PIVENS

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Sanyal AJ, et al. "Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis". The New England Journal of Medicine. 2010. 362(18):1675-1685.
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Clinical Question

Among patients without diabetes and with nonalcoholic steatohepatitis, does pioglitazone or vitamin E perform better than placebo for the treatment of disease?

Bottom Line

Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes, and pioglitazone may also have efficacy.

Major Points

Nonalcoholic steatohepatitis is a common liver disease that is characterized histologically by hepatic steatosis, lobular inflammation, and hepatocellular ballooning; it can progress to cirrhosis in up to 15% of patients. There is currently no therapy that is of proven benefit for nonalcoholic steatohepatitis. The disease is closely associated with insulin resistance and features of the metabolic syndrome such as obesity, hypertriglyceridemia, and type 2 diabetes. In addition to insulin resistance, oxidative stress has been implicated as a key factor contributing to hepatic injury in patients with nonalcoholic steatohepatitis. Thus, both insulin resistance and oxidative stress are attractive targets for therapy in patients with this disease.

Several pilot studies have provided evidence that insulin sensitizers such as thiazolidinediones and antioxidants such as vitamin E improve clinical and histologic features of nonalcoholic steatohepatitis. The medical evidence of a benefit, however, is limited, because these studies had small samples and were performed at single centers. Moreover, a recent multicenter trial showed a reduction in hepatic steatosis but no improvement in markers of cell injury after a year of rosiglitazone therapy. The value of these drugs remains uncertain.

The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) was established by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to address unmet research needs in the field. As a part of this mandate, the NASH CRN conducted the Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial, a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of pioglitazone or vitamin E for the treatment of adults without diabetes who had biopsy-confirmed nonalcoholic steatohepatitis.

Guidelines

There are three guideline recommendations set forth by the American Association for the Study of Liver Diseases in 2012.[1]

  • Pioglitazone can be used to treat steatohepatitis in patients with biopsy-proven NASH. However, it should be noted that majority of the patients who participated in clinical trials that investigated pioglitazone for NASH were non-diabetic and that long term safety and efficacy of pioglitazone in patients with NASH is not established.
  • Vitamin E (a-tocopherol) administered at daily dose of 800 IU/day improves liver histology in non-diabetic adults with biopsy-proven NASH and therefore it should be considered as a first-line pharmacotherapy for this patient population.
  • Until further data supporting its effectiveness become available, vitamin E is not recommended to treat NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis

Design

  • Phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial
  • N=247
    • Placebo (n=83)
    • Vitamin E (n=84)
    • Pioglitazone (n=80)
  • Setting: 9 participating clinical centres around the United States
  • Enrolment: January 2005 to January 2007
  • Mean follow up: After randomization, subjects were followed according to a predetermined schedule for assessment of the safety and tolerability of the study drugs. A liver biopsy was performed 96 weeks after randomization, after which the study drugs were discontinued. Subjects were then followed for an additional 24 weeks.
  • Analysis: Intention-to-treat
  • Primary outcome: improvement in histologic findings
  • Secondary outcomes:
    • Changes in the overall activity score for nonalcoholic fatty liver disease, as well as in individual component scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis
    • Changes in serum aminotransferase levels
    • Anthropometric measures
    • Insulin resistance
    • Lipid profiles
    • Change in health-related quality of life from baseline to the end of treatment, as assessed with the use of the SF-36

Population

Inclusion Criteria

  • Biopsy-confirmed nonalcoholic steatohepatitis, including:
    • Definite or possible steatohepatitis with an activity score of 5 or more, or
    • Definite steatohepatitis (confirmed by two pathologists) with an activity score of 4.
    • A score of at least 1 for hepatocellular ballooning was required in all cases

Exclusion Criteria

  • Excessive alcohol consumption
    • > 20 g/day in women and > 30 g/day in men
  • Cirrhosis, hepatitis C, or other liver diseases
  • Heart failure (NYHA class II to IV)
  • Receiving drugs known to cause steatohepatitis
  • Diabetes mellitus

