Diabetes mellitus in combination with COVID-19: modern views on therapy





COVID-19, angiotensin-converting enzyme 2, diabetes mellitus


Diabetic patients are in the spotlight from the early stages of a pandemic, as growing epidemiological data show they are at higher risk for severe clinical outcomes from COVID-19. As the global COVID-19 pandemic continues to evolve, it is also becoming increasingly apparent that the interactions between COVID-19 and diabetes mellitus (DM) are complex pathophysiological mechanisms. The outcome of COVID-19 is more severe in people with DM, which has the potential to accelerate the onset of acute metabolic complications of DM such as diabetic ketoacidosis and hyperglycemia. These mechanisms underlying these associations remain unclear, but they likely include the angiotensin converting enzyme receptor 2, a binding site for SARS-CoV-2, which is expressed in key metabolic organs such as in the pancreas, in particular in β-cells. The potential β-cell tropism of SARS-CoV-2 can damage cells and impair insulin secretion, causing hyperglycemia and ketoacidosis. Understanding the bidirectional interaction between DM and COVID-19 will be critical to protecting and treating people with DM. Current epidemiological data on COVID-19 do not support the hypothesis that diabetic patients are at increased risk of infection compared to the general population. To date, it has been established that decompensated DM is an independent factor that aggravates the course of coronavirus infection and significantly increases the risk of a fatal outcome of the disease.
The review provides a brief summary of the evolution of pathogenetic and clinical aspects for understanding the mechanisms of this pathological tandem, as well as therapeutic strategies for treating patients with COVID-19 and DM. As the incidence of DM continues to rise globally, more than ever, diabetes prevention and control must be a priority for health systems around the world.

Author Biographies

V.I. Tsymbaliuk, NAMS of Ukraine

MD, professor, president of the NAMS of Ukraine, academician of the NAMS of Ukraine, corresponding member of the NAS of Ukraine

M.D. Tronko, NAMS of Ukraine; SI “V.P. Komisarenko Institute of Endocrinology and Metabolism of the NAMS of Ukraine”

MD, professor, vice-president of the NAMS of Ukraine, academician of the NAMS of Ukraine, corresponding member of the NAS of Ukraine;


Y.G. Antypkin, NAMS of Ukraine; SI “O.M. Lukyanova Institute of Pediatrics, Obstetrics and Gynecology of the NAMS of Ukraine”

MD, professor, academician of the NAMS of Ukraine, academician-secretary of the Clinical Medicine Department of the NAMS of Ukraine;


S.V. Kushnirenko, Shupyk National Healthcare University of Ukraine

MD, associate professor, Department of nephrology and renal replacement therapy, dean of Therapeutic Faculty

V.V. Popova, SI “V.P. Komisarenko Institute of Endocrinology and Metabolism of the NAMS of Ukraine”

MD, head of the Department of Preventive Diabetology


Rothan, H.A., Byrareddy, S.N. “The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak.” J Autoimmun 109 (2020): 102433.

Ugwueze, C.V., Ezeokpo, B.C., Nnolim B.I., et al. “COVID-19 and diabetes mellitus: The link and clinical implications.” Dubai Diabetes Endocrinol J 26 (2020): 69–77.

Poutanen, S.M. “Etiologic agents of infectious diseases.” In: Long SS, editor. Principles and practice of paediatric infectious diseases. 4th ed. (2012): 1547–712.

Huang, C., Wang Y., Li X., et al. “Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.” Lancet 395.10223 (2020): 497–506.

World Health Organization. “Naming the coronavirus disease (COVID-19) and the virus that causes it 2020.” [Online]. Available from: [https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it], last accessed Feb 22, 2021.

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 323.13 (2020): 1239–42.

Guan, W., Ni, Z., Hu, Yu., et al. “Clinical characteristics of coronavirus disease 2019 in China.” N Engl J Med 382 (2020):1708–20.

Zhou, F., Yu, T., Du, R., et al. “Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.” Lancet 395.10229 (2020): 1054–62.

Yang, J., Zheng, Y., Gou, X., et al. “Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis.” Int J Infect Dis 94 (2020): 91–5.

Wan, Y., Shang, J., Graham, R., et al. “Receptor recognition by novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS.” J Virol 94.7 (2020): e00127–20.

Hulswit, R.J., de Haan, C.A., Bosch, B.J. “Coronavirus spike protein and tropism changes.” Adv Virus Res 96 (2016): 29–57.

Fernandez, C., Rysä, J., Almgren, P., et al. “Plasma levels of the proprotein convertase furin and incidence of diabetes and mortality.” J Intern Med 284.4 (2018): 377–87.

Guo, Y., Cao, Q., Hong, Z. “The origin, transmission, and clinical therapies on corona virus disease 2019 (COVID-19) outbreak-an update on the status.” Mil Med Res 7.1 (2020): 11.

World Health Organization. Diabetes [Online]. Available from: [https://www.who.int/health-topics/diabetes], last accessed Feb 22, 2021.

American Diabetes Association. “Standards of Medical care in diabetes.” Diabetes Care 2 Suppl 1 (2021).

