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

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; Salim S Hayek; Pennelope Blakely; Hanna Berlin; Tariq U Azam; Husam Shadid; Michael Pan; Patrick O'Hayer; Izzet Altintas; Marius Stauning; Morten Baltzer Houlind; Mette B Lindstrøm; Hejdi Gamst-Jensen; Line Jee Hartmann Rasmussen; Jan O Nehlin; Thomas Kallemose; Christian Rasmussen; Ove Andersen; Jens Tingleff; ISIC Study Group:

doi:10.2337/dc21-2102

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

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-StoutSubramaniam Pennathur, Matthias Kretzler, Sven H Loosen, Athanasios Chalkias, Frank Tacke, Evangelos J Giamarellos-Bourboulis, Jochen Reiser, Jesper Eugen-Olsen (Medlem af forfattergruppering), Eva L Feldman, Rodica Pop-Busui, Salim S Hayek, Salim S Hayek, Pennelope Blakely, Hanna Berlin, Tariq U Azam, Husam Shadid, Michael Pan, Patrick O'Hayer, Izzet Altintas (Medlem af forfattergruppering), Marius Stauning (Medlem af forfattergruppering), Morten Baltzer Houlind (Medlem af forfattergruppering), Mette B Lindstrøm (Medlem af forfattergruppering), Hejdi Gamst-Jensen (Medlem af forfattergruppering), Line Jee Hartmann Rasmussen (Medlem af forfattergruppering), Jan O Nehlin (Medlem af forfattergruppering), Thomas Kallemose (Medlem af forfattergruppering), Christian Rasmussen (Medlem af forfattergruppering), Ove Andersen (Medlem af forfattergruppering), Jens Tingleff (Medlem af forfattergruppering), ISIC Study Group:

52 Citationer (Scopus)

Abstract

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 (ISIC), 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 than those without DM. Among 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 hyperinflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation.

Originalsprog	Engelsk
Artikelnummer	dc212102
Tidsskrift	Diabetes Care
Vol/bind	45
Udgave nummer	3
Sider (fra-til)	692-700
Antal sider	9
ISSN	1935-5548
DOI	https://doi.org/10.2337/dc21-2102
Status	Udgivet - 1 mar. 2022

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Vasbinder, A., Anderson, E., Shadid, H., Berlin, H., Pan, M., Azam, T. U., Khaleel, I., Padalia, K., Meloche, C., O'Hayer, P., Michaud, E., Catalan, T., Feroze, R., Blakely, P., Launius, C., Huang, Y., Zhao, L., Ang, L., Mikhael, M., ... ISIC Study Group: (2022). Inflammation, Hyperglycemia, and Adverse Outcomes in Individuals With Diabetes Mellitus Hospitalized for COVID-19. Diabetes Care, 45(3), 692-700. Artikel dc212102. https://doi.org/10.2337/dc21-2102

Vasbinder, A, Anderson, E, Shadid, H, Berlin, H, Pan, M, Azam, TU, Khaleel, I, Padalia, K, Meloche, C, O'Hayer, P, Michaud, E, Catalan, T, Feroze, R, Blakely, P, Launius, C, Huang, Y, Zhao, L, Ang, L, Mikhael, M, Mizokami-Stout, K, Pennathur, S, Kretzler, M, Loosen, SH, Chalkias, A, Tacke, F, Giamarellos-Bourboulis, EJ, Reiser, J, Eugen-Olsen, J, Feldman, EL, Pop-Busui, R, Hayek, SS, Hayek, SS, Blakely, P, Berlin, H, Azam, TU, Shadid, H, Pan, M, O'Hayer, P, Altintas, I, Stauning, M, Baltzer Houlind, M , Lindstrøm, MB, Gamst-Jensen, H, Hartmann Rasmussen, LJ , Nehlin, JO , Kallemose, T , Rasmussen, C , Andersen, O , Tingleff, J & ISIC Study Group: 2022, 'Inflammation, Hyperglycemia, and Adverse Outcomes in Individuals With Diabetes Mellitus Hospitalized for COVID-19', Diabetes Care, bind 45, nr. 3, dc212102, s. 692-700. https://doi.org/10.2337/dc21-2102

