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

Fenofibrate causes an acute, sustained rise in plasma/serum creatinine in patients with type 2 diabetes, as shown in the FIELD and ACCORD trials.

“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.”

• Also stated in: § Introduction · plain

  “Two recent large-scale, double-blind, randomised, placebocontrolled clinical trials, Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD), have shown an early, sustained rise in serum creatinine with fenofibrate in patients with type 2 diabetes [1,2].”

• cites [1] The FIELD Study Investigators (2005) Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD Study): randomised controlled trial. Lancet 366:1849–1861 sourceNot checked — no full text of the source
• cites [2] The ACCORD Study Group (2010) Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 362:1563–1574 sourcePartly supported

  The Results > Safety passage reports that serum creatinine rose in the ACCORD fenofibrate group within the first year and remained relatively stable thereafter. It says increases were also noted in other fenofibrate trials, citing FIELD, but does not establish that the rise in FIELD had the same acute, sustained course. Page numbers are unavailable in our copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

The initial plasma creatinine rise associated with fenofibrate appears to be partly due to a decrease in creatinine clearance without reduced inulin-derived GFR.

“The rise appears to be partly due to a decrease in creatinine clearance [16,21] without reduced inulinderived GFR [16,24]”

• cites [16] Ansquer J-C, Dalton RN, Causse E, Crimet D, Malicot KL, Foucher C (2008) Effect of fenofibrate on kidney function: a 6-week randomized crossover trial in healthy people. Am J Kidney Dis 51:904–913 sourceNot checked — no full text of the source
• cites [21] Forsblom C, Hiukka A, Leinonen E, Sundvall J, Groop PH, Taskinen M-R (2010) Effects of long-term fenofibrate treatment on markers of renal function in type 2 diabetes: FIELD Helsinki Substudy. Diab Care 33:215–220 sourceSupported
• cites [24] Hottelart C, Esper NE, Achard JM, Pruna A, Fournier A (1999) Fenofibrate increases blood creatinine, but does not change the glomerular filtration rate in patients with mild renal insufficiency. Néphrologie 20:41–44Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In FIELD, fenofibrate had significant beneficial effects on lower limb amputations, including in instances regarded as having a predominantly microvascular aetiology.

“In FIELD, there was evidence that fenofibrate had significant beneficial effects on laser treatment for diabetic retinopathy [4] and lower limb amputations, including in instances regarded as having a predominantly microvascular aetiology [5].”

• cites [5] Rajamani K, Colman PG, Li LP et al (2009) Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD Study): a prespecified analysis of a randomised controlled trial. Lancet 373:1780–1788 sourceSupported

Re-analysis of the data using the EPI-CKD estimated GFR formula did not alter the conclusions.

“Re-analysis of our data using an estimated GFR formula (EPI-CKD) with greater accuracy at higher estimated GFR levels [44] did not alter our conclusions (slightly smaller but still significant benefit [data not shown]).”

• cites [44] Levey AS, Stevens LA, Schmid CH et al (2009) A new equation to estimate glomerular filtration Rate. Ann Intern Med 150:604–612 sourceSupported

The annual progression rate to micro- or macroalbuminuria in FIELD placebo-treated patients (2.8%) is similar to rates in the UK Prospective Diabetes Study (2.5%) and the MICRO-HOPE Study (2.2%).

“which is similar to progression rates in the UK Prospective Diabetes Study (2.5%) and the Microalbuminuria, Cardiovascular, and Renal Outcomes-Heart Outcomes Prevention Evaluation (MICRO-HOPE) Study (2.2%) [40,41].”

• cites [40] Retnakaran R, Cull CA, Thorne KI, Adler AI, Holman RR, for the UKPDS Study Group (2006) Risk factors for renal dysfunction in type 2 diabetes. UKPDS 74. Diabetes 55:1832–1839 sourcePartly supported

  The paper’s introductory passage reports that 24.9% of UKPDS patients developed microalbuminuria within 10 years and that annual transitions between successive renal stages were 2–3%. This is consistent with an approximate 2.5% annual rate, but the paper does not state a 2.5% annual rate for progression to either micro- or macroalbuminuria. The FIELD and MICRO-HOPE figures are not attributed to this source by the citing sentence. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [41] Gerstein HC, Yusuf S, Mann JFE et al (2000) Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE Substudy. Lancet 355:253–259 sourceNot checked — no full text of the source

Renal assessment through inulin and p-amino hippurate clearance is impractical in large trials.