Yang, P., Feng, J., Peng, Q., et al. “Advanced glycation end products: potential mechanism and therapeutic target in cardiovascular complications under diabetes.” Oxid Med Cell Longev (2019): 9570616. DOI: 10.1155/2019/9570616

Williams, R., Karuranga, S., Malanda, B., et al. “Global and regional estimates and projections of diabetes-related health expenditure: Results from the International Diabetes Federation Diabetes Atlas, 9th edition.” Diabetes Res Clin Pract 162 (2020): 108072.

Pearson-Stuttard, J., Blundell, S., Harris, T., et al. “Diabetes and infection: assessing the association with glycaemic control in population-based studies.” Lancet Diabetes Endocrinol 4.2 (2016): 148–58.

McDonald, H.I., Nitsch, D., Millett, E.R., et al. “New estimates of the burden of acute community-acquired infections among older people with diabetes mellitus: a retrospective cohort study using linked electronic health records.” Diabet Med 31.5 (2014): 606–14.

Li, S., Wang, J., Zhang, B., et al. “Diabetes mellitus and cause-specific mortality: a population-based study.” Diabetes Metab J 43.3 (2019): 319–41.

Knapp, S. “Diabetes and infection: is there a link? – A mini-review.” Gerontology 59.2 (2013): 99–104.

Schoen, K., Horvat, N., Guerreiro, N.F.C., et al. “Spectrum of clinical and radiographic findings in patients with diagnosis of H1N1 and correlation with clinical severity.” BMC Infect Dis 19.1 (2019): 964.

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.” Diabet Med 23.6 (2006): 623–8.

Banik, G.R., Alqahtani, A.S., Booy, R., Rashid, H. “Risk factors for severity and mortality in patients with MERS-CoV: Analysis of publicly available data from Saudi Arabia.” Virol Sin 31.1 (2016): 81–4.

Onder, G., Rezza, G., Brusaferro, S. “Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy.” JAMA 323.18 (2020): 1775–6.

Pal, R., Bhansali, A. “COVID-19, diabetes mellitus and ACE2: The conundrum.” Diabetes Res Clin Pract 162 (2020): 108132.

Jafar, N., Edriss, H., Nugent, K. “The effect of short-term hyperglycemia on the innate immune system.” Am J Med Sci 351.2 (2016): 201–11.

Geerlings, S.E., Hoepelman, A.I. “Immune dysfunction in patients with diabetes mellitus (DM).” FEMS Immunol Med Microbiol 26.3–4 (1999): 259–65.

Petrie, J.R., Guzik, T.J., Touyz, R.M. “Diabetes, hypertension, and cardiovascular disease: clinical insights and vascular mechanisms.” Can J Cardiol 34.5 (2018): 575–84.

Ilyas, R., Wallis, R., Soilleux, E.J., et al. “High glucose disrupts oligosaccharide recognition function via competitive inhibition: a potential mechanism for immune dysregulation in diabetes mellitus.” Immunobiology 216.1–2 (2011): 126–31.

Ranganath Muniyappa, Sriram Gubbi. “COVID-19 pandemic, coronaviruses, and diabetes mellitus.” Am J Physiol Endocrinol Metab 318 (2020): E736–41.

Li, X.C., Zhang, J., Zhuo, J.L. “The vasoprotective axes of the renin-angiotensin system: physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases.” Pharmacol Res 125 Pt A (2017): 21–38.

Lambert, D.W., Yarski, M., Warner F.J., et al. “Tumor necrosis factor-α convertase (ADAM17) mediates regulated ectodomain shedding of severe acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2).” J Biol Chem 280.34 (2005): 30113–9.

Du, L., He, Y., Zhou, Y., et al. “The spike protein of SARS-CoV: a target for vaccine and therapeutic development.” Nat Rev Microbiol 7.3 (2009): 226–36.

Palau, V., Riera, M., Soler, M.J. “ADAM17 inhibition may exert a protective effect on COVID-19.” Nephrol Dial Transplant 35.6 (2020): 1–2.

Cesaro, A., Abakar-Mahamat, A., Brest, P., et al. “Differential expression and regulation of ADAM17 and TIMP3 in acute inflamed intestinal epithelia.” Am J Physiol Gastrointest Liver Physiol 296.6 (2009): G1332–43.

Salem, E.S., Grobe, N., Elased, K.M. “Insulin treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice.” Am J Physiol Renal Physiol 306.6 (2014): F629–39.

Heurich, A., Hofmann-Winkler, H., Gierer, S., et al. “TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein.” J Virol 88.2 (2014): 1293–307.

Letko, M., Marzi, A., Munster, V. “Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses.” Nat Microbiol 5.4 (2020): 562–9.

Li, W., Moore, M.J., Vasilieva, N., et al. “Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.” Nature 426.6965 (2003): 450–4.

Hoffmann, M., Kleine-Weber, H., Schroeder, S., et al. “SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.” Cell 181.2 (2020): 271–80.

Song, Z., Xu, Y., Bao, L., et al. “From SARS to MERS, Thrusting coronaviruses into the spotlight.” Viruses 11.1 (2019): E59.

Gheblawi, M., Wang, K., Viveiros, A., et al. “Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system. Celebrating the 20th anniversary of the discovery of ACE2.” Circ Res 126.10 (2020): 1456–74.

