Lanifibranor and semaglutide demonstrate multiple metabolic benefits in free-choice diet induced obese hamster models of MASH and MetALD.

Obesity is associated with several comorbidities including Heart Failure with preserved Ejection Fraction (HFpEF), Metabolic dysfunction-Associated SteatoHepatitis (MASH), also termed MetALD when MASH patients have increased alcohol intake. The worldwide epidemic of obesity creates a constant need for new therapies and animal models to test their effectiveness. In the present study, we evaluated the effects of the GLP-1 receptor agonist semaglutide and the pan-PPAR agonist lanifibranor in the free choice diet induced obese MASH hamster, a preclinical model with human-like lipoprotein metabolism, MASH and HFpEF. The same model was exposed to ethanol to evaluate the effects of both semaglutide and lanifibranor on chronic alcohol intake. To set up a model of MetALD, obese MASH hamsters were also challenged to alcohol binge drinking and the preventative effects of lanifibranor were evaluated. Compared with vehicle, semaglutide transiently reduced food intake and significantly reduced fructose and alcohol consumption. This effect was associated with significant body weight loss, lower HOMA-IR index of insulin resistance, improved dyslipidemia and HFpEF, but semaglutide only reduced hepatic fat content. Lanifibranor showed the same cardiometabolic benefits but had superior effects in the liver, with significant improvement in MASH and MetALD. As observed in humans, lanifibranor and semaglutide showed multiple metabolic benefits in free-choice diet induced obese hamster models of MASH and MetALD. These hamster models demonstrated good translability regarding the effects observed in clinical trials and will be helpful to evaluate novel therapies targeting obesity and associated comorbidities, including MetALD.