Lipid-Lowering Drugs Protect Against Peripheral Diabetic Neuropathy

A major epidemiological study conducted over eight years in Australia has shown that two classes of lipid- lowering drugs -- statins and fibrates -- significantly lower the risk of developing nerve damage known as peripheral sensory diabetic neuropathy, according to a report presented today at the American Diabetes Association's 67th Annual Scientific Sessions.

"Statins and fibrates, drugs already highly recommended for people with type 2 diabetes to help prevent heart attacks, now also appear to help prevent one form of diabetic nerve damage called 'peripheral neuropathy,' a common complication of diabetes," said Timothy Davis, MD, PhD, Professor of Medicine, at the University of Western Australia, and principal investigator of the study, in a recent interview. "Statins or fibrates reduced the risk of developing peripheral neuropathy by 35% or 48%, respectively, although these should be considered comparable risk reductions because of the wide confidence intervals." A correct estimate falls into a statistical range called a confidence interval, and the range in this instance means that the two estimates are indistinguishable, statistically speaking.

Peripheral neuropathy is the most common form of nerve damage caused by diabetes, affecting approximately 50% of those with diabetes. Damaged nerves can cause stinging or burning sensations, tingling, pain, numbness or weakness in the hands and feet. Although many medications have been used to treat the condition's symptoms, many fail, and preventing the condition by means other than controlling blood glucose levels, has also proven difficult. The project was essentially two studies in one: a large cross-sectional snapshot and a longitudinal five-year study of a subsection of the larger group.

Nearly 21 million Americans have diabetes, a group of serious diseases characterized by high blood glucose levels that result from defects in the body's ability to produce and/or use insulin. Diabetes can lead to severely debilitating or fatal complications, such as heart disease, blindness, kidney disease, nerve damage, and amputations. It is the fifth leading cause of death by disease in the U.S.

All of the study participants had type 2 diabetes, which involves insulin resistance -- the body's inability to properly use its own insulin. Type 2 used to occur mainly in adults who were overweight and ages 40 and older. Now, as more children and adolescents become overweight and inactive, type 2 diabetes is occurring more often in young people.

METHODOLOGY AND FINDINGS

The researchers assessed the relationship between lipid-lowering therapy and the prevalence and incidence of peripheral neuropathy, based on scoring on the Michigan Neuropathy Screening Instrument -- one of the most sensitive and specific tools for screening for the condition -- in a large representative cohort of adults. Prevalence measures how much of a disease or condition there is in a population at a particular point in time. Incidence measures the rate of occurrence of new cases of a disease or condition.

The cross-sectional sample was comprised of all 1,294 of those recruited to the Fremantle Diabetes Study between 1993 and 1996.

At their entrance into the study, the participants average age was 64 years, with their diabetes diagnosed four years previously, 48.8% were male, and 30.9% had neuropathy. Fibrates and statins were used by 3.5% and 6.8%, respectively.

Older age, longer diabetes duration, central adiposity, increasing height, higher fasting plasma glucose, higher systolic blood pressure, higher urinary albumin to creatinine ratios, and indigenous racial background were all independently associated with prevalent peripheral neuropathy at baseline, while use of fibrates was associated with a 70% reduction in neuropathy prevalence.

The longitudinal sub-group was comprised of 531 people who had attended six comprehensive annual health assessments by November 2001. Use of fibrates and statins increased to 10.4% and 36.5%, respectively, during the five years of follow-up. The results were controlled for potential confounding variables, including changes in A1C levels, a measure of long-term blood glucose control.

Time to development of newly diagnosed peripheral neuropathy in the longitudinal sub-group showed that fibrates and statins reduced neuropathy risk by 48% and 35% respectively. Further, they may have independent action. "In our analysis, the beneficial effects of the drugs were independent of each other and they may work through different mechanisms," said Dr. Davis. "It's just a hypothesis, but taking both drugs may yield greater benefit than taking either drug alone."

At the outset, in the cross-sectional study, the fibrate participants were using gemfibrozil, and the statins in use were atorvastatin, simvastatin and pravastatin. At the end of the longitudinal study, gemfibrozil continued to be the primary fibrate used, although some had begun to use fenofibrate. By then atorvastatin was the predominant statin, although simvastatin and pravastatin also continued to be in use.

"We believe these benefits are class effects of these drugs," said Dr. Davis. While many mechanisms have been proposed, their mechanism of action in neuropathy remains unknown. The leading theory for statins seems to be a reduction of both inflammation and oxidative stress.

RECOMMENDATIONS

Although laboratory and animal studies have provided evidence that both statins and fibrates may protect against nerve damage, anecdotal clinical reports have associated their use with a reversible clinical neuropathy. In light of the new findings, Dr. Davis suggested that such reports may have been coincidence -- the individuals were developing neuropathy anyway -- or perhaps that there may be a small number of people who were sensitive to the drug but, he emphasized, with greater numbers who may benefit from taking it.

"People with diabetes should not shy away from taking these drugs for both heart and neuropathy benefits," he said. "Whether a fibrate or statin should be taken is never an easy choice, but a statin is usually the first line drug because of the strong evidence of cardiovascular disease prevention benefits."

