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COMMENT

Except for glycemic and blood pressure control, attempts to alleviate through pharmacological intervention the huge personal and societal burden of diabetic nephropathy have been inconclusive so far. Despite currently available treatments, diabetes is still a leading cause of renal damage and end-stage renal disease.(1) In the STENO-2 study conducted in patients with type 2 diabetes, multifactorial treatment did not prevent the development of renal disease in 25% of patients over 13 years.(2) There is an obvious need to reduce the residual risk of diabetic nephropathy in patients receiving even the most stringent treatments of type 2 diabetes.

The FIELD study was one of the largest randomized trials examining pre-specified renal outcomes in patients with type 2 diabetes. These pre-specified analyses yielded two remarkable findings.

First, the well-known increase in plasma creatinine associated with fenofibrate therapy is reversible and, as the authors state, “does not represent true nephrotoxicity.” During the 6-week fenofibrate run-in period before randomization, mean plasma creatinine increased by 10.0 μmol/l. In participants who were then allocated fenofibrate, plasma creatinine remained 10 to 12 μmol/l higher than in placebo-treated patients (p<0.001). However, the long-term plasma creatinine rise was smaller with fenofibrate than with placebo. At the end of the washout period, plasma creatinine in patients who had received fenofibrate for 5 years fell below that of the placebo-treated patients.

Second, the significantly lesser loss of renal function, as measured by eGFR, which occurred among those receiving fenofibrate compared to those receiving placebo over 5 years is indicative of a renoprotective effect of fenofibrate, since the natural history of eGFR in type 2 diabetes is characterized by progressive, relentless decline. This renoprotective effect of fenofibrate was sizeable: after washout, fenofibrate spared 5.0 ml min−1 1.73 m−2 (95% CI 2.3–7.7, p<0.001) of estimated glomerular filtration. Renal protection was also evidenced by the significant reduction of albuminuria in fenofibrate-treated patients.

Evidence of greater benefit in terms of preservation of eGFR was present in those with baseline hypertriglyceridemia (≥2.3 mmol/l) or “marked dyslipidemia” (TG >2.3 mmol/L plus HDL-C <1.03 mmol/L in men <1.29 mmol/L in women; in other words, atherogenic dyslipidemia) compared with those without (p=0.03 for interaction, for both). As the greater decrease in albuminuria with fenofibrate than with placebo was independent of baseline characteristics, different underlying mechanisms, which remain to be fully elucidated, are likely involved.

These findings are clinically meaningful: the number needed to treat (NNT) to prevent one patient worsening by at least one eGFR grouping (<30, 30 to <60, 60 to <90 or ≥90 ml min−1 1.73 m−2) was 25, and only 10 for patients with atherogenic dyslipidemia. The NNT to prevent one patient progressing to micro- or macroalbuminuria was 54.

Previous reports from the FIELD study have already shown a protective effect of fenofibrate on two other major microvascular complications of diabetes: diabetic retinopathy()3 and lower-limb amputations, including those caused predominantly by microangiopathy(4)

This new report published by Davis et al. is also consistent with the ACCORD trial, in which patients with type 2 diabetes received a statin with or without fenofibrate. In ACCORD, fenofibrate caused an acute plasma creatinine rise as well as a long-term reduction of micro- and macroalbuminuria, with no adverse effect on end-stage renal disease compared with placebo.(5) The washout study results from FIELD thus provide further compelling evidence for a comprehensive renoprotective effect of fenofibrate in type 2 diabetes, and support to consider this PPAR-α receptor agonist as a “new” drug to reduce residual vascular risk of renal morbidity in patients with type 2 diabetes on standards of care.

In addition, the ACCORD Eye sub-study showed a significantly less progression of diabetic retinopathy, another dramatic microvascular complications of diabetes, in patients treated with fenofibrate on top of background statin therapy.(6,7)

The new findings stemming from the FIELD study have raised much interest in the nephrology and diabetology communities, as they may have important clinical implications in terms of reduction residual risk of diabetic nephropathy. Both the reasons behind the initial plasma creatinine rise and the mechanisms underlying the renoprotective effect associated with fenofibrate have yet to be fully ascertained.

* However, the authors write that a post-hoc analysis suggests a greater benefit in men than in women.