Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes

Lihua Zhu, Zhi-Gang She, Xu Cheng, Juan-Juan Qin, Xiao-Jing Zhang, Jingjing Cai, Fang Lei, Haitao Wang, Jing Xie, Wenxin Wang, Haomiao Li, Peng Zhang, Xiaohui Song, Xi Chen, Mei Xiang, Chaozheng Zhang, Liangjie Bai, Da Xiang, Ming-Ming Chen, Yanqiong Liu, Youqin Yan, Mingyu Liu, Weiming Mao, Jinjing Zou, Liming Liu, Guohua Chen, Pengcheng Luo, Bing Xiao, Changjiang Zhang, Zixiong Zhang, Zhigang Lu, Junhai Wang, Haofeng Lu, Xigang Xia, Daihong Wang, Xiaofeng Liao, Gang Peng, Ping Ye, Jun Yang, Yufeng Yuan, Xiaodong Huang, Jiao Guo, Bing-Hong Zhang, Hongliang Li, Lihua Zhu, Zhi-Gang She, Xu Cheng, Juan-Juan Qin, Xiao-Jing Zhang, Jingjing Cai, Fang Lei, Haitao Wang, Jing Xie, Wenxin Wang, Haomiao Li, Peng Zhang, Xiaohui Song, Xi Chen, Mei Xiang, Chaozheng Zhang, Liangjie Bai, Da Xiang, Ming-Ming Chen, Yanqiong Liu, Youqin Yan, Mingyu Liu, Weiming Mao, Jinjing Zou, Liming Liu, Guohua Chen, Pengcheng Luo, Bing Xiao, Changjiang Zhang, Zixiong Zhang, Zhigang Lu, Junhai Wang, Haofeng Lu, Xigang Xia, Daihong Wang, Xiaofeng Liao, Gang Peng, Ping Ye, Jun Yang, Yufeng Yuan, Xiaodong Huang, Jiao Guo, Bing-Hong Zhang, Hongliang Li

Abstract

Type 2 diabetes (T2D) is a major comorbidity of COVID-19. However, the impact of blood glucose (BG) control on the degree of required medical interventions and on mortality in patients with COVID-19 and T2D remains uncertain. Thus, we performed a retrospective, multi-centered study of 7,337 cases of COVID-19 in Hubei Province, China, among which 952 had pre-existing T2D. We found that subjects with T2D required more medical interventions and had a significantly higher mortality (7.8% versus 2.7%; adjusted hazard ratio [HR], 1.49) and multiple organ injury than the non-diabetic individuals. Further, we found that well-controlled BG (glycemic variability within 3.9 to 10.0 mmol/L) was associated with markedly lower mortality compared to individuals with poorly controlled BG (upper limit of glycemic variability exceeding 10.0 mmol/L) (adjusted HR, 0.14) during hospitalization. These findings provide clinical evidence correlating improved glycemic control with better outcomes in patients with COVID-19 and pre-existing T2D.

Keywords: COVID-19; SARS-CoV-2; blood glucose control; diabetes mellitus; mortality.

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Study Inclusion Criteria A schematic overview illustrating participant enrollment in the cohort study and the various exclusion and inclusion criteria among the initial case group. Briefly, a total of 9,663 patients with COVID-19 were included. After various exclusion criteria, 2,326 patients were removed from the study. Of the remaining 7,337 patients, data from 6,385 patients without diabetes (non-T2D) were placed in one group, while 952 individuals with type 2 diabetes (T2D) were placed in a second group. Of the 952 cases with T2D, 142 cases were further excluded due to hypoglycemia or lack of BG readings. Of the remaining 810 cases of T2D, 282 were considered to have well-controlled BG, while 528 had poorly controlled BG. And of these two T2D groups, 250 of each were used for propensity score-matched analysis.
Figure 2
Figure 2
Dynamics of BG, Lymphocytes, Neutrophils, IL-6, CRP, and LDH in Well-Controlled and Poorly Controlled BG Groups during Hospitalization Dynamic trajectories of blood glucose (A), lymphocytes (C), and neutrophils (E), and relative levels for IL-6 (B), CRP (D), and LDH (F) during the 28-day follow-up duration, with 95% confidence interval represented by shaded regions, in patients with poorly controlled BG (orange) or patients with well-controlled BG (blue). The BG represents the averaged median BG of patients on the day tested.
Figure 3
Figure 3
Survival Curves of Patients with Well-Controlled BG or Poorly Controlled BG in the PSM Model Kaplan-Meier Curves for cumulative probability of COVID-19 mortality during the 28-day follow-up duration in the well-controlled BG (blue) or poorly controlled BG (orange) cohort among 500 patients with T2D in the PSM model. The blips on the curve indicate censoring of cases during 28 days of follow-up.