Co-authors with Dr. Davis were Bu Yeap, MD, PhD, David G. Bruce, MD, PhD, and Wendy A. Davis, PhD, all of the University of Western Australia.

The American Diabetes Association is the nation's leading voluntary health organization supporting diabetes research, information and advocacy. Founded in 1940, the Association has offices in every region of the country, providing services to hundreds of communities.

American Diabetes Association
http://www.diabetes.org

Treatment shows promise against diabetes

Tuesday, April 10, 2007 · Last updated 1:00 p.m. PT
By LINDSEY TANNER
AP MEDICAL WRITER

CHICAGO -- Thirteen young diabetics in Brazil have ditched their insulin shots and need no other medication thanks to a risky, but promising treatment with their own stem cells - apparently the first time such a feat has been accomplished.

Though too early to call it a cure, the procedure has enabled the young people, who have Type I diabetes, to live insulin-free so far, some as long as three years. The treatment involves stem cell transplants from the patients' own blood.

"It's the first time in the history of Type 1 diabetes where people have gone with no treatment whatsoever ... no medications at all, with normal blood sugars," said study co-author Dr. Richard Burt of Northwestern University's medical school in Chicago.

While the procedure can be potentially life-threatening, none of the 15 patients in the study died or suffered lasting side effects. But it didn't work for two of them.

Larger, more rigorous studies are needed to determine if stem cell transplants could become standard treatment for people with the disease once called juvenile diabetes. It is less common than Type 2 diabetes, which is associated with obesity.

The hazards of stem cell transplantation also raise questions about whether the study should have included children. One patient was as young as 14.

Dr. Lainie Ross, a medical ethicist at the University of Chicago, said the researchers should have studied adults first before exposing young teens to the potential harms of stem cell transplant, which include infertility and late-onset cancers.

In addition, Ross said that the study should have had a comparison group to make sure the treatment was indeed better than standard diabetes care.



Burt, who wrote the study protocol, said the research was done in Brazil because U.S. doctors were not interested in the approach. The study was approved by ethics committees in Brazil, he said, adding that he personally believes it was appropriate to do the research in children as well as adults, as long as the Brazilian ethics panels approved.
Burt and other diabetes experts called the results an important step forward.

"It's the threshold of a very promising time for the field," said Dr. Jay Skyler of the Diabetes Research Institute at the University of Miami.

Skyler wrote an editorial in the Journal of the American Medical Association, which published the study, saying the results are likely to stimulate research that may lead to methods of preventing or reversing Type I diabetes.

"These are exciting results. They look impressive," said Dr. Gordon Weir of Joslin Diabetes Center in Boston.

Still, Weir cautioned that more studies are needed to make sure the treatment works and is safe. "It's really too early to suggest to people that this is a cure," he said.

The patients involved were ages 14 to 31 and newly diagnosed with Type 1 diabetes. An estimated 12 million to 24 million people worldwide - including 1 to 2 million in the United States - have this form of diabetes, which is typically diagnosed in children or young adults. An autoimmune disease, it occurs when the body attacks insulin-producing cells in the pancreas.

Insulin is needed to regulate blood sugar levels, which when too high, can lead to heart disease, blindness, nerve problems and kidney damage.

Burt said the stem cell transplant is designed to stop the body's immune attack on the pancreas.

A study published last year described a different kind of experimental transplant, using pancreas cells from donated cadavers, that enabled a few diabetics to give up insulin shots. But that requires lifelong use of anti-rejection medicine, which isn't needed by the Brazil patients since the stem cells were their own.

The 15 diabetics were treated at a bone marrow center at the University of Sao Paulo.

All were newly diagnosed, before their insulin-producing cells had been destroyed.

That timing is key, Burt said. "If you wait too long," he said, "you've exceeded the body's ability to repair itself."

The procedure involves stimulating the body to produce new stem cells and harvesting them from the patient's blood. Next comes several days of high-dose chemotherapy, which virtually shuts down the patient's immune system and stops destruction of the few remaining insulin-producing cells in the body. This requires hospitalization and potent drugs to fend off infection. The harvested stem cells, when injected back into the body, build a new healthier immune system that does not attack the insulin-producing cells.

Patients were hospitalized for about three weeks. Many had side effects including nausea, vomiting and hair loss. One developed pneumonia, the only severe complication.

Doctors changed the drug regimen after the treatment failed in the first patient, who ended up needing more insulin than before the study. Another patient also relapsed.

The remaining 13 "live a normal life without taking insulin," said study co-author Dr. Julio Voltarelli of the University of Sao Paulo. "They all went back to their lives."

The patients enrolled in the study at different times so the length of time they've been insulin-free also differs.

Burt has had some success using the same procedure in 170 patients with other autoimmune diseases, including lupus and multiple sclerosis; one patient with an autoimmune form of blindness can now see, Burt said.

"The body has tremendous potential to repair," he said.

The study was partly funded by the Brazilian Ministry of Health, Genzyme Corp. and a maker of blood sugar monitoring products.

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AP reporter Carla K. Johnson in Chicago contributed to this report.

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On the Net:

JAMA: http://jama.ama-assn.org

Juvenile Diabetes Research Foundation: http://www.jdrf.org