A form of Vitamin E taken daily significantly improved a particular form of chronic liver disease, according to a Virginia Commonwealth University-led study published today in the New England Journal of Medicine.
The Nonalcoholic Steatohepatitis (NASH) Clinical Research Network of the National Institute of Diabetes, Digestive and Kidney Diseases, or NIDDK, reported that 800 IU of rrr α-tocopherol, a form of Vitamin E, taken daily significantly improved this condition in a paper published in the advance online edition of the New England Journal of Medicine on April 28. Pioglitazone given at a dose of 30 mg/day also improved many features of NASH but was associated with weight gain.
NASH is a chronic liver disease that is linked to weight gain and obesity and can lead to cirrhosis, liver cancer and death. It is believed to be caused by abnormal metabolism of fats that cause increased levels of oxidants in the liver. There is currently no approved treatment of NASH.
In the Pioglitazone or Vitamin E for NASH Study (PIVENS), investigators from the NASH clinical research network, or CRN, compared two different treatments — vitamin E and pioglitazone — to placebo for the treatment of NASH. Vitamin E functions as an anti-oxidant, while pioglitazone improves the sensitivity of cells to insulin, a hormone that controls both sugar and fat metabolism.
After 96 weeks of treatment, Vitamin E improved all features of NASH with the exception of the amount of scar tissue in the liver. Forty-three percent of those treated with vitamin E met the primary endpoint of the trial, which was a composite of the scores for several features of NASH indicative of disease activity, compared to only 19 percent of those who received a placebo.
Pioglitazone also improved many features of NASH and met the primary endpoint in 34 percent of individuals who received it, but fell short of being statistically significant. Pioglitazone also led to an average weight gain of 10 pounds over the 96-week duration of the study. The liver enzyme tests, which are commonly used to assess liver injury, also improved in those who received either pioglitazone or vitamin E. However, upon stopping the medications, the liver enzymes worsened again, suggesting the need for long-term treatment.
“This is an important landmark in the treatment of NASH,” said Pat Robuck Ph.D., project scientist for the NASH Clinical Research Network and director of the Clinical Trials Program within the Division of Digestive Diseases and Nutrition at NIDDK. “It is the largest clinical trial of drug therapy for NASH, a disease that affects about 3 percent to 4 percent of the U.S. population and can not only lead to death from cirrhosis, but also increases the risk of death from cardiovascular disease.
“It shows that both vitamin E and pioglitazone, two drugs with very different mechanisms of action, improve NASH although only the improvement with vitamin E was statistically significant,” she said.
Arun Sanyal, M.D., NASH CRN co-chair and PIVENS principal investigator, professor of medicine and chairman of VCU’s Division of Gastroenterology, cautioned that: “While PIVENS provides evidence for a benefit for vitamin E for NASH, it should not be considered a panacea.
“This study was conducted in those with NASH who did not have diabetes and the benefits of either drug in those with NASH who also have diabetes remains unknown,” he said. “Also, the study lasted for two years only and the potential long-term benefits and risks of taking vitamin E or pioglitazone in these doses are still uncertain.”
The study also reported that, while vitamin E and pioglitazone were both better than placebo for improvement of several features of NASH, many individuals receiving these treatments did not improve.
“This mandates the need for careful follow up to assess response in those who are started on drug therapy,” Sanyal added.
A liver biopsy is the best way to assess response to treatment for NASH. The NASH CRN is currently engaged in studies to define simple non-invasive methods to determine if an individual patient is responding to drug therapy.
“The PIVENS trial provides key evidence to support the use of vitamin E for selected patients with NASH. However, before prescribing either drug to patients with NASH, physicians must not only weigh the potential risks and benefits of treatment, particularly with long-term therapy but also the need for future liver biopsies to assess the response to treatment,” said Stephen P. James, M.D., director of the Division of Digestive Diseases and Nutrition, NIDDK, sponsor of PIVENS. “Use of vitamin E for NASH at these doses should be monitored by a physician.”
PIVENS was conducted by researchers at the following centers: Case Western Reserve University; Duke University; Indiana University; Johns Hopkins University; Saint Louis University; University of California-San Diego; University of California-San Francisco; VCU; Virginia Mason Medical Center; and Washington University in St. Louis.
Information about PIVENS is available at www.clinicaltrials.gov. Information about the NASH CRN is at http://www.jhucct.com/nash/open/centers/centers.htm.