Diabetes drugs attack another disease of obesity
Several years ago, Carlos Herrera Macias, 55, learned that he had type 2 diabetes. He already knew about that obesity-related disease—his mother had had it too. But his doctors soon delivered a second diagnosis that was unfamiliar to Macias. "They told me that something was wrong with my liver," he recalls.
Macias has fatty liver disease, a condition in which deposits of fat accumulate in the liver and eventually impair the organ's capacity to filter blood. In his case, the problem had progressed to a condition known as nonalcoholic steatohepatitis (NASH), which is characterized by liver inflammation and formation of scar tissue in the organ. People who are obese or who have diabetes are more likely to develop NASH than other people are.
After Macias got his double diagnosis, the 5'8", 210 pounder from Leming, Texas, followed his doctors' recommendation and began trying to lose weight. The former marine also enlisted in a clinical trial that put him on the front lines of a struggle against a growing but largely unrecognized epidemic.
Researchers estimate that among people who aren't alcoholics, fatty liver disease affects 45 to 65 million U.S. adults, and in perhaps 20 percent of those people, the disease has advanced to NASH. Most of these people don't show symptoms of liver problems and don't know that they are at increased risk of liver failure.
NASH especially concerns doctors because it sometimes leads to cirrhosis. Viral hepatitis or alcoholic fatty liver disease, which results from heavy long-term drinking, can also cause cirrhosis, the symptoms of which may include fatigue, weight loss, frequent infections, and esophageal bleeding. Nationwide, cirrhosis kills about 27,000 people per year.
It's not clear how often or how rapidly fatty liver progresses to NASH, or how typical it is for NASH to lead to cirrhosis, but physicians worry about a possible boost in cirrhosis deaths.
"With the epidemic of obesity and the epidemic of diabetes, which promote [fatty liver], in 5 or 10 years, we're going to have a major public health problem," says endocrinologist Kenneth Cusi of the University of Texas Health Science Center in San Antonio. "We're going to have a lot more people with damaged livers."
For now, weight loss is the only useful treatment. There is no specific therapy for NASH, but that might soon change.
Recent drug studies, including the trial in which Macias participated, have suggested a slate of potential therapies. The three leading candidates are already proved treatments for type 2 diabetes.
Macias was one of 55 men and women with NASH who participated in the recent trial of pioglitazone (Actos). Researchers had suspected that pioglitazone and some other diabetes drugs might work against fatty liver because they act as insulin sensitizers. That is, they increase cells' responsiveness to the hormone.
In people with type 2 diabetes, the drugs restore insulin's role in triggering cells to properly metabolize blood sugar. Insulin also promotes the storage of fatty acids in specialized fat cells. If the hormone isn't doing that second job, fatty acids circulate in the blood and can end up in the liver.
"Most people think that insulin resistance is a major factor contributing to fat accumulation in the liver," says endocrinologist Kristina Utzschneider of the University of Washington in Seattle.
In the recent trial of pioglitazone, all the participants had either type 2 diabetes or impaired glucose tolerance, a condition sometimes called prediabetes, but they hadn't been prescribed medication for those conditions. Doctors had unambiguously diagnosed NASH in the participants by using long needles to extract liver samples for biopsy.
For 6 months, Macias and 28 other randomly selected volunteers received 30 to 45 milligrams of pioglitazone per day, which is within the range of doses that doctors use to treat diabetes. The other 26 volunteers got a daily placebo pill instead.
Everyone in the trial also received frequent counseling from a dietitian, who worked with volunteers to reduce their calorie consumption. Those who took the placebo lost 3.2 kilograms on average. But pioglitazone is known to cause weight gain, and the volunteers who took the drug gained an average of 2.5 kg during the study, despite the dietitian's efforts.
At the study's conclusion, liver and blood tests showed that the drug had outperformed the placebo by several measures. For example, biopsies revealed a 54-percent decrease in the livers' fat content in pioglitazone-treated participants, while the comparison group showed no change in liver fat.
