Baseline Circulating FGF21 Concentrations and Increase after Fenofibrate Treatment Predict More Rapid Glycemic Progression in Type 2 Diabetes: Results from the FIELD Study

It is not known whether circulating fibroblast growth factor 21 (FGF21) concentrations are associated with glycemic progression in patients with established type 2 diabetes. This study reports this relationship in type 2 diabetes patients participating in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. Plasma FGF21 was quantified in 9697 study participants. Among patients with lifestyle-only glucose control measures at baseline, glycemic progression was defined as the initiation of oral hypoglycemic agents or insulin therapy. We assessed the relationship of FGF21 concentrations with glycohemoglobin (Hb A ), the homeostasis model assessment of β-cell function (HOMA-B) and insulin resistance (HOMA-IR), and glycemic progression. Among 2584 patients with lifestyle-only glycemic therapy at baseline, plasma FGF21 concentrations were positively associated with HOMA-IR (5.1% increase per 100% increase in FGF21 concentrations). Patients with higher baseline plasma FGF21 concentrations had higher risk of glycemic progression over a 5-year period ( = 0.02), but the association was not significant after further adjusting for alanine aminotransferase (ALT) enzyme activity. During the fenofibrate active run-in phase, higher tertiles of fenofibrate-induced increase in FGF21 concentrations were associated with higher risk of glycemic progression (adjusted hazards ratio = 1.09 and 1.18 for tertiles 2 and 3, respectively, for trend = 0.01), even after adjusting for ALT enzyme activity. This association was statistically significant in the fenofibrate group only ( = 0.01). Higher baseline and fenofibrate-induced increase in FGF21 concentrations predict more rapid glycemic progression in type 2 diabetes patients. This association may be partly explained by hepatic function.