“Renal assessment through inulin and p-amino hippurate clearance is impractical in large trials and estimated GFR has limitations [13].”

• cites [13] Chudleigh RA, Dunseath G, Evans W et al (2007) How reliable is estimation of glomerular filtration rate at diagnosis of type 2 diabetes? Diab Care 30:300–305 sourcePartly supported

  The Results section says eGFR has significant limitations, supporting that part of the citing sentence. The Clinical and Laboratory methods describe measurement using 51Cr-EDTA, but our copy does not say that inulin and p-amino hippurate clearance are impractical in large trials. Searches for those clearance methods and for the practicality of direct GFR measurement found no supporting passage. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Estimated GFR loss was less on fenofibrate than on placebo (1.19 vs 2.03 ml min−1 1.73 m−2 annually, p<0.001).

“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).”

The chronic annual rise in plasma creatinine was slower on fenofibrate than on placebo (1.62 vs 1.89 μmol/l annually, p=0.01).

“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).”

In participants allocated fenofibrate, plasma creatinine remained 10 to 12 μmol/l higher than placebo.

“In participants allocated fenofibrate, plasma creatinine remained 10 to 12 μmol/l higher than placebo (p<0.001;Fig. 2a), with an apparently greater fall in estimated GFR (87.6 to 70.5 vs 87.8 to 79.9 ml min -1 1.73 m -2 ) from prerun-in (baseline) to close-out.”

Greater preservation of estimated GFR with fenofibrate was observed with baseline hypertriacylglycerolaemia combined with low HDL-cholesterol (n=140 vs 520 without).

“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).”

The long-term plasma creatinine rise (4 months to close-out) was smaller with fenofibrate than with placebo overall (7.9 μmol/l vs 9.2 μmol/l, p=0.01).

“However, the long-term plasma creatinine rise (4 months to close-out) was smaller with fenofibrate than with placebo, both overall (7.9 μmol/l vs 9.2 μmol/l, p=0.01;Fig. 2a), and within each subgroup of baseline estimated GFR (ESM Fig. 1).”

Greater preservation of estimated GFR with fenofibrate was observed with reductions of ≥0.48 mmol/l in triacylglycerol over the active run-in period (pre-randomisation) (n=356 vs 303 without).

“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).”

In those subsequently randomised to placebo, plasma creatinine then increased by 1.7 μmol/l per year.

“In those subsequently randomised to placebo, levels at the next visit (4 months) fell back to baseline levels, but then increased by 1.7 μmol/l per year (Fig. 2a).”

After washout, estimated GFR had fallen from baseline by 6.9 ml min−1 1.73 m−2 on placebo (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).”

• AssumptionRests on an assumption: The washout sub-study participants (n=661) are representative of the full FIELD cohort.

After washout, estimated GFR had fallen less from baseline on fenofibrate than on placebo, sparing 5.0 ml min−1 1.73 m−2 (95% CI 2.3-7.7, 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).”

• AssumptionRests on an assumption: The washout sub-study participants (n=661) are representative of the full FIELD cohort.

Fenofibrate resulted in 18% more albuminuria regression than placebo (p<0.001).

“Fenofibrate reduced urine albumin concentrations and hence albumin/creatinine ratio by 24% vs 11% (p<0.001;mean difference 14% [95% ; p<0.001), with 14% less progression and 18% more albuminuria regression (p<0.001)than in participants on”

In those subsequently randomised to placebo, plasma creatinine levels at the next visit (4 months) fell back to baseline levels.

“In those subsequently randomised to placebo, levels at the next visit (4 months) fell back to baseline levels, but then increased by 1.7 μmol/l per year (Fig. 2a).”

Fenofibrate resulted in 14% less progression of albuminuria than placebo (p<0.001).

“Fenofibrate reduced urine albumin concentrations and hence albumin/creatinine ratio by 24% vs 11% (p<0.001;mean difference 14% [95% ; p<0.001), with 14% less progression and 18% more albuminuria regression (p<0.001)than in participants on”

Mean plasma creatinine increased 10.0 μmol/l during the pre-randomisation 6 week fenofibrate run-in period.