Yang, J.K., Lin, S.S., Ji, X.J., Guo, L.M. “Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes.” Acta Diabetol 47.3 (2010): 193–9.

Tucker, M.E. “ESC says continue hypertension meds despite COVID-19 concern.” Medscape [Online] (2020). Available from: [https://www.medscape.com/viewarticle/926838], last accessed Feb 22, 2021.

Zheng, Y.Y., Ma, Y.T., Zhang, J.Y., Xie, X. “COVID-19 and the cardiovascular system.” Nat Rev Cardiol 17.5 (2020): 259–60.

Gurwitz, D. “Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics.” Drug Dev Res (2020).

Hussain, A., Bhowmik, B., do Vale Moreira, N.C. “COVID-19 and diabetes: Knowledge in progress.” Diabetes Res Clin Pract 162 (2020): 108142.

Vickers, C., Hales, P., Kaushik, V., et al. “Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase.” J Biol Chem 277 (2002): 14838–43.

Benter, I.F., Yousif, M.H., Dhaunsi, G.S., et al. “Angiotensin-(1-7) prevents activation of NADPH oxidase and renal vascular dysfunction in diabetic hypertensive rats.” Am J Nephrol 28 (2008): 25–33.

El-Hashim, A.Z., Renno, W.M., Raghupathy, R., et al. “Angiotensin-(1-7) inhibits allergic inflammation, via the MAS1 receptor, through suppression of ERK1/2- and NF-κBdependent pathways.” Br J Pharmacol 166 (2012): 1964–76.

Santos, R.A. “Angiotensin-(1-7)”. Hypertension 63.6 (2014): 1138–47.

Santos, R.A., Simoes e Silva, A.C., Maric, C., et al. “Angiotensin-(1-7) is an endogenous ligand for the G proteincoupled receptor Mas.” Proc Natl Acad Sci USA 100.14 (2003): 8258–63.

Chamsi-Pasha, M.A., Shao, Z., Tang, W.H. “Angiotensin-converting enzyme 2 as a therapeutic target for heart failure.” Curr Heart Fail Rep 11.1 (2014): 58–63.

Rice, G.I., Jones, A.L., Grant, P.J., et al. “Circulating activities of angiotensin-converting enzyme, its homolog, angiotensin-converting enzyme 2, and neprilysin in a family study.” Hypertension 48.5 (2006): 914–20.

Anguiano, L., Riera, M., Pascual, J., et al. ”Circulating angiotensin-converting enzyme 2 activity in patients with chronic kidney disease without previous history of cardiovascular disease.” Nephrol Dial Transplant 30.7 (2015): 1176–85.

Gilbert, A., Liu, J., Cheng, G., et al. “A review of urinary angiotensin converting enzyme 2 in diabetes and diabetic nephropathy.” Biochem Med 29.1 (2019): 010501.

Benigni, A., Cassis, P., Remuzzi, G. “Angiotensin II revisited: New roles in inflammation, immunology and aging.” EMBO Mol Med 2.7 (2010): 247–57.

Swirski, F.K., Nahrendorf, M., Etzrodt, M., et al. “Identification of splenic reservoir monocytes and their deployment to inflammatory sites.” Science 325.5940 (2009): 612–6.

Thomas, M.C., Pickering, R.J., Tsorotes, D., et al. “Genetic Ace2 deficiency accentuates vascular inflammation and atherosclerosis in the ApoE knockout mouse.” Circ Res 107.7 (2010): 888–97.

Alghamri, M.S., Weir, N.M., Anstadt, M.P., et al. “Enhanced angiotensin II-induced cardiac and aortic remodeling in ACE2 knockout mice.” J Cardiovasc Pharmacol Ther 18.2 (2013): 138–51.

Rodrigues, P.T.R., Rocha, N.P., Miranda, A.S., et al. “The anti-inflammatory potential of ACE2/angiotensin-(1-7)/mas receptor axis: Evidence from basic and clinical research.” Curr Drug Targets 18.11 (2017): 1301–13.

Bineshfar, N., Mirahmadi, A., Karbasian, F., et al. “Acute pancreatitis as a possible unusual manifestation of COVID-19 in children.” Case Rep Pediatr 2021 (2021): 6616211.

Agarwal, S., Agarwal, S.K. “Endocrine changes in SARS-CoV-2 patients and lessons from SARS-CoV.” Postgrad Med J 96.1137 (2020): 412–6.

Xiao, L., Sakagami, H., Miwa, N. “ACE2: The key molecule for understanding the pathophysiology of severe and critical conditions of COVID-19: demon or angel?” Viruses 12 (2020): 491.

Hsueh, W.A., Wyne K. “Renin-angiotensin-aldosterone system in diabetes and hypertension.” J Clin Hypertens 13.4 (2011): 224–37.

Munger, M.A. “Use of angiotensin receptor blockers in cardiovascular protection: Current evidence and future directions.” P T 36.1 (2011): 22–40.

Tikellis, C., Thomas, M.C. “Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease.” Int J Pept 2012 (2012): 256294.

Imai, Y., Kuba, K., Rao, S., et al. “Angiotensin -converting enzyme 2 protects from severe acute lung failure.” Nature 436 (2005): 112–6.

