Effects of interleukin-1 antagonism and corticosteroids on fibroblast growth factor-21 in patients with metabolic syndrome

Fahim Ebrahimi, Sandrine Andrea Urwyler, Matthias Johannes Betz, Emanuel Remigius Christ, Philipp Schuetz, Beat Mueller, Marc Yves Donath, Mirjam Christ-Crain, Fahim Ebrahimi, Sandrine Andrea Urwyler, Matthias Johannes Betz, Emanuel Remigius Christ, Philipp Schuetz, Beat Mueller, Marc Yves Donath, Mirjam Christ-Crain

Abstract

Fibroblast growth factor-21 (FGF21) is elevated in patients with the metabolic syndrome. Although the exact underlying mechanisms remain ill-defined, chronic low-grade inflammation with increased Interleukin-(IL)-1β expression may be responsible. The aim of this study was to investigate effects of two different anti-inflammatory treatments (IL-1 antagonism or high-dose corticosteroids) on FGF21 in patients with the metabolic syndrome. This is a secondary analysis of two interventional studies in patients with obesity and features of the metabolic syndrome. Trial A was an interventional trial (n = 73) investigating short-term effects of the IL-1 antagonist anakinra and of dexamethasone. Trial B was a randomized, placebo-controlled, double-blinded trial (n = 67) investigating longer-term effects of IL-1 antagonism. In total, 140 patients were included in both trials. Median age was 55 years (IQR 44-66), 26% were female and median BMI was 37 kg/m2 (IQR 34-39). Almost half of the patients were diabetic (45%) and had increased c-reactive protein levels of 3.4 mg/L. FGF21 levels correlated with fasting glucose levels, HOMA-index, C-peptide levels, HbA1c and BMI. Short-term treatment with anakinra led to a reduction of FGF21 levels by - 200 pg/mL (95%CI - 334 to - 66; p = 0.004). No effect was detectable after longer-term treatment (between-group difference: - 8.8 pg/mL (95%CI - 130.9 to 113.3; p = 0.89). Acute treatment with dexamethasone was associated with reductions of FGF21 by -175 pg/mL (95%CI - 236 to - 113; p < 0.001). Anti-inflammatory treatment with both, IL-1 antagonism and corticosteroids reduced FGF21 levels at short-term in individuals with the metabolic syndrome.Trial registration: ClinicalTrials.gov Identifiers NCT02672592 and NCT00757276.

Conflict of interest statement

MD is an inventor on patent WO 2004002512 A1. The other authors have nothing to disclose.

Figures

Figure 1
Figure 1
Box plots of FGF21 levels at baseline (dark blue) and after short-term treatment (medium blue) as well as after longer-term treatment (light blue) in patients randomized to placebo or anakinra from Trial B, respectively. P-values were determined using a linear mixed model. Each box signifies the upper and lower quartiles, while the median is represented by a line within the box. Whiskers represent the upper and lower adjacent values, outliers are depicted as dots.
Figure 2
Figure 2
Box plots of FGF21 levels at baseline (blue) and after short-term treatment with dexamethasone (light blue) for patients from Trial A (n = 73). P-values were determined by Wilcoxon signed-rank test. Each box signifies the upper and lower quartiles, while the median is represented by a line within the box. Whiskers represent the upper and lower adjacent values; outliers are depicted as dots.
Figure 3
Figure 3
Effects of dexamethasone on serum FGF21 levels. Bar graph with mean absolute differences in FGF21 levels (± 95% confidence interval) between the baseline value and measurements at day 1 in patients without (blue) and with diabetes mellitus (light blue). P-value determined by linear regression stratified by the history of diabetes mellitus included as interaction term.

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