“Mean plasma creatinine increased 10.0 μmol/l during the pre-randomisation 6 week fenofibrate run-in period.”

This was paralleled by slower estimated GFR loss (5.8 vs 9.9 ml min−1 1.73 m−2, respectively, p<0.001).

“This was paralleled by slower estimated GFR loss (5.8 vs 9.9 ml min -1 1.73 m -2 , respectively, p<0.001;Fig. 2b).”

The plasma creatinine increase during fenofibrate run-in quickly reversed on placebo assignment.

“During fenofibrate run-in, plasma creatinine increased by 10.0 μmol/l (p<0.001),but quickly reversed on placebo assignment.”

Greater preservation of estimated GFR with fenofibrate was observed with baseline hypertriacylglycerolaemia alone (n=169 vs 491 without).

“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).”

In participants allocated fenofibrate, estimated GFR fell apparently more from baseline to close-out (87.6 to 70.5 vs 87.8 to 79.9 ml min−1 1.73 m−2).

“In participants allocated fenofibrate, plasma creatinine remained 10 to 12 μmol/l higher than placebo (p<0.001;Fig. 2a), with an apparently greater fall in estimated GFR (87.6 to 70.5 vs 87.8 to 79.9 ml min -1 1.73 m -2 ) from prerun-in (baseline) to close-out.”

Plasma creatinine remained higher on fenofibrate than on placebo.

“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).”

The long-term plasma creatinine rise (4 months to close-out) was smaller with fenofibrate than with placebo within each subgroup of baseline estimated GFR.

“However, the long-term plasma creatinine rise (4 months to close-out) was smaller with fenofibrate than with placebo, both overall (7.9 μmol/l vs 9.2 μmol/l, p=0.01;Fig. 2a), and within each subgroup of baseline estimated GFR (ESM Fig. 1).”

End-stage renal event frequency was similar between fenofibrate and placebo (n=21 vs 26, p=0.48).

“Endstage renal event frequency was similar (n=21 vs 26, p=0.48).”

Fenofibrate reduced urine albumin concentrations and hence albumin/creatinine ratio by 24% vs 11% (p<0.001; mean difference 14%).

“Fenofibrate reduced urine albumin concentrations and hence albumin/creatinine ratio by 24% vs 11% (p<0.001;mean difference 14% [95% ; p<0.001), with 14% less progression and 18% more albuminuria regression (p<0.001)than in participants on”

Placebo patients requiring renin-angiotensin system blockers at entry had greater estimated GFR loss than other participants.

“Placebo patients requiring renin-angiotensin system blockers at entry also had greater estimated GFR loss than other participants (p=0.004),possibly representing indication bias.”

During fenofibrate run-in, plasma creatinine increased by 10.0 μmol/l (p<0.001).

“During fenofibrate run-in, plasma creatinine increased by 10.0 μmol/l (p<0.001),but quickly reversed on placebo assignment.”

Baseline risk factors for greater plasma creatinine rise and estimated GFR loss during placebo treatment over 5 years included elevated urinary ACR, older age, lower HDL-cholesterol and higher HbA1c.

“Baseline risk factors for greater plasma creatinine rise and estimated GFR loss during placebo treatment over 5 years included elevated urinary ACR, older age, lower HDL-cholesterol and higher HbA 1c (p<0.001 for all).”

After washout, estimated GFR had fallen from baseline by 1.9 ml min−1 1.73 m−2 on fenofibrate (p=0.065).

“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).”

• AssumptionRests on an assumption: The washout sub-study participants (n=661) are representative of the full FIELD cohort.

In the 661 washout sub-study participants, plasma creatinine changes (baseline to closeout) were comparable to those in the whole cohort.

“In the 661 washout sub-study participants, plasma creatinine changes (baseline to closeout) were comparable to those in the whole cohort, but levels at 8 weeks after withdrawal of study treatment were significantly lower in participants allocated fenofibrate than in those on placebo (p<0.001;Fig. 3a).”

The chronic underlying decline in renal function among fenofibrate-treated patients was still about twice that associated with normal ageing in the absence of diabetes (1.9 vs 0.9 ml min -1 1.73 m -2 per year).

