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As a member of the fibroblast growth factor (FGF) superfamily, FGF21 has attracted considerable attention owing to its endocrine actions and potential beneficial effects on metabolic disorders, including obesity, type 2 diabetes, dyslipidemia, and nonalcoholic steatohepatitis (NASH) [1,2]. More recently, administration of exogenous FGF21 was also found to ameliorate vascular inflammation and atherosclerosis in various models [3,4]. It was suggested that FGF21 exerts its pleiotropic effects against obesity-related complications by coordinating inter-organ communications between the brain, adipose tissue, liver, muscle, and blood vessels [5,6]. However, the clinical and pre-clinical studies of FGF21 analogues so far are controversial, with mixed results [6]. Recent studies have shown limited efficacy of FGF21 analogues on lowering blood glucose levels and body weight control, but better efficacy on NASH [1,6]. These findings may preclude FGF21 as a stand-alone medication for type 2 diabetes. Furthermore, FGF21 in its native form has a poor pharmacokinetic profile, with a short half-life of only 0.5 to 2 hours in vivo [7]. In addition, FGF21 analogues and mimetics are susceptible to proteolytic cleavage with a high tendency for aggregation under physiological conditions [8,9]. These properties affect the clinical applicability of FGF21. Recent studies have shown that FGF21 and glucagon-like peptide-1 (GLP-1) have interplays in energy expenditure, body weight control and glucose metabolism; specifically, GLP-1 analogues can stimulate hepatic FGF21 production and activate the invariant natural killer T cell-FGF21 axis [10,11]. These findings indicate that GLP-1 and FGF21 have promising synergistic functions in vivo, and the complementary functions of GLP-1 and FGF21 have stimulated interest in testing whether a combination of these two pleiotropic hormones could provide a superior effect on treating type 2 diabetes and its comorbidities. Indeed, recent studies explored the potential synergistic actions of FGF21 with GLP-1 by generating a GLP-1-FGF21 fusion protein connected by an elastin-like polypeptide linker (GLP-1-ELP-FGF21) or GLP-1-Fc-FGF21 [12,13]. These studies showed that FGF21 activation acts synergistically with GLP1 activation to allow greater weight loss and more potent glucose-lowering efficacy than what can be achieved with GLP-1 or FGF21 alone. In this issue of Endocrinology and Metabolism, Kim et al.

endocrinology and metabolism

Unlocking the Therapeutic Potential of Glucagon-Like Peptide-1 Analogue and Fibroblast Growth Factor 21 Combination for the Pathogenesis of Atherosclerosis in Type 2 Diabetes