Pan-PPAR agonist lanifibranor improves insulin resistance and hepatic steatosis in patients with T2D and MASLD

Abstract

BACKGROUND & AIMS: Lanifibranor is a pan-PPAR agonist that improves glucose/lipid metabolism and reverses steatohepatitis and fibrosis in adults with metabolic dysfunction-associated steatohepatitis (MASH). We tested its effect on insulin resistance (IR) at the level of different target tissues in relation to changes in intrahepatic triglyceride (IHTG) content. METHODS: H-MRS). The main prespecified secondary endpoint was the change in hepatic, muscle and adipose tissue insulin sensitivity using the gold-standard euglycemic hyperinsulinemic clamp technique to measure glucose turnover. Other secondary endpoints included changes in cardiometabolic parameters (i.e., HbA1c, lipid profile, adiponectin). RESULTS: Lanifibranor significantly lowered IHTG compared to placebo (full analysis set [FAS] -44% vs. -12%, respectively; least squares mean difference -31%, 95% CI -51 to -12%; in completers -50% vs. -16%; both p <0.01). More patients in the lanifibranor group (vs. the placebo group) achieved a ≥30% IHTG reduction (FAS 65% vs. 22%; completers 79% vs. 29%; both p <0.01) and steatosis resolution (FAS 25% vs. 0%; p <0.05). Lanifibranor significantly improved hepatic and peripheral IR (i.e. fasting endogenous [primarily hepatic] glucose production, hepatic IR, and insulin-stimulated muscle glucose disposal or Rd). Secondary metabolic endpoints also improved (fasting glucose, insulin, HOMA-IR, HbA1c, HDL-C), and adiponectin increased 2.4-fold (all p <0.001). Lanifibranor caused modest weight gain (+2.7%). Adverse events were mild (gastrointestinal side effects, hemoglobin decrease) and drug-related treatment-emergent adverse events leading to study discontinuation were balanced between groups. CONCLUSIONS: Lanifibranor significantly improves hepatic, muscle and adipose tissue IR. Lanifibranor treatment was safe and effective in reducing hepatic steatosis and cardiometabolic risk factors associated with metabolic dysfunction. IMPACT AND IMPLICATIONS: No prior studies have evaluated the effect of lanifibranor on insulin sensitivity at the level of muscle, liver and adipose tissue and its relationship to changes in intrahepatic triglyceride (IHTG) content in insulin-resistant individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes. We observed a significant decrease in IHTG after 24 weeks of treatment (by ∼50%, p <0.001 vs. placebo) that was associated with a major improvement in hepatic and peripheral (Rd) insulin sensitivity, restoration of adipose tissue function and improvement in cardiometabolic risk factors. This study has important clinical implications because it offers proof-of-concept that targeting the key underlying metabolic defects in MASLD (i.e. insulin resistance, lipotoxicity and hyperglycemia) can restore cardiometabolic health. It offers a compelling rationale for lanifibranor treatment in individuals with MASLD, either alone or in combination with weight loss and other treatment strategies. GOV IDENTIFIER: NCT03459079.

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