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

In the paper

“Although estimated GFR may underestimate true glomerular filtration rate [13], particularly at >90 ml min -1 1.73 m -2 , our analyses focused on changes over time and between treatments, rather than absolute values.”

What the sources say

• Supported

  The Conclusions state that both Cockcroft–Gault and MDRD estimates significantly underestimated isotopically measured GFR in newly diagnosed patients with type 2 diabetes, particularly when measured GFR was at least 90 ml/min per 1.73 m². This supports the citing sentence’s hedged claim in the population studied. (LLM, conf=0.94)

  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 source

In the paper

“Fenofibrate has been shown to decrease albuminuria in a mouse model of type 2 diabetes [10] and in humans [1,2,11].”

What the sources say

• Supported

  Citation [10] supports the mouse-model clause; the human clause is attributed to other citations. In “Urine volume and albuminuria,” the paper reports that fenofibrate reduced urinary albumin excretion in type 2 diabetic db/db mice. Page numbers were not provided. (LLM, conf=0.94)

  cites [10] Park CW, Zhang Y, Zhang X et al (2006) PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice. Kidney Int 69:1511–1517 source
• ?Not checked — no full text of the sourcecites [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 source
• Supported

  The Discussion reports reduced microalbuminuria and macroalbuminuria in the fenofibrate group. This supports the human finding for which this paper is cited; the mouse-model finding is attributed to a different citation. (LLM, conf=0.92)

  cites [2] The ACCORD Study Group (2010) Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 362:1563–1574 source
• ?Not checked — no full text of the sourcecites [11] Ansquer J-C, Foucher C, Rattier S, Taskinen M-R, Steiner G (2005) Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS). Am J Kidney Dis 45:485–493 source

In the paper

“Despite multifactorial treatment in the STENO-2 trial, renal disease still developed in 25% of patients over 13 years [15].”

What the sources say

• Supported

  The Results (p. 586) report that diabetic nephropathy developed in 20 patients in the intensive-therapy group during the entire observation period. The Study Design says 80 patients were assigned to that group, making 20 of 80 equal to 25%; the paper describes the follow-up as 13.3 years. (LLM, conf=0.92)

  cites [15] Gaede P, Lund-Andersen H, Parving H-H, Pedersen O (2008) Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 358:580–591 source

In the paper

“Interestingly, fenofibrate use in a mouse model of type 2 diabetes was linked with reduction in albuminuria, as well as histopathological improvements, e.g.reduced glomerular hypertrophy and reduced mesangial expansion [10].”

What the sources say

• Supported

  The Discussion reports that fenofibrate reduced urinary albumin excretion and improved renal histopathology in type II diabetic db/db mice, including reduced glomerular hypertrophy and mesangial matrix expansion. The urine volume and albuminuria section also reports persistently reduced albuminuria during treatment. (LLM, conf=0.95)

  cites [10] Park CW, Zhang Y, Zhang X et al (2006) PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice. Kidney Int 69:1511–1517 source

In the paper

“The ACCORD Lipid trial, which examined patients on a background of statin treatment and high use of renin-angiotensin system blockade, recently confirmed our finding that fenofibrate caused an acute plasma creatinine rise and long-term reduction of micro-and macroalbuminuria, with no adverse effect on end-stage renal disease compared with placebo [1,2].”

What the sources say

• ?Not checked — no full text of the sourcecites [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 source
• Partly supported

  The Results (Safety; page unavailable) report an early rise in serum creatinine with fenofibrate and no significant between-group difference in end-stage renal disease or hemodialysis. The Discussion (page unavailable) reports reductions in both microalbuminuria and macroalbuminuria. The Methods confirm background simvastatin treatment, but the passages found do not establish the citing sentence’s additional claim of high renin–angiotensin system blockade use. (LLM, conf=0.85)

  cites [2] The ACCORD Study Group (2010) Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 362:1563–1574 sourceExperimental — accuracy not yet measured

In the paper

“However, the study had no washout phase and was therefore not able to unmask the underlying GFR preservation demonstrated now by us.”

What the sources say

• Supported

  Research Design and Methods describes five years of fenofibrate or placebo treatment, and Laboratory Analyses places the baseline examination before treatment; the reported assessments do not include a post-treatment washout. The Conclusions say the available data cannot establish the significance of the treatment-related renal-marker changes. The GFR preservation 'demonstrated now by us' is the citing authors’ own finding, not one attributed to this source. Page numbers were not available in our copy. (LLM, conf=0.84)

  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 source

In the paper

“They also found a greater fall in estimated GFR in patients allocated fenofibrate compared with placebo, in keeping with our on-study findings.”

