Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study

Abstract

Aims/hypothesis Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. We assessed fenofibrate's renal effects overall and in a FIELD washout sub-study. Methods Type 2 diabetic patients (n=9,795) aged 50 to 75 years were randomly assigned to fenofibrate (n=4,895) or placebo (n=4,900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin/creatinine ratio measured at baseline, year 2 and close-out) and estimated GFR, measured four to six monthly according to the Modification of Diet in Renal Disease Study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n=661). Analysis was by intention-to-treat. Results During fenofibrate run-in, plasma creatinine increased by 10.0 μmol/l (p<0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 vs 1.89 μmol/l annually, p=0.01), with less estimated GFR loss (1.19 vs 2.03 ml min −1 1.73 m −2 annually, p<0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min −1 1.73 m −2 , p=0.065) than on placebo (6.9 ml min −1 1.73 m −2 , p<0.001), sparing 5.0 ml min

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

“…In a recent study of 1,136 Chinese patients with type 2 diabetes, higher circulating FGF21 levels predicted estimated GFR decline over 4 years, even in a subgroup of 559 patients with normal estimated GFR and normoalbuminuria [28]. Fenofibrate is also known to cause an increase in plasma creatinine [19]. However, in this study, we have demonstrated a significant association of baseline log e -transformed FGF21 levels with baseline total microvascular disease and nephropathy, as well as new on-study total microvascular disease after adjusting for risk factors including plasma creatinine and treatment allocation.…”

“…Urine albumin was measured by immunonephelometry on an Array 360 analyser (Beckman, Fullerton, CA, USA). In a separate analysis, the association of baseline FGF21 levels with baseline and new on-study abnormal estimated GFR (<60 ml min −1 1.73 m −2 ), as well as abnormal estimated GFR at 8 weeks after treatment cessation at study close (washout substudy, n=661 [19]), was assessed. As fenofibrate increased plasma creatinine levels [19], the analysis of new on-study abnormal estimated GFR was limited to the placebo group only.…”

Lipid-lowering agents in chronic kidney disease: do fibrates have a role?

“…10 Fibrates also increase the serum creatinine level after therapy initiation, but this effect could be a response to the blunting of creatinine secretion rather than true renal injury. 11 In post-trial analysis of the FIELD 12 and ACCORD 9 data sets, acute changes in the creatinine level with fibrate therapy were not associated with adverse effects on major clinical renal outcomes, and indeed suggest the possibility of long-term renal benefit. 10 Taken together, fibrates are likely to improve lipid profiles and prevent CVD in patients with CKD.…”

Treatment and impact of dyslipidemia in diabetic nephropathy

“…In this study, fenofibrate reduced the worsening of urine albumin excretion and the effects were mainly observed in the progression from normoalbuminuria to microalbuminuria. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study also evaluated the effect of fenofibrate on type 2 diabetes [30]. From this study, it was proved that fenofibrate is effective in lowering the decline of the estimated glomerular filtration rate (eGFR) and reducing the progression of albuminuria.…”