Kuba, K., Imai, Y., Rao, S., et al. “A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.” Nat Med 11.8 (2005): 875–9.

AlGhatrif, M., Cingolani, O., Lakatta, E.G. “The dilemma of coronavirus disease 2019, aging, and cardiovascular disease: Insights from cardiovascular aging science.” JAMA Cardiol 5.7 (2020): 747–8.

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 Intern Med 180.7 (2020): 934–43.

Wrapp, D., Wang, N., Corbett, K.S., et al. “Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.” Science 367.6483 (2020): 1260–3.

Fang, L., Karakiulakis, G., Roth, M. “Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?” Lancet Respir Med 8.4 (2020): e21.

Qiao, W., Wang, C., Chen, B., et al. “Ibuprofen attenuates cardiac fibrosis in streptozotocin-induced diabetic rats.” Cardiology 131.2 (2015): 97–106.

Zhang, W., Li, C., Liu, B., et al. “Pioglitazone upregulates hepatic angiotensin converting enzyme 2 expression in rats with steatohepatitis.” Ann Hepatol 12.6 (2013): 892–900.

Shiobara, T., Chibana, K., Watanabe, T., et al. “Dipeptidyl peptidase-4 is highly expressed in bronchial epithelial cells of untreated asthma and it increases cell proliferation along with fibronectin production in airway constitutive cells.” Respir Res 17 (2016): 28.

Dong, C., Li, X., Song Qifa, et al. “Hypokalemia and clinical implications in patients with coronavirus disease 2019 (COVID-19).” [Online]. Infectious Diseases (except HIV/AIDS) (2020). DOI: 10.1101/2020.02.27.20028530

Li, B., Yang, J., Zhao, F., et al. “Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China.” Clin Res Cardiol 109.5 (2020): 531–8.

Fadini, G.P., Morieri, M.L., Longato, E., Avogaro, A. “Prevalence and impact of diabetes among people infected with SARS-CoV-2.” J Endocrinol Invest 43.6 (2020): 867–9.

Pinheiro, M., Pinheiro, J., Pinheiro, F., et al. “Editorial – COVID-19 pandemic: is it time to learn about DPP-4/CD26?” Cell 8 (2020): e2835.

Liu, J., Li, S., Liu, J., et al. “Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients.” EBioMedicine 55 (2020): 102763.

Anderluh, M., Kocic, G., Tomovic, K., et al. “DPP-4 inhibition: А novel therapeutic approach to the treatment of pulmonary hypertension?“ Pharmacol Ther 201 (2019): 1–7.

Nieto-Fontarigo, J.J., González-Barcala, F.J., San José, E, et al. “CD26 and asthma: a comprehensive review.” Clin Rev Allergy Immunol 56.2 (2019): 139–60.

Wang, L., Gao, P., Zhang, M., et al. “Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013.” JAMA 317.24 (2017): 2515–23.

Drucker D.J. “Coronavirus Infections and type 2 diabetes.” Endocrine Reviews 41.3 (2020): 1–13.

Gupta, R., Ghosh, A., Singh, A.K., Misra, A. “Clinical considerations for patients with diabetes in times of COVID-19 epidemic”. Diabetes Metab Syndr 14.3 (2020): 211–2.

Pal, R., Bhadada, S.K. “Should anti-diabetic medications be reconsidered amid COVID-19 pandemic?” Diabetes Res Clin Pract 10 (2020): 108146.

Chen, Y., Yang, D., Cheng, B., et al. “Clinical characteristics and outcomes of patients with diabetes and COVID-19 in association with glucose-lowering medication.” Diabetes Care 43.7 (2020): 1399–407.

Gupta, R., Hussain, A., Misra, A. “Diabetes and COVID-19: evidence, current status and unanswered research questions.” Eur J Clin Nutr 74 (2020): 864–70.

Tripathy, D., Daniele, G., Fiorentino, T.V., et al. “Pioglitazone improves glucose metabolism and modulates skeletal muscle TIMP-3–TACE dyad in type 2 diabetes mellitus: a randomised, double-blind, placebo-controlled, mechanistic study.” Diabetologia 56.10 (2013): 2153–63.

Romaní-Pérez, M., Outeiriño-Iglesias, V., Moya, C.M., et al. “Activation of the GLP-1 receptor by liraglutide increases ACE2 expression, reversing right ventricle hypertrophy, and improving the production of SP-A and SP-B in the lungs of type 1 diabetes rats.” Endocrinology 156.10 (2015): 3559–69.

Kawanami, D., Matoba, K., Takeda, Y., et al. “SGLT2 inhibitors as a therapeutic option for diabetic nephropathy.” Int J Mol Sci 18.5 (2017):1083.

Klonoff, D.C., Umpierrez, G.E. “Letter to the Editor: COVID-19 in patients with diabetes: risk factors that increase morbidity.” Metabolism 108 (2020): 154224.

Iacobellis, G. “COVID-19 and diabetes: Can DPP4 inhibition play a role?” Diabetes Res Clin Pract 162 (2020): 108125.

Ceriello, A., Stoian, A.P., Rizzo, M. “COVID-19 and diabetes management: What should be considered?“ Diabetes Res Clin Pract 163 (2020): 108151.

