Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in patients with Type 2 Diabetes Mellitus

Abstract

Nonalcoholic fatty liver disease (NAFLD) is believed to be the most common chronic liver disease, affecting at least one-third of the population worldwide. The more aggressive form is known as nonalcoholic steatohepatitis (NASH) and characterized by hepatocyte necrosis and inflammation. The presence of fibrosis is not uncommon. Fibrosis indicates a more aggressive course and patients with NASH that are at high-risk of cirrhosis and premature mortality, as well as at increased risk of hepatocellular carcinoma (HCC). Patients with type 2 diabetes mellitus (T2DM) are at the highest risk for the development of NASH, even in the setting of normal plasma aminotransferase levels. The presence of dysfunctional adipose tissue in most overweight and obese subjects, combined with insulin resistance, hyperglycemia, and atherogenic dyslipidemia, contribute to their increased cardiovascular risk. Many therapeutic agents have been tested for the treatment of NASH but few studies have focused in patients with T2DM. At the present moment, the only FDA-approved agents that in controlled studies have shown to significantly improve liver histology in patients with diabetes are pioglitazone and liraglutide. Current research efforts are centering on the mechanisms for intrahepatic triglyceride accumulation and for the development of steatohepatitis, the role of mitochondrial dysfunction in NASH, and the impact of improving glycemic control per se on the natural history of the disease. This brief review summarizes our current knowledge on the pharmacological agents available for the treatment of NASH to assist healthcare providers in the management of these challenging patients.

From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options

“…Among insulin-sensitizers, metformin does not significantly impact resolution of NASH or fibrosis, as reviewed elsewhere 171 and is considered neutral by current guidelines. 2,172 Pioglitazone has shown beneficial effects in NASH.…”

Association between PPARGC1A single nucleotide polymorphisms and increased risk of nonalcoholic fatty liver disease among Iranian patients with type 2 diabetes mellitus

“…The peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) protein is encoded by this gene and plays a role in energy metabolism, including insulin resistance, oxidative phosphorylation, hepatic gluconeogenesis, and mitochondrial biogenesis and respiration, which are important in the development of NAFLD [6]. Moreover, there are some reports regarding the role of PGC-1α in the homeostatic control of systemic energy metabolism, regulation of lipid and carbohydrate metabolism, development of obesity, and control of blood pressure [7,8].…”

Practical strategies for improving outcomes in T2DM: The potential role of pioglitazone and DPP4 inhibitors

“…The modulation of lipid metabolism and the anti‐inflammatory property is the probable mechanism through which pioglitazone exerts powerful positive effects on nonalcoholic steatohepatitis (NASH) . The latter effect is of importance not only because of the potential evolution of NASH toward steatohepatitis, fibrosis and hepato‐carcinoma, but also because NASH can contribute to inflammatory status and CV risk in T2DM …”

“…31 The latter effect is of importance not only because of the potential evolution of NASH toward steatohepatitis, fibrosis and hepato-carcinoma, but also because NASH can contribute to inflammatory status and CV risk in T2DM. 32 Treatment with glitazones is commonly associated with an increase in body weight. This is the result of a reduction in visceral fat, at the expense of an increase in subcutaneous fat, a more benign fat tissue with milder metabolic implications.…”