“The chronic underlying decline in renal function among fenofibrate-treated patients was nevertheless still about twice that associated with normal ageing in the absence of diabetes (1.9 vs 0.9 ml min -1 1.73 m -2 per year) [17].”

• cites [17] Rowe JW, Anderes R, Tobin JD, Norris AH, Shock NW (1976) The effect of age on creatinine clearance in men: a cross-sectional and longtitudinal study. J Gerontol 31:155–163 sourceNot checked — no full text of the source

In the washout sub-study, plasma creatinine levels at 8 weeks after withdrawal of study treatment were significantly lower in participants allocated fenofibrate than in those on placebo.

“In the 661 washout sub-study participants, plasma creatinine changes (baseline to closeout) were comparable to those in the whole cohort, but levels at 8 weeks after withdrawal of study treatment were significantly lower in participants allocated fenofibrate than in those on placebo (p<0.001;Fig. 3a).”

There was rapid reversion to pre-treatment plasma creatinine levels in those subsequently allocated placebo after the run-in phase.

“there was rapid reversion to pre-treatment levels in those subsequently allocated placebo after the run-in phase”

In the FIELD study, the reduction in the secondary endpoint of total cardiovascular events was no smaller in participants with larger creatinine increases and on fenofibrate than in others.

“The reduction in the secondary endpoint of total cardiovascular events was no smaller in participants with larger creatinine increases and on fenofibrate than in others (ESM Fig. 3).”

In the FIELD study, plasma creatinine doubling was often transient.

“but was often transient”

Plasma creatinine after washout at 5 years in those allocated fenofibrate fell below that of the placebo-treated patients.

“In addition, plasma creatinine after washout at 5 years in those allocated fenofibrate fell below that of the placebo-treated patients.”

Fenofibrate causes an initial plasma creatinine rise.

“an initial, well-recognised plasma creatinine rise [16]”

• cites [16] Ansquer J-C, Dalton RN, Causse E, Crimet D, Malicot KL, Foucher C (2008) Effect of fenofibrate on kidney function: a 6-week randomized crossover trial in healthy people. Am J Kidney Dis 51:904–913 sourceNot checked — no full text of the source

Fenofibrate reduces decline of estimated GFR in type 2 diabetes patients.

“We demonstrate here that fenofibrate reduces albuminuria progression and decline of estimated GFR in type 2 diabetes patients, despite a small initial plasma creatinine rise.”

• AssumptionRests on an assumption: Estimated GFR after washout accurately reflects true GFR, so that preservation of estimated GFR indicates structural renal preservation.

In the FIELD study, plasma creatinine doubling seldom led to withdrawal (7 vs 2, p=0.1).

“seldom led to withdrawal (7 vs 2, p=0.1)”

In the FIELD study, plasma creatinine doubling was more common in participants on fenofibrate than in those on placebo (3.0% vs 1.8%, p<0.001).

“Plasma creatinine doubling was more common in participants on fenofibrate than in those on placebo (3.0% vs 1.8%, p<0.001), but was often transient and seldom led to withdrawal (7 vs 2, p=0.1).”

Independently statistically significant estimated GFR preservation with fenofibrate occurred in most subgroups.

“Independently statistically significant estimated GFR preservation with fenofibrate occurred in most subgroups.”

The fall in urinary ACR was greater in participants on fenofibrate (23.7% vs 11.5%; mean difference 13.9% [95% CI 9.2-18.3]; p<0.001).

“The fall was greater in participants on fenofibrate (23.7% vs 11.5%; mean difference 13.9% [95% CI 9.2-18.3];p<0.001).”

The greater decrease in albuminuria with fenofibrate than with placebo was independent of baseline characteristics (except sex).

“The greater decrease in albuminuria with fenofibrate than with placebo was independent of baseline characteristics (except sex)”

Determinants of less than average improvement in urinary ACR were low urinary ACR or high plasma creatinine at baseline, current smoking, longer diabetes duration and older age.

“Determinants of less than average improvement were low urinary ACR or high plasma creatinine at baseline, current smoking, longer diabetes duration and older age.”

Fenofibrate reduces albuminuria progression in type 2 diabetes patients.

