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1 January 2011
Fenofibrate exerts renoprotective effects in patients with type 2 diabetes

In patients with type 2 diabetes, fenofibrate administered for 5 years on top of recommended usual care reduced renal function decline assessed by changes in estimated glomerular and urinary albumin:creatinine ratio. A milestone achievement for the reduction of residual risk of diabetic nephropathy..

Davis TM, Ting R, Best JD, Donoghoe MW, Drury PL, Sullivan DR, Jenkins AJ,OConnell RL, Whiting MJ, Glasziou PP, Simes RJ, Kesäniemi YA, Gebski VJ, Scott RS, Keech AC
Summary
Comments & References
STUDY SUMMARY
Objectives To assess in the FIELD study population the effects of long-term fenofibrate treatment on pre-specified renal outcomes during treatment, and after drug cessation (prespecified washout substudy).
Methods

Main study

  • Population: 9,795 type 2 diabetic patients aged 50 to 75 years with:
    • baseline plasma total cholesterol between 3.0 and 6.5 mmol/l
    • total cholesterol/HDL-cholesterol ratio ≥4.0 or plasma triglycerides ranging from 1.0 to 5.0 mmol/l,
    • no need of lipid-lowering drugs
    • plasma creatinine ≤130 μmol/l, no liver or gallbladder disease, no cardiovascular event within 3 months prior to recruitment
  • Intervention: patient randomly assigned to fenofibrate 200 mg or placebo daily for 5 years on average.
  • Outcomes:
    • changes in renal function (estimated glomerular filtration rate, eGFR)
    • plasma creatinine
    • changes in urinary albumin:creatinine (ACR) ratio

Washout substudy

  • Population: 661 patients re-assessed 52±13 days after close-out
  • Outcomes: plasma creatinine
Main results Main study
  • Chronic rise of plasma creatinine, significantly higher on fenofibrate than on placebo (1.62 vs1.89 μmol/l annually, p=0.01)
  • Significantly lower secular decrease in eGFR on fenofibrate than on placebo (-1.19 vs -2.03 ml min−1 1.73 m−2 annually, p<0.001)
  • In both groups, urinary ACR fell over 5 years. The fall was greater in participants on fenofibrate (23.7% vs 11.5%; mean difference 13.9% [95% CI 9.2–18.3]; p<0.001)
  • 14% less progression, and 18% more albuminuria regression (p<0.001) than in participants on placebo

Fenofibrate washout substudy

  • Population: 661 patients re-assessed 52±13 days after close-out
  • Significantly lower decrease from baseline of eGFR in patients exposed to fenofibrate (-1.9 ml min−1 1.73 m−2, p=0.065) than in those on on placebo (-6.9 ml min−1 1.73 m−2, p<0.001)
Authors’ conclusion Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine. These results support to consider the use of fenofibrate in type 2 diabetes to reduce renal morbidity.

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.

References
  1. Molitch ME, DeFronzo RA, et al.; American Diabetes Association. Diabetic nephropathy. Diabetes Care. 2003;26 Suppl:S94-8.
  2. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580-91.
  3. Keech AC, Mitchell P, Summanen PA, O'Day J, Davis TM, Moffitt MS, Taskinen MR, Simes RJ, Tse D, Williamson E, Merrifield A, Laatikainen LT, d'Emden MC, Crimet DC, O'Connell RL, Colman PG; FIELD study investigators. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007;370:1687-97.
  4. Rajamani K, Colman PG, Li LP, Best JD, Voysey M, D'Emden MC, Laakso M, Baker JR, Keech AC; FIELD study investigators. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet 2009;373:1780-8.
  5. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC Jr, Cushman WC, Simons-Morton DG, Byington RP. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
  6. ACCORD Study Group; ACCORD Eye Study Group, Chew EY, Ambrosius WT, Davis MD, Danis RP, Gangaputra S, Greven CM, Hubbard L, Esser BA, Lovato JF, Perdue LH, Goff DC Jr, Cushman WC, Ginsberg HN, Elam MB, Genuth S, Gerstein HC, Schubart U, Fine LJ. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;363:233-44.
  7. Hermans MP. Prevention of microvascular diabetic complications by fenofibrate: Lessons from FIELD and ACCORD. Diab Vasc Dis Res 2011 (DOI: 10.1177/1479164111407783).