COVID-19 in people with diabetes: understanding the reasons for worse outcomes

Matteo Apicella, Maria Cristina Campopiano, Michele Mantuano, Laura Mazoni, Alberto Coppelli, Stefano Del Prato, Matteo Apicella, Maria Cristina Campopiano, Michele Mantuano, Laura Mazoni, Alberto Coppelli, Stefano Del Prato

Abstract

Since the initial COVID-19 outbreak in China, much attention has focused on people with diabetes because of poor prognosis in those with the infection. Initial reports were mainly on people with type 2 diabetes, although recent surveys have shown that individuals with type 1 diabetes are also at risk of severe COVID-19. The reason for worse prognosis in people with diabetes is likely to be multifactorial, thus reflecting the syndromic nature of diabetes. Age, sex, ethnicity, comorbidities such as hypertension and cardiovascular disease, obesity, and a pro-inflammatory and pro-coagulative state all probably contribute to the risk of worse outcomes. Glucose-lowering agents and anti-viral treatments can modulate the risk, but limitations to their use and potential interactions with COVID-19 treatments should be carefully assessed. Finally, severe acute respiratory syndrome coronavirus 2 infection itself might represent a worsening factor for people with diabetes, as it can precipitate acute metabolic complications through direct negative effects on β-cell function. These effects on β-cell function might also cause diabetic ketoacidosis in individuals with diabetes, hyperglycaemia at hospital admission in individuals with unknown history of diabetes, and potentially new-onset diabetes.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Figure
Figure
Synopsis of the reciprocal effects of diabetes and COVID-19 The relationship between diabetes and COVID-19 is biunivocal. On one hand, people with diabetes have worse outcomes because of multiple associated conditions enhancing the risk. On the other hand, SARS-CoV-2, because of its tropism for the β-cell, might cause new-onset diabetes or sustain hyperglycaemia at hospital admission. The impairment of β-cell function along with the inflammatory cytokine storm and counter-regulatory hormonal responses can precipitate further acute metabolic complications (DKA or HHS). New-onset diabetes, hyperglycaemia at admission, and acute metabolic deterioration, in turn, can further worsen COVID-19 outcomes. DKA=diabetic ketoacidosis. HHS=hyperglycaemic hyperosmolar syndrome.

References

    1. Healthmap Novel coronavirus (COVID-19)
    1. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020 https//:doi.org.10.1001/jama.2020.2648 published online Feb 24.
    1. Zhang Y, Cui Y, Shen M, et al. Association of diabetes mellitus with disease severity and prognosis in COVID-19: a retrospective cohort study. Diabetes Res Clin Pract. 2020;165
    1. Kumar A, Arora A, Sharma P, et al. Is diabetes mellitus associated with mortality and severity of COVID-19? A meta-analysis. Diabetes Metab Syndr Clin Res Rev. 2020;14:535–545.
    1. Booth CM. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA. 2003;289:2801–2809.
    1. Shi Q, Zhang X, Jiang F, et al. Clinical characteristics and risk factors for mortality of COVID-19 patients with diabetes in Wuhan, China: a two-center, retrospective study. Diabetes Care. 2020;43:1382–1391.
    1. Williamson E, Walker AJ, Bhaskaran K, et al. Factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients. J Chem Inf Model. 2019;53:1689–1699.
    1. Garbati MA, Fagbo SF, Fang VJ, et al. A comparative study of clinical presentation and risk factors for adverse outcome in patients hospitalised with acute respiratory disease due to MERS coronavirus or other causes. PLoS One. 2016;11
    1. Schoen K, Horvat N, Guerreiro NFC, de Castro I, de Giassi KS. Spectrum of clinical and radiographic findings in patients with diagnosis of H1N1 and correlation with clinical severity. BMC Infect Dis. 2019;19:964.