“We demonstrate here that fenofibrate reduces albuminuria progression and decline of estimated GFR in type 2 diabetes patients, despite a small initial plasma creatinine rise.”

Significant renal function decline was seen in all washout subgroups receiving placebo.

“Significant renal function decline was seen in all washout subgroups receiving placebo (Fig. 4).”

Evidence of greater benefit was present in those with baseline hypertriacylglycerolaemia (≥2.3 mmol/l) or dyslipidaemia compared with those without.

“Evidence of greater benefit was present in those with baseline hypertriacylglycerolaemia (≥2.3 mmol/l) or dyslipidaemia compared with those without (p=0.03for interaction, for both; Fig. 4).”

Other predictors of less than average improvement in urinary ACR included increased plasma homocysteine, HbA1c and renin-angiotensin-system blocker use.

“Other predictors (also associated with decline in estimated GFR) included increased plasma homocysteine, HbA 1c and renin-angiotensin-system blocker use (p<0.05 for all).”

In the FIELD study, end-stage renal disease did not differ between the fenofibrate and placebo groups (21 vs 26, p=0.48).

“End-stage renal disease (creatinine >400 μmol/l [n=6 vs 3], dialysis [n=16 vs 21], renal transplant [n=0 vs 0] and/or renal death [n=1 vs 4]) did not differ between groups (21 in fenofibrate group vs 26 for placebo, p=0.48;Table 2).”

The estimated GFR preservation effect is most evident after treatment withdrawal.

“The latter is most evident after treatment withdrawal.”

In both groups, urinary ACR fell over 5 years.

“In both groups, urinary ACR fell over 5 years (Fig. 2c).”

In FIELD, patients receiving cimetidine had significantly greater increases in plasma creatinine in response to fenofibrate than others (p=0.002).

“In support of this possibility we observed significantly greater increases in plasma creatinine in response to fenofibrate in FIELD patients receiving cimetidine (a well recognised inhibitor of this tubular secretion) than those seen in others (p=0.002).”

In FIELD, doubling of serum creatinine occurred in 148 (3.0%) fenofibrate-treated patients vs 90 (1.8%) placebo-treated patients.

“Doubling of serum creatinine 90 (1.8) 148 (3.0) 238 (2.4)”

Commencement of other lipid medications did not influence fenofibrate benefit.

“and did not influence benefit.”

In FIELD, doubling of serum creatinine or ESRD excluding renal deaths occurred in 152 (3.1%) fenofibrate-treated patients vs 103 (2.1%) placebo-treated patients.

“Doubling of serum creatinine or ESRD b,c 103 (2.1) 152 (3.1) 255 (2.6)”

The fenofibrate-associated changes in urinary ACR were highly significant.

“Urinary ACR was measured in FIELD less often than plasma creatinine, but the fenofibrate-associated changes were nevertheless highly significant.”

Improvement in urinary ACR with fenofibrate was twofold greater than with placebo.

“Improvement in urinary ACR with fenofibrate was twofold greater than with placebo.”

Subsequent initiation of renin-angiotensin system blockers was higher in the placebo arm (30.1% vs 25.3% in fenofibrate group, p<0.001).

“As the subsequent initiation of renin-angiotensin system blockers was higher in the placebo arm (30.1% vs 25.3% in fenofibrate group, p<0.001)”

In FIELD placebo-treated patients, 2.8% developed micro- or macroalbuminuria each year.

“with 2.8% developing micro-or macroalbuminuria each year”

In FIELD, fenofibrate had significant beneficial effects on laser treatment for diabetic retinopathy.

“In FIELD, there was evidence that fenofibrate had significant beneficial effects on laser treatment for diabetic retinopathy [4] and lower limb amputations, including in instances regarded as having a predominantly microvascular aetiology [5].”

• cites [4] Keech AC, Mitchell P, Summanen PA et al (2007) Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD Study): a randomised controlled trial. Lancet 370:1687–1697 sourceNot checked — no full text of the source

Three-quarters of FIELD placebo-treated patients were normoalbuminuric at baseline.

“Three-quarters of FIELD placebo-treated patients were normoalbuminuric at baseline”

The absolute fall in estimated GFR in the placebo group was 8% over 5 years.

