Treatments for Fatty Liver Disease (NASH) Study: PIVENS
The NIDDK funded the Pioglitazone versus Vitamin E versus Placebo for the Treatment of Non-Diabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) study to research effective treatments for nonalcoholic steatohepatitis (NASH) in adults. This study is part of NIDDK’s NASH Clinical Research Network (NASH CRN), which also conducted a similar study in children. At the time, this study was the largest clinical trial of treatments ever conducted in people with NASH.
NASH is a serious form of nonalcoholic fatty liver disease (NAFLD). NASH involves a buildup of fat in the liver, inflammation, and liver damage. This fat buildup is not caused by heavy alcohol use. Over time, NASH may lead to cirrhosis—a condition in which the liver is permanently damaged and is unable to work normally—liver cancer, or liver failure. Currently, no medicines are approved to treat NASH.
NASH affects approximately 1.5 to 6.45 percent of the U.S. population.1 Some racial or ethnic groups are more likely to develop NASH—such as Hispanics/Latinos, American Indians, and people of South Asian descent—and would benefit even more from effective treatments.
Researchers found that a daily dose of the natural form of vitamin E—the type of vitamin E that comes from food sources and is not synthetic (laboratory-made)—improved NASH in study participants overall. The medicine pioglitazone, another study treatment, also improved some features of NASH, although researchers could not prove the improvements were statistically significant (did not occur randomly).
Despite these positive outcomes, many study participants taking pioglitazone gained weight, and many participants did not improve from either treatment. Researchers also found that changes in quality of life did not differ much between the treatment groups. Additional studies are needed to explore whether treatment with vitamin E or pioglitazone causes long-term risks and whether either improve NASH in people who have diabetes.
Some ongoing studies are helping to refine methods and tests to better measure if individuals respond to treatment. For example, researchers who studied participants’ blood levels of alanine transaminase (ALT), a liver enzyme, found that liver damage is usually improved when blood ALT levels decrease to normal. Participants in the PIVENS study who received vitamin E had lower blood ALT levels compared with those receiving a placebo. As a result, researchers suggest that ALT levels can be used as a fairly reliable test to detect improvements in liver function in NASH.
NASH CRN researchers have continued to analyze PIVENS data to better understand many aspects of NASH and NASH treatment. For example, researchers looked at the relationship between NASH and metabolic syndrome—a group of conditions that increase the risk of type 2 diabetes and heart disease. The researchers found that, among people without diabetes who have NAFLD, those who have metabolic syndrome are more likely to have NASH.
NASH CRN researchers have also used PIVENS data to study the relationship between NASH and dyslipidemia—abnormal levels of fats in the blood—which is a risk factor for cardiovascular disease. These studies suggest that dyslipidemia is common in people with NASH, and improvements in NASH are associated with improvements in some aspects of dyslipidemia.
Study Size, Participant Demographics, and Study Design
The PIVENS study took place from 2005 to 2009 and involved 247 adults who had NASH and did not have cirrhosis or diabetes at the start of the study. Participants were assigned to one of three treatment groups for 96 weeks.
- One group received a pill with a form of vitamin E (800 International Units).
- The second group received a pill with pioglitazone (30 mg).
- A third group received a placebo–a pill that contains no medicine.
Before the study began, all participants had a liver biopsy. All participants also had a liver biopsy at the end of the study to see if the treatments in the study had an effect on the liver. Blood tests for liver function, blood glucose or blood sugar, fat, and insulin (a hormone that helps control blood glucose levels) were done throughout the study. Measurements such as body weight, height, waist and hip size, and body fat percentage were also taken. Questionnaires were given to participants throughout the study to assess their lifestyle and quality of life.
PIVENS was conducted by researchers at the following centers
- Case Western Reserve University and the Cleveland Clinic, Cleveland, Ohio
- Duke University, Raleigh-Durham, North Carolina
- Indiana University, Indianapolis, Indiana
- Johns Hopkins University, Baltimore, Maryland
- Saint Louis University and Washington University, St. Louis, Missouri
- University of California San Diego, San Diego, California
- University of California San Francisco, San Francisco, California
- Virginia Commonwealth University, Richmond, Virginia
- Virginia Mason Medical Center and the University of Washington, Seattle, Washington
Related Health Information
Scientific Publications and Resources
- PIVENS Study on ClinicalTrials.gov
- PIVENS Study Documents and Resources from the NIDDK Central Repository–samples and data are available for future studies
- PIVENS Grant Award Information from dkNET
- Kanwar P, Nelson JE, Yates K, Kleiner DE, Unalp-Arida A, Kowdley KV. Association between metabolic syndrome and liver histology among NAFLD patients without diabetes. BMJ Open Gastroenterology. 2016;3(1):e000114. eCollection 2016.
- Corey KE, Vuppalanchi R, Wilson LA, Cummings OW, Chalasani N; NASH CRN. NASH resolution is associated with improvements in HDL and triglyceride levels but not improvement in LDL or non-HDL-C levels. Alimentary Pharmacology & Therapeutics. 2015;41(3):301–309.
- Hoofnagle JH, Van Natta ML, Kleiner DE et al. Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis. Alimentary Pharmacology and Therapeutics. 2013;38(2):134–143.
- Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. The New England Journal of Medicine. 2010;362(18):1675–1685.
- Chalasani NP, Sanyal AJ, Kowdley KV, et al. Pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis: PIVENS trial design. Contemporary Clinical Trials Communications. 2009;30(1):88–96.