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

Background & Aims: Lanifibranor is a pan-PPAR agonist that improves glucose/lipid metabolism and reverses steatohepatitis and fibrosis in adults with MASH. We tested its effect on insulin resistance at the level of different target tissues in relationship to change in intrahepatic triglyceride (IHTG) content.

Methods: This phase 2, single center, study randomized (1:1) 38 patients with T2D and MASLD to receive lanifibranor 800 mg or placebo for 24 weeks. The primary endpoint was the change in IHTG (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 measuring glucose turnover. Other secondary endpoints included changes in cardiometabolic parameters (i.e., HbA1c, lipid profile, adiponectin).

Results: Lanifibranor compared to placebo significantly lowered IHTG (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 reached ≥30% IHTG reduction with lanifibranor compared to placebo (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 insulin resistance (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 TEAE leading to study discontinuation were balanced between groups.

Conclusions: Lanifibranor significantly improves hepatic, muscle and adipose tissue insulin resistance. 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 subjects with MASLD and T2D. We observed a significant decrease in IHTG after 24 weeks of treatment (by ∼50%, p < 0.001 versus placebo) that was associated with a major improvement in hepatic and peripheral (Rd) insulin sensitivity, restoration of adipose tissue function with more than two-fold increase in plasma adiponectin concentration and improvement in cardiometabolic risk factors. This is the first in-depth study on how a pan-PPAR approach reverses steatosis and metabolic dysfunction in patients with T2D and MASLD. It has important clinical implications because it offers proof-of-concept that by targeting the key underlying metabolic defects in MASLD (i.e., insulin resistance, lipotoxicity and hyperglycemia) one can restore cardiometabolic health and offers a compelling rationale for treating with lanifibranor individuals with MASLD, either alone or in combination with weight loss and other treatment strategies.

Gov Identifier: NCT03459079.