Stoian, A.P., Banerjee, Y., Rizvi, A.A., Rizzo, M. “Diabetes and the COVID-19 pandemic: how insights from recent experience might guide future management.” Metab Syndr Relat Disord 18.4 (2020): 173–5.

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 11 (2021): 600439.

Grasselli, G., Zangrillo, A., Zanella, A., et al. “Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy.” JAMA 323.16 (2020): 1574–81.

Solerte, S.B., D’Addio, F., Trevisan, R., et al. “Sitagliptin treatment at the time of hospitalization was associated with reduced mortality in patients with type 2 diabetes and COVID-19: a multicenter, case-control, retrospective, observational study.” Diabetes Care 43.12 (2020): 2999–3006.

Bornstein, S.R., Rubino, F., Khunti, K., et al. “Practical recommendations for the management of diabetes in patients with COVID-19.” Lancet Diabetes Endocrinol 8.6 (2020): 546–50.

Diaz-Ramos, A., Eilbert, W., Marquez, D. “Euglycemic diabetic ketoacidosis associated with sodium-glucose cotransporter-2 inhibitor use: a case report and review of the literature.” Int J Emerg Med 12.1 (2019): 27.

Centers for Disease Control and Prevention.“Coronavirus disease 2019 (COVID-19) and diabetes: the importance of prevention, management, and support.” Available from: [www.cdc.gov/coronavirus/2019-ncov/cdcresponse/about-COVID-19.html], last accessed Feb 22, 2021.

Korytkowski, M., Antinori-Lent, K., Drincic, A., et al. “A pragmatic approach to inpatient diabetes management during the COVID-19 pandemic.” J Clin Endocrinol & Metab 105.9 (2020): 342.

Ng, K.E., Rickard, J.P. “The effect of COVID-19 on patients with diabetes”. US Pharm 45.11 (2020): 9–12.

Prattichizzo, F., La Sala, L., Rydén, L., et al. “Glucose-lowering therapies in patients with type 2 diabetes and cardiovascular diseases.” Eur J Prev Cardiol 26 Suppl 2 (2019): 73–80.

Wilding, J., Fernando, K., Milne, N, et al. “SGLT2 inhibitors in type 2 diabetes management: key evidence and implications for clinical practice.” Diabetes Ther 9.5 (2018): 1757–73.

Meyer, E.J., Gabb, G., Jesudason, D. “SGLT2 inhibitor-associated euglycemic diabetic ketoacidosis: a South Australian clinical case series and Australian spontaneous adverse event notifications.” Diabetes Care 41.4 (2018): e47–9.

Cao, X. “COVID-19: immunopathology and its implications for therapy.” Nat Rev Immunol 20 (2020): 269–70.

European Medicines Agency. “EMA advises continued use of medicines for hypertension, heart or kidney disease during COVID-19 pandemic.” Available from: [https://www.ema.europa. eu/en/news/ema-advises-continued-use-medicines-hypertension-heart-kidney-disease-during-covid-19-pandemic], last accessed Feb 22, 2021.

Gomez-Peralta, F., Abreu, C., Gomez-Rodriguez, S., et al. “Safety and efficacy of DPP4 inhibitor and basal insulin in type 2 diabetes: an updated review and challenging clinical scenarios.” Diabetes Ther 9.5 (2018): 1775–89.

Rizzo, M., Nikolic, D., Banach, M., et al. “Incretin-based therapies, glucometabolic health and endovascular inflammation.” Curr Pharm Des 20.31(2014): 4953–60.

Rizzo, M., Nikolic, D., Patti, A.M., et al. “GLP-1 receptor agonists and reduction of cardiometabolic risk: Potential underlying mechanisms.” Biochim Biophys Acta Mol Basis Dis 1864.9 Pt B (2018): 2814–21.

He, J., Yuan, G., Cheng, F., et al. “Mast cell and M1 macrophage infiltration and local pro-inflammatory factors were attenuated with incretin-based therapies in obesity-related glomerulopathy.” Metab Syndr Relat Disord 15.7 (2017): 344–53.

Amin, E.F., Rifaai, R.A., Abdel-Latif, R.G. “Empagliflozin attenuates transient cerebral ischemia/reperfusion injury in hyperglycemic rats via repressing oxidative-inflammatory-apoptotic pathway.” Fundam Clin Pharmacol 34.5 (2020): 548–58.

Ceriello, A. “Thiazolidinediones as anti-inflammatory and anti-atherogenic agents.” Diabetes Metab Res Rev 24.1 (2008): 14–26.

Deane, A.M., Horowitz, M. “Comment. Is incretin-based therapy ready for the care of hospitalized patients with type 2 diabetes?” Diabetes Care 37.2 (2014): e40–1.

Inzucchi, S.E., Bergenstal, R.M., Buse, J.B., et al. “Management of hyperglycemia in type 2 diabetes: a patient-centered approach: Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).” Diabetes Care 35.6 (2012): 1364–79.

Bangash, M.N., Patel, J., Parekh, D. ”COVID-19 and the liver: little cause for concern.” Lancet Gastroenterol Hepatol 5.6 (2020): 529–30.

