Predictors of peripheral neuropathy and effects of fenofibrate among 9,795 subjects with type 2 diabetes: the fenofibrate intervention and event lowering in diabetes (FIELD) study
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Authors: Keech,A. C.;Rajamani,J. K.;Best,J. D.;Hankey,G.;Donoghoe,M. W.;Li,L.;Jenkins,A. J.;Ting,R.;Davis,T. M. E.;Phillips,P.;Barter,P.
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Background and aims: Peripheral neuropathy, a significant microvascular complication of diabetes, leads to impaired quality of life, and lower limb ulcer formation and amputation. The aim of this analysis was to explore characteristics associated with neuropathy and the effects on it of long-term treatment with the lipid-modifying drug, fenofibrate. Materials and methods: 9,795 patients with type 2 diabetes mellitus were randomised to co-micronised fenofibrate 200 mg/day or matching placebo for 5 years. The presence of neuropathy symptoms was recorded at baseline and sensation tested using a standard 10-G monofilament, repeated at 2 years and study close. All non-traumatic lower limb amputations were recorded, and classified as major or minor. Risk models used exhaustive search methods in logistic regression.
Results: 17.2% (1689 of 9795) of participants had features of peripheral neuropathy at baseline (1125 had symptoms without abnormal monofilament; 564 had abnormal monofilament). Factors associated with onset of new neuropathy included age, diabetes duration, high HbA1c, prior retinopathy, hypertriglyceridaemia, history of CVD, and height (all p<0.03). The prevalence of an abnormal monofilament test at study close was significantly lower among those allocated to receive fenofibrate than placebo (6.9% versus 8.2%; RR 0.81 [95%CI 0.72-0.93, p=0.002 adjusted for baseline, with significantly less new neuropathy with fenofibrate treatment, and significant reversal of baseline monofilament abnormality with treatment (RR=1.28, [95% CI 1.06- 1.55], p=0.01). Neuropathy was one of the strongest predictors of amputation, increasing the risk of a first amputation approximately sixteen-fold for those with both symptoms and an abnormal monofilament test at baseline (P<0.001) in whom the number needed to treat (NNT) over 5 years to avoid a first on-study amputation with fenofibrate treatment was only 16.
Conclusion: Treatment with fenofibrate reduced overall monofilament abnormality as a marker of neuropathy and increased the reversal of pre-existing monofilament abnormality in type 2 diabetes, although the mechanisms remain unknown. These benefits could potentially explain the large 37% reduction seen in amputations with fenofibrate use in the FIELD study.