"For the first time, we have a pharmacological agent that appears to reduce the amount of fat in the liver and possibly reduce the long-term complications," says Cusi. He and his colleagues reported their findings in the Nov. 30, 2006 New England Journal of Medicine.
Cusi's team obtained one-third of its funding for the study from pioglitazone's manufacturer, Takeda Pharmaceuticals of Deerfield, Ill., and Cusi and one of his colleagues have done work for Eli Lilly and Co. of Indianapolis, which also has rights to make the drug.
"We need to wait for larger, placebo-controlled studies to solidify use of [pioglitazone] as a treatment for NASH," comments Utzschneider.
Pioglitazone is "promising but not ready for prime time," says Arthur McCullough of the Cleveland Clinic and neighboring Case Western Reserve University. More patients must be studied, he says, and "the study period was extremely short for this disease. Future studies need to be at least 1 to 2 years in duration."
"Any therapy shown to be effective [against NASH] will need to be lifelong, making careful assessment of the risk-benefit ratio paramount," McCullough adds.
McCullough, who has financial ties to Takeda, is a principal investigator in a newly begun placebo-controlled trial of pioglitazone. The 2-year study, which aims to include 240 patients, is also testing vitamin E against the disease (see "Weighing All Options," below).
That study is supported by the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md., and conducted by the NASH Clinical Research Network, which includes researchers at eight medical institutions.
Some researchers are considering a related insulin-sensitizing compound called rosiglitazone (Avandia). In a preliminary, manufacturer-funded study published in 2003, liver specialist Brent Tetri of Saint Louis University Hospital and his colleagues found that 48 weeks of rosiglitazone treatment for 25 NASH patients produced improvements in insulin sensitivity and reduced liver fat, inflammation, and fibrosis. Here, too, weight gain was a problem—two-thirds of the volunteers gained weight while taking the drug.
Utzschneider, too, is conducting a trial of rosiglitazone. Her 6-month, placebo-controlled test of 48 people who have NASH will also examine a cholesterol-lowering drug.
Aiming at insulin
Metformin is the most widely used therapy for type 2 diabetes, and the American Diabetes Association recommends it as the first-line treatment for the disease. It's generally less expensive than rosiglitazone and pioglitazone, which scientists classify as peroxisome proliferators–activated receptor (PPAR)-gamma ligands. Those compounds bind to receptors in cell nuclei, altering the activity of metabolism-related genes.
On the other hand, metformin reduces the liver's production of glucose, which in turn lowers insulin production, says gastroenterologist John W. Haukeland of Aker University Hospital in Oslo. Since insulin boosts cell metabolism of sugar and signals the liver to synthesize fat, a drop in insulin production could be therapeutic for fatty liver disease.
Several studies have tested metformin against NASH. In the largest, 55 people took the drug daily for nearly a year, while a similar number of volunteers received either daily vitamin E or dietary counseling. During the study, metformin-treated volunteers experienced the greatest improvements in insulin sensitivity and liver-enzyme concentrations, a group of Italian researchers reported in 2005.
At least some patients who received metformin in that trial also lost liver fat. But that finding is tentative because only 17 volunteers' livers were evaluated by biopsy at the study's end.
Haukeland is conducting a 6-month trial in which he aims to give either metformin or a placebo to 90 people who have fatty liver or NASH and either diabetes or prediabetes. In this trial, all volunteers will undergo liver biopsy at the beginning and end of treatment.
"The metformin studies that I've seen have not been very impressive," says Tetri. "It might have a role in conjunction with rosiglitazone or pioglitazone, just as it does in diabetes."
"No medications have been shown to be clearly effective [against NASH]," Haukeland says. "We have no established therapy, except for weight loss."
But if the trials under way prove that any of the drugs are effective in stopping NASH, he adds, it will be an important coup for preventive medicine.
