Prevalence of Non-alcoholic Fatty Liver Disease (NAFLD) in Hispanics With Diabetes Mellitus Type 2 (T2DM) and Role of Treatment

2014-08-27 03:18:22 | BioPortfolio


Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition frequently associated with type 2 diabetes (T2DM) and characterized by insulin resistance and hepatic fat accumulation. Liver fat may range from simple steatosis to severe steatohepatitis with necroinflammation and variable degrees of fibrosis (nonalcoholic steatohepatitis or NASH). Up to 40% of patients with NAFLD develop NASH in recent series. Risk factors for progression to NASH are unclear, but appears to be more common and progress more rapidly in older individuals, those of Hispanic ancestry and in the presence of T2DM. Because the VA population in San Antonio, Texas, frequently combine these risk factors for NASH it was felt that a study targeting this very high-risk population was needed.

This study will establish the long-term efficacy (primary endpoint: liver histology) and safety of pioglitazone for the treatment of VA Hispanic patients with T2DM and NASH. All patients diagnosed with NASH will be offered lifestyle modification/weight loss (current standard of care) while being randomized to pioglitazone or placebo for up to 3 years. We believe that in such a high-risk population for complications from NASH, a substantial benefit may be expected from early detection and treatment.


Many NAFLD studies have found that the progression from "benign" steatosis to severe necroinflammation and cirrhosis as observed in NASH varies widely depending upon the initial stage at diagnosis, as well the presence or absence of specific risk factors associated with disease progression. The factors that promote necroinflammation and fibrosis development are complex, but are frequently associated with the presence of long-standing obesity, metabolic syndrome, and in particular, of T2DM. Indeed, hyperglycemia has been identified as the single most consistent factor for disease progression in many studies (Angulo et al, Hepatology 1999) Marceau et al, JCEM 1999; Luyckx et al, Obes Relat Metab Disord, 1998; Mofrad et al, Hepatology 2003; many others; reviewed by Cusi, Current Diabetes Reports, 2009).

Given the worse prognosis of NASH in patients with T2DM, it is quite surprising that few studies have focused on the prevalence of the disease and on early screening and treatment of patients with diabetes for NASH. A prospective study conducted by Gupte et al (Gastroenterology & Hepatology, 2004) reported biopsy-proven NASH in 87% of diabetics, 22% having moderate to severe disease. In a retrospective analysis of 44 patients with T2DM worked-up for NAFLD, Younussi et al also found that cirrhosis was more prevalent in diabetics vs. nondiabetics (25% vs. 10%, p<0.001) (Hepatology 2004). In recent years, the diagnosis of fatty liver has been made easier with the standardization of liver magnetic resonance and spectroscopy (MRS) which has allowed a fast and highly reproducible test for NAFLD. With this screening tool we have found that NAFLD is present in >80% of unselected patients with T2DM. In non-diabetic patients a handful of small studies with paired biopsies indicate that fibrosis progresses over time in 32-41% of patients with NAFLD (reviewed by Ali & Cusi, Annals of Medicine, 2009). Obesity and T2DM were the 2 most prominent factors of poor prognosis, while elevated liver enzymes (ALT or AST/ALT ratio) were of lesser value (Mofrad et al, Hepatology 2003; Sorrentino et al, Hepatology 2004; Kunde et al, Hepatology 2005).

This study aims at establishing the role of pioglitazone in VA Hispanic patients. Weight loss remains the standard of care because no therapy has conclusively proven to be effective in the long-term. Pharmacological therapies with modest effects have included pentoxifylline, orlistat, cytoprotective agents, ursodeoxycholic acid and lipid-lowering agents, while insulin-sensitizers such as metformin and thiazolidinediones have yielded more provocative results in small uncontrolled studies in NASH. Our research group recently demonstrated in a randomized, double-blind, placebo-controlled trial, that pioglitazone treatment for 6 months in patients with T2DM and NASH significantly improved glycemic control, glucose tolerance, insulin sensitivity and systemic inflammation (Belfort et al, NEJM 2006). This was associated with a ~50% decrease in steatohepatitis (p<0.001) and a 37% reduction of fibrosis within the pioglitazone-treated group (-37%, p<0.002), although this fell short of statistical significance when compared with placebo (p=0.08). Our results provided "proof-of-principle" that pioglitazone may be the first agent capable of altering the natural history of the disease. However, definitive proof requires establishing its safety and efficacy in a large number of subjects treated for a longer period of time. The CRN is conducting the PIVENS trial (; NCT 00063622) examining the role of pioglitazone, vitamin E or placebo in NASH, but the study design excluded diabetics, only ~5% of patients were Hispanic and studied a younger population than that typical from VA Medical Centers. Also, this important multicenter trial did not perform the in-depth metabolic measurements this trial will carry out (i.e., insulin clamps with glucose turnover measurements, indirect calorimetry, etc.).

