The role of metformin in the treatment of elderly patients with type 2 diabetes mellitus and coronavirus infection

DOI: https://doi.org/10.29296/25877305-2022-06-08
Issue: 
6
Year: 
2022

O. Belousova(1), MD, M. Chupakha(1), A. Rukavishnikov(2), Candidate of Medical Sciences, S. Lenkin(3), Candidate of Medical Sciences
1-Belgorod State National Research University
2-N.K. Orlov Dolinsk Central District Hospital, Dolinsk, Sakhalin Region
3 -Medical center «Paid KVD», Moscow

Since December 2019, the world has been gripped by the coronavirus infection (COVID-19) pandemic caused by SARS-CoV-2. At the end of January 2022, there were 356,028,523 infections and 5,613,346 deaths with a significant proportion of deaths occurring in elderly and senile patients. Numerous studies have shown that the majority of elderly patients who experienced COVID-19 had comorbidities (diabetes mellitus (DM), hypertensive disease, and cardiovascular disease). About 10-20% of older patients with COVID-19 had generally DM. The investigations conducted by US scientists indicate that people with obesity and type 2 diabetes (T2D) are more vulnerable to coronavirus infection. Thus, elderly patients with DM need more attention to both the prevention during the pandemic and outpatient and inpatient treatment in the presence of COVID-19. The antioxidant, anti-inflammatory, immunomodulatory, and antiviral properties of metformin allow it to be considered as an additional therapy in elderly patients with T2D and COVID-19.
Keywords: 
infectious diseases
endocrinology
type 2 diabetes mellitus
coronavirus infection
metformin
diabetes mellitus treatment
insulin therapy
chronic diseases

References: 
  1. Standards of specialized diabetes care. Ed. by I.I. Dedov, M.V. Shestakova, A.Yu. Mayorov. 9th ed. M., 2019 (in Russ.). DOI: 10.14341/DM221S1
  2. Osipova O.A., Belousova O.N., Efremova O.A. et al. Dynamics of proinflammatory cytokines on the background of drug therapy in patients with chronic heart failure. International journal of experimental education. 2013; 6: 44–6.
  3. Flood D., Seiglie J.A., Dunn M. et al. The state of diabetes treatment coverage in 55 low-income and middle-income countries: a cross-sectional study of nationally representative, individual-level data in 680 102 adults. The Lancet Healthy Longevity. 2021; 2 (6): 340–51. DOI: 10.1016/s2666-7568(21)00089-1
  4. Singh A.K., Gupta R., Ghosh A. et al. Diabetes in COVID-19: Prevalence, pathophysiology, prognosis and practical considerations. Diabetes Metab Syndrome. 2020; 14 (4): 303–10. DOI: 10.1016/j.dsx.2020.04.004
  5. Dennis J.M., Mateen B.A., Sonabend R. et al. Type 2 Diabetes and COVID-19-Related Mortality in the Critical Care Setting: A National Cohort Study in England, March-July 2020. Diabetes Care. 2021; 44 (1): 50–7. DOI: 10.2337/dc20-1444
  6. Lenti M.V., Corazza G.R., Di Sabatino A. Carving out a place for internal medicine during COVID-19 epidemic in Italy. J Internal Med. 2020; 288 (2): 263–5. DOI: 10.1111/joim.13079
  7. Saeedi P., Petersohn I., Salpea P. et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract. 2019; 157: 107843. DOI: 10.1016/j.diabres.2019.107843
  8. Bousquet J., Zuberbier T., Anto J.M. et al. Cabbage and fermented vegetables: from death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19. Allergy. 2021; 76 (3): 735–50. DOI: 10.1111/all.14549
  9. Козлов В.А., Тихонова Е.П., Савченко А.А. и др. Клиническая иммунология. Практическое пособие для инфекционистов. Красноярск: Поликор, 2021; 563 c. Kozlov V.A., Tikhonova E.P., Savchenko A.A. et al. Klinicheskaya immunologiya. Prakticheskoe posobie dlya infektsionistov. Krasnoyarsk: Polikor, 2021; 563 p. (in Russ.).
  10. Temporary guidelines «Prevention, diagnosis and treatment of new coronavirus infection (COVID-19). Version 14 (27.12.2021)» (approved by the Ministry of Health of Russia). Access from the «ConsultantPlus» legal reference system (in Russ.).
