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 GLP-1 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. [14] evaluated the effects of a low-dose combination of a GLP-1 analogue and FGF21 on the pathogenesis of atherosclerosis, as well as body weight and blood glucose concentration, in a type 2 diabetes mouse model and in vitro studies. Notably, they showed that a 6-week treatment with a low-dose combination of liraglutide (0.1 mg/kg/day) and FGF21 (2.5 mg/kg/day) reduced atheromatous plaque areas in the aorta to a significantly greater extent than either liraglutide alone or FGF21 alone in high-fat diet-induced obese mice. These mice with a low-dose combination of liraglutide and FGF21 treatment had lower body weight, food intake, and blood glucose concentrations and higher adiponectin levels than the control mice. The low-dose combination of liraglutide and FGF21 reduced the initiation and progression of atherosclerosis by alleviating inflammation in vascular smooth muscle cells. This research contributes to our understanding of how the combination of a GLP-1 analogue and FGF21 interact, and the findings could inform promising therapeutic approaches to treat atherosclerosis in type 2 diabetes.

Interestingly, the low-dose combination of liraglutide and FGF21 was more potent than the control treatments, liraglutide alone, or FGF21 alone in terms of the mRNA expression of uncoupling protein-1 (UCP1) in liver cells, which remains an intriguing question. Since the regulatory promoter region of the UCP1 gene contains two putative cyclic AMP (cAMP)-responsive elements [15], to explore the pathways that mediate UCP1 expression, measuring tissue-specific cAMP level responses to the combination of GLP-1 and FGF21 could be considered as a direction for future research.

A recent study by Pan et al. [13] showed that, in HEK293 cells expressing both GLP-1 receptor and β-Klotho, a novel long-acting dual agonist (GLP-1-Fc-FGF21) was 10-fold more active than GLP-1 alone in terms of the cAMP activation pathway, which could be mediated by high-affinity binding of GLP-1-Fc-FGF21 to β-Klotho, which recruited GLP-1 to the cell surface and increased its local concentration. The results suggest that the combination of GLP-1 and FGF21 could synergistically increase cAMP levels and achieve stronger activation than is possible with either liraglutide alone or FGF21 alone.

Because blood vessels (with undetectable β-Klotho expression) are not the direct target of FGF21, the anti-atherogenic effect of FGF21 could be attributed to its actions in adipose tissue and the liver. Thus, it is important to further elucidate the tissue-specific signaling pathways by which the GLP-1/FGF21 combination exerts its effects on adipocytes and hepatocytes. Additionally, regarding the atherosclerosis process, it would be valuable to evaluate the effects of GLP-1/FGF21 combination on endothelial dysfunction, foam cell formation, and cholesterol biosynthesis.

It is certainly time for further research on combinations of FGF21-based pharmacotherapy with GLP-1 analogues or other glucose-lowering agents, and the findings of Kim et al. [14] are sufficiently encouraging to confirm the importance of such studies in type 2 diabetes.