Jardiance (Empagliflozin) Shows Unexpected Benefit for Fatty Liver Disease (MASH)

What Is MASH and Why Is It Hard to Treat?

Metabolic dysfunction-associated steatohepatitis (MASH, formerly known as NASH or non-alcoholic steatohepatitis) affects an estimated 3-5% of the global adult population and is the fastest-growing cause of liver transplantation in Western countries. The disease is characterized by hepatic fat accumulation (steatosis) combined with inflammation and hepatocyte injury (ballooning), which can progress to fibrosis, cirrhosis, and hepatocellular carcinoma. MASH is closely linked to obesity, type 2 diabetes, and metabolic syndrome, with over 70% of patients having concurrent insulin resistance.

In March 2024, resmetirom (Rezdiffra), a thyroid hormone receptor beta agonist, became the first FDA-approved drug for MASH with moderate-to-advanced fibrosis. However, its efficacy is modest (approximately 25-30% of patients achieve fibrosis improvement at 1 year based on the MAESTRO-NASH trial), it requires liver function monitoring, and its long-term safety profile is still being established. The unmet need for effective, well-tolerated MASH therapies remains enormous, driving interest in repurposing existing medications with favorable safety records, including SGLT2 inhibitors.

How Does Empagliflozin Help the Liver?

Several clinical trials have demonstrated that empagliflozin reduces liver fat in patients with type 2 diabetes and fatty liver disease. The E-LIFT trial, a randomized controlled study published in Diabetes Care in 2018, found that empagliflozin 10 mg daily significantly reduced MRI-measured liver fat over 20 weeks compared with standard care in patients with type 2 diabetes and NAFLD. Subsequent studies and meta-analyses of SGLT2 inhibitors have consistently shown reductions in liver fat content, improvements in liver enzyme levels (ALT, AST), and favorable effects on metabolic parameters. Some studies have also reported improvements in non-invasive fibrosis markers, though large-scale histological data from liver biopsies are still needed.

SGLT2 inhibitors work by blocking glucose reabsorption in the kidney, causing urinary glucose excretion of approximately 60-80 grams per day (240-320 kcal). This caloric loss drives a metabolic shift from carbohydrate to fat oxidation, reducing hepatic lipogenesis and steatosis. Beyond this metabolic effect, empagliflozin reduces circulating insulin levels, suppresses hepatic inflammation, and may directly improve hepatic mitochondrial function. Boehringer Ingelheim and other pharmaceutical companies have signaled interest in pursuing larger trials to evaluate SGLT2 inhibitors specifically for MASH indications, with histological endpoints and long-term follow-up.