Using fenofibrate to lower blood fats in people with type 2 diabetes reduces the risk of a first diabetes-related amputation by 36 percent, according to the FIELD study, published in the May 22 diabetes special issue of the Lancet.
Fenofibrate is sold under the brand name Tricor and Trilipix by Abbott Laboratories in Abbott Park, Ill., Lofibra by Teva Pharmaceutical Industries in Tikva, Israel, Lipanthyl by Solvay Pharmaceuticals in Weesp, Netherlands and Fenocor-67 by Ordain Health Care in Tamil Nadu, India.
Anthony Keech, PhD, and Kushwin Rajamani, MD, from the National Health and Medical Research Council Clinical Trials Centre at the University of Sydney in Australia, and colleagues, analyzed 9,795 diabetic patients aged 50-75 that took part in the randomized, controlled FIELD trial. Patients received either fenofibrate 200mg per day (4,895) or placebo (4,900) for five years. Information on amputation--a pre-specified tertiary endpoint of the trial--was routinely gathered.
Amputations were deemed minor if below the ankle and major if above the ankle. They were also classified based on whether or not large-vessel disease was present in the limb, to distinguish amputations related to large-artery atherosclerosis from those related to diabetic microvascular disease.
The researchers found that 115 patients had lower-limb amputations due to diabetes. Previous cardiovascular disease, microvascular disease, previous non-traumatic amputation or skin ulcer, smoking and longer duration of diabetes were more frequent in patients who had amputations during the trial than in those who had other cardiovascular (CV) events, or in those who had neither CV events nor amputations.
The risk of first amputation was 36 percent lower for all patients given fenofibrate compared with placebo; the risk of minor amputations without known large vessel disease was 47 percent lower for the fenofibrate group, according to the researchers. Risk of major amputations did not differ significantly between the two groups. Furthermore, the authors identified height as a major predictor of amputations, with a 1.6 fold increase in amputation risk for every increase of 10cm in height.
"An amputation due to diabetes occurs around every 30 seconds somewhere in the world," the authors wrote. Amputations substantially impair quality of life and impose a major burden on healthcare systems, with annual costs in the U.K. estimated at about £252 million ($350 million U.S.). "Most of this expenditure is related to type 2 diabetes, with less than 10 percent accounted for by type 1 diabetes. Indirect costs would further increase these figures substantially," they wrote.
"Classic markers of macrovascular and microvascular risk were associated with lower extremity amputations in patients with type 2 diabetes. Treatment with fenofibrate was associated with a lower risk of amputations, particularly minor amputations without known large-vessel disease," the authors concluded. "These findings could lead to a change in standard treatment for the prevention of diabetes-related lower-limb amputations... [The results] showed a reduction in amputation rates that seemed to emerge after just 1.5 years of fenofibrate use."
Keech added that the "risk of having an amputation is a real threat for diabetes patients, even when their blood glucose and blood pressure are kept under control, and the risk is dramatically greater for those who have already had skin ulcer or amputation. Fenofibrate treatment appears to substantially reduce this risk."
In an accompanying editorial, Sergio Fazio, MD, and MacRae F. Linton, MD, from Vanderbilt University Medical Center in Nashville, Tenn., said that "we should marvel at the unexpectedly large effects of treatment with a fibrate on both diabetic retinopathy and amputations." They added that, as development and care of skin ulcers are formidable predictors of future amputations, "one has to wonder whether some of the effects of fenofibrate can be attributed to improvement in wound healing."
"This effect--more so than anti-inflammatory, antioxidant, or endothelium-mediated effects--would set apart fibrates from the many agents (statins, anti-hypertensives, aspirin and vitamin E) that have so far been unable to reduce amputations in people with diabetes," Fazio and Linton wrote.