  11. Iacobellis G. COVID-19 and diabetes: Can DPP4 inhibition play a role? Diabetes Res Clin Pract. 2020; 162: 108125. DOI: 10.1016/j.diabres.2020.108125
  12. Belousova O.N., Sirotina S.S, Jakunchenko T.I. et al. Molecular and genetic mechanisms of the pathogenesis of type 2 diabetes. Scientific bulletin of Belgorod State University. Series: Medicine. Pharmacy. 2015; 16 (2013): 12–9 (in Russ.).
  13. Yang J.K., Feng Y., Yuan M.Y. et al. Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS. Diabetic Med. 2006; 23 (6): 623–8. DOI: 10.1111/j.1464-5491.2006.01861.x
  14. Wang Z., Du Z., Zhu F. Glycosylated hemoglobin is associated with systemic inflammation, hypercoagulability, and prognosis of COVID-19 patients. Diabetes Res Clin Pract. 2020; 164: 108214. DOI: 10.1016/j.diabres.2020.108214
  15. Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019 – United States, February 12 – March 28. MMWR Morb Mortal Wkly Rep. 2020; 69 (13): 382–6. DOI: 10.15585/mmwr.mm6913e2
  16. Huang C., Wang Y., Li X. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395 (10223): 497–506. DOI: 10.1016/S0140-6736(20)30183-5
  17. Wu C., Chen X., Cai Y. et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Internal Med. 2020; 180 (7): 934–43. DOI: 10.1001/jamainternmed.2020.0994
  18. Yang J., Zheng Y., Gou X. et al. Prevalence of comorbidities and its effects in coronavirus disease 2019 patients: A systematic review and meta-analysis. Int J Infect Dis. 2020; 94: 91–5. DOI: 10.1016/j.ijid.2020.03.017
  19. Chen Y., Gong X., Wang L. et al. Effects of hypertension, diabetes and coronary heart disease on COVID-19 diseases severity: a systematic review and meta-analysis. medRxiv. 2020.; 14 (4): 303–10. DOI: 10.1101/2020.03.25.20043133
  20. Chen T., Wu D., Chen H. et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020; 368: m1091. DOI: 10.1136/bmj.m1295
  21. Wu Z., McGoogan J.M. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020; 323 (13): 1239–42. DOI: 10.1001/jama.2020.2648
  22. Cameron A.R., Morrison V.L., Levin D. et al. Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status. Circ Res. 2016; 119 (5): 652–65. DOI: 10.1161/CIRCRESAHA.116.308445
  23. Crouse A.B., Grimes T., Li P. et al. Metformin Use Is Associated With Reduced Mortality in a Diverse Population With COVID-19 and Diabetes. Front Endocrinol. 2020; 11: 600439. DOI: 10.3389/fendo.2020.600439
  24. Drucker D.J. Coronavirus Infections and Type 2 Diabetes-Shared Pathways with Therapeutic Implications. Endocr Rev. 2020; 41 (3): bnaa011. DOI: 10.1210/endrev/bnaa011
  25. Samuel S.M., Ghosh S., Majeed Y. et al. Metformin represses glucose starvation induced autophagic response in microvascular endothelial cells and promotes cell death. Biochem Pharmacol. 2017; 132: 118–32. DOI: 10.1016/j.bcp.2017.03.001
  26. Triggle C.R., Ding H. Metformin is not just an antihyperglycaemic drug but also has protective effects on the vascular endothelium. Acta Physiol (Oxf). 2017; 219 (1): 138–51. DOI: 10.1111/apha.12644
  27. Samuel S.M., Varghese E., Kubatka P. et al. Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer. Biomolecules. 2019; 9 (12): 846. DOI: 10.3390/biom9120846
  28. Varghese S., Samuel S.M., Varghese E. et al.. High Glucose Represses the Anti-Proliferative and Pro-Apoptotic Effect of Metformin in Triple Negative Breast Cancer Cells. Biomolecules. 2019; 9 (1): 16. DOI: 10.3390/biom9010016
  29. Samuel S.M., Varghese E., Büsselberg D. Therapeutic Potential of Metformin in COVID-19: Reasoning for its Protective Role. Trends Microbiol. 2021; 29 (10): 894–907. DOI: 10.1016/j.tim.2021.03.004