References

    1. Alqahtani F.Y., Aleanizy F.S., Ali El Hadi Mohamed R., Alanazi M.S., Mohamed N., Alrasheed M.M., Abanmy N., Alhawassi T. Prevalence of comorbidities in cases of Middle East respiratory syndrome coronavirus: a retrospective study. Epidemiol. Infect. 2018;147:e35.
    1. Booth C.M., Matukas L.M., Tomlinson G.A., Rachlis A.R., Rose D.B., Dwosh H.A., Walmsley S.L., Mazzulli T., Avendano M., Derkach P. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA. 2003;289:2801–2809.
    1. Bornstein S.R., Rubino F., Khunti K., Mingrone G., Hopkins D., Birkenfeld A.L., Boehm B., Amiel S., Holt R.I., Skyler J.S. Practical recommendations for the management of diabetes in patients with COVID-19. Lancet Diabetes Endocrinol. 2020 doi: 10.1016/S2213-8587(20)30152-2. Published online April 23, 2020.
    1. Candido R., Jandeleit-Dahm K.A., Cao Z., Nesteroff S.P., Burns W.C., Twigg S.M., Dilley R.J., Cooper M.E., Allen T.J. Prevention of accelerated atherosclerosis by angiotensin-converting enzyme inhibition in diabetic apolipoprotein E-deficient mice. Circulation. 2002;106:246–253.
    1. Chen N., Zhou M., Dong X., Qu J., Gong F., Han Y., Qiu Y., Wang J., Liu Y., Wei Y. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395:507–513.
    1. Chinese Diabetes Society Guidelines for the prevention and control of type 2 diabetes in China (2017 Edition) Zhongguo Shiyong Neike Zazhi. 2018;38:53.
    1. Deng S.Q., Peng H.J. Characteristics of and public health responses to the coronavirus disease 2019 outbreak in China. J. Clin. Med. 2020;9:E575.
    1. Forbes A., Murrells T., Mulnier H., Sinclair A.J. Mean HbA1c, HbA1c variability, and mortality in people with diabetes aged 70 years and older: a retrospective cohort study. Lancet Diabetes Endocrinol. 2018;6:476–486.
    1. Fuso L., Pitocco D., Antonelli-Incalzi R. Diabetic lung, an underrated complication from restrictive functional pattern to pulmonary hypertension. Diabetes Metab. Res. Rev. 2019;35:e3159.
    1. Gando S., Wada H., Thachil J., Scientific and Standardization Committee on DIC of the International Society on Thrombosis and Haemostasis (ISTH) Differentiating disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of trauma-shock (COT/ACOTS) J. Thromb. Haemost. 2013;11:826–835.
    1. Guan W.J., Ni Z.Y., Hu Y., Liang W.H., Ou C.Q., He J.X., Liu L., Shan H., Lei C.L., Hui D.S.C., China Medical Treatment Expert Group for Covid-19 Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 2020 doi: 10.1056/NEJMoa2002032. Published online February 28, 2020.
    1. Haneuse S., VanderWeele T.J., Arterburn D. Using the E-value to assess the potential effect of unmeasured confounding in observational studies. JAMA. 2019;321:602–603.
    1. Ho D.E., Imai K., King G., Stuart E.A. Matching as nonparametric preprocessing for reducing model dependence in parametric causal inference. Polit. Anal. 2007;15:199–236.
    1. Hoffmann M., Kleine-Weber H., Schroeder S., Krüger N., Herrler T., Erichsen S., Schiergens T.S., Herrler G., Wu N.H., Nitsche A. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271–280.e8.
    1. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., Zhang L., Fan G., Xu J., Gu X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506.
    1. Kellum J.A., Lameire N., Aspelin P., Barsoum R.S., Burdmann E.A., Goldstein S.L., Herzog C.A., Joannidis M., Kribben A., Levey A.S. Kidney disease: improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int. Suppl. 2012;2:1–138.
    1. Kuba K., Imai Y., Rao S., Gao H., Guo F., Guan B., Huan Y., Yang P., Zhang Y., Deng W. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat. Med. 2005;11:875–879.
    1. Kulcsar K.A., Coleman C.M., Beck S.E., Frieman M.B. Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection. JCI Insight. 2019;4:131774.
    1. Kumar Nathella P., Babu S. Influence of diabetes mellitus on immunity to human tuberculosis. Immunology. 2017;152:13–24.