Baseline Characteristics

Comparisons are placebo vs. vitamin E vs. pioglitazone

  • Demographic factors
    • Age (yr): 45.4 vs. 46.6 vs. 47.0
    • Female sex (%): 58 vs. 62 vs. 59
    • Hispanic (%): 7 vs. 19 vs. 19
    • Nonwhite (%): 11 vs. 15 vs. 8
  • Quality of life
    • SF-36, physical component: 47 vs. 49 vs. 49
    • SF-36, mental component: 47 vs. 49 vs. 49
  • Serum biochemical levels
    • ALT (U/L): 81 vs. 86 vs. 82
    • AST (U/L): 55 vs. 59 vs. 54
    • GGT (U/L): 69 vs. 56 vs. 60
    • ALP (U/L): 82 vs. 77 vs. 86
    • Total bilirubin (mg/dl): 0.76 vs. 0.75 vs. 0.77
  • Lipids
    • Triglycerides (mg/dl): 165 vs. 166 vs. 162
    • Total cholesterol (mg/dl): 199 vs. 195 vs. 195
    • HDL (mg/dl): 43 vs. 44 vs. 45
    • LDL (mg/dl): 125 vs. 119 vs. 120
  • Metabolic factors
    • Fasting serum glucose (mg/dl): 95 vs. 95 vs. 92
    • Insulin resistance: 5.5 vs. 5.2 vs. 5.0
    • Weight (kg): 99 vs. 94 vs. 97
    • BMI: 35 vs. 34 vs. 34
    • Waist circumference (cm): 109 vs. 107 vs. 108
    • Body composition (% fat): 40 vs. 39 vs. 40
  • Liver histologic findings
    • Total NAFLD activity score: 4.8 vs. 5.1 vs. 5.0
    • Steatosis: 1.9 vs. 1.9 vs. 2.0
    • Lobular inflammation: 1.6 vs. 1.8 vs. 1.8
    • Hepatocellular ballooning: 1.3 vs. 1.3 vs. 1.1
    • Fibrosis stage: 1.6 vs. 1.5 vs. 1.4
    • Absence of ballooning on central review (%): 17 vs. 18 vs. 28

Interventions

  • Subjects who met all eligibility criteria and provided written informed consent were randomly assigned to one of three groups for 96 weeks of study treatment:
    • a group receiving pioglitazone (at a dose of 30 mg once daily) and a vitamin E–like placebo (once daily),
    • a group receiving vitamin E (800 IU, natural form, once daily) and a pioglitazone-like placebo (once daily);
    • or a group receiving a pioglitazone-like placebo (once daily) and a vitamin E–like placebo (once daily).
  • After randomization, subjects were followed according to a predetermined schedule for assessment of the safety and tolerability of the study drugs.
  • A liver biopsy was performed 96 weeks after randomization, after which the study drugs were discontinued. Subjects were then followed for an additional 24 weeks.

Outcomes

Comparisons are placebo vs. vitamin E vs. pioglitazone; P-values are "Vitamin E vs. Placebo" and "Pioglitazone vs. placebo"

Primary Outcomes

Subjects with improvement (%)

  • 19 vs. 43 vs. 34 (P=0.001, P=0.04)

Secondary Outcomes

Subjects with steatosis improvement (%)

  • 31 vs. 54 vs. 69 (P=0.005, P=<0.001)

Subjects with lobular inflammation improvement (%)

  • 35 vs. 54 vs. 60 (P=0.02, P=0.004)

Subjects with hepatocellular ballooning improvement (%)

  • 29 vs. 50 vs. 44 (P=0.01, P=0.08)

Total NAFLD activity score (mean change)

  • -0.5 vs. -1.9 vs. -1.9 (P=<0.001, P=<0.001)

Subjects with fibrosis improvement

  • 31 vs. 41 vs. 44 (P=0.24, P=0.12)

Resolution of definite nonalcoholic steatohepatitis (%)

  • 21 vs. 36 vs. 47 (P=0.05, P=0.001)

