Anti-diabetic drug and NASH: Current Options in 2022

Introduction and Background

Nonalcoholic steatohepatitis (NASH) is a more aggressive form of nonalcoholic fatty liver disease, which can increase the risk of cirrhosis, advanced liver fibrosis, hepatocellular carcinoma, and liver transplantation.(1,2) Patients with obesity and/or type 2 diabetes mellitus (T2DM) have been linked with a 2- to 3-fold increased risk of NASH and may also lead to more advanced fibrosis and hepatocellular carcinoma in this population.(3,4) While NASH has a number of underlying causes and treatment remains challenging.(5) the increased levels of liver triglycerides resulting from insulin-resistant (IR) dysfunctional adipose tissue is a major alarm.(6,7)

Role of Pioglitazone in T2DM and NASH

Since there is no approved therapy for NASH, looking for ways to prevent or reverse the disease is of utmost importance. As of now, among the insulin sensitizers currently available on the market, only pioglitazone has been shown to have some positive effects on NASH (improved histology and biochemistry).*8-10) In this review, we discuss the rationale for pioglitazone treatment of NASH in patients with T2DM.

Pioglitazone works by activating a peroxisome proliferator-activated receptor (PPARs) in adipose tissue, improving lipid storage, lipid redistribution and glucose utilization.(11) It has a beneficial impact on reducing gluconeogenesis in the liver and lowers insulin resistance in the liver, muscles, and adipose tissue. The efficacy of this agent was proven in an early randomized clinical trails, patients with diabetes or prediabetes and biopsy-proven NASH.8 Based on recent guidelines, pioglitazone improves liver histology in patients with and without T2DM that have biopsy-proven NASH, and it found to be useful in treating such patients.(12,13) According to a clinical guideline published by the American Association of Clinical Endocrinology (AACE-2022), pioglitazone is recommended for patients with T2DM and biopsy-proven NASH.(14) Furthermore, clinicians should consider this drug when NASH is suspected based on elevated plasma aminotransferase levels and noninvasive tests in patients with diabetes.(14) Figure 1 summarizes the benefits of pioglitazone for treating NASH in obese, prediabetes or T2DM patients.

Figure 1: Treatment algorithm for NASH

Evidences from Studies

While not yet established, interventions targeting nonalcoholic fatty liver disease and hepatic IR may decrease the risk of developing T2DM,(15,16) as is evident when pioglitazone is administered to people at risk of diabetes, which reduces the progression from prediabetes to T2DM by 70% to 80%.(17,18) Over 72 weeks, individuals with obesity, prediabetes or T2DM who received placebo progressed at 26.9% compared to 7.9% who received pioglitazone.(19)

A single-center study in 101 persons with obesity, and either prediabetes or T2DM, confirmed the sustained benefit of pioglitazone on glucose and lipid metabolism and NASH over 36 months of follow-up. With pioglitazone treatment (45 mg), 58% of individuals achieved the primary outcome of a reduction of at least 2 points in NAS, while 51% had resolution of NASH (treatment difference of 41% and 32% vs placebo, respectively; both P<0.001 vs placebo).(19) There was also an improvement in the mean fibrosis score (P=0.039).(19) A significant improvement in the resolution of NASH may indicate a specific mechanism of pioglitazone in T2DM.The results of the meta-analysis on NASH patients regardless of the presence of T2DM showed that pioglitazone can significantly improve advanced fibrosis (OR, 3.15; 95% CI: 1.25-7.93; P=0.01), fibrosis of any stage (OR, 1.66; 95% CI: 1.12-2.47; P=0.01).(20) The findings of this meta-analysis suggest that pioglitazone not only reversed the NASH but also improved advanced fibrosis.

A study by Bril et al. compared the metabolic and histologic responses to pioglitazone in patients with and without T2DM. The study highlighted that both patient populations were benefited from pioglitazone, however, after 18-months of follow-up patients with diabetes have shown significantly reduced liver fibrosis and increased adipose tissue insulin sensitivity compared to the patients without diabetes.(21) It was noted that long-term use of pioglitazone for up to 24-months was beneficial in terms of reversal of advanced fibrosis stage in patients with NASH.(22,23) Similar benefits were also observed with patients without diabetes which may prompt the extension for pioglitazone use.

Conclusion

Overall findings suggest that pioglitazone therapy is associated with prevention or delay inNASH in patients with NASH prediabetes and T2DM. Additionally, it can significantly improve metabolic and histologic performance of the liver and insulin sensitivity. However, further studies are needed with large samples and long-term follow-up to determine the efficacy of pioglitazone to better guide clinical decision-making, patient selection and clinical practice guidelines in T2DM with NASH.

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