    1. Lu R., Zhao X., Li J., Niu P., Yang B., Wu H., Wang W., Song H., Huang B., Zhu N. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395:565–574.
    1. Marrone G., Vaccaro F.G., Biolato M., Miele L., Liguori A., Araneo C., Ponziani F.R., Mores N., Gasbarrini A., Grieco A. Drug-induced liver injury 2017: the diagnosis is not easy but always to keep in mind. Eur. Rev. Med. Pharmacol. Sci. 2017;21(Suppl):122–134.
    1. Mathur M.B., Ding P., Riddell C.A., VanderWeele T.J. Web site and R package for computing E-values. Epidemiology. 2018;29:e45–e47.
    1. National Health Commission of China . National Health Commission of China; 2020. New Coronavirus Pneumonia Prevention and Control Program.
    1. Philips B.J., Meguer J.X., Redman J., Baker E.H. Factors determining the appearance of glucose in upper and lower respiratory tract secretions. Intensive Care Med. 2003;29:2204–2210.
    1. Rodriguez-Gutierrez R., Gonzalez-Gonzalez J.G., Zuñiga-Hernandez J.A., McCoy R.G. Benefits and harms of intensive glycemic control in patients with type 2 diabetes. BMJ. 2019;367:l5887.
    1. Sekhon J.S. Multivariate and propensity score matching software with automated balance optimization: the matching package for R. J. Stat. Softw. 2011;42 doi: 10.18637/jss.v042.i07.
    1. Therneau T.M., Pankratz P.M.G.S. Penalized survival models and frailty. J. Comput. Graph. Stat. 2003;12:156–175.
    1. Van den Berghe G., Wilmer A., Hermans G., Meersseman W., Wouters P.J., Milants I., Van Wijngaerden E., Bobbaers H., Bouillon R. Intensive insulin therapy in the medical ICU. N. Engl. J. Med. 2006;354:449–461.
    1. VanderWeele T.J., Ding P. Sensitivity analysis in observational research: introducing the E-value. Ann. Intern. Med. 2017;167:268–274.
    1. Waljee A.K., Mukherjee A., Singal A.G., Zhang Y., Warren J., Balis U., Marrero J., Zhu J., Higgins P.D. Comparison of imputation methods for missing laboratory data in medicine. BMJ Open. 2013;3:e002847.
    1. Wang L., Gao P., Zhang M., Huang Z., Zhang D., Deng Q., Li Y., Zhao Z., Qin X., Jin D. Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013. JAMA. 2017;317:2515–2523.
    1. Wang D., Hu B., Hu C., Zhu F., Liu X., Zhang J., Wang B., Xiang H., Cheng Z., Xiong Y. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020 doi: 10.1001/jama.2020.1585. Published online February 7, 2020.
    1. World Health Organization . World Health Organization; 2020. Laboratory testing for 2019 novel coronavirus (2019-nCoV) in suspected human cases: interim guidance.
    1. Wu Z., McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020 doi: 10.1001/jama.2020.2648. Published online February 24, 2020.
    1. Xu M., Liu P.P., Li H. Innate immune signaling and its role in metabolic and cardiovascular diseases. Physiol. Rev. 2019;99:893–948.
    1. Yang J.K., Feng Y., Yuan M.Y., Yuan S.Y., Fu H.J., Wu B.Y., Sun G.Z., Yang G.R., Zhang X.L., Wang L. Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS. Diabet. Med. 2006;23:623–628.
    1. Zhang J.J., Dong X., Cao Y.Y., Yuan Y.D., Yang Y.B., Yan Y.Q., Akdis C.A., Gao Y.D. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy. 2020 doi: 10.1111/all.14238. Published online February 19, 2020.
    1. Zhang P., Zhu L., Cai J., Lei F., Qin J.J., Xie J., Liu Y.M., Zhao Y.C., Huang X., Lin L. Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circ. Res. 2020 doi: 10.1161/CIRCRESAHA.120.317134. Published online April 17, 2020.
    1. Zhou F., Yu T., Du R., Fan G., Liu Y., Liu Z., Xiang J., Wang Y., Song B., Gu X. 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 N., Zhang D., Wang W., Li X., Yang B., Song J., Zhao X., Huang B., Shi W., Lu R., China Novel Coronavirus Investigating and Research Team A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 2020;382:727–733.

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