Dardano, A., Del Prato, S. “Metformin: an inexpensive and effective treatment in people with diabetes and COVID-19?” Lancet Healthy Longev 2.1 (2021): e6–e7.

Smith, G.D., Amos, T.A., Mahler, R., Peters, T.J. “Effect of chloroquine on insulin and glucose homoeostasis in normal subjects and patients with non-insulin-dependent diabetes mellitus.” Br Med J (Clin Res Ed) 294.6570 (1987): 465–7.

Quatraro, A., Consoli, G., Magno, M., et al. “Hydroxychloroquine in decompensated, treatment-refractory noninsulin-dependent diabetes mellitus. A new job for an old drug?“ Ann Intern Med 112.9 (1990): 678–81.

Rekedal, L.R., Massarotti, E., Garg, R., et al. “Changes in glycosylated hemoglobin after initiation of hydroxychloroquine or methotrexate treatment in diabetes patients with rheumatic diseases.” Arthritis Rheum 62.12 (2010): 3569–73.

Gerstein, H.C., Thorpe, K.E., Taylor, D.W., Haynes, R.B. “The effectiveness of hydroxychloroquine in patients with type 2 diabetes mellitus who are refractory to sulfonylureas – a randomized trial.” Diabetes Res Clin Pract 55.3 (2002): 209–19.

Emami, J., Pasutto, F.M., Mercer, J.R., Jamali, F. “Inhibition of insulin metabolism by hydroxychloroquine and its enantiomers in cytosolic fraction of liver homogenates from healthy and diabetic rats.” Life Sci 64.5 (1999): 325–35.

Penlioglou, T., Papachristou, S., Papanas, N. “COVID-19 and diabetes mellitus: May old anti-diabetic agents become the new philosopher’s stone?“ Diabetes Ther 11 (2020): 1195–7.

Mercuro, N.J., Yen, C.F., Shim, D.J., et al. “Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19).” JAMA Cardiol 5.9 (2020): 1036–41.

Bessière, F., Roccia, H., Delinière, A., et al. “Assessment of QT intervals in a case series of patients with coronavirus disease 2019 (COVID-19) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit.” JAMA Cardiol 5.9 (2020): 1067–9.

Satarker, S., Ahuja, T., Banerjee, M., et al. “Hydroxychloroquine in COVID-19: potential mechanism of action against SARS-CoV-2.” Curr Pharmacol Rep 6 (2020): 203–11.

Wasko, M.C.M., McClure, C.K., Kelsey, S.F, et al. “Antidiabetogenic effects of hydroxychloroquine on insulin sensitivity and beta cell function: a randomized trial.” Diabetologia 58.10 (2015): 2336–43.

Chakravarti, H.N., Nag, A. “Efficacy and safety of hydroxychloroquine as add-on therapy in uncontrolled type 2 diabetes patients who were using two oral antidiabetic drugs.” J Endocrinol Invest 44.3 (2021): 481–92.

Gupta, A. “Real-world clinical effectiveness and tolerability of hydroxychloroquine 400 mg in uncontrolled type 2 diabetes subjects who are not willing to initiate insulin therapy (HYQ-Real-World study).” Curr Diabetes Rev 15.6 (2019): 510–9.

Shojania, K., Koehler, B.E., Elliott, T. “Hypoglycemia induced by hydroxychloroquine in a type II diabetic treated for polyarthritis”. J Rheumatol 26.1 (1999): 195–6.

Stoian, A.P., Catrinoiu, D., Rizzo, M., Ceriello, A. “Hydroxychloroquine, COVID-19 and diabetes. Why it is a different story.” Diabetes Metab Res Rev (2020). DOI: 10.1002/dmrr.3379

The COVID-19 RISK and Treatments (CORIST) Collaboration. “Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: Findings from the observational multicentre Italian CORIST study.” Eur J Intern Med 82 (2020): 38–47.

Hernandez, A.V., Roman, Y., Pasupuleti, V., et al. “Hydroxychloroquine or chloroquine for treatment or prophylaxis of COVID-19: a living systematic review.” Ann Intern Med 173.4 (2020): 287–96.

Lim, S., Bae, J.H., Kwon, H.S., Nauck, M.A. “COVID-19 and diabetes mellitus: from pathophysiology to clinical management.“ Nat Rev Endocrinol 17.1 (2021): 11–30.

Carrasco-Sánchez, F.J., López-Carmona, M.D., Martínez-Marcos, F.J., et al. “Admission hyperglycaemia as a predictor of mortality in patients hospitalized with COVID-19 regardless of diabetes status: data from the Spanish SEMI-COVID-19 Registry.” Ann Med 53.1 (2021): 103–16.

Mendez, C.E., Umpierrez, G.E. “Pharmacotherapy for hyperglycemia in noncritically ill hospitalized patients.” Diabetes Spectr 27.3 (2014): 180–8.

Moghissi, E.S., Korytkowski, M.T., DiNardo, M., et al. “American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control.” Diabetes Care 32.6 (2009): 1119–31.

Riddle, M.C., Buse, J.B., Franks, P.W., et al. “COVID-19 in people with diabetes: urgently needed lessons from early reports.” Diabetes Care 43.7 (2020): 1378–81.

