Diabetes mellitus and COVID-19: current issues of pathogenesis, clinic and therapy. Literature review





COVID-19, diabetes, therapy


Currently, due to the rapid spread of COVID-19 with the manifestation of severe acute respiratory syndrome, extensive discussions are underway on a number of topical issues related to the best optimal ways to treat patients with diabetes mellitus (DM) during coronavirus pandemic, including problems of susceptibility to this new infection, presence of comorbid pathology, the disease severity and its course, the risks of complications and mortality, as well as the role of drugs used to control glycemia. The coronavirus pandemic is a severe acute respiratory syndrome SARS-CoV2 (COVID-19) dictates the need for immediate study and deep fundamental understanding of the general pathophysiology of the new disease, potentially determines the choice of therapeutic strategy in patients with DM, affected by coronavirus infection.

Currently available epidemiological data on COVID-19 do not support the hypothesis that patients with diabetes 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 coronavirus infection and significantly increases the risk of fatal disease outcome. Thus, there are the scientific and clinical needs to obtain new data on the methods of treatment currently used in patients with DM infected with COVID-19 to determine their effectiveness and select the optimal treatment strategy, provide a less severe course and better prognosis of disease.

Our knowledge of the new coronavirus infection is deepening day by day and the lessons dealing with this new pandemic around the world are extremely important and very valuable in determining the best approach to fighting against this disease. This review provides a brief summary of the general characteristics of COVID-19, and also based on the literature data provides an analytical characteristics of the relationship between this new infectious disease and DM in order to promote a better understanding of the pathogenetic and clinical aspects of this pathological combination, as well as the selection of the most effective therapeutic strategies for patients with COVID-19 and DM

Author Biographies

В. І. Цимбалюк, SI “V.P. Romodanov Institute of Neurosurgery of the NAMS of Ukraine”, Kyiv

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

М. Д. Тронько, SI “V.P. Komisarenko Institute of Endocrinology and Metabolism of the NAMS of Ukraine”, Kyiv

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

Ю. Г. Антипкін, SI “O.M. Lukyanova Institute of Pediatrics, Obstetrics and Gynecology of the NAMS of Ukraine”, Kyiv

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

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

MD, head of the Department of Preventive Diabetology


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

World Health Organization. Rolling updates on coronavirus disease (COVID-19) 2020. Available from: [https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen].

World Health Organization. Coronavirus disease (COVID-19) Pandemic 2020. Available from: [https://www.who. int/emergencies/diseases/novel-coronavirus-2019].

Coronavirus update (live). Available from: [https://www.worldometers.info /coronavirus/].

Center for Public Health of the MoH of Ukraine. Available from: [https://phc.org.ua].

Wu, Z., McGoogan, J.M. “Characteristics of 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, Y., et al. “Clinical characteristics of coronavirus disease 2019 in China.” N Engl J Med 382 (2020): 1708–20.

Wang, D., Hu, B., Hu, C., et al. “Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.” JAMA (2020).

Zhang, J.J., Dong, X., Cao, Y.Y., et al. “Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China.” Allergy (2020).

Hussain, A., Bhowmik, B., do Vale Moreira, N.C. “COVID-19 and diabetes: Knowledge in progress.” Diabetes Res Clin Pract 162 (2020): 108–42.

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.

Muniyappa, R., Gubbi, S. “COVID-19 pandemic, coronaviruses, and diabetes mellitus.” Am J Physiol Endocrinol Metab 318.5 (2020): E736–E741.

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.

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.

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.

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.” 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.

Lippi, G., Plebani, M. “Laboratory abnormalities in patients with COVID-2019 infection.” Clin Chem Lab Med (2020).

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.

Popov, D., Simionescu, M. “Alterations of lung structure in experimental diabetes, and diabetes associated with hyperlipidaemia in hamsters.” Eur Respir J 10.8 (1997): 1850–8.

Lange, P., Groth, S., Kastrup, J., et al. “Diabetes mellitus, plasma glucose and lung function in a cross-sectional population study.” Eur Respir J 2.1 (1989): 14–9.

Dunn, E.J., Grant, P.J. “Type 2 diabetes: an atherothrombotic syndrome.” Curr Mol Med 5.3 (2005): 323–32.

Ellison, R.T. III. “What's the duration of immunity to SARS-CoV-2?” N Engl J Med (2020).

Li, J., Fan, J.G. “Characteristics and mechanism of liver injury in 2019 Coronavirus disease.” J Clin Translat Hepatology 8.1 (2020): 13–17.

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.

Sommerstein, R. “Preventing a Covid-19 pandemic.” BMJ 368 (2020).

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 (2005): 2605–10.

Gheblawi, M., Wang, K., Viveiros, A., et al. “Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system.” Circulation Research 126 (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 (2020).

Christopher, H., Manaf, Z., Stock, E., et al. “Impact of angiotensin-converting enzyme inhibitors and statins on viral pneumonia.” Proc (Bayl Univ Med Cent) 31.4 (2018): 419–23.

Mortensen, E.M., Pugh, M.J., Copeland, L.A., et al. “Impact of statins and angiotensin-converting enzyme inhibitors on mortality of subjects hospitalised with pneumonia.” Eur Respir J 31.3 (2008): 611–7.

