Aim: Glucagon-like peptide-1 receptor (GLP1R) agonists are currently used in the clinic for the treatment of type 2 diabetes mellitus and obesity. Recently, it was shown that combined agonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the GLP1R is superior to single GLP1R agonism in terms of glycemic control and lowering body weight in individuals with obesity (Frias, Diabetes Obes Metab 2020; Jastreboff, NEJM 2022). As both GIPR and GLP1R signaling have also been implicated in improving inflammatory responses and (postprandial) lipid handling, here we investigated the effects of combined GIPR/GLP1R agonism on metabolic dysfunction-associated fatty liver disease (MAFLD) development and atherosclerosis.

Methods: APOE*3-Leiden.CETP mice as a well-established model for cardiometabolic disease development, were fed a high-fat high-cholesterol diet (60% fat; 1% cholesterol) to induce MAFLD, or a Western-type diet (16% fat; 0.15% cholesterol) to induce dyslipidemia and atherosclerosis, and were treated with either vehicle, a GIPR agonist (GIPFA-085), a GLP1R agonist (GLP-140) or both agonists. Livers were analyzed and scored for hepatic steatosis and atherosclerosis development was assessed in the aortic root area.

Results: Combined GIPR/GLP1R agonism markedly lowered plasma triglyceride (TG) levels, and strongly reduced hepatic steatosis as explained by enhanced TG catabolism, and lowered hepatic inflammation. Upon the Western-type diet, the reduction in TGs was explained by a lowered hepatic VLDL-TG production and an increased TG-derived fatty acid uptake by the adipose tissues. Finally, combined GIPR/GLP1R agonism attenuated the development of severe atherosclerotic lesions, while single treatments only showed non-significant improvements.

Conclusions: Combined GIPR/GLP1R agonism lowers MAFLD development and attenuates atherosclerosis severity by increasing TG turnover and diminishing inflammation. We anticipate that combined GIPR/GLP1R agonism is a promising strategy to lower MAFLD and atherosclerotic cardiovascular disease risk in humans.