Key Takeaways on the Emerging Role of PPAR Agonists in MASLD/MASH: ADA 2026 Update

The presentation highlighted the following key insights, which include:

1. PPARs regulate multiple pathways involved in MASLD/MASH

PPARs are ligand-activated nuclear receptors that regulate the expression of genes involved in glucose metabolism, lipid metabolism, inflammation, and energy homeostasis. The three major isoforms—PPAR-α, PPAR-γ, and PPAR-δ—are expressed in different tissues but collectively influence multiple stages of MASLD/MASH progression, including insulin resistance, adipose tissue dysfunction, increased free fatty acid influx into the liver, hepatic steatosis, inflammation, lipotoxicity, and fibrosis. Since PPARs are involved throughout the disease pathway, they may have the potential to target both the metabolic and hepatic components of MASLD/MASH.

2. Pioglitazone established the proof of concept for PPAR therapy

Pioglitazone was presented as the first PPAR agonist to demonstrate that targeting insulin resistance can improve liver histology in MASH. As a predominantly PPAR-γ agonist, it improves insulin sensitivity, increases adiponectin levels, reduces hepatic glucose production, and improves glycemic control. These metabolic effects translate into reduced hepatic steatosis and inflammation.

Evidence from the 96-week PIVENS trial showed significant histologic improvement without worsening fibrosis (34% vs. 19%; P=0.04), along with higher rates of NASH resolution (47% vs. 21%; P=0.001) compared with placebo. Similarly, the Cusi et al. study demonstrated superior liver histology improvement in patients with prediabetes or type 2 diabetes, with significant benefits in steatosis, inflammation, fibrosis, insulin sensitivity, and hepatic triglyceride content. Despite these benefits, pioglitazone has its limitations, including weight gain, edema due to fluid retention, and increased fracture risk with long-term use. Because of its potential to cause fluid retention, it should be avoided or used cautiously in patients with symptomatic heart failure, particularly those with NYHA class III–IV heart failure. Although pioglitazone is approved for type 2 diabetes, it remains an off-label treatment for MASH in many countries. However, several professional society guidelines support its use in patients with MASH and type 2 diabetes.

3. Saroglitazar combines metabolic and hepatic benefits

Saroglitazar is a dual PPAR-α/γ agonist with predominant PPAR-α activity. Through PPAR-α activation, it increases lipoprotein lipase activity, lowers triglycerides and VLDL-C, and increases HDL-C. PPAR-γ activation improves insulin sensitivity, glucose uptake, and glycemic control. Together, these complementary mechanisms improve lipid and glycemic profiles while reducing inflammation in both the liver and adipose tissue.

Saroglitazar has accumulated substantial clinical experience in India. It was first approved in 2013 for diabetic dyslipidemia and hypertriglyceridemia in patients with type 2 diabetes inadequately controlled on statins, followed by approval as an add-on to metformin in T2DM. In 2020, it also received approval in India for the treatment of MASLD/MASH, providing long-term real-world clinical experience across metabolic and liver diseases.

4. Latest 2026 Indian data strengthen the evidence for Saroglitazar in MASH

The session also reviewed interim findings from the ongoing Phase 4 prospective, multicenter, open-label study by Sanyal et al. (Liver International, 2026) conducted across tertiary care centers in India. Patients with MASH received Saroglitazar 4 mg for 52 weeks, with interim analysis performed at 24 weeks in the first 500 patients.

The study demonstrated significant improvements in liver stiffness, hepatic steatosis, liver enzymes, HbA1c, and triglyceride levels, while body weight and BMI remained largely stable. These findings suggest that Saroglitazar may improve both hepatic and metabolic parameters, adding to the growing real-world evidence supporting its use in MASLD/MASH.

Saroglitazar Regulatory Milestones

Saroglitazar's regulatory journey has progressed steadily since its approval in India in 2013 for diabetic dyslipidemia and hypertriglyceridemia in patients with type 2 diabetes inadequately controlled on statins, followed by additional approvals in 2020 as an add-on therapy to metformin for T2DM and for NAFLD/non-cirrhotic NASH. In a recent significant development in 2026, the US FDA has granted saroglitazar a priority review for its NDA in primary biliary cholangitis (PBC)².

5. Lanifibranor expands the scope of PPAR therapy

Unlike earlier agents, lanifibranor is a pan-PPAR agonist, activating PPAR-α, PPAR-δ, and PPAR-γ simultaneously. By targeting all three receptors, it addresses the major pathological components of MASH, including steatosis, inflammation, and fibrosis. The findings of the phase IIb NATIVE trial have demonstrated early promise in MASH, and the Phase III NaTiV3 trial is underway.

6. PPAR agonists may improve metabolic health beyond the liver

An important theme throughout the presentation was that therapies for MASLD/MASH should address the underlying metabolic dysfunction in addition to liver pathology. Improvements in insulin sensitivity, glycemic control, triglycerides, cholesterol, and other metabolic parameters observed with PPAR agonists highlight their potential to influence multiple components of metabolic syndrome, alongside improvements in liver disease.

7. Combination therapy is likely to shape the future of MASH management

The MASH treatment landscape is evolving rapidly, with multiple therapies already available or in late-stage clinical development. Since MASLD/MASH is driven by multiple pathogenic pathways, no single therapy is expected to address every aspect of disease progression. Instead, therapies with complementary mechanisms, including PPAR agonists, are likely to become part of combination treatment strategies aimed at improving histological response while optimizing cardiometabolic and liver outcomes.

8. Proactive Identification of MASLD in Clinical Practice

As MASLD/MASH becomes an increasingly important metabolic disease, clinicians should actively identify patients with type 2 diabetes at high risk of advanced fibrosis. Treatment decisions should extend beyond glycemic control to include liver health, with PPAR agonists emerging as a potential therapeutic option alongside future combination therapies.

Key Takeaways

• PPAR agonists target multiple pathogenic pathways in MASLD/MASH, addressing insulin resistance, steatosis, inflammation, fibrosis, and the underlying metabolic dysfunction.
• Evidence from pioglitazone established the proof of concept, while saroglitazar and lanifibranor are expanding the role of PPAR-targeted therapy with growing clinical evidence across different stages of MASLD.
• Saroglitazar, backed by over a decade of Indian clinical experience and emerging Phase 4 evidence, has demonstrated improvements in both hepatic and metabolic parameters, highlighting its relevance in real-world practice.
• As MASLD/MASH management evolves, combination therapy and individualized treatment strategies are expected to play an increasingly important role in improving both liver and cardiometabolic outcomes.

Abbreviations:

ADA: American Diabetes Association, PPAR: Peroxisome Proliferator-Activated Receptor, MASLD: Metabolic Dysfunction-Associated Steatotic Liver Disease, MASH: Metabolic Dysfunction-Associated Steatohepatitis, PPAR-α: Peroxisome Proliferator-Activated Receptor Alpha, PPAR-γ: Peroxisome Proliferator-Activated Receptor Gamma, PPAR-δ: Peroxisome Proliferator-Activated Receptor Delta, NASH: Nonalcoholic Steatohepatitis, T2D: Type 2 Diabetes, VLDL-C: Very Low-Density Lipoprotein Cholesterol, HDL-C: High-Density Lipoprotein Cholesterol, LDL-C: Low-Density Lipoprotein Cholesterol, HbA1c: Glycated Hemoglobin, BMI: Body Mass Index, PBC: Primary Biliary Cholangitis, US FDA: United States Food and Drug Administration, NAFLD: Nonalcoholic fatty liver disease, NYHA: New York Heart Association