Reversibility of Fenofibrate Therapy–Induced Renal Function Impairment in ACCORD Type 2 Diabetic Participants

OBJECTIVE To assess the reversibility of the elevation of serum creatinine levels in patients with diabetes after 5 years of continuous on-trial fenofibrate therapy. RESEARCH DESIGN AND METHODS An on-drug/off-drug ancillary study to the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial to investigate posttrial changes in serum creatinine and cystatin C. Eligible participants were recruited into a prospective, nested, three-group study based on retrospective on-trial serum creatinine levels: fenofibrate case subjects (n = 321, ≥20% increase after 3 months of therapy); fenofibrate control subjects (n = 175, ≤2% increase); and placebo control subjects (n = 565). Serum creatinine and cystatin C were measured at trial end and 6–8 weeks after discontinuation of trial therapy. RESULTS At trial end, case subjects had the highest adjusted serum creatinine (± SE) mg/dL (1.11 ± 0.02) and the lowest adjusted estimated glomerular filtration rate (eGFR) (± SE) mL/min/1.73 m2 (68.4 ± 1.0) versus control subjects (1.01 ± 0.02; 74.8 ± 1.3) and placebo subjects (0.98 ± 0.01; 77.8 ± 0.7). After 51 days off-drug, serum creatinine in case subjects was still higher (0.97 ± 0.02) and eGFR still lower (77.8 ± 1.0) than control subjects (0.90 ± 0.02; 81.8 ± 1.3) but not different from placebo subjects (0.99 ± 0.01; 76.6 ± 0.7). Changes in serum cystatin C recapitulated the serum creatinine changes. CONCLUSIONS Participants with significant initial on-trial increases in serum creatinine (≥20%) returned to the same level of renal function as participants receiving placebo while participants who had ≤2% increase in serum creatinine had net preservation of renal function compared with the same unselected placebo reference group. The fenofibrate-associated on-trial increases in serum creatinine were reversible, and the reversal was complete after 51 days off-drug. The similarity of the cystatin C results suggests that the mechanism of this change is not specific for serum creatinine.

[1]  J. Stockman,et al.  A New Equation to Estimate Glomerular Filtration Rate , 2011 .

[2]  V. Gebski,et al.  Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study , 2011, Diabetologia.

[3]  Lukasz Januszkiewicz.  [The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus]. , 2010, Kardiologia polska.

[4]  John B Buse,et al.  Effects of combination lipid therapy in type 2 diabetes mellitus. , 2010, The New England journal of medicine.

[5]  C. Schmid,et al.  A new equation to estimate glomerular filtration rate. , 2009, Annals of internal medicine.

[6]  J. Ansquer,et al.  Effect of fenofibrate on kidney function: a 6-week randomized crossover trial in healthy people. , 2008, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[7]  C. Schmid,et al.  Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD. , 2008, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[8]  Lawrence A Leiter,et al.  Evolution of the lipid trial protocol of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. , 2007, The American journal of cardiology.

[9]  D. Goff,et al.  Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. , 2007, The American journal of cardiology.

[10]  P Glasziou,et al.  Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial , 2005, The Lancet.

[11]  M. Taskinen,et al.  Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS). , 2005, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[12]  J. Frohlich,et al.  Effect of fenofibrate-mediated increase in plasma homocysteine on the progression of coronary artery disease in type 2 diabetes mellitus. , 2004, The American journal of cardiology.

[13]  J. Achard,et al.  Fenofibrate Increases Creatininemia by Increasing Metabolic Production of Creatinine , 2002, Nephron.

[14]  A. Bostom.  Effects of fenofibrate and gemfibrozil on plasma homocysteine , 2001, The Lancet.

[15]  O. Devuyst,et al.  Deterioration in renal function associated with fibrate therapy. , 2001, Clinical nephrology.

[16]  D. Abramowicz,et al.  Fibrate-induced increase in blood urea and creatinine: is gemfibrozil the only innocuous agent? , 2000, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[17]  A. Levey,et al.  A More Accurate Method To Estimate Glomerular Filtration Rate from Serum Creatinine: A New Prediction Equation , 1999, Annals of Internal Medicine.

[18]  J. Achard,et al.  [Fenofibrate increases blood creatinine, but does not change the glomerular filtration rate in patients with mild renal insufficiency]. , 1999, Nephrologie.

[19]  M. de Lorgeril,et al.  The long-term effects of the lipid-lowering agent fenofibrate in hyperlipidemic heart transplant recipients. , 1994, Transplantation.

[20]  S. Rössner,et al.  Fenofibrate therapy of hyperlipoproteinaemia. A dose-response study and a comparison with clofibrate. , 1981, Atherosclerosis.