    1. Guan WJ, Liang WH, Zhao Y, et al. Comorbidity and its impact on 1590 patients with Covid-19 in China: a nationwide analysis. Eur Respir J. 2020;55
    1. Li B, Yang J, Zhao F, et al. Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clin Res Cardiol. 2020;109:531–538.
    1. Fadini GP, Morieri ML, Longato E, Avogaro A. Prevalence and impact of diabetes among people infected with SARS-CoV-2. J Endocrinol Invest. 2020;43:867–869.
    1. Petrilli CM, Jones SA, Yang J, et al. Factors associated with hospitalization and critical illness among 4,103 patients with COVID-19 disease in New York City. BMJ. 2020 https//:doi.org.10.1101/2020.04.08.32444366 published online April 11.
    1. Roncon L, Zuin M, Rigatelli G, Zuliani G. Diabetic patients with COVID-19 infection are at higher risk of ICU admission and poor short-term outcome. J Clin Virol. 2020;127
    1. 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. 2020;395:1054–1062.
    1. Zhu L, She ZG, 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;31:1068–1077.
    1. Yan Y, Yang Y, Wang F, et al. Clinical characteristics and outcomes of patients with severe covid-19 with diabetes. BMJ Open Diabetes Res Care. 2020 https//:doi.org.10.1136/bmjdrc-2020-001343 published online April 8.
    1. Sardu C, D'Onofrio N, Balestrieri ML, et al. Outcomes in patients with hyperglycemia affected by Covid-19: can we do more on glycemic control? Diabetes Care. 2020;43:1408–1415.
    1. 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;94:91–95.
    1. 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 doi: 10.1016/S2213-8587(20)30272-2. published online Aug 13.
    1. Guo W, Li M, Dong Y, et al. Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes Metab Res Rev. 2020 https//:doi.org.10.1002/dmrr.3319 published online March 31.
    1. EpiCentro Portale di epidemiologia per gli operatori sanitari.
    1. Cariou B, Hadjadj S, Wargny M, et al. Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study. Diabetologia. 2020 https//:doi.org.10.1007/s00125-020-05180-x published online May 29.
    1. 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 doi: 10.1016/S2213-8587(20)30271-0. published online Aug 13.
    1. Ebekozien OA, Noor N, Gallagher MP, Alonso GT. Type 1 diabetes and COVID-19: preliminary findings from a multicenter surveillance study in the US. Diabetes Care. 2020 https//:doi.org.10.2337/dc20-1088 published online June 5.
    1. Dudley JP, Lee NT. Disparities in age-specific morbidity and mortality from SARS-CoV-2 in China and the Republic of Korea. Clin Infect Dis. 2020 https//:doi.org.10.1093/cid/ciaa354 published online March 31.
    1. The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China. China CDC Wkly. 2020;2:113–122.
    1. 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;43:1399–1407.
    1. Haynes N, Cooper LA, Albert MA, Association of Black Cardiologists At the heart of the matter: unmasking and addressing COVID-19's toll on diverse populations. Circulation. 2020 https//:doi.org.10.1161/CIRCULATIONAHA.120.048126 published online May 4.
    1. The Washington Post
    1. Coronavirus Resource Center. Johns Hopkins University and Medicine
    1. Jüni P, Rothenbühler M, Bobos P, et al. Impact of climate and public health interventions on the COVID-19 pandemic: a prospective cohort study. CMAJ. 2020;192:566–573.
    1. Cheng Y, Luo R, Wang K, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int. 2020;97:829–838.
    1. Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis. Int J Infect Dis. 2020;94:91–95.
    1. Xu X, Chen P, Wang J, et al. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci China Life Sci. 2020;63:457–460.
    1. Hamming I, Timens W, Bulthuis MLC, Lely AT, Navis GJ, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203:631–637.
    1. Arendse LB, Jan Danser AH, Poglitsch M, et al. Novel therapeutic approaches targeting the renin-angiotensin system and associated peptides in hypertension and heart failure. Pharmacol Rev. 2019;71:539–570.