Chamberlain, J.J., Rhinehart, A.S., Shaefer, C.F. Jr, Neuman, A. “Diagnosis and management of diabetes: Synopsis of the 2016 American Diabetes Association Standards of medical care in diabetes.” Ann Intern Med 164.8 (2016): 542–52.

Gullestad, L., Aukrust, P., Ueland, T., et al. “Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure.” J Am Coll Cardiol 34.7 (1999): 2061–7.

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.

Hamming, I., Timens, W., Bulthuis, M.L., et al. “Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.” J Pathol 203 (2004): 631–7.

Crackower, M.A., Sarao, R., Oudit, G.Y., et al. “Angiotensin-converting enzyme 2 is an essential regulator of heart function.” Nature 417 (2002): 822–8.

Feng, Y., Yue, X., Xia, H., et al. “Angiotensin-converting enzyme 2 overexpression in the subfornical organ prevents the angiotensin II-mediated pressor and drinking responses and is associated with angiotensin II type 1 receptor downregulation.” Circ Res 102 (2008): 729–36.

Lambert, D.W., Yarski, M., Warner, F.J., et al. “Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severeacute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2).” J Biol Chem 280 (2005): 30113–9.

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 (2014): 1293–1307.

Matsuyama, S., Nagata, N., Shirato, K., et al. “Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by the transmembrane protease TMPRSS2.” J Virol 84 (2010): 12658–64.

Shulla, A., Heald-Sargent, T., Subramanya, G., et al. “A transmembrane serine protease is linked to the severe acute respiratory syndrome coronavirus receptor and activates virus entry.” J Virol 85 (2011): 873–82.

Glowacka, I., Bertram, S., Herzog, P., et al. “Differential downregulation of ACE2 by the spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus NL63.” J Virol 84 (2010): 1198–1205.

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.

Matsuyama, S., Nao, N., Shirato, K., et al. “Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells.” Proc Natl Acad Sci USA (2020).

Donoghue, M., Hsieh, F., Baronas, E., et al. “A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9.” Circ Res 87 (2000): E1–E9.

Turner, A.J., Tipnis, S.R., Guy, J.L., et al. “ACEH/ACE2 is a novel mammalian metallocarboxypeptidase and a homologue of angiotensin-converting enzyme insensitive to ACE inhibitors.” Can J Physiol Pharmacol 80 (2002): 346–53.

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.

Wang, G., Lai, F.M., Kwan, B.C., et al. “Expression of ACE and ACE2 in patients with hypertensive nephrosclerosis.” Kidney Blood Press Res 34.3 (2011): 141–9.

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.

Hashimoto, T., Perlot, T., Rehman, A., et al. “ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation.” Nature 487.7408 (2012): 477–81.

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): 1–8.

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

Kiely, D.G., Cargill, R.I., Wheeldon, N.M., et al. “Haemodynamic and endocrine effects of type 1 angiotensin II receptor blockade in patients with hypoxaemic cor pulmonale.” Cardiovasc Res 33 (1997): 201–8.

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.

Zou, Z., Yan, Y., Shu, Y., et al. “Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections.” Nat Commun 5 (2014): 3594.

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 (2020).

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.

Pal, R., Bhadada, S.K. “COVID-19 and diabetes mellitus: An unholy interaction of two pandemics.” Diabetes Metab Syndr 14.4 (2020): 513–7.

Peng, Y.D., Meng, K., Guan, H.Q., et al. “Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV.” Zhonghua Xin Xue Guan Bing Za Zhi 48.0 (2020): E004.

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.

Romaní-Pérez, M., Outeiriño-Iglesias, V., Moya, C.M., et al. “Activation of the ГПП-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.

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

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 (2020): 1–3.

Mirabelli, M., Chiefari, E., Puccio, L., et al. “Potential benefits and harms of novel antidiabetic drugs during COVID-19 crisis.” Int J Environ Res Public Health 17.10 (2020): 3664.

Pinheiro, M., Pinheiro, J., Pinheiro, F., et al. “COVID-19 pandemic: is it time to learn about DPP-4/CD26?” CellR4 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 (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.

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.

Iacobellis, G. “COVID-19 and diabetes: Can DPP-4 inhibition play a role?” Diabetes Res Clin Pract 162 (2020): 108125.

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. “Insufficient evidence' to recommend ДПП-IV inhibitor treatment in type 2 diabetes with COVID-19.” Endocr Rev (2020).

Ceriello, A. “Management of diabetes today: An exciting confusion.” Diabetes Res Clin Pract 162 (2020): 108129.

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 (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 (2020): dc200660.

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.

Fadini, G.P., Morieri, M.L., Longato, E., Avogaro, A. “Prevalence and impact of diabetes among people infected with SARS-CoV-2.” J Endocrinol Investig (2020): 1–3.

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

Salem, E.S.B., Grobe, N., Elased, K.M. “Insulin treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice.” Am J Physiol-Ren Physiol 306 (2014): F629–39.

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.