Novack, V., Eisinger, M., Frenkel, A., et al. “The effects of statin therapy on inflammatory cytokines in patients with bacterial infections: a randomized double-blind placebo controlled clinical trial.” Intensive Care Med 35.7 (2009): 1255–60.

Papazian, L., Roch, A., Charles, P.E., et al. “Effect of statin therapy on mortality in patients with ventilator-associated pneumonia: a randomized clinical trial.” JAMA 310.16 (2013): 1692–700.

Zhang, X.J., Qin, J.J., Cheng, X., et al. “In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19.” Cell Metab 32.2 (2020): 176–87.

Chen, N., Zhou, M., Dong, X., et al. “Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.” Lancet 395 (2020): 507–13.

Klok, F.A., Kruip, M.J.H.A., van der Meer, N.J.M., et al. “Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis.” Thromb Res 191 (2020):148–50.

Connors, J.M., Levy, J.H. “COVID-19 and its implications for thrombosis and anticoagulation.” Blood 135.23 (2020): 2033–40.

Tang, N., Li, D., Wang, X., Sun, Z. “Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.” J Thromb Haemost 18.4 (2020): 844–7.

Moores, L.K., Tritschler, T., Brosnahan, S., et al. “Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019: CHEST guideline and expert panel report.” Chest 158.3 (2020): 1143–63.

Oxford, A.E., Halla, F., Robertson, E.B., Morrison, B.E. “Endothelial cell contributions to COVID-19”. Pathogens 9.10 (2020): 785.

Ferrario, C.M., Jessup, J., Chappell, M.C., et al. “Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2.” Circulation 111.20 (2005): 2605–10.

Varga, Z., Flammer A.J., Steiger, P., et al. “Endothelial cell infection and endotheliitis in COVID-19.” Lancet 395.10234 (2020): 1417–8.

Fei, Y., Tang, N., Liu, H., Cao, W. “Coagulation dysfunction: a hallmark in COVID-19.” Arch Pathol Lab Med 144.10 (2020): 1223–9.

Chung, W.S., Lin, C.L., Kao, C.H. “Diabetes increases the risk of deep-vein thrombosis and pulmonary embolism. A population-based cohort study.” Thromb Haemost 114.4 (2015): 812–8.

Zhao, Z., Wang, S., Ma, W., et al. “Diabetes mellitus increases the incidence of deep vein thrombosis after total knee arthroplasty.” Arch Orthop Trauma Surg 134.1 (2014): 79–83.

Galana, P., Bertoletti, L., Amitrano, M., et al. “Predictors of post-thrombotic ulcer after acute DVT: the RIETE registry.” Thromb Haemost 118.2 (2018): 320–8.

Olesen, K.K.W., Madsen, M., Gyldenkerne, C., et al. “Diabetes mellitus is associated with increased risk of ischemic stroke in patients with and without coronary artery disease.” Stroke 50.12 (2019): 3347–54.

Overvad, T.F., Skjøth, F., Lip, G.Y., et al. “Duration of diabetes mellitus and risk of thromboembolism and bleeding in atrial fibrillation: nationwide cohort study.” Stroke 46.8 (2015): 2168–74.

Arepally, G.M., Ortel, T.L. “Changing practice of anticoagulation: will target-specific anticoagulants replace warfarin?” Annu Rev Med 66 (2015): 241–53.

Tang, N., Bai, H., Chen, X., et al. “Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.” J Thromb Haemost 18.5 (2020): 1094–9.

Lim, S., Lee, G.Y., Park, H.S., et al. “Attenuation of carotid neointimal formation after direct delivery of a recombinant adenovirus expressing glucagon-like peptide-1 in diabetic rats.” Cardiovasc Res 113.2 (2017): 183–94.

Vinué, Á., Navarro, J., Herrero-Cervera, A., et al. “The GLP-1 analogue lixisenatide decreases atherosclerosis in insulin-resistant mice by modulating macrophage phenotype.” Diabetologia 60.9 (2017): 1801–12.

Gerstein, H.C., Colhoun, H.M., Dagenais, G.R., et al. “Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.” Lancet 394.10193 (2019): 121–30.

Li, H., Zhou, Y., Zhang, M., et al. “Updated approaches against SARS-CoV-2.” Antimicrob Agents Chemother 64.6 (2020): e00483–20.

World Health Organization. “Overview of the types/classes of candidate therapeutics 2020.” (2020).

Kupferschmidt, K., Cohen, J. “Race to find COVID-19 treatments accelerates.” Science 367.6485 (2020): 1412–3.

Hoffmann, M., Kleine-Weber, H., Schroeder, S., et al. “SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.” Cell 181.2 (2020): 271–80.

Ito, T., Otsuki, M., Itoi, T., et al. “Pancreatic diabetes in a follow-up survey of chronic pancreatitis in Japan.” J Gastroenterol 42.4 (2007): 291–7.

Jia, D., Taguchi, M., Otsuki, M. “Synthetic protease inhibitor camostat prevents and reverses dyslipidemia, insulin secretory defects, and histological abnormalities of the pancreas in genetically obese and diabetic rats.” Metabolism 54.5 (2005): 619–27.