Understanding the long-term impact of thiazolidinediones in Hispanic patients with NASH and T2DM, who are believed to be at the highest risk for liver disease progression, will have important implications not only for the treatment of NASH but for drug selection and treatment algorithms in T2DM, as an insulin-sensitizer approach of pioglitazone (in addition to metformin) would be preferred over therapies such as sulfonylureas or insulin, if proven to be effective to treat NASH in T2DM. However, currently the most common strategy to treat T2DM is an insulin secretion-based approach (i.e., sulfonylureas and/or insulin) that has little impact on liver fat and promotes weight gain without a major improvement in insulin sensitivity, promoting chronic hyperinsulinemia and self-perpetuating the metabolic milieu that promotes hepatic lipogenesis and fatty liver disease.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment


Nonalcoholic Steatohepatitis


placebo, pioglitazone


VA South Texas Health Care System, San Antonio
San Antonio
United States


Not yet recruiting


Department of Veterans Affairs

Results (where available)

View Results


Published on BioPortfolio: 2014-08-27T03:18:22-0400

Clinical Trials [418 Associated Clinical Trials listed on BioPortfolio]

Role of Pioglitazone in the Treatment of Non-alcoholic Steatohepatitis (NASH)

To determine the role of pioglitazone in the treatment of nonalcoholic steatohepatitis (NASH) in patients with glucose intolerance or type 2 diabetes mellitus (T2DM).

Pioglitazone vs Vitamin E vs Placebo for Treatment of Non-Diabetic Patients With Nonalcoholic Steatohepatitis (PIVENS)

The purpose of this study is to determine if therapy with pioglitazone or vitamin E will lead to an improvement in liver histology in non-diabetic adult patients with non-alcoholic steatoh...

A Study in Adult Patients With Nonalcoholic Steatohepatitis Who Also Have Type 2 Diabetes

The purpose of this study is to assess the effect of TEV-45478, as compared with placebo, on liver health and liver fat content in patients with T2DM who also have Nonalcoholic Steatohepat...

Colesevelam Versus Placebo in the Treatment of Nonalcoholic Steatohepatitis

The purpose of the study is to see if the drug colesevelam is a potential treatment for Nonalcoholic Steatohepatitis(NASH).

Safety and Efficacy of Solithromycin in the Treatment of Nonalcoholic Steatohepatitis Without Cirrhosis

The purpose of this study is to evaluate the effects of solithromycin on hepatic histology and biomarkers in patients with nonalcoholic steatohepatitis.

PubMed Articles [1206 Associated PubMed Articles listed on BioPortfolio]

Rates and Factors Associated With Placebo Response in Trials of Pharmacotherapies for Nonalcoholic Steatohepatitis: Systematic Review and Meta-analysis.

Understanding the extent of the placebo effect in randomized controlled trials of studying nonalcoholic steatohepatitis (NASH) is important for optimal trial design, including sample size calculations...

Factors Associated with Histologic Response in Adult Patients with Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a leading cause of liver transplantation and many trials are underway to evaluate potential therapies. The farnesoid X receptor ligand obeticholic acid in NASH t...

Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. Most cases are diagnosed incidentally in the primary care or hospital setting on the basis of elevated liver enz...

GS-0976 Reduces Hepatic Steatosis and Fibrosis Markers in Patients with Nonalcoholic Fatty Liver Disease.

De novo lipogenesis is increased in livers of patients with nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase catalyzes the rate-limiting step in this process. We evaluated the safety and ef...

Simtuzumab Is Ineffective for Patients with Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis.

Lysyl oxidase like 2 (LOXL2) contributes to fibrogenesis by catalyzing cross linkage of collagen. We evaluated the safety and efficacy of simtuzumab, a monoclonal antibody against LOXL2, in a phase 2b...

Medical and Biotech [MESH] Definitions

Cytoplasmic hyaline inclusions in HEPATOCYTES. They are associated with ALCOHOLIC STEATOHEPATITIS and non-alcoholic STEATOHEPATITIS, but are also present in benign and malignant hepatocellular neoplasms, and metabolic, toxic, and chronic cholestatic LIVER DISEASES.

Misunderstanding among individuals, frequently research subjects, of scientific methods such as randomization and placebo controls.

An effect usually, but not necessarily, beneficial that is attributable to an expectation that the regimen will have an effect, i.e., the effect is due to the power of suggestion.

More From BioPortfolio on "Prevalence of Non-alcoholic Fatty Liver Disease (NAFLD) in Hispanics With Diabetes Mellitus Type 2 (T2DM) and Role of Treatment"

Quick Search


Relevant Topic

Hepatology is the study of liver, gallbladder, biliary tree, and pancreas, and diseases associated with them. This includes viral hepatitis, alcohol damage, cirrhosis and cancer. As modern lifestyles change, with alcoholism and cancer becoming more promi...

Searches Linking to this Trial