Serum enzymes and bilirubin

ALT (U/L)

  • -20.1 vs. -37.0 vs. -40.8 (P=0.001, P=<0.001)

AST (U/L)

  • -3.8 vs. -21.3 vs. -20.4 (P=<0.001, P=<0.001)

GGT (U/L)

  • -4.0 vs. -14.0 vs. -21.1 (P=0.003, P=<0.001)

ALP (U/L)

  • -3.8 vs. -9.3 vs. -12.0 (P=0.008, P=0.004)

Total bilirubin (mg/dl)

  • 0.06 vs. 0.04 vs. -0.04 (P=0.56, P=0.07)

Lipids

Triglycerides (mg/dl)

  • -6.7 vs. -0.6 vs. -19.8 (P=0.45, P=0.16)

Total cholesterol (mg/dl)

  • -9.6 vs. -13.6 vs. -11.4 (P=0.25, P=0.50)

HDL (mg/dl)

  • -1.9 vs. -0.9 vs. 1.1 (P=0.51, P=0.008)

LDL (mg/dl)

  • -5.8 vs. -12.0 vs. -8.1 (P=0.07, P=0.26)

Metabolic factors

Fasting serum glucose (mg/dl)

  • 1.8 vs. 1.8 vs. -3.1 (P=0.81, P=0.006)

Insulin resistance

  • 0.4 vs. 0.4 vs. -0.7 (P=0.80, P=0.03)

Weight (kg)

  • 0.7 vs. 0.4 vs. 4.7 (P=0.65, P=<0.001)

BMI

  • 0.4 vs. 0.1 vs. 1.8 (P=0.50, P=<0.001)

Waist circumference (cm)

  • 0.2 vs. -0.4 vs. 3.3 (P=0.53, P=0.06)

Body composition (% fat)

  • 0 vs. 0.4 vs. 2.7 (P=0.50, P=<0.001)

Quality of life

SF-36 score, physical component

  • -0.3 vs. 0.4 vs. -0.9 (P=0.45, P=0.93)

SF-36 score, mental component

  • 0.4 vs. -0.5 vs. -1.9 (P=0.76, P=0.23)

Criticisms

  • The largest methodologically sound, systematic review of antioxidant trials to date have reported that vitamin E given singly or combined with other antioxidants increases the risk of death. [2] There are no long-term prospective studies involving patients with nonalcoholic steatohepatitis to assess the dose-dependent effect of natural vitamin E on liver-related and cardiovascular mortality.
  • The study was not powered to test any safety-related hypotheses.
  • Patients were allowed to continue taking statins during the study, which are known to normalize vitamin E blood levels. [3]
  • It is unclear from the study whether vitamin E really exerted an antioxidant effect, since the investigators do not provide values for oxidative stress and vitamin E blood levels before and after treatment. The role of antioxidant activity is crucial, since it has been shown that vitamin E supplementation does not exert any antioxidant effect if it is administered to subjects with normal blood values of vitamin E. [4]
  • The study was not designed to compare vitamin E to pioglitazone and no conclusions can be drawn about their relative efficacy.

Funding

  • Supported by grants from the National Institutes of Health (NIH), by the intramural program of the National Cancer Institute, and by NIH General Clinical Research Center grants or Clinical and Translational Science Awards.
  • Additional funding was provided by Takeda Pharmaceuticals North America through a Cooperative Research and Development Agreement with the NIH.
  • The vitamin E softgels and matching placebo were provided by Pharmavite through a Clinical Trial Agreement with the NIH.
  • Dr. Chalasani is named on patents pending for biomarkers of nonalcoholic steatohepatitis held by Indiana University.
  • Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Further Reading

  1. The Diagnosis and Management of Non-Alcoholic Fatty Liver Disease. AASLD, 2012.
  2. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA, 2007.
  3. Early decrease of oxidative stress by atorvastatin in hypercholesterolaemic patients: effect on circulating vitamin E. Eur Heart J, 2008.
  4. Effects of vitamin E on lipid peroxidation in healthy persons. JAMA, 2001.