Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study

T. M E Davis, R. Ting, J. D. Best, M. W. Donoghoe, P. L. Drury, D. R. Sullivan, A. J. Jenkins, R. L. O'Connell, M. J. Whiting, P. P. Glasziou, R. J. Simes, Y. A. Kesäniemi, V. J. Gebski, R. S. Scott, A. C. Keech

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Abstract

Aims/hypothesis: Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. We assessed fenofibrate's renal effects overall and in a FIELD washout sub-study. Methods: Type 2 diabetic patients (n = 9,795) aged 50 to 75 years were randomly assigned to fenofibrate (n = 4,895) or placebo (n = 4,900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin/creatinine ratio measured at baseline, year 2 and close-out) and estimated GFR, measured four to six monthly according to the Modification of Diet in Renal Disease Study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n = 661). Analysis was by intention-to-treat. Results: During fenofibrate run-in, plasma creatinine increased by 10.0 μmol/l (p < 0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 vs 1.89 μmol/l annually, p = 0.01), with less estimated GFR loss (1.19 vs 2.03 ml min-1 1.73 m-2 annually, p < 0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min-1 1.73 m-2, p = 0.065) than on placebo (6.9 ml min-1 1.73 m-2, p < 0.001), sparing 5.0 ml min-1 1.73 m-2 (95% CI 2.3-7.7, p < 0.001). Greater preservation of estimated GFR with fenofibrate was observed with baseline hypertriacylglycerolaemia (n = 169 vs 491 without) alone, or combined with low HDL-cholesterol (n = 140 vs 520 without) and reductions of ≥0.48 mmol/l in triacylglycerol over the active run-in period (pre-randomisation) (n = 356 vs 303 without). Fenofibrate reduced urine albumin concentrations and hence albumin/creatinine ratio by 24% vs 11% (p < 0.001; mean difference 14% [95% CI 9-18]; p < 0.001), with 14% less progression and 18% more albuminuria regression (p < 0.001) than in participants on placebo. End-stage renal event frequency was similar (n = 21 vs 26, p = 0.48). Conclusions/interpretation: Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited. Trial registration: ISRCTN64783481 Funding: The study was funded by grants from Laboratoires Fournier SA (Dijon, France; now part of Abbott Pharmaceuticals) and the National Health and Medical Research Council, Australia

Original languageEnglish
Pages (from-to)280-290
Number of pages11
JournalDiabetologia
Volume54
Issue number2
DOIs
Publication statusPublished - Feb 2011
Externally publishedYes

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Fenofibrate
Type 2 Diabetes Mellitus
Kidney
Creatinine
Albuminuria
Placebos
Albumins
Diet Therapy
Withholding Treatment
Intention to Treat Analysis
Organized Financing
Random Allocation
HDL Cholesterol
France

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Davis, T. M E ; Ting, R. ; Best, J. D. ; Donoghoe, M. W. ; Drury, P. L. ; Sullivan, D. R. ; Jenkins, A. J. ; O'Connell, R. L. ; Whiting, M. J. ; Glasziou, P. P. ; Simes, R. J. ; Kesäniemi, Y. A. ; Gebski, V. J. ; Scott, R. S. ; Keech, A. C. / Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus : The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. In: Diabetologia. 2011 ; Vol. 54, No. 2. pp. 280-290.
@article{f889381ad2ce4e468b5ec9bbee80cdce,
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abstract = "Aims/hypothesis: Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. We assessed fenofibrate's renal effects overall and in a FIELD washout sub-study. Methods: Type 2 diabetic patients (n = 9,795) aged 50 to 75 years were randomly assigned to fenofibrate (n = 4,895) or placebo (n = 4,900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin/creatinine ratio measured at baseline, year 2 and close-out) and estimated GFR, measured four to six monthly according to the Modification of Diet in Renal Disease Study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n = 661). Analysis was by intention-to-treat. Results: During fenofibrate run-in, plasma creatinine increased by 10.0 μmol/l (p < 0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 vs 1.89 μmol/l annually, p = 0.01), with less estimated GFR loss (1.19 vs 2.03 ml min-1 1.73 m-2 annually, p < 0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min-1 1.73 m-2, p = 0.065) than on placebo (6.9 ml min-1 1.73 m-2, p < 0.001), sparing 5.0 ml min-1 1.73 m-2 (95{\%} CI 2.3-7.7, p < 0.001). Greater preservation of estimated GFR with fenofibrate was observed with baseline hypertriacylglycerolaemia (n = 169 vs 491 without) alone, or combined with low HDL-cholesterol (n = 140 vs 520 without) and reductions of ≥0.48 mmol/l in triacylglycerol over the active run-in period (pre-randomisation) (n = 356 vs 303 without). Fenofibrate reduced urine albumin concentrations and hence albumin/creatinine ratio by 24{\%} vs 11{\%} (p < 0.001; mean difference 14{\%} [95{\%} CI 9-18]; p < 0.001), with 14{\%} less progression and 18{\%} more albuminuria regression (p < 0.001) than in participants on placebo. End-stage renal event frequency was similar (n = 21 vs 26, p = 0.48). Conclusions/interpretation: Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited. Trial registration: ISRCTN64783481 Funding: The study was funded by grants from Laboratoires Fournier SA (Dijon, France; now part of Abbott Pharmaceuticals) and the National Health and Medical Research Council, Australia",
author = "Davis, {T. M E} and R. Ting and Best, {J. D.} and Donoghoe, {M. W.} and Drury, {P. L.} and Sullivan, {D. R.} and Jenkins, {A. J.} and O'Connell, {R. L.} and Whiting, {M. J.} and Glasziou, {P. P.} and Simes, {R. J.} and Kes{\"a}niemi, {Y. A.} and Gebski, {V. J.} and Scott, {R. S.} and Keech, {A. C.}",
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doi = "10.1007/s00125-010-1951-1",
language = "English",
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Davis, TME, Ting, R, Best, JD, Donoghoe, MW, Drury, PL, Sullivan, DR, Jenkins, AJ, O'Connell, RL, Whiting, MJ, Glasziou, PP, Simes, RJ, Kesäniemi, YA, Gebski, VJ, Scott, RS & Keech, AC 2011, 'Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study' Diabetologia, vol. 54, no. 2, pp. 280-290. https://doi.org/10.1007/s00125-010-1951-1

Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus : The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. / Davis, T. M E; Ting, R.; Best, J. D.; Donoghoe, M. W.; Drury, P. L.; Sullivan, D. R.; Jenkins, A. J.; O'Connell, R. L.; Whiting, M. J.; Glasziou, P. P.; Simes, R. J.; Kesäniemi, Y. A.; Gebski, V. J.; Scott, R. S.; Keech, A. C.

In: Diabetologia, Vol. 54, No. 2, 02.2011, p. 280-290.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus

T2 - The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study

AU - Davis, T. M E

AU - Ting, R.

AU - Best, J. D.

AU - Donoghoe, M. W.

AU - Drury, P. L.

AU - Sullivan, D. R.

AU - Jenkins, A. J.

AU - O'Connell, R. L.

AU - Whiting, M. J.

AU - Glasziou, P. P.

AU - Simes, R. J.

AU - Kesäniemi, Y. A.

AU - Gebski, V. J.

AU - Scott, R. S.

AU - Keech, A. C.

PY - 2011/2

Y1 - 2011/2

N2 - Aims/hypothesis: Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. We assessed fenofibrate's renal effects overall and in a FIELD washout sub-study. Methods: Type 2 diabetic patients (n = 9,795) aged 50 to 75 years were randomly assigned to fenofibrate (n = 4,895) or placebo (n = 4,900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin/creatinine ratio measured at baseline, year 2 and close-out) and estimated GFR, measured four to six monthly according to the Modification of Diet in Renal Disease Study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n = 661). Analysis was by intention-to-treat. Results: During fenofibrate run-in, plasma creatinine increased by 10.0 μmol/l (p < 0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 vs 1.89 μmol/l annually, p = 0.01), with less estimated GFR loss (1.19 vs 2.03 ml min-1 1.73 m-2 annually, p < 0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min-1 1.73 m-2, p = 0.065) than on placebo (6.9 ml min-1 1.73 m-2, p < 0.001), sparing 5.0 ml min-1 1.73 m-2 (95% CI 2.3-7.7, p < 0.001). Greater preservation of estimated GFR with fenofibrate was observed with baseline hypertriacylglycerolaemia (n = 169 vs 491 without) alone, or combined with low HDL-cholesterol (n = 140 vs 520 without) and reductions of ≥0.48 mmol/l in triacylglycerol over the active run-in period (pre-randomisation) (n = 356 vs 303 without). Fenofibrate reduced urine albumin concentrations and hence albumin/creatinine ratio by 24% vs 11% (p < 0.001; mean difference 14% [95% CI 9-18]; p < 0.001), with 14% less progression and 18% more albuminuria regression (p < 0.001) than in participants on placebo. End-stage renal event frequency was similar (n = 21 vs 26, p = 0.48). Conclusions/interpretation: Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited. Trial registration: ISRCTN64783481 Funding: The study was funded by grants from Laboratoires Fournier SA (Dijon, France; now part of Abbott Pharmaceuticals) and the National Health and Medical Research Council, Australia

AB - Aims/hypothesis: Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. We assessed fenofibrate's renal effects overall and in a FIELD washout sub-study. Methods: Type 2 diabetic patients (n = 9,795) aged 50 to 75 years were randomly assigned to fenofibrate (n = 4,895) or placebo (n = 4,900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin/creatinine ratio measured at baseline, year 2 and close-out) and estimated GFR, measured four to six monthly according to the Modification of Diet in Renal Disease Study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n = 661). Analysis was by intention-to-treat. Results: During fenofibrate run-in, plasma creatinine increased by 10.0 μmol/l (p < 0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 vs 1.89 μmol/l annually, p = 0.01), with less estimated GFR loss (1.19 vs 2.03 ml min-1 1.73 m-2 annually, p < 0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min-1 1.73 m-2, p = 0.065) than on placebo (6.9 ml min-1 1.73 m-2, p < 0.001), sparing 5.0 ml min-1 1.73 m-2 (95% CI 2.3-7.7, p < 0.001). Greater preservation of estimated GFR with fenofibrate was observed with baseline hypertriacylglycerolaemia (n = 169 vs 491 without) alone, or combined with low HDL-cholesterol (n = 140 vs 520 without) and reductions of ≥0.48 mmol/l in triacylglycerol over the active run-in period (pre-randomisation) (n = 356 vs 303 without). Fenofibrate reduced urine albumin concentrations and hence albumin/creatinine ratio by 24% vs 11% (p < 0.001; mean difference 14% [95% CI 9-18]; p < 0.001), with 14% less progression and 18% more albuminuria regression (p < 0.001) than in participants on placebo. End-stage renal event frequency was similar (n = 21 vs 26, p = 0.48). Conclusions/interpretation: Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited. Trial registration: ISRCTN64783481 Funding: The study was funded by grants from Laboratoires Fournier SA (Dijon, France; now part of Abbott Pharmaceuticals) and the National Health and Medical Research Council, Australia

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