Weighing All Options
Potential liver treatments abound
An array of potential therapies besides the insulin-sensitizing drugs is being tested against fatty liver disease. They range from surgery to bonus bacteria and include some that have shown promise in people in at least one clinical trial.
- Weight-loss Researchers are evaluating the effect of gastric-bypass surgery on fatty liver disease. That procedure shrinks the stomach and leads to reduced calorie intake and weight loss, which is known to reverse the liver condition. The weight-loss medication orlistat (Xenical), which blocks intestinal fat absorption, has also decreased volunteers' liver fat in pilot trials. However, excessively rapid weight loss that the surgery or orlistat might cause could paradoxically aggravate fatty liver.
- Herbs and spices Chinese and Japanese scientists have collaborated to test several traditional Asian herbal remedies in rats that are predisposed to fatty liver. Last October at a meeting of the American College of Gastroenterology in Las Vegas, researchers led by Hisao Takayama of Tottori University in Japan reported that a diet composed of 6 percent cinnamon by weight decreased the fat in the animals' livers.
- Vitamin Antioxidants Studies suggest they might prevent inflammation and therefore reduce formation of scar tissue in the liver. A 2003 trial of 45 people found that a combination of the antioxidant vitamins E and C reduced liver scar tissue over a 6-month period. Researchers, however, observed no change in inflammation. Now, some volunteers in trials of pioglitazone or metformin are receiving vitamin E in addition to one of the drugs.
- Good fats In a yearlong Italian study of 56 people, liver fat declined in those who each day took a capsule containing 1 gram of polyunsaturated fatty acids. The report appeared in the April 15, 2006 Alimentary Pharmacology & Therapeutics. Animal data from other studies suggest that these healthful fatty acids act as pioglitazone and rosiglitazone do.
- Iron-depletion therapy Doctors conducting a small U.S. study are bleeding patients—although, unlike medieval physicians, they're extracting blood with sterilized needles rather than leeches or lacerations. The rationale behind the study, which is sponsored by the National Institutes of Health in Bethesda, Md., is that removing excess iron from the body by withdrawing blood may improve insulin activity.
- Beneficial bacteria Preliminary studies hint that disturbances in naturally occurring bacteria in the gut may contribute to fatty liver disease. Last year, for example, researchers at Imperial College London and the University of Oxford in England found that unidentified intestinal microbes tend to use up the dietary supply of the nutrient choline in a strain of mice that's susceptible to fatty liver. Choline deficiency has been linked to fatty liver in lab animals, so the bacteria may contribute to that strain's high rates of fatty liver disease. However, researchers at Johns Hopkins University in Baltimore recently conducted a trial that tested a probiotic bacterium—a harmless bug that might control harmful ones—in people who have fatty liver disease. The researchers found no benefit from the bacterial strain that they used.
University of Texas Health Science Center, San Antonio
Diabetes Division, Room 3.380S
7703 Floyd Curl Drive
San Antonio, TX 78229-3900
Imperial College London
Faculty of Medicine
Sir Alexander Fleming Building
South Kensington, London SW7 2AZ
John W. Haukeland
Aker University Hospital
MetroHealth Medical Center
Division of Gastroenterology
2500 MetroHealth Drive
Cleveland, OH 44109-1998
James E. Nelson
Department of Medicine
Division of Gastroenterology
University of Washington Medical Center
1959 N.E. Pacific Street
Seattle, WA 98195
Jeffrey B. Schwimmer
Division of Gastroenterology, Hepatology, and Nutrition
Department of Pediatrics
University of California, San Diego
200 West Arbor Drive, MC 8450
San Diego, CA 92103
Brent A. Tetri
Saint Louis University Hospital
Division of Gastroenterology
3635 Vista Avenue
St. Louis, MO 63110
University of Washington
Seattle VA Puget Sound Health Care System
1660 South Columbian Way
UW Mailbox 358280 (151)
Seattle, WA 98108