Contact: Will Sansom
Phone: (210) 567-2579
Pioglitazone, an oral drug that improves Type 2 diabetics’ blood sugar control, also has substantial beneficial effects on the liver, according to a San Antonio-based clinical trial published Nov. 30 in The New England Journal of Medicine
In a placebo-controlled trial involving 55 patients, the drug markedly reduced the most severe form of nonalcoholic fatty liver disease. “Although this liver abnormality is largely overlooked by patients and physicians, it is serious, affects up to one in three Americans, and is strongly associated with Type 2 diabetes and obesity,” said study lead author Kenneth Cusi, M.D., associate professor of medicine at The University of Texas Health Science Center at San Antonio and staff physician with the South Texas Veterans Health Care System, Audie L. Murphy Division.
The study used novel imaging and other techniques to gauge the changes in patients randomly assigned to pioglitazone (brand name: Actos®) and a weight-reducing diet versus diet and a placebo. Some of the patients were recruited from Brooke Army Medical Center in San Antonio.
“The current standard of care for these patients is a weight-reducing diet,” Dr. Cusi said. “We prescribed moderate weight reduction for all patients, but added pioglitazone for half of them. The dietary instruction was done very carefully.”
More than 1,100 outpatient visits and follow-ups were done to ensure patient compliance with the diet and drug regimen. At the beginning and conclusion of the study, researchers performed magnetic resonance spectroscopy, which Dr. Cusi said is “the gold standard for examining the amount of fat in the liver. Only a few centers in the U.S. have this available.”
Abnormal concentrations of fat in the liver and high levels of inflammation can result in cell death leading to end-stage liver disease, or cirrhosis. The pioglitazone-treated patients not only saw their liver fat cut in half, but the inflammation was reduced by the same degree.
“Pioglitazone has proven to be a good drug for treating type 2 diabetes, but we didn’t know it would work for this, as well,” Dr. Cusi said. “Because we haven’t had any effective treatments for this condition, we have advised people to lose weight and exercise. Liver biopsies have not been very strongly indicated because they do entail a small degree of risk and for many patients would not have changed our overall approach to treatment.
“This finding may change the way we approach patients with the severe form of this disease, because now liver biopsies may be more frequently recommended as our results with pioglitazone offer new promise. A biopsy will best establish the baseline severity of the disease and how subsequent pioglitazone treatment is working. This study may also encourage a more frequent use of magnetic resonance spectroscopy to diagnose and monitor liver fat content, although much more work is needed in this area.”
This is only the first step toward examining the long-term benefit of this medication for patients. “The long-term clinical benefit of pioglitazone awaits larger controlled trials of longer duration, but it is a very exciting first step,” Dr. Cusi said. “It may encourage patients and health care providers to screen for this condition more carefully.” About nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
Up to one-third of Americans (an estimated 100 million) have excessive fat in the liver, a chronic condition that frequently is associated with obesity and Type 2 diabetes. This condition tends to worsen lipid and blood sugar control and may damage the liver. It is formally called nonalcoholic fatty liver disease (NAFLD) when alcohol abuse is ruled out as a cause.
The most severe form of NAFLD is associated with inflammation and liver injury, and is known as (NASH). The true prevalence of NASH is uncertain (3 percent to 5 percent of adults may have it), but over time, end-stage liver disease (cirrhosis) is estimated to develop in as many as one-third of patients with NASH. Unfortunately, NASH usually is a silent problem, presenting few symptoms or laboratory findings.
Fifty-five subjects with “pre-diabetes” (impaired glucose tolerance) or Type 2 diabetes agreed to participate. After excluding other causes for liver disease, the diagnosis of NASH was confirmed by liver biopsy following standard clinical indications. Researchers performed baseline imaging (magnetic resonance spectroscopy at the Health Science Center’s Research Imaging Center), as well as in-depth metabolic studies and whole-body fat determination by dual energy X-ray absorptiometry at the Frederic C. Bartter General Clinical Research Center, a National Institutes of Health-supported program of the Health Science Center and the South Texas Veterans Health Care System.
The X-ray technique determined the extent of abdominal and liver fat in each patient. The metabolic studies measured several blood hormones linked to fatty liver disease and evaluated the capacity of liver and muscles to utilize glucose (sugar) following oral glucose administration.
Once the baseline measurements were completed, patients were randomly assigned to a low-calorie diet plus pioglitazone or a low-calorie diet plus an inactive placebo. They returned for follow-up visits every two weeks for six months to ensure compliance with medication and assess their well-being. After six months, all the baseline studies were repeated.
Compared to diet and placebo, diet and pioglitazone improved glucose and lipid levels, and the way the liver and muscles used glucose following oral glucose administration. Diet plus pioglitazone restored to normal the elevated liver enzymes characteristic of patients with NASH. (These enzymes, formally known as transaminases, are a crude indicator of liver inflammation.) Liver images revealed that hepatic fat decreased by more than 50 percent. When the liver biopsies were repeated at six months, pioglitazone compared to placebo markedly reduced hepatic fat content, inflammation and the number of liver cells showing signs of dying. Scarring of the liver (technically known as fibrosis) improved within the pioglitazone-treated patients, but fell short of achieving a statistically significant improvement versus placebo. In summary, pioglitazone improved metabolic and histologic (liver biopsy) abnormalities of patients with NASH.
This clinical trial was an investigator-initiated study funded by the Frederic C. Bartter General Clinical Research Center, in collaboration with the Veterans Administration (VA) Merit Fund and the Health Science Center’s Research Imaging Center. Actos® (pioglitazone) is made by Takeda Pharmaceuticals, and is approved for the treatment of Type 2 diabetes, but not for the treatment of NASH. Takeda Pharmaceuticals North America provided study medication and placebo tablets as well as additional funds.
Gastroenterology expertise and patient recruitment came from Steven Harrison, M.D., of Brooke Army Medical Center and Steven Schenker, M.D., and Ken Brown, M.D., of the Health Science Center, with approximately half the patients being recruited from each center. Volunteers were referred to the Diabetes Division at the Health Science Center where Renata Belfort, M.D., and Bogdan Balas, M.D., (both research fellows) and Kenneth Cusi, M.D. (principal investigator) evaluated them, and performed all of the metabolic studies, follow-ups and data analysis. Fermin Tio, M.D., of the Health Science Center, and Joseph Pulcini, M.D., of Brooke Army Medical Center, conducted blinded reviews of the liver biopsies. Jean Hardies, Ph.D., and colleagues from the Research Imaging Center conducted the magnetic resonance spectroscopy. Dietary instruction was done by research dietician Celia Darland, R.D., at the Bartter Center.
# # #
The University of Texas Health Science Center at San Antonio is the leading research institution in South Texas and one of the major health sciences universities in the world. With an operating budget of $500 million, the Health Science Center is the chief catalyst for the $14 billion biosciences and health care industry, the leading sector in San Antonio’s economy. The Health Science Center has had an estimated $34 billion impact on the region since inception and has expanded to six campuses in San Antonio, Laredo, Harlingen and Edinburg. More than 22,000 graduates (physicians, dentists, nurses, scientists and allied health professionals) serve in their fields, including many in Texas. Our faculty are international leaders in cancer, cardiovascular disease, diabetes, aging, stroke, kidney disease, orthopaedics, research imaging, transplant surgery, psychiatry and clinical neurosciences, pain management, genetics, nursing, allied health, dentistry and many other fields. For more information, visit www.uthscsa.edu.