“absolute fall in estimated GFR in the placebo group (8% over 5 years)”

Hypertriacylglycerolaemia and the degree to which it is reduced were the only characteristics that predicted greater than average preservation of estimated GFR with fenofibrate.

“Hypertriacylglycerolaemia and the degree to which it is reduced were the only characteristics that predicted greater than average preservation of estimated GFR with fenofibrate.”

In FIELD, increases in plasma creatinine correlated weakly with increases in creatine phosphokinase after 6 weeks run-in (r=0.09, p<0.001) and at 5 years (r=0.14, p<0.001).

“while increases in plasma creatinine correlated weakly with increases in creatine phosphokinase (after 6 weeks run-in, r=0.09, p <0.001; at 5 years, r = 0.14, p < 0.001)”

In FIELD, plasma creatine phosphokinase rose 2.4% in those on fenofibrate vs 0.5% in those on placebo over 5 years (p=0.06 for difference).

“In FIELD, plasma creatine phosphokinase rose 2.4% in those on fenofibrate vs 0.5% in those on placebo (p=0.06 for difference) over 5 years of follow-up”

Commencement of other lipid medications, including statins, was greater in placebo-allocated patients (36.2% vs 19.3% in fenofibrate group).

“Similarly, commencement of other lipid medications, including statins, was greater in placebo-allocated patients (36.2% vs 19.3% in fenofibrate group)”

In FIELD, total patients with ESRD were 26 (0.5%) in the placebo group vs 21 (0.4%) in the fenofibrate group.

“Total patients with ESRD 26 (0.5) 21 (0.4) 47 (0.5)”

In pre-specified analyses, fenofibrate reduces albuminuria progression.

“In conclusion, we demonstrated in pre-specified analyses that fenofibrate reduces albuminuria progression and may reduce loss of renal function.”

Fenofibrate may reduce loss of renal function.

“In conclusion, we demonstrated in pre-specified analyses that fenofibrate reduces albuminuria progression and may reduce loss of renal function.”

The number needed to treat with fenofibrate to prevent one patient progressing to micro- or macroalbuminuria is 54.

“The number needed to treat with fenofibrate to prevent one patient progressing to micro-or macroalbuminuria is 54.”

The study found no evidence that the initial plasma creatinine rise represented true renal injury.

“We found no evidence that the initial plasma creatinine rise represented true renal injury, a finding that has important implications for clinical care.”

The groups were well matched including for renal function, blood pressure and glycaemia.

“The groups were well matched including for renal function, blood pressure and glycaemia (Table 1).”

Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients.

“Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients.”

• AssumptionRests on an assumption: The FIELD population is representative of type 2 diabetes patients generally.

Different underlying mechanisms are likely for the albuminuria reduction and GFR preservation effects of fenofibrate.

“Therefore, different underlying mechanisms are likely.”

The early plasma creatinine change does not represent true nephrotoxicity.

“The early plasma creatinine change does not represent true nephrotoxicity, since there was rapid reversion to pre-treatment levels in those subsequently allocated placebo after the run-in phase.”

Based on FIELD data, there is no evidence of permanent renal injury.

“Based on our data, there is no evidence of permanent renal injury.”

The washout timepoint of 52±13 days after close-out minimised any drug withdrawal rebound effect.

“Given that fenofibrate has a 20 h elimination half-life, this timepoint minimised any drug withdrawal rebound effect.”

• AssumptionRests on an assumption: Fenofibrate has a 20 h elimination half-life.

The increase in creatinine appears to be a separate process from the underlying renal preservation which is masked during active treatment.

“appears to be a separate process from the underlying renal preservation which is 'masked' during active treatment.”

The reno-protection provided by fenofibrate may have been underestimated.

“the reno-protection provided by fenobrate may have been underestimated.”

For patients with macroalbuminuria, the 11 mg/mmol difference in mean ACR would represent a 1% lower absolute 5-year risk of cardiovascular disease, based on a diabetes-specific risk calculator.

“in whom the 11 mg/mmol difference in mean ACR would represent a 1% lower absolute 5 year risk of cardiovascular disease, based on a diabetes-specific risk calculator [42].”

