title: 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.
  
  
  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.
authors.affiliation: Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, Virginia, USA. jcm6t@virginia.edu
authors.forename: Josyf C
authors.initials: JC
authors.lastname: Mychaleckyj
authors.forename: Timothy
authors.initials: T
authors.lastname: Craven
authors.forename: Uma
authors.initials: U
authors.lastname: Nayak
authors.forename: John
authors.initials: J
authors.lastname: Buse
authors.forename: John R
authors.initials: JR
authors.lastname: Crouse
authors.forename: Marshall
authors.initials: M
authors.lastname: Elam
authors.forename: Kent
authors.initials: K
authors.lastname: Kirchner
authors.forename: Daniel
authors.initials: D
authors.lastname: Lorber
authors.forename: Santica
authors.initials: S
authors.lastname: Marcovina
authors.forename: William
authors.initials: W
authors.lastname: Sivitz
authors.forename: Joann
authors.initials: J
authors.lastname: Sperl-Hillen
authors.forename: Denise E
authors.initials: DE
authors.lastname: Bonds
authors.forename: Henry N
authors.initials: HN
authors.lastname: Ginsberg
mesh_terms: D000368:Aged; D003404:Creatinine / Q000097:blood; D011345:Fenofibrate / Q000009:adverse effects* / Q000627:therapeutic use*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D000960:Hypolipidemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged; D051437:Renal Insufficiency / Q000097:blood / Q000139:chemically induced*
chemical_list: D000960:Hypolipidemic Agents; D003404:Creatinine; D011345:Fenofibrate