Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial

Abstract

SummaryBackgroundAmputations in people with type 2 diabetes mellitus substantially impair their quality of life and impose high costs on health-care systems. Our aim was to assess the effect of fenofibrate on amputation events in a large cohort of patients with type 2 diabetes.MethodsIn the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, 9795 patients aged 50–75 years with type 2 diabetes were randomly assigned by computer-generated randomisation sequence to receive fenofibrate 200 mg per day (n=4895) or matching placebo (n=4900) for 5 years' duration. Information about non-traumatic amputation—a prespecified tertiary endpoint of the study—was routinely gathered. Clinicians who were masked to treatment allocation adjudicated amputations as minor or major (below or above the ankle, respectively). Amputations were also classified on the basis of whether or not large-vessel disease was present in the limb, to distinguish those related to large-artery atherosclerosis from those predominantly related to microvascular disease. Analysis was by intention to treat (ITT). The FIELD study is registered as an International Standard Randomised Controlled Trial, number ISRCTN64783481.FindingsAll 9795 patients were included in the ITT population. 115 patients had one or more non-traumatic 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 events or in those who had neither event (all p<0·001 for three-way comparison). Mean lipid concentrations differed between patients who had on-study amputations and those who had other cardiovascular events or neither event, but by no more than 0·2 mmol/L. The risks of first amputation (45 vs 70 events; hazard ratio [HR] 0·64, 95% CI 0·44–0·94; p=0·02) and minor amputation events without known large-vessel disease (18 vs 34 events; 0·53, 0·30–0·94; p=0·027) were lower for patients assigned to fenofibrate than for patients assigned to placebo, with no difference between groups in risk of major amputations (24 vs 26 events; 0·93, 0·53–1·62; p=0·79).InterpretationClassic 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, probably through non-lipid mechanisms. These findings could lead to a change in standard treatment for the prevention of diabetes-related lower-limb amputations.FundingLaboratoires Fournier SA (now part of Solvay Pharmaceuticals) and National Health and Medical Research Council of Australia.

Relationship of fibroblast growth factor 21 with baseline and new on-study microvascular disease in the Fenofibrate Intervention and Event Lowering in Diabetes study

“…nephropathy, retinopathy, neuropathy and microvascular amputation). Information on microvascular diseases in the FIELD study has been given elsewhere [9][10][11]18].…”

“…All amputations that had occurred during the study follow-up (on-study amputations) were adjudicated by two clinicians (separately masked to treatment allocation) and any discrepancies were resolved by mutual agreement [11]. Pre-study amputations were adjudicated in the same fashion [11].…”

“…All amputations that had occurred during the study follow-up (on-study amputations) were adjudicated by two clinicians (separately masked to treatment allocation) and any discrepancies were resolved by mutual agreement [11]. Pre-study amputations were adjudicated in the same fashion [11]. In the present study, we only included amputations of digits and forefoot without previous or concurrent large-vessel disease (including angioplasty and bypass surgery) in the same limb or evidence of causative embolism.…”

“…In the present study, we only included amputations of digits and forefoot without previous or concurrent large-vessel disease (including angioplasty and bypass surgery) in the same limb or evidence of causative embolism. These amputations were classified as minor amputations without known large-vessel disease and were judged to be related to microvascular disease [11].…”

“…In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, fenofibrate treatment has been demonstrated to reduce the risk of total cardiovascular disease (CVD) events as well as the risks of albuminuria, laser treatment for diabetic retinopathy and amputation in patients with type 2 diabetes over a follow-up period of 5 years [9][10][11]. Recently, we have reported that higher FGF21 levels at baseline predict a higher risk of total cardiovascular disease (CVD) events in patients with type 2 diabetes taking part in the FIELD study [12].…”