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

abstract = "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 (ISIC), 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 than those without DM. Among 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 hyperinflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation.",

keywords = "Biomarkers, COVID-19, Diabetes Mellitus/epidemiology, Female, Hospital Mortality, Hospitalization, Humans, Hyperglycemia, Inflammation, Male, Middle Aged, SARS-CoV-2",

author = "Alexi Vasbinder and Elizabeth Anderson and Husam Shadid and Hanna Berlin and Michael Pan and Azam, {Tariq U} and Ibrahim Khaleel and Kishan Padalia and Chelsea Meloche and Patrick O'Hayer and Erinleigh Michaud and Tonimarie Catalan and Rafey Feroze and Pennelope Blakely and Christopher Launius and Yiyuan Huang and Lili Zhao and Lynn Ang and Monica Mikhael and Kara Mizokami-Stout and Subramaniam Pennathur and Matthias Kretzler and Loosen, {Sven H} and Athanasios Chalkias and Frank Tacke and Giamarellos-Bourboulis, {Evangelos J} and Jochen Reiser and Jesper Eugen-Olsen and Feldman, {Eva L} and Rodica Pop-Busui and Hayek, {Salim S} and Hayek, {Salim S} and Pennelope Blakely and Hanna Berlin and Azam, {Tariq U} and Husam Shadid and Michael Pan and Patrick O'Hayer and Izzet Altintas and Marius Stauning and {Baltzer Houlind}, Morten and Lindstr{\o}m, {Mette B} and Hejdi Gamst-Jensen and {Hartmann Rasmussen}, {Line Jee} and Nehlin, {Jan O} and Thomas Kallemose and Christian Rasmussen and Ove Andersen and Jens Tingleff and {ISIC Study Group:}",

note = "{\textcopyright} 2022 by the American Diabetes Association.",

year = "2022",

month = mar,

day = "1",

doi = "10.2337/dc21-2102",

language = "English",

volume = "45",

pages = "692--700",

journal = "Diabetes Care",

issn = "1935-5548",

publisher = "American Diabetes Association",

number = "3",

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TY - JOUR

T1 - Inflammation, Hyperglycemia, and Adverse Outcomes in Individuals With Diabetes Mellitus Hospitalized for COVID-19

AU - Vasbinder, Alexi

AU - Anderson, Elizabeth

AU - Shadid, Husam

AU - Berlin, Hanna

AU - Pan, Michael

AU - Azam, Tariq U

AU - Khaleel, Ibrahim

AU - Padalia, Kishan

AU - Meloche, Chelsea

AU - O'Hayer, Patrick

AU - Michaud, Erinleigh

AU - Catalan, Tonimarie

AU - Feroze, Rafey

AU - Blakely, Pennelope

AU - Launius, Christopher

AU - Huang, Yiyuan

AU - Zhao, Lili

AU - Ang, Lynn

AU - Mikhael, Monica

AU - Mizokami-Stout, Kara

AU - Pennathur, Subramaniam

AU - Kretzler, Matthias

AU - Loosen, Sven H

AU - Chalkias, Athanasios

AU - Tacke, Frank

AU - Giamarellos-Bourboulis, Evangelos J

AU - Reiser, Jochen

AU - Feldman, Eva L

AU - Pop-Busui, Rodica

AU - Hayek, Salim S

AU - Blakely, Pennelope

AU - Berlin, Hanna

AU - Azam, Tariq U

AU - Shadid, Husam

AU - Pan, Michael

AU - O'Hayer, Patrick

AU - ISIC Study Group:

A2 - Eugen-Olsen, Jesper

A2 - Altintas, Izzet

A2 - Stauning, Marius

A2 - Baltzer Houlind, Morten

A2 - Lindstrøm, Mette B

A2 - Gamst-Jensen, Hejdi

A2 - Hartmann Rasmussen, Line Jee

A2 - Nehlin, Jan O

A2 - Kallemose, Thomas

A2 - Rasmussen, Christian

A2 - Andersen, Ove

A2 - Tingleff, Jens

PY - 2022/3/1

Y1 - 2022/3/1

N2 - 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 (ISIC), 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 than those without DM. Among 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 hyperinflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation.

AB - 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 (ISIC), 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 than those without DM. Among 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 hyperinflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation.

KW - Biomarkers

KW - COVID-19

KW - Diabetes Mellitus/epidemiology

KW - Female

KW - Hospital Mortality

KW - Hospitalization

KW - Humans

KW - Hyperglycemia

KW - Inflammation

KW - Male

KW - Middle Aged

KW - SARS-CoV-2

UR - http://www.scopus.com/inward/record.url?scp=85129353776&partnerID=8YFLogxK

U2 - 10.2337/dc21-2102

DO - 10.2337/dc21-2102

M3 - Journal article

C2 - 35045184

SN - 1935-5548

VL - 45

SP - 692

EP - 700

JO - Diabetes Care

JF - Diabetes Care

IS - 3

M1 - dc212102

ER -

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

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