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."
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