019;140(4):303-315. doi: https://doi.org/10.1161/CIRCULATIONAHA.118.037418

48. Sano M, Goto S. Possible mechanism of hematocrit elevation by sodium glucose cotransporter 2 inhibitors and associated beneficial renal and cardiovascular effects. Circulation. 2019;139(17):1985-1987. doi: https://doi.org/10.1161/CIRCULATIONAHA.118.038881

49. Dispinseri S, Lampasona V, Secchi M, et al. Robust neutralizing antibodies to SARS-CoV-2 develop and persist in subjects with diabetes and COVID-19 pneumonia. J Clin Endocrinol Metab. 2021;106(5):1472-1481. doi: https://doi.org/10.1210/clinem/dgab055

50. Bermingham C, Morgan J, Nafilyan V. Deaths involving COVID-19 by vaccination status, England: deaths occurring between 2 January and 24 September 2021. [Internet]. 2021 [cited 11.10.22]. Available from: www.gov.uk/government/statistics/deaths-involving-covid-19-by-vaccinationstatus-%0Aengland-deaths-occurring-between-2-january-and-24-september-2021