Albarazanji, K., Jennis, M., Cavanaugh, C.R., et al. “Intestinal serine protease inhibition increases FGF21 and improves metabolism in obese mice.” Am J Physiol Gastrointest Liver Physiol 316.5 (2019): G653–67.

Katulanda, P., Dissanayake, H.A., Ranathunga I., et al. “Prevention and management of COVID-19 among patients with diabetes: an appraisal of the literature.” Diabetologia 63.8 (2020): 1440–52.

Bonaventura, A., Montecucco, F. “Steroid-induced hyperglycemia: an underdiagnosed problem or clinical inertia? A narrative review.” Diabetes Res Clin Pract 139 (2018): 203–20.

The RECOVERY Collaborative Group. “Dexamethasone in hospitalized patients with Covid-19 – preliminary report.” N Engl J Med (2020). DOI: 10.1056/NEJMoa2021436

Tomazini, B.M., Maia, I.S., Cavalcanti, A.B., et al. “Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial.” JAMA 324.13 (2020): 1307–16.

The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. “Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis.” JAMA 324.13 (2020): 1330–41.

Angus, D.C., Derde, L., Al-Beidh, F., et al. “Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.” JAMA 324.13 (2020): 1317–29.

Dequin, P.F., Heming, N., Meziani, F., et al. “Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial.” JAMA 324.13 (2020): 1298–306.

Russell, C.D., Millar, J.E., Baillie, J.K. “Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.” Lancet 395.10223 (2020): 473–5.

Clore, J.N., Thurby-Hay, L. “Glucocorticoid-induced hyperglycemia.” Endocr Pract 15.5 (2009): 469–74.

Anesi, G.L., Manaker, S., Finlay, G. “Coronavirus disease 2019 (COVID-19): Critical care issues. UpToDate.” Available from: [https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-critical-care-issues], last accessed Feb 22, 2021.

Caly, L., Druce, J.D., Catton, M.G., et al. “The FDA approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antiviral Research.” DOI: 10.1016/j.antiviral.2020.104787

Li, Y.N., Su, Y. “Remdesivir attenuates high fat diet (HFD)-induced NAFLD by regulating hepatocyte dyslipidemia and inflammation via the suppression of STING.” Biochem Biophys Res Commun 526.2 (2020): 381–8.

Beigel, J.H., Tomashek, K.M., Dodd L.E., et al. “Remdesivir for the treatment of Covid-19 – preliminary report.” N Engl J Med 383 (2020): 1813–26.

Wang, Y., Zhang, D., Du, G., et al. “Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebocontrolled, multicentre trial.” Lancet 395.10236 (2020): 1569–78.

Food and Drug Administration. “Remdesivir: EUA letter of authorisation.” (2020). Available from: [https://www.fda.gov/media/137564/download], last accessed Feb 22, 2021.

Chu, C.M., Cheng, V.C.C., Hung, I.F.N., et al. “Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings.” Thorax 9.3 (2004): 252–6.

Hull, M.W., Montaner, J.S.G. “Ritonavir-boosted protease inhibitors in HIV therapy.” Ann Med 43.5 (2011): 375–88.

Woerle, H.J., Szoke, E., Meyer, C., et al. “Mechanisms for the deterioration in glucose tolerance associated with HIV protease inhibitor regimens.” Diabetes Am J Physiol Endocrinol Metab 290.1 (2006): E67–E77.

Tsiodras, S., Mantzoros, C., Hammer, S., Samore, M. “Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5-year cohort study.” Arch Intern Med 160.13 (2000): 2050–6.

Brown, T.T., Cole, S.R., Li, X., et al. “Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study.” Arch Intern Med 165.10 (2005): 1179–84.

Kan, V.L., Nylen, E.S. “Diabetic ketoacidosis in an HIV patient: a new mechanism of HIV protease inhibitor-induced glucose intolerance.” AIDS 13.14 (1999): 1987–9.

Cao, B., Wang, Y., Wen, D., et al. “A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19.” N Engl J Med 382 (2020): 1787–99.

Zhou, Y., Vedantham, P., Lu, K., et al. “Protease inhibitors targeting coronavirus and filovirus entry.” Antiviral Res 116 (2015): 76–84.

Pardi, N., Hogan, M.J., Porter, F.W., Weissman, D. “mRNA vaccines – a new era in vaccinology.” Nat Rev Drug Discov 17.4 (2018): 261–79.

Hodgson, J. “The pandemic pipeline”. Nat Biotechnol 38.5 (2020): 523–32.

Parnham, M.J., Haber, V.E., Giamarellos-Bourboulis, E.J., et al. “Azithromycin: Mechanisms of action and their relevance for clinical applications.” Pharmacol Ther 143.2 (2014): 225–45.

Gautret, P., Lagier, J.-C., Parola, P., et al. “Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial.” Int J Antimicrob Agents 56.1 (2020): 105949.

Duan, K., Liu, B., Li, C., et al. “Effectiveness of convalescent plasma therapy in severe COVID-19 patients”. Proc Natl Acad Sci U S A 117.17 (2020): 9490–6.

Rubino, F., Amiel, S.A., Zimmet, P., et al. “New-onset diabetes in Covid-19.” New Engl J Med 383.8 (2020): 789–90. DOI: 10.1056/NEJMc2018688






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