    1. Igase M, Strawn WB, Gallagher PE, Geary RL, Ferrario CM. Angiotensin II AT1 receptors regulate ACE2 and angiotensin–(1–7) expression in the aorta of spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol. 2005;289:533–539.
    1. Ohnishi ET, Murakami K. Renin–angiotensin system research: from molecules to the whole body. J Physiol Sci. 2019;69:581–587.
    1. Caldeira D, Alarcão J, Vaz-Carneiro A, Costa J. Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis. BMJ. 2012;345
    1. Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Renin–angiotensin–aldosterone system blockers and the risk of Covid-19. N Engl J Med. 2020;382:2431–2440.
    1. Meng J, Xiao G, Zhang J, et al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect. 2020;9:757–760.
    1. Reynolds HR, Adhikari S, Pulgarin C, et al. Renin–angiotensin–aldosterone system inhibitors and risk of Covid-19. N Engl J Med. 2020;382:2441–2448.
    1. Kim IC, Kim JY, Kim HA, Han S. COVID-19-related myocarditis in a 21-year-old female patient. Eur Heart J. 2020;41
    1. Sala S, Peretto G, Gramegna M, et al. Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection. Eur Heart J. 2020;41:1861–1862.
    1. Buja LM, Wolf D, Zhao B, et al. The emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (COVID-19): report of 3 autopsies from Houston, Texas, and review of autopsy findings from other United States cities. Cardiovasc Pathol. 2020;48
    1. Li JW, Han TW, Woodward M, et al. The impact of 2019 novel coronavirus on heart injury: a systemic review and meta-analysis. Prog Cardiovasc Dis. 2020 https//:doi.org.10.1016/j.pcad.2020.04.008 published online April 16.
    1. Babapoor-Farrokhran S, Gill D, Walker J, Rasekhi RT, Bozorgnia B, Amanullah A. Myocardial injury and COVID-19: possible mechanisms. Life Sci. 2020;253
    1. Caussy C, Pattou F, Wallet F, et al. Prevalence of obesity among adult inpatients with COVID-19 in France. Lancet Diabetes Endocrinol. 2020;8:562–564.
    1. Sattar N, McInnes IB, McMurray JJ V. Obesity a risk factor for severe COVID-19 infection: multiple potential mechanisms. Circulation. 2020 https//:doi.org.10.1161/CIRCULATIONAHA.120.047659 published online April 22.
    1. Simonnet A, Chetboun M, Poissy J, et al. High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation. Obesity. 2020;28:1195–1199.
    1. Connors J, States U, Levy J, States U. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135:2033–2040.
    1. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18:1094–1099.
    1. Wichmann D, Sperhake J-P, Lütgehetmann M, et al. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study. Ann Intern Med. 2020 https//:doi.org.10.7326/M20-2003 published online May 6.
    1. Zhao L. Obesity accompanying COVID-19: the role of epicardial fat. Obesity. 2020 https//:doi.org.10.1002/oby.22867 published online May 4.
    1. Nagy E, Jermendy AL, Merkely B, Maurovich-Horvat P. Clinical importance of epicardial adipose tissue. Arch Med Sci. 2017;13:864–874.
    1. Zheng KI, Gao F, Wang X-B, et al. Obesity as a risk factor for greater severity of COVID-19 in patients with metabolic associated fatty liver disease. Metabolism. 2020;108
    1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of non-alcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84.
    1. Lei F, Liu YM, Zhou F, et al. Longitudinal association between markers of liver injury and mortality in COVID-19 in China. Hepatology. 2020 https//:doi.org.10.1002/hep.31301 published May 2.
    1. Zippi M, Sirio F, Occhigrossi G, Hong W. Hypertransaminasemia in the course of infection with SARS-CoV-2: incidence and pathogenetic hypothesis. World J Clin Cases. 2020;8:1385–1390.
    1. Mitchell F. Vitamin-D and COVID-19: do deficient risk a poorer outcome? Lancet Diabetes Endocrinol. 2020;8:570.
    1. 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. 2020;395:507–513.
