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Inflammation, Hyperglycemia, and Adverse Outcomes in Individuals With Diabetes Mellitus Hospitalized for COVID-19

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posted on 19.01.2022, 21:29 by Alexi Vasbinder, Elizabeth Anderson, Husam Shadid, Hanna Berlin, Michael Pan, Tariq U. Azam, Ibrahim Khaleel, Kishan Padalia, Chelsea Meloche, Patrick O’Hayer, Erinleigh Michaud, Tonimarie Catalan, Rafey Feroze, Pennelope Blakely, Christopher Launius, Yiyuan Huang, Lili Zhao, Lynn Ang, Monica Mikhael, Kara Mizokami-Stout, Subramaniam Pennathur, Matthias Kretzler, Sven H. Loosen, Athanasios Chalkias, Frank Tacke, Evangelos J. Giamarellos-Bourboulis, Jochen Reiser, Jesper Eugen-Olsen, Eva L. Feldman, Rodica Pop-Busui, Salim S. Hayek, the ISIC group
Objective: Diabetes mellitus (DM) is a major risk factor for severe coronavirus disease 2019 (COVID-19) for reasons that are unclear.

Research Design and Methods: We leveraged The International Study of Inflammation in COVID-19, a multicenter observational study of 2,044 patients hospitalized with COVID-19, to characterize the impact of DM on in-hospital outcomes and assess the contribution of inflammation and hyperglycemia to the risk attributed to DM. We measured biomarkers of inflammation collected at hospital admission and collected glucose levels and insulin data throughout hospitalization. The primary outcome was the composite of in-hospital death, need for mechanical ventilation, and need for renal replacement therapy.

Results: Among participants (mean age, 60 years; 58.2% males), those with DM (n=686, 33.5%) had a significantly higher cumulative incidence of the primary outcome (37.8% vs. 28.6%) and higher levels of inflammatory biomarkers compared to those without DM. Amongst biomarkers, DM was only associated with higher soluble urokinase plasminogen activator receptor (suPAR) levels in multivariable analysis. Adjusting for suPAR levels abrogated the association between DM and the primary outcome (adjusted odds ratio 1.23[95%CI:0.78,1.37]). In mediation analysis, we estimated the proportion of the effect of DM on the primary outcome mediated by suPAR at 84.2%. Hyperglycemia and higher insulin doses were independent predictors of the primary outcome, with effect sizes unaffected by adjusting for suPAR levels.

Conclusions: Our findings suggest that the association between DM and outcomes in COVID-19 is largely mediated by hyper-inflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation.


AV is supported by a NHLBI funded post-doctoral fellowship (T32HL007853). SSH is funded by NHLBI 1R01HL153384-01, NIDDK 1R01DK12801201A1, U01-DK119083-03S1, and the Frankel Cardiovascular Center COVID-19: Impact Research Ignitor (U-M G024231) award. RPB is supported by NIH/NIDDK-1-R01-DK-107956-01, NIH U01 DK119083, the Juvenile Diabetes Research Foundation 5-COE-2019-861-S-B, and by a Pilot and Feasibility Grant from the Michigan Diabetes Research Center (NIH Grant P30-DK020572). EGB is supported by the Hellenic Institute for the Study of Sepsis. FT is supported through intramural funds from Charité Universitaetsmedizin Berlin and the Berlin Institute of Health. SP is supported by the University of Michigan O’Brien Kidney Translational Core Center (NIDDK P30DK081943). The funders had no role in design or conduct of the study; collection, management, analysis, or interpretation of the data; and preparation, review, or decision to publish the manuscript.