Negative impact of hyperglycemia on Tocilizumab therapy in COVID-19 patients

Abstract

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.

Tocilizumab: The Key to Stop Coronavirus Disease 2019 (COVID-19)-Induced Cytokine Release Syndrome (CRS)?

“…TCZ also has inevitable limitations and clinical defects in the treatment of COVID-19. For example, Optimal COVID-19 infection management with TCZ is not achieved during hyperglycaemia in both diabetic and non-diabetic patients that TCZ administration neither decreases IL-6 levels nor attenuates risk of severe outcomes (55). Similarly, the use of TCZ fails to decrease the mortality rate at 30 days of patients with severe COVID-19 acute respiratory distress syndrome with hyperinflammation, after correction for pre-existing comorbidities and the need for respiratory support (56).…”

Prognostic factors in patients with diabetes hospitalized for COVID-19: Findings from the CORONADO study and other recent reports

“…As such, tocilizumab has been proposed as a therapeutic option for compassionate use in patients with COVID-19 [66]. A recent observation has found that hyperglycaemia, both at admission and during the hospital stay, was associated with higher IL-6 levels and a reduced efficacy of tocilizumab, leading to poorer outcomes in COVID-19 patients regardless of the presence or not of known diabetes [67]. However, further studies are now necessary to confirm this finding.…”

The role of Interleukin 6 inhibitors in therapy of severe COVID-19

“…Severe adverse drug reactions related to TCZ were noted in 11 (59%) patients; infections (as a complication of the main disease) were reported in 13 (6.3%) patients. According to Marfella et al [ 65 ], during treatment with TCZ in COVID-19 patients, hyperglycemia is associated with higher risk as compared to the patients with normal blood glucose levels (P < 0.009).…”