    1. Palm NW, Medzhitov R. Not so fast: adaptive suppression of innate immunity. Nat Med. 2007;13:1142–1144.
    1. Muniyappa R, Gubbi S. COVID-19 pandemic, coronaviruses, and diabetes mellitus. Am J Physiol Endocrinol Metab. 2020;318:e736–e741.
    1. Kyriazopoulou E, Leventogiannis K, Norrby-Teglund A, et al. Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis. BMC Med. 2017;15:172.
    1. Henry BM, Helena M, De Oliveira S, Benoit S. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis. Clin Chem Lab Med. 2020;58:1021–1028.
    1. Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8:420–422.
    1. Chen Y, Feng Z, Diao B, et al. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly decimates human spleens and lymph nodes. medRxiv. 2020 https//:doi.org.10.1101/2020.03.27.20045427 published online March 31.
    1. Diao B, Feng Z, Wang C, et al. Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. medRxiv. 2020 https//:doi.org.10.1101/2020.03.04.20031120 published online April 10.
    1. Zhang JJ, Dong X, Cao YY, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy. 2020 https//:doi.org.10.1111/all.14238 published online Feb 19.
    1. 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 https//:doi.org.10.1001/jamainternmed.2020.0994 published online March 13.
    1. Chen G, Wu D, Guo W, et al. Clinical and immunologic features in severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130:2620–2629.
    1. 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. 2020;18:844–847.
    1. Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020 https//:doi.org.10.1056/NEJMoa2015432 published online May 21.
    1. McGonagle D, O'Donnell JS, Sharif K, Emery P, Bridgewood C. Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia. Lancet Rheumatol. 2020;2:e437–e445.
    1. Dunn E, Grant P. Type 2 diabetes: an atherothrombotic syndrome. Curr Mol Med. 2005;5:323–332.
    1. Li X, Xu S, Yu M, et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J Allergy Clin Immunol. 2020 https//:doi.org.10.1016/j.jaci.2020.04.006 published online April 12.
    1. Scheen AJ, Marre M, Thivolet C. Prognostic factors in patients with diabetes hospitalized for COVID-19: findings from the CORONADO study and other recent reports. Diabetes Metab. 2020 https//:doi.org.10.1016/j.diabet.2020.05.008 published online May 21.
    1. Pornet C, Bourdel-Marchasson I, Lecomte P, et al. Trends in the quality of care for elderly people with type 2 diabetes: the need for improvements in safety and quality (the 2001 and 2007 ENTRED surveys) Diabetes Metab. 2011;37:152–161.
    1. Iacobellis G, Penaherrera CA, Bermudez LE, Bernal Mizrachi E. Admission hyperglycemia and radiological findings of SARS-COV-2 in patients with and without diabetes. Diabetes Res Clin Pract. 2020;164
    1. Zhang Y, Li H, Zhang J, et al. The clinical characteristics and outcomes of patients with diabetes mellitus and secondary hyperglycaemia with coronavirus disease 2019: a single-center, retrospective, observational study in Wuhan. Diabetes Obes Metab. 2020 https//:doi.org.10.1111/dom.14086 published online May 14.
    1. Li H, Tian S, Chen T, et al. Newly diagnosed diabetes is associated with a higher risk of mortality than known diabetes in hospitalized patients with COVID-19. Diabetes Obes Metab. 2020 doi: 10.1111/dom.14099. published online May 29.
    1. Wang F, Yang Y, Dong K, et al. Clinical characteristics of 28 patients with diabetes and COVID-19 in Wuhan, China. Endocr Pract. 2020;26:668–674.
    1. Bode B, Garrett V, Messler J, et al. Glycemic characteristics and clinical outcomes of COVID-19 patients hospitalized in the United States. J Diabetes Sci Technol. 2020;14:813–821.
    1. Rayman G, Lumb A, Kennon B, et al. Guidance on the management of diabetic ketoacidosis in the exceptional circumstances of the COVID-19 pandemic. Diabet Med. 2020;37:1214–1216.