  30. Allard R., Leclerc P., Tremblay C. et al. Diabetes and the severity of pandemic influenza A (H1N1) infection. Diabetes Care. 2010; 33 (7): 1491–3. DOI: 10.2337/dc09-2215
  31. Kulcsar K.A., Coleman C.M., Beck S.E. et al. Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection. JCI Insight. 2019; 4 (20): e131774. DOI: 10.1172/jci.insight.131774
  32. Erener S. Diabetes, infection risk and COVID-19. Mol Metab. 2020; 39: 101044. DOI: 10.1016/j.molmet.2020.101044
  33. 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): 1068–77.e3. DOI: 10.1016/j.cmet.2020.04.021
  34. Lisco G., De Tullio A., Giagulli V.A. et al. Hypothesized mechanisms explaining poor prognosis in type 2 diabetes patients with COVID-19: a review. Endocrine. 2020; 70 (3): 441–53. DOI: 10.1007/s12020-020-02444-9
  35. Teuwen L.A., Geldhof V., Pasut A. et al. COVID-19: the vasculature unleashed. Nat Rev Immunol. 2020; 20 (7): 389–91. DOI: 10.1038/s41577-020-0343-0
  36. Sun Q., Li J., Gao F. New insights into insulin: The anti-inflammatory effect and its clinical relevance. World J Diabetes. 2014; 5 (2): 89–96. DOI: 10.4239/wjd.v5.i2.89
  37. Sardu C., D’Onofrio N., Balestrieri M.L. et al. Outcomes in Patients With Hyperglycemia Affected by COVID-19: Can We Do More on Glycemic Control? Diabetes Care. 2020; 43 (7): 1408–15. DOI: 10.2337/dc20-0723
  38. Sharma S., Ray A., Sadasivam B. Metformin in COVID-19: A possible role beyond diabetes. Diabetes Res Clin Pract. 2020; 164: 108183. DOI: 10.1016/j.diabres.2020.108183
  39. Bramante C.T., Buse J., Tamaritz L. et al. Outpatient metformin use is associated with reduced severity of COVID-19 disease in adults with overweight or obesity. J Med Virol. 2021; 93 (7): 4273–9. DOI: 10.1002/jmv.26873
  40. Hariyanto T.I., Kurniawan A. Metformin use is associated with reduced mortality rate from coronavirus disease 2019 (COVID-19) infection. Obes Med. 2020; 19: 100290. DOI: 10.1016/j.obmed.2020.100290
  41. Lalau J.D., Al-Salameh A., Hadjadj S. et al. Metformin use is associated with a reduced risk of mortality in patients with diabetes hospitalised for COVID-19. Diabetes Metab. 2020; 47 (5): 101216. DOI: 10.1016/j.diabet.2020.101216
  42. Giannarelli R., Aragona M., Coppelli A. et al. Reducing insulin resistance with metformin: the evidence today. Diabetes Metab. 2003; 29 (4, Part 2): 6S28–6S35. DOI: 10.1016/s1262-3636(03)72785-2
  43. Lim S., Bae J.H., Kwon H.S. et al. COVID-19 and diabetes mellitus: from pathophysiology to clinical management. Nat Rev Endocrinol. 2021; 17 (1): 11–30. DOI: 10.1038/s41574-020-00435-4
  44. Zimmet P., Collier G. Clinical Efficacy of Metformin against Insulin Resistance Parameters. Drugs. 1999; 58 (1): 21–8. DOI: 10.2165/00003495-199958001-00007
  45. Bramante C.T., Ingraham N.E., Murray T.A. et al. Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis. Lancet Healthy Longev. 2021; 2 (1): e34–e41. DOI: 10.1016/S2666-7568(20)30033-7
  46. Tsai S., Clemente-Casares X., Zhou A.C. et al. Insulin Receptor-Mediated Stimulation Boosts T Cell Immunity during Inflammation and Infection. Cell Metab. 2018; 28 (6): 922–34.e4. DOI: 10.1016/j.cmet.2018.08.003
  47. ClinicalTrials.gov. Adaptive Study to Demonstrate Efficacy and Safety of Metformin Glycinate for the Treatment of Hospitalized Patients With Severe Acute Respiratory Syndrome Secondary to SARS-CoV-2. Randomized, Double-Blind, Phase IIIb. 2021 [cited 2021 Feb 10]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04625985?term=metformin&cond=COVID&draw=2&rank=3
  48. Dedov D. Novel coronavirus infection (COVID-19): epidemiology, clinical characteristics of patients, risk of complications, prevention, use of selenium-containing drugs. Vrach. 2022; 33 (5); 58–62 (in Russ.). DOI: 10.29296/25877305-2022-05-12