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

Abstract

OBJECTIVETo 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 METHODSAn 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.RESULTSAt 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.CONCLUSIONSParticipants 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.

Association of Urinary Biomarkers of Inflammation, Injury, and Fibrosis with Renal Function Decline: The ACCORD Trial

“…Serum creatinine was determined using the Roche Creatinine Plus Enzymatic Assay with spectrometric analysis on a Roche Double Modular P Analytics Analyzer (Roche Diagnostics, Indianapolis, IN). The results are traceable to the isotope dilution mass spectrometry reference method (16). eGFR was calculated from the measured serum creatinine by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (17,18).…”

Dyslipidemia aterogenna w codziennej praktyce — interdyscyplinarny konsensus polskich ekspertów

“…W badaniu wykazano również możliwość korzystnego efektu terapii skojarzonej w postaci redukcji o 30% incydentów sercowo-naczyniowych u osób z równoczesnym wysokim stężeniem TG (≥ 204 mg/dl) i niskim stężeniem HDL-C (≤ 34 mg/dl). W żadnym z wymienionych badań przejściowy wzrost stężenia kreatyniny w surowicy krwi nie skutkował działaniami niepożądanymi w zakresie poważnych zdarzeń nerkowych, co sugeruje możliwe korzyści przy długotrwałej terapii [38][39][40][41][42].…”

Residual Microvascular Risk in Type 2 Diabetes in 2014: Is it Time for a Re-Think? A Perspective from the Residual Risk Reduction Initiative (R3i)

“…Of these patients, about one-quarter subsequently received a reduced dose of fenofibrate, and about one-third stopped study treatment [50]. However, in both the FIELD and ACCORD Lipid studies the increase in serum creatinine was transient and reversible within 6-8 weeks [40,51,52]. Furthermore, subsequent analyses showed that the increase in serum creatinine in fenofibrate-treated patients was unexpectedly associated with slower (rather than higher) secular loss of renal function.…”

“…Over the course of the 5-year follow-up in the FIELD study, the decline in estimated glomerular filtration rate (eGFR) was reduced by 73% with fenofibrate compared with placebo [51]. Additionally, in the Renal Ancillary study of ACCORD Lipid, among patients in the fenofibrate treatment group who were chosen because they did not show any increase in serum creatinine (≤ 2% change from pre-treatment levels), mean eGFR at the end of study was higher compared with those in the placebo group (81.8 versus 77.8 mL/min/1.73 m 2 ), raising the possibility that there was net preservation of renal function over time in this group [52] Attainment of lipid goals for high-density lipoprotein (HDL) cholesterol, triglycerides and non-HDL cholesterol reduced the risk of diabetic complications (retinopathy, nephropathy or neuropathy, all p<0.0001). Data from Toth et al [38] * Adjusted multivariate Cox regression analysis for patients at lipid goal versus those who did not achieve lipid goal.…”