Reversibility of fenofibrate therapy-induced renal function impairment in ACCORD type 2 diabetic participants

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00000620.

Figure 1

Time course values of adjusted serum creatinine and cystatin C by ACCORD Renal Study Group. A: The changes in serum creatinine in units of mg/dL. B: Changes in cystatin C in units of mg/dL. The horizontal trial time point axis is not shown to scale. The study group trends are shown as: black circles, fenofibrate cases; red triangles, fenofibrate controls; blue crosses, placebo controls. Base, baseline visit; M4, month 4 visit; Close, close-out visit; Post, postclose-out visit. (A high-quality color representation of this figure is available in the online issue.)

Figure 2

Time course values of adjusted eGFR and cGFR by ACCORD Renal Study Group. A: The changes in eGFR in units of mL/min/1.73 m². B: Changes in cGFR in units of mL/min/1.73 m². The horizontal trial time point axis is not shown to scale. The study group trends are shown as: black circles, fenofibrate cases; red triangles, fenofibrate controls; blue crosses, placebo controls. Base, baseline visit; M4, month 4 visit; Close, close-out visit; Post, postclose-out visit. (A high-quality color representation of this figure is available in the online issue.)