What the sources say

• Supported

  The Abstract Results report significant decreases in estimated GFR during fenofibrate treatment. The Conclusions state that fenofibrate reduced several measures of renal function more than placebo and describe a more modest eGFR reduction in the placebo group. Our copy provides no page number for these passages. (LLM, conf=0.93)

  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 source

In the paper

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

What the sources say

• Supported

  The Abstract concludes that the Cockcroft–Gault and MDRD equations significantly underestimate measured GFR in newly diagnosed patients with type 2 diabetes, particularly those with preserved renal function. The Conclusions also explicitly describe significant limitations of eGFR outside the setting of chronic kidney disease. The cited paper therefore supports the attributed statement that estimated GFR has limitations. (LLM, conf=0.94)

  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 source

In the paper

“but has been shown in animals and humans to be reno-protective [35]”

What the sources say

• Partly supported

  The Results passage (page unavailable in our copy) associates higher HDL cholesterol with a lower risk of a rise in creatinine in humans, but this observational finding does not show that HDL itself protects the kidney. The paper’s discussion of animal models reports reduced renal injury after lipid-lowering treatment, not a protective effect specifically attributable to HDL. (LLM, conf=0.87)

  cites [35] Muntner P, Coresh J, Smith JC, Eckfeldt J, Klag MJ (2000) Plasma lipids and risk of developing renal dysfunction: the Atherosclerosis Risk in Communities Study. Kidney Int 58:293–301 sourceExperimental — accuracy not yet measured

In the paper

“Implications for cardiovascular protection may be relatively small for normoalbuminuric patients, but are greater for those with macroalbuminuria (ESM Fig. 2) [9]”

What the sources say

• Partly supported

  The Clinical outcomes section reports higher cardiovascular risk with albuminuria than without it, and the Discussion identifies macroalbuminuria as a marker of roughly doubled CVD risk. That supports a possible greater need for cardiovascular protection, but not a greater protective effect of treatment: the paper reports no significant treatment-by-albuminuria subgroup interaction. Page numbers were not available in our copy. (LLM, conf=0.82)

  cites [9] Drury P, Ting R, Zannino D et al. (2010) Estimated glomerular filtration rate and albuminuria are independent predictors of cardiovascular events and death in type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia. doi: 10.1007/s00125-010-1854-1 sourceExperimental — accuracy not yet measured

In the paper

“A very similar rise in serum cystatin C was also demonstrated in the Helsinki sub-study [21], but measurements were not repeated after treatment withdrawal.”

What the sources say

• Supported

  The paper identifies itself as the FIELD Helsinki substudy (Conclusions). Its Results report that cystatin C rose by 14.1% in the fenofibrate group, compared with 3.6% in the placebo group (P < 0.001). (LLM, conf=0.93)

  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 source

In the paper

“In the same group, estimated GFR fell proportionately and below 90 ml min -1 1.73 m -2 at a rate of approximately 5% per annum.”

In the paper

“This reflected a 5-year fall in estimated GFR of 1.9 ml min -1 1.73 m -2 in the fenofibrate group (from 89.2 to 87.3; p=0.07) vs 6.9 ml min -1 1.73 m -2 in the placebo group (from 87.5 to 80.6; p<0.001), such that fenofibrate spared an average of 5.0 ml min -1 1.73 m -2 (p<0.001) or ~1 ml min -1 1.73 m -2 annually (Fig. 3b).”

In the paper

“Benefit also differed by treatment response according to the extent of plasma triacylglycerol lowering with fenofibrate (during active run-in), being observed continuously (p=0.002) and categorically (p=0.02 for interaction; ESM Table 3), but independently of all other variables (including other baseline lipids, blood pressure and renin-angiotensin system blocker use; Fig. 4) and on-study commenc”

In the paper

“estimated GFR preservation was greater in patients with baseline dyslipidaemia and greater fenofibrate-related plasma triacylglycerol reduction.”

In the paper

“These benefits were similar for all subgroups (including reninangiotensin system blocker use), except sex, with larger effects among men than women (post hoc analysis, data not shown).”

In the paper

“The mean annual rates of plasma creatinine rise and estimated GFR decline were 1.62 vs 1.89 μmol/l and 1.19 vs 2.03 ml min -1 1.73 m -2 respectively for patients on fenofibrate vs those on placebo.”

In the paper

“A fall in urinary creatinine concentration was observed with fenofibrate, but this was exceeded by the decrease in urinary albumin concentration, reducing the ratio.”

In the paper

“This equated to a 0.2 mg/mmol difference in mean ACR at close-out (fenofibrate 1.1 vs placebo 1.3 mg/mmol), reflecting 11.7, 1.0 and 0.1 mg/mmol differences among macro-, microand normoalbuminuric participants respectively (ESM Fig. 2).”

In the paper

“A shift across categories occurred, favouring fenofibrate, with 14% less progression (11.1% vs 12.9%) and 18% more regression (11.2% vs 9.5%; p<0.001;ESM Table 4).”

