CHICAGO — Lipid-lowering therapy was associated with a significant reduction in the risk of developing peripheral sensory neuropathy in a large Australian observational investigation involving adults with type 2 diabetes mellitus.
Peripheral neuropathy, the most common form of nerve damage caused by diabetes, affects roughly half of those with the disease.
Animal studies have shown that both statins and fibrates may protect against nerve damage, but clinical studies have also linked their use with reversible clinical neuropathy.
The study produced no evidence that use of either statins or fibrates increased the risk of developing neuropathy or amputations, principal investigator Dr. Timothy Davis said at the annual scientific sessions of the American Diabetes Association.
He suggested that previous reports may have been coincidental, in that the individuals were developing neuropathy anyway, or that there may be a small number of patients who were sensitive to the drug.
“Statins and fibrates are relatively safe, but still have a side-effect profile that needs to be respected,” he said. However, statins are typically a first-line drug because of strong evidence of their cardiovascular disease prevention benefits.
The ADA recommends statins for individuals with diabetes aged 40 years and older with a total cholesterol level greater than 135 mg/dL and no overt cardiovascular disease; for those younger than age 40 years with no overt cardiovascular disease, but at increased risk; and for any patient with diabetes and overt cardiovascular disease.
Dr. Davis and colleagues at the University of Western Australia in Fremantle used the Michigan Neuropathy Screening Instrument to determine the prevalence and incidence of peripheral neuropathy in two populations. The first was a cross-sectional sample of 1,294 patients with type 2 diabetes recruited to the Fremantle Diabetes Study between 1993 and 1996.
At admission, fibrates and statins were used by 3.5% and 6.8% of patients, respectively. Gemfibrozil was the fibrate used, and the statins in use were atorvastatin, simvastatin, and pravastatin.
Patients' mean age was 64 years, 49% were male, and 31% had peripheral neuropathy. The median diabetes duration was 4 years.
In multiple logistic regression analysis, older age, longer diabetes duration, central adiposity, increasing height, higher fasting plasma glucose levels, higher systolic blood pressure, higher urinary albumin-to-creatinine ratios, and indigenous racial background were all independently associated with prevalent peripheral neuropathy.
Fibrate use was associated with a 70% reduction in neuropathy, but the use of statins was not associated with a significant reduction in neuropathy, Dr. Davis said.
The investigators then evaluated a longitudinal subgroup of 531 people who had undergone six comprehensive annual health assessments by November 2001. Fibrate and statin use increased to 10.4% and 36.5% during the 5 years of follow-up. Gemfibrozil continued to be the primary fibrate used, although some patients had begun to use fenofibrate. Atorvastatin was the predominant statin. In all, 26% of patients had peripheral neuropathy at baseline.
In a Cox proportional analysis that controlled for a variety of confounding variables, including changes in hemoglobin A1c levels, fibrates and statins reduced the risk of developing neuropathy by 48% and 35%, respectively.
Analysis of the data also indicated that the beneficial effects of the lipid-lowering drugs were independent of each other and may work through different mechanisms.
“It's possible, because of the independent effect of these drugs, that combination therapy with these drugs could have an additive effect,” Dr. Davis said.
During a press briefing at the meeting, Dr. Aaron I. Vinik, director of the Diabetes Research Institute at Eastern Virginia Medical School, Norfolk, said the data “may change the way clinicians look at neuropathy in the future, and may even change the way we think about treating neuropathy.” The only two drugs approved in the United States for the treatment of neuropathy are for pain relief, and neither addresses the underlying pathogenic disorder of the condition, he said.
Dr. Paul Jellinger, past president of American Association of Clinical Endocrinologists, called the data intriguing, but emphasized that whereas lipid-lowering drugs may prevent the occurrence of neuropathy, they do not reverse it.
If lipid-lowering drugs are to be used for neuropathy prevention, they would have to be introduced early in the disease process, he said.
“To me, the message here is to confirm this evidence with prospective trials, and, if confirmed, to use this as an additional mandate to diagnose impaired glucose tolerance earlier and to consider applying statin or fibrate therapy independent of their lipid levels,” said Dr. Jellinger, who is in private practice in Hollywood, Fla.