• cites [42] Davis WA, Knuiman MW, Davis TME (2010) An Australian cardiovascular risk equation for type 2 diabetes: the Fremantle Diabetes Study. Intern Med J 40:286–292 sourceNot checked — no full text of the source

Triacylglycerols have been linked to nephropathy through VLDL induction of PAI-1 with upregulated coagulation and intra-renal microthrombi.

“and through VLDL induction of plasminogen activating inhibitor-1 (PAI-1) with upregulated coagulation and intra-renal microthrombi [33].”

• cites [33] Olufadi R, Byrne CD (2006) Effects of VLDL and remnant particles on platelets. Pathophysiol Haemost Thromb 35:281–291 sourceNot checked — no full text of the source

Very few participants withdrew due to plasma creatinine rises.

“Moreover, very few participants withdrew due to plasma creatinine rises and, to our knowledge, the washout study is the first of its type among agents with renal effects.”

Fenofibrate-associated increased muscle turnover may have contributed in part to the creatininaemia.

“suggesting fenofibrate-associated increased muscle turnover may have contributed in part to the creatininaemia.”

Comparative temporal within-patient changes in estimated GFR and particularly plasma creatinine in the large sample are likely to remain robust.

“Nevertheless, comparative temporal within-patient changes in estimated GFR and particularly plasma creatinine in our large sample are likely to remain robust [43].”

• cites [43] Toffaletti JG, McDonnell EH (2008) Variation of serum creatinine, cystatin C, and creatinine clearance tests in persons with normal renal function. Clin Chim Acta 395:115–119 sourceNot checked — no full text of the source

The benefits of fenofibrate may not be solely lipid-mediated.

“the benefits of fenofibrate may not be solely lipid-mediated.”

Regression to the mean is unlikely to play a major role in these data.

“Regression to the mean is unlikely to play a major role in these data, as there was no entry criterion related to albuminuria and baseline measures of albuminuria and estimated GFR were both derived as the mean of two pre-randomisation values.”

The washout sub-study was adequately powered for the outcomes examined.

“The washout sub-study was relatively small, but nevertheless adequately powered for the outcomes examined and with highly statistically significant results obtained.”

The pattern of early plasma creatinine rise and subsequent attenuation of the rate of renal decline with fenofibrate therapy is similar to that seen with ACE inhibitors, albeit through different mechanisms.

“The pattern of early plasma creatinine rise and subsequent attenuation of the rate of renal decline with fenofibrate therapy is similar to that seen with ACE inhibitors, albeit through different mechanisms.”

Based on the placebo rate of estimated GFR loss over 5 years, fenofibrate's estimated GFR benefit would be equivalent to 3.6 kidney-years saved.

“However, based on the placebo rate of estimated GFR loss over 5 years, fenofibrate's estimated GFR benefit would be the equivalent of 3.6 kidney-years saved.”

The increase in creatinine due to fenofibrate is definitely reversible.

“Regardless of the physiology underlying the increase in creatinine, it is definitely reversible and appears to be a separate process from the underlying renal preservation which is 'masked' during active treatment.”

Statin trials have not consistently shown renoprotective effects despite moderate triacylglycerol reduction.

“As statin trials have not consistently shown renoprotective effects, despite moderate triacylglycerol reduction [28][29][30]”

• cites [28] Collins R, Armitage J, Parish S, Sleight P, Peto R, for the Heart Protection Study Collaborative Group (2003) MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 361:2005–2016 sourceNot checked — no full text of the source
• cites [29] Colhoun HM, Betteridge DJ, Durrington PN et al (2009) Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am J Kidney Dis 54:810–819 sourceNot checked — no full text of the source
• cites [30] Shepherd J, Kastelein JJP, Bittner V et al (2007) Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) Study. Clin J Am Soc Nephrol 2:1131–1139 sourceNot checked — no full text of the source

The protective effect of fenofibrate on diabetic retinopathy and lower limb amputations is consistent with the present findings of a slowing of the progression of diabetic microvascular renal disease.

“The protective effect of fenofibrate on these two microvascular complications of diabetes is consistent with the present findings of a slowing of the progression of diabetic microvascular renal disease.”

Because of greater cardiovascular therapy and statin uptake in the placebo group, the NNTs may be underestimates.

“Because of greater cardiovascular therapy and statin uptake in the placebo group, these may be underestimates.”