key: cord-0905028-5okcoovv
authors: Marfella, R.; Paolisso, P.; Sardu, C.; Bergamaschi, L.; D' Angelo, E. C.; Barbieri, M.; Rizzo, M. R.; Messina, V.; Maggi, P.; Coppola, N.; Pizzi, C.; Biffi, M.; Viale, P. L.; Galie, N.; Paolisso, G.
title: Negative impact of hyperglycemia on Tocilizumab therapy in COVID-19 patients
date: 2020-05-04
journal: nan
DOI: 10.1101/2020.04.29.20076570
sha: 50c41d0f82b650af4e82747c3de28122351cd385
doc_id: 905028
cord_uid: 5okcoovv

Tocilizumab is used for treating moderate-severe Covid-19 pneumonia by targeting IL-6 receptors (IL-6R) and reducing cytokine release, but the pooled rate ratio among diabetic patients with adverse vs those with the more favorable course was 2.26. To date, the hyperglycemia has been shown to increase IL-6 and IL-6R, which has been suggested as a severity predictor in lung diseases of Covid-19 patients. However, there are no data about the effects of tocilizumab therapy on outcomes of hyperglycemic Covid-19 patients with pneumonia. To investigate this unsolved need, 475 Covid-19 positive patients were retrospectively studied since March 1st, 2020. Among them, 78 patients with pneumonia disease and treated with tocilizumab were further evaluated for a severe outcome (encompassing both the use of mechanical ventilation and/or death). Thirty-one (39.7%) hyperglycemic and 47 (60.3%) normoglycemic Covid-19 positive patients (blood glucose levels >140 mg/dl, at admission and/or during hospital stay) were evaluated. Noteworthy, 20 (64%) of hyperglycemic and 11 (23.4%) of normoglycemic patients were also diabetics (P<0.01). At admission, more elevated IL-6 levels in hyperglycemic patients were found and persists even after Tocilizumab administration. In a risk adjusted Cox-regression analysis, Tocilizumab in hyperglycemic did not attenuate the risks of severe outcome as did in normoglycemic patients (p<0.009). Therefore, we could conclude that reduced effects of Tocilizumab in hyperglycemic patients may due to the higher plasma IL-6 levels. Interestingly, when we added IL-6 levels in a Cox regression model the significance for the tocilizumab effect was lost (p<0.07). In this context, our observations evidence that optimal Covid-19 infection management with tocilizumab is not achieved during hyperglycemia both in diabetic and non-diabetic patients.

To calm inflammatory storm, tocilizumab was used for treating moderate-severe Covid-19 pneumonia by targeting IL-6 receptors (IL-6R) and reducing cytokine release (1). Despite the optimal management of Covid-19 infection including tocilizumab, the pooled rate ratio among diabetic patients with adverse vs those with the more favorable course was 2.26 (2) . An important factor in any form of infection control in patients with diabetes seems to be the glucose control (2) .

Hyperglycemia has been shown to increaseIL-6 and IL-6R (3) (4) . Noteworthy, 20 (64%) of hyperglycemic and 11 (23.4%) of normoglycemic patients were also diabetics (P<0.01). Admission glucose levels were All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Along with the hospitalization, mean glucose levels were 157±15 vs 122 ±12 mg/dl (p<0.01) in hyperglycemic vs normoglycemic patients. At admission, more elevated IL-6 levels in hyperglycemic patients were found and persists even after Tocilizumab administration (Figure-A) . In a risk adjusted Cox-regression analysis, Tocilizumab in hyperglycemic did not attenuate the risks of severe outcome as did in normoglycemic patients (p<0.009) (Figure-B) .

The reduced effects of Tocilizumab in hyperglycemic patients may due to the higher plasma IL-6 levels. Previous study evidenced that tocilizumab efficacy was inversely proportional to the baseline IL-6 levels in patients with rheumatoid arthritis (5) . Accordingly, our data evidence that hyperglycemic patients had IL-6 levels at admission 5-fold higher as compared to the normoglycemic patients. Interestingly, when we added IL-6 levels in a Cox regression model the significance for the tocilizumab effect was lost (p<0.07). In this context, our observations evidence that optimal Covid-19 infection management with tocilizumab is not achieved during hyperglycemia both in diabetic and non-diabetic patients. Thus, these data may be of interest for ongoing clinical trials on tocilizumab effects on Covid-19 patients and for the optimal control of glycemia in this subset. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 4, 2020. . https://doi.org/10.1101/2020.04.29.20076570 doi: medRxiv preprint 4 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 4, 2020. . https://doi.org/10.1101/2020.04.29.20076570 doi: medRxiv preprint

The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality

Covid-19 and diabetes mellitus: unveiling the interaction of two pandemics

Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress

Diabetes Care in the Hospital: Standards of Medical Care in Diabetes-2020

Changes in serum interleukin-6 levels as possible predictor of efficacy of tocilizumab treatment in rheumatoid arthritis

heart diseases, hypertension, dyslipidemia, current smoking, beta-blockers, ace-inhibitors, calcium inhibitors, thiazide diuretics, aspirin. All statistical analyses were performed with SPSS

A 2-sided P <0.05 was considered statistically significant

All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 4, 2020. . https://doi.org/10.1101/2020.04.29.20076570 doi: medRxiv preprint All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 4, 2020. . https://doi.org/10.1101/2020.04.29.20076570 doi: medRxiv preprint