Fenofibrate May Lower Risk for First Type 2 Diabetes-Related Amputation

Laurie Barclay, MD

May 26, 2009

May 26, 2009 — Use of fenofibrate to lower blood fats in people with type 2 diabetes may lower the risk for a first diabetes-related amputation, according to the results of a study reported in the May 23 issue of The Lancet.

"Amputations in people with type 2 diabetes mellitus substantially impair their quality of life and impose high costs on health-care systems," write Kushwin Rajamani, MBBCh, from the University of Sydney in Sydney, Australia, and colleagues from the Fenofibrate Intervention and Event Lowering in Diabetes study. "Our aim was to assess the effect of fenofibrate on amputation events in a large cohort of patients with type 2 diabetes."

With use of computer-generated randomization, 9795 patients aged 50 to 75 years with type 2 diabetes were randomly assigned to receive fenofibrate 200 mg per day (n = 4895) or matching placebo (n = 4900) for 5 years. A prespecified, tertiary endpoint of the study was nontraumatic amputation, about which information was gathered routinely.

Amputations were characterized as minor (below the ankle) or major (above the ankle) by clinicians who were blinded to treatment assignment. To differentiate amputations caused by large-artery atherosclerosis from those mostly related to microvascular disease, clinicians also classified amputations according to the presence or absence of large-vessel disease.

The intent-to-treat population included all 9795 patients, of whom 115 patients had at least 1 nontraumatic, diabetes-related lower-limb amputation. Compared with patients who had other cardiovascular events or those who had no cardiovascular events, those who had amputations during the trial had higher rates of previous cardiovascular disease, microvascular disease, previous nontraumatic amputation or skin ulcer, and smoking, as well as longer duration of diabetes (all P < .001 for 3-way comparison).

Differences in mean lipid concentrations between patients who had limb amputations during the study and those who had other cardiovascular events or neither event did not exceed 0.2 mmol/L. Compared with patients receiving placebo, those receiving fenofibrate had lower risks for first amputation (45 vs 70 events; hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.44 - 0.94; = .02) and for minor amputations without known large-vessel disease (18 vs 34 events; HR, 0·53; 95% CI, 0·30 - 0·94; P = .027). However, the risk for major amputations was not significantly different between groups (24 vs 26 events; HR, 0.93; 95% CI, 0·53 - 1·62; P = .79).

"Classic markers of macrovascular and microvascular risk were associated with lower extremity amputations in patients with type 2 diabetes," the study authors write. "Treatment with fenofibrate was associated with a lower risk of amputations, particularly minor amputations without known large-vessel disease, probably through non-lipid mechanisms. These findings could lead to a change in standard treatment for the prevention of diabetes-related lower-limb amputations."

Limitations of this study include lack of standardized routine testing, such as angiography or ankle-brachial index, at baseline.

"These findings support the use of fenofibrate, irrespective of the presence of dyslipidaemia, for the treatment of patients with type 2 diabetes who are at high risk for amputation (including those with peripheral vascular disease, existing microvascular complications, and a long duration of diabetes)," the study authors conclude. "This approach could help to reduce the substantial morbidity, mortality, and economic burden associated with amputation due to diabetes."

In an accompanying comment, Sergio Fazio and MacRae F. Linton from Vanderbilt University Medical Center in Nashville, Tennessee, suggest that some of the benefits of fenofibrate may relate to improved wound healing.

"Fibrates have been shown to induce keratinocyte differentiation and improve the epidermal barrier in vivo," Drs. Fazio and Linton write. "This effect — more so than anti-inflammatory, antioxidant, or endothelium-mediated effects — would set fibrates apart from the many agents (statins, antihypertensives, aspirin, and vitamin E) that have so far been unable to reduce amputations in people with diabetes."

Funding Laboratoires Fournier SA (now part of Solvay Pharmaceuticals) and National Health and Medical Research Council of Australia supported this study. Some of the study authors have disclosed various financial relationships with Eli Lilly, Novo Nordisk, GlaxoSmithKline, sanofi-aventis, BayHill, Medtronic, AstraZeneca, Merck Sharp & Dohme, Bristol-Myers Squibb, Pfizer, Novartis, Fournier, Takeda, Solvay, Abbott, Roche Diagnostics, and Medicines Australia. One study author has been named in a patent application related to fenofibrate and diabetic retinopathy.

Dr. Fazio has received honoraria for lectures from Merck, Schering-Plough, GlaxoSmithKline, and Abbott. Dr. Linton has received honoraria for lectures from Merck, Schering-Plough, AstraZeneca, and Abbott. Both editorialists have received support for clinical trials from Merck Schering-Plough, ISIS, Genzyme, and AstraZeneca.

Lancet. 2009;373:1740-1741, 1780-1788.

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