Reversibility of fenofibrate therapy-induced renal function impairment in ACCORD type 2 diabetic participants
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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 m(2) (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.
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