    1. Kim NY, Ha E, Moon JS, Lee Y-HH, Choi EY. Acute hyperglycemic crises with coronavirus disease-19: case reports. Diabetes Metab J. 2020;44:349–353.
    1. Li J, Wang X, Chen J, Zuo X, Zhang H, Deng A. COVID-19 infection may cause ketosis and ketoacidosis. Diabetes Obes Metab. 2020 https//:doi.org.10.1111/dom.14057 published online April 20.
    1. Sobngwi E, Choukem SP, Agbalika F, et al. Ketosis-prone type 2 diabetes mellitus and human herpesvirus 8 infection in sub-Saharan Africans. JAMA. 2008;299:2770–2776.
    1. Jie Chee Y, Jia Huey Ng S, Yeoh E. Diabetic ketoacidosis precipitated by Covid-19 in a patient with newly diagnosed diabetes mellitus. Diabetes Res Clin Pract. 2020;164
    1. Bornstein SR, Rubino F, Khunti K, et al. Practical recommendations for the management of diabetes in patients with COVID-19. Lancet Diabetes Endocrinol. 2020;8:546–550.
    1. Sharma S, Ray A, Sadasivam B. Metformin in COVID-19: a possible role beyond diabetes. Diabetes Res Clin Pract. 2020;164
    1. Cure E, Cumhur Cure M. Can dapagliflozin have a protective effect against COVID-19 infection? A hypothesis. Diabetes Metab Syndr Clin Res Rev. 2020;14:405–406.
    1. Mazidi M, Karimi E, Rezaie P, Ferns GA. Treatment with GLP1 receptor agonists reduce serum CRP concentrations in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. J Diabetes Complications. 2017;31:1237–1242.
    1. Viby NE, Isidor MS, Buggeskov KB, Poulsen SS, Hansen JB, Kissow H. Glucagon-like peptide-1 (GLP-1) reduces mortality and improves lung function in a model of experimental obstructive lung disease in female mice. Endocrinology. 2013;154:4503–4511.
    1. Bloodworth MH, Rusznak M, Pfister CC, et al. Glucagon-like peptide 1 receptor signaling attenuates respiratory syncytial virus–induced type 2 responses and immunopathology. J Allergy Clin Immunol. 2018;142:683–687.
    1. Sun Q, Zhang Y, Huang J, et al. DPP4 regulates the inflammatory response in a rat model of febrile seizures. Biomed Mater Eng. 2017;28:S139–S152.
    1. Raj VS, Mou H, Smits SL, et al. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature. 2013;495:251–254.
    1. Iacobellis G. COVID-19 and diabetes: can DPP4 inhibition play a role? Diabetes Res Clin Pract. 2020;162
    1. Unübol M, Ayhan M, Guney E. Hypoglycemia induced by hydroxychloroquine in a patient treated for rheumatoid arthritis. J Clin Rheumatol. 2011;17:46–47.
    1. Aoki Y, Maeno T, Aoyagi K, et al. Pioglitazone, a peroxisome proliferator-activated receptor gamma ligand, suppresses bleomycin-induced acute lung injury and fibrosis. Respiration. 2009;77:311–319.
    1. Barbarin V, Nihoul A, Misson P, et al. The role of pro- and anti-inflammatory responses in silica-induced lung fibrosis. Respir Res. 2005;6:112.
    1. Paengsai N, Jourdain G, Salvadori N, et al. Recommended first-line antiretroviral therapy regimens and risk of diabetes mellitus in HIV-infected adults in resource-limited settings. Open Forum Infect Dis. 2019;6:1–7.
    1. Bruno R, Sacchi P, Maiocchi L, Patruno S, Filice G. Hepatotoxicity and antiretroviral therapy with protease inhibitors: a review. Dig Liver Dis. 2006;38:363–373.
    1. Liverpool COVID-19 interactions.

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