Prevalence of Non-alcoholic Fatty Liver Disease (NAFLD) in Hispanics With Diabetes Mellitus Type 2 (T2DM) and Role of Treatment
Condition: Nonalcoholic Steatohepatitis
MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease
Study type: Interventional
Phase: Phase 4

Summary: 
      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, and in the presence of obesity and 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 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, vitamin E 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.

      Specifically, the arms are: a) pioglitazone + vitamin E; b) vitamin E + placebo of
      pioglitazone; c) placebo of both. Patients are randomized to one of these 3 arms, and
      followed in a double-blind fashion for up to 18 months. Patients are then offered to continue
      into an open-label phase with pioglitazone + vitamin E or vitamin E alone for another 18
      months.
    

Detailed description: 
      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 and of vitamin E in VA 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 (www.ClinicalTrials.gov; 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 and of vitamin E in 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. Therefore, understanding the role
      of pioglitazone and vitamin combined, of vitamin e alone (plus pioglitazone placebo tablets
      as control) and compared to a third arm with placebo of both (pioglitazone and vitamin E) is
      important to move the field forward.

      Of note, the study started at the San Antonio VAMC, TX where ~60% of the population was
      Hispanic. However, once Dr. Kenneth Cusi (principal investigator) moved to the Gainesville
      VAMC, FL the study was transferred to Gainesville and recruitment continued in this new site
      where the prevalence of Hispanics is only 5% (75% Caucasians, 20% African American).
      Therefore, the final patient mix will reflect more the latter ethnic mix.
    

Intervention name(s): pioglitazone-placebo; pioglitazone; Vitamin E; pioglitazone-placebo; Vitamin E; Vitamin E-placebo
Intervention type(s): Drug; Drug; Dietary Supplement; Drug; Dietary Supplement; Drug
Intervention description(s): This is a RCT in which all patients will be educated on a -500 kcal/day diet and a healthy lifestyle. Depending on randomization, subjects adjudicated to placebo will be started at the same time as the active (pioglitazone) arm following completion of the baseline measurements and continued on placebo for the rest of the clinical trial.; Pioglitazone will be started on 30 mg/day, titrated to the maximal dose (45 mg/day) at two months and continued at this dose for the rest of the clinical trial.; All participants will receive vitamin E 400 IU orally twice daily.; This is a RCT in which all patients will be educated on a -500 kcal/day diet and a healthy lifestyle. Depending on randomization, subjects adjudicated to placebo will be started at the same time as the active (pioglitazone) arm following completion of the baseline measurements and continued on placebo for the rest of the clinical trial.; All participants will receive vitamin E 400 IU orally twice daily.; Placebo of vitamin E will be given to arm 3.
Other intervention name(s): Actos
Intervention MeSH terms: Vitamins; Vitamin E; Tocopherols; Tocotrienols; alpha-Tocopherol; Pioglitazone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: steatohepatitis; type 2 diabetes; fatty liver