The Effects of LY2405319, an FGF21 Analog, in Obese Human Subjects with Type 2 Diabetes

Abstract

Fibroblast growth factor 21 (FGF21) is a recently discovered metabolic regulator. Exogenous FGF21 produces beneficial metabolic effects in animal models; however, the translation of these observations to humans has not been tested. Here, we studied the effects of LY2405319 (LY), a variant of FGF21, in a randomized, placebo-controlled, double-blind proof-of-concept trial in patients with obesity and type 2 diabetes. Patients received placebo or 3, 10, or 20 mg of LY daily for 28 days. LY treatment produced significant improvements in dyslipidemia, including decreases in low-density lipoprotein cholesterol and triglycerides and increases in high-density lipoprotein cholesterol and a shift to a potentially less atherogenic apolipoprotein concentration profile. Favorable effects on body weight, fasting insulin, and adiponectin were also detected. However, only a trend toward glucose lowering was observed. These results indicate that FGF21 is bioactive in humans and suggest that FGF21-based therapies may be effective for the treatment of selected metabolic disorders.

Role of Circulating Fibroblast Growth Factor 21 Measurement in Primary Prevention of Coronary Heart Disease Among Chinese Patients With Type 2 Diabetes Mellitus

“…Treatment with FGF21 conferred beneficial effects on body weight, glucose, and lipid metabolism in animal studies,2 and similar benefits were demonstrated in humans treated with FGF21 analogues 3, 4. On the other hand, raised FGF21 levels have been found in various cardiometabolic conditions in clinical studies, suggesting a reactive change to FGF21 resistance or the underlying metabolic disturbances 1.…”

Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?

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“…This increase in FGF21 plasma levels may reflect a state of FGF21 resistance. Nevertheless, FGF21 action was investigated in obese human subjects with type 2 diabetes by the use of an analog, LY2405319 (Gaich et al, 2013). In this clinical trial, the FGF21 analog produced significant improvements in dyslipidemia, body weight and fasting plasma insulin decreased, but only at higher concentrations of the analog.…”

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“…Therefore, it is important not only to acutely activate thermogenesis in brown adipocytes but also to increase their number and their capacity for thermogenesis [64]. Among the approaches being investigated are mimetics of irisin and fibroblast growth factor-21 [65,66], though recent work casts doubt on the role of irisin because many studies have used commercial ELISA kits to detect irisin that cross-react with other proteins [67].…”