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. “COVID-19 in patients with diabetes: risk factors that increase morbidity.” Metabolism (2020): 154224.

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

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

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.

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.

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.

Driggin, E., Madhavan, M.V., Bikdeli, B., et al. “Cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (COVID-19) pandemic.” J Am Coll Cardiol 75.18 (2020): 2352–71.

Li, Y., Wang, M., Zhou, Y., et al. “Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study.” SSRN (2000).

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

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.

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.

Li, H., Zhou, Y., Zhang, M., et al. “Updated approaches against SARS-CoV-2.” Antimicrob agents chemother (2020): 00483–20.

World Health Organization. Overview of the types/classes of candidate therapeutics 2020. Available from: [https://www.who.int/blueprint/priority-diseases/key-action/ Table_of_ therapeutics_Appendix_17022020.pdf?ua=1].

Wang, M., Cao, R., Zhang, L., et al. “Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.” Cell Res 3.30 (2020): 269–71.

Gao, J., Tian, Z., Yang, X. “Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies.” Biosci Trends 14.1 (2020): 72–3.

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 (2020): 1–13.

Cortegiani, A., Ingoglia, G., Ippolito, M., et al. “A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19.” J Crit Care 57 (2020): 279–83.

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?].

World Health Organization. WHO welcomes preliminary results about dexamethasone use in treating critically ill COVID-19 patients (2020). Available from: [https://www.who.int/news-room/detail/16-06-2020-who-welcomes-preliminary-results-about-dexamethasone-use-in-treating-critically-ill-covid-19-patients].

Food and Drug Administration. Remdesivir: EUA letter of authorisation (2020). Available from: [https://www.fda. gov/media/137564/download].

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 59.3 (2004): 252–6.

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

Liu, F., Xu, A., Zhang, Y., et al. “Patients of COVID-19 may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of COVID-19 progression.” Int J Infect Dis (2020).

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.

Liu, M.A. “DNA Vaccines.” J Intern Med 253.4 (2003): 402–10.

Inovio Pharmaceuticals, Inc. Inovio Accelerates Timeline for COVID-19 DNA Vaccine INO-4800 (2020).

Schommer, N.N., Nguyen, J., Yung, B.S., et al. “Active immunoprophylaxis and vaccine augmentations mediated by a novel plasmid DNA formulation.” Hum Gene Ther 30.4 (2019): 523–33.

Diehl, M.C., Lee, J.C., Daniels, S.E., et al. “Tolerability of intramuscular and intradermal delivery by CELLECTRA® adaptive constant current electroporation device in healthy volunteers.” Hum Vaccin Immunother 9.10 (2013): 2246–52.

Callaway, E. “Coronavirus vaccines: five key questions as trials begin.” Nature 579.7800 (2020): 481.

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 (2020): 105949.

Goldstein, E.J.C., Owens, R.C. Jr, Nolin, T.D. “Antimicrobial-associated QT interval prolongation: pointes of interest.” Clin Infect Dis 43.12 (2006): 1603–11.

Ray, W.A., Murray, K.T., Hall, K., et al. “Azithromycin and the risk of cardiovascular death.” N Engl J Med 366.20 (2012): 1881–90.

Svanström, H., Pasternak, B., Hviid, A. “Use of azithromycin and death from cardiovascular causes.” N Engl J Med 368.18 (2013): 1704–12.

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

Baker, W.L., Couch, K.A. “Azithromycin for the secondary prevention of coronary artery disease: a meta-analysis.” Am J Health Syst Pharm 64.8 (2007): 830–6.

Yang, X., Yu, Y., Xu, J., et al. “Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.” Lancet Respir Med 8.5 (2020): 475–81.

Vaur, L., Bobrie, G., Dutrey-Dupagne, C., et al. “Short-term effects of withdrawing angiotensin converting enzyme inhibitor therapy on home self-measured blood pressure in hypertensive patients.” Am J Hypertens 11.2 (1998): 165–73.

World Health Organization (on Twitter). “Q: Could #ibuprofen worsen disease for people with #COVID19? A: Based on currently available information, WHO does not recommend against the use of of ibuprofen.” Available from: [https://t.co/n39DFt2amF].

Food and Drug Administration. FDA advises patients on use of non-steroidal anti-inflammatory drugs (NSAIDs) for COVID-19 (2020).

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.

Barrera, F.J., Shekhar, S., Wurth, R., et al. “Prevalence of Diabetes and Hypertension and their Associated Risks for Poor Outcomes in Covid-19 Patients.” Journal of the Endocrine Society (2020): bvaa102. DOI: 10.1210/jendso/bvaa102.

Rubino, F., Amiel, S.A., Zimmet, P., et al. “New-onset diabetes in Covid-19.” NEJM (2020). DOI: 10.1056/NEJMc2018688

Apicella, M., Campopiano, M.C., Mantuano, M. “COVID-19 in people with diabetes: understanding the reasons for worse outcomes.” The Lancet Diabetes & Endocrinology (2020). DOI: 10.1016/S2213-8587(20)30238-2

Cariou, B., Hadjadj, S. “Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study.” Diabetologia 63 (2020): 1500–15.





Interdisciplinary consilium