R3i Editorial

Microvascular and macrovascular diseases related to diabetes contribute to its morbidity and mortality burden and have a substantial impact on quality of life. Guidelines for the management of type 2 diabetes consider intensive control of cardiometabolic risk factors as central to therapeutic management.(1)

As shown by the Steno-2 study, the benefits of an intensive multifactorial approach – lifestyle intervention, tight blood glucose control, use of renin-angiotensin system blockers, aspirin and statins – are remarkable over the long-term period.(2)

Nevertheless, neither control of glycemia or blood pressure nor lowering of cholesterol, as observed in many statin trials, has prevented the risk of lower-limb amputation, underscoring the importance of any further therapeutic option available to prevent the morbidity and mortality associated with amputations in patients with type 2 diabetes.

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial was designed to measure the effects of fenofibrate versus placebo on clinical macro- and microvascular outcomes in patients with type 2 diabetes. The investigators included laser treatment for diabetic retinopathy, progression and regression of microalbuminuria, and rates of non-traumatic amputations as tertiary outcome measures. Results related to these tertiary outcomes are turning out to be of great scientific interest and of potentially wider clinical relevance than are those for the macrovascular targets. Among the 9795 patients included in the original FIELD population, 115 had one or more non-traumatic lower-limb amputations due to diabetes. A recent report from the FIELD investigators shows a marked beneficial effect of treatment with fenofibrate on the rate of amputations during the 5-year study.(3)

The study confirmed that many factors are associated with risk of foot amputation – the strongest of which being previous amputation and diabetic skin ulcer – whereas they noted only a small association with baseline lipid concentrations. The positive effect of fenofibrate was entirely due to a 46% reduction (p=0.007) in so-called “minor” amputations, defined as below the ankle and without evidence of macrovascular disease in the ipsilateral leg (as judged by negative angiogram or ultrasound data, and no history of arterial embolism). No significant effect (9% reduction; p= 0.37) was reported for either minor or major amputations attributed to atherosclerosis. The reduction in amputation rates seemed to emerge after just 1.5 years of fenofibrate use. The number of patients needed to treat (NNT) with fenofibrate over 5 years to prevent at least one amputation in one patient was 197, but only 25 for those with previous foot ulcer and albuminuria. These results should be considered in the context of the comprehensive benefit of fenofibrate therapy on microvascular complication (reduction by 31% of the need for laser therapy for retinopathy, by 15% of progression of albumin excretion rate) observed in FIELD: the NNTs with fenofibrate were 17 and 90 to prevent laser treatment for retinopathy in patients with and without a history of retinopathy respectively,(4) and 68 to prevent progression of albuminuria.(5)

It has been suggested that some of the benefit of fenofibrate on amputation could be attributed to improvement in wound healing, supported by evidence of the effects of fibrates on keratinocyte differentiation and the epidermal barrier, while inhibition of oxidative stress, prevention of endothelial cell migration in the retina and reduction in local inflammation appear to be more relevant when considering the effect of fenofibrate on diabetic retinopathy.(6)

These recent findings support the use of fenofibrate, irrespective of the presence of dyslipidemia, for the treatment of patients with type 2 diabetes who are at high risk for amputation.

References

1. American Diabetes Association. Standards of medical care in diabetes–2008.