Using fenofibrate to lower blood fats in people with type 2 diabetes reduces the risk of a first diabetes-related amputation by 36%. This is among the conclusions of the FIELD study, reported in an Article in this week's diabetes special issue of The Lancet.
Professor Anthony Keech and Dr Kushwin Rajamani, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Australia, and colleagues, analysed the 9795 diabetic patients aged 50-75 that took part in the FIELD study — a randomised controlled trial. Patients received either fenofibrate 200mg day (4895) or placebo (4900) for 5 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 or amputations. The risk of first amputation was 36% lower for all patients given fenofibrate compared with placebo; the risk of minor amputations without known large vessel disease was 47% lower for the fenofibrate group. 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.
The authors say: "An amputation due to diabetes occurs around every 30 seconds somewhere in the world. Amputations substantially impair quality of life and impose a major burden on health-care systems, with annual costs in the UK estimated at about £252 million and in the USA at about US$1648 million. Most of this expenditure is related to type 2 diabetes, with less than 10% accounted for by type 1 diabetes. Indirect costs would further increase these figures substantially."
They conclude: "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... 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."
Professor Keech adds*: "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 Comment, Dr Sergio Fazio and Dr MacRae F Linton, Vanderbilt University Medical Center, Nashville, TN, USA, say that 'we should marvel at the unexpectedly large effects of treatment with a fibrate on both diabetic retinopathy and amputations'. They add 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'.
They conclude: "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."
Professor Anthony Keech, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Australia (currently in Europe) T) +61 414 625004 E) Tony@ctc.usyd.edu.au
Dr Kushwin Rajamani, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Australia T) +61 2-9562-5317 kushwin@yahoo.com
Dr Sergio Fazio, Vanderbilt University Medical Center, Nashville, TN, USA T) +1 615 936 1450 E) Sergio.fazio@vanderbilt.edu
For full Article and Comment, see: http://press.thelancet.com/fenofibrate.pdf
Note to editors: *Quote directly from Professor Keech which is not found in text of the Article
Journal
The Lancet