In the paper

“Fenofibrate benefits were independent of blood pressure despite an associated lowering of systolic BP by approximately 2 mmHg.”

In the paper

“This protection was observed across most subgroups and was irrespective of baseline or on-study commencement of renin-angiotensin system blockers.”

In the paper

“In the FIELD study, the number needed to treat to prevent one patient worsening by at least one estimated GFR grouping (<30, 30 to <60, 60 to <90 or ≥90 ml min -1 1.73 m -2 ) was 25 and only 10 for dyslipidaemic patients.”

In the paper

“Eligibility was confirmed during run-in independently of adherence or biochemical changes.”

In the paper

“A telephone computer randomisation service using dynamic balancing to stratify patients by prognostic variables was used.”

In the paper

“All investigators, except the authorised study statistician, were masked to treatment allocation before and after randomisation.”

In the paper

“All measurements of albuminuria and creatinine were performed in the central laboratories with regular quality assurance through participation in national schemes.”

In the paper

“Two-sided p values were significant at p<0.05 and were unadjusted for multiple comparisons.”

In the paper

“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.”

• Also stated in: § Randomisation and interventions · plain

  “Pre-specified renal endpoints were: (1) renal function changes; (2) urinary albumin: creatinine ratio (ACR) changes; and (3) end-stage renal disease, defined as plasma creatinine >400 μmol/l, dialysis, transplant or renal disease death.”

In the paper

“FIELD was a randomised, double-blind placebo controlled trial with the primary outcome of coronary events.”

In the paper

“Plasma creatinine was measured by the Jaffe reaction (alkaline picrate-kinetic) on a clinical chemistry analyser (Hitachi 917; Roche Diagnostics, Basel, Switzerland), using calibrators supplied by the manufacturer, with interassay CVs over 5 years of 1.3% at a concentration of 170 μmol/l and 1.9% at 600 μmol/l.”

In the paper

“Analysis was by intention-to-treat.”

In the paper

“Urine albumin was measured by immunonephelometry on an analyser (Array 360; Beckman, Fullerton, CA, USA), with interassay CVs over 5 years of 2.8% at a concentration of 10 mg/l and 2.5% at 50 mg/l.”

In the paper

“This definition was revised to be sex-specific after the study was unmasked.”

In the paper

“In analyses pre-specified 6 months prior to unmasking of the study, 661 patients were re-assessed 52±13 days after close-out to further evaluate the known fenofibrate-associated changes in plasma creatinine.”

In the paper

“Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine.”

In the paper

“This registered study had ethics committee approval in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines.”

In the paper

“All patients provided written informed consent and then completed a 16 week run-in period comprising 4 weeks of diet, 6 weeks of single-blind placebo and 6 weeks of single-blind fenofibrate.”

In the paper

“They had similar baseline characteristics to non-participants and balanced characteristics by treatment allocation (Electronic supplementary material [ESM] Table 1).”

In the paper

“This method showed excellent agreement with isotope-dilution mass spectrometry and recovered the certified values assigned to the reference material.”

In the paper

“Only the analyses relating to changes in estimated GFR from baseline to the end of the washout period according to baseline characteristics and changes in biomarkers during active run-in were post hoc, in that the associations between the prespecified variables and the pre-specified outcomes were not expressly stated in the statistical analysis plan.”

In the paper

“These effects can be differentiated through a washout study, without which structural preservation may be missed [18].”

What the sources say

• ?Not checked — no full text of the sourcecites [18] Heerspink HL, de Zeeuw D (2010) Composite renal endpoints: was ACCOMPLISH accomplished? Lancet 375:1140–1142 source

In the paper

“Hottelart et al. demonstrated increased creatinuria with no fall in creatinine clearance [25].”

What the sources say

• ?Not checked — no full text of the sourcecites [25] Hottelart C, Esper NE, Rose F, Achard J-M, Fournier A (2002) Fenofibrate increases creatinemia by increasing metabolic production of creatinine. Nephron 92:536–541 source

In the paper

“Fenofibrate effects on renal plasma flow in these two studies were also contrasting [16,25], but both concluded there was no loss of glomerular function.”

What the sources say

• ?Not checked — no full text of the sourcecites [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 source
• ?Not checked — no full text of the sourcecites [25] Hottelart C, Esper NE, Rose F, Achard J-M, Fournier A (2002) Fenofibrate increases creatinemia by increasing metabolic production of creatinine. Nephron 92:536–541 source

In the paper

“*Values for estimated GFR in patients while on fenofibrate may be unreliable and may underestimate true GFR”

In the paper

“Triacylglycerols have been linked to nephropathy through mesangial cell uptake of very low-density lipoprotein (VLDL), inducing foam cell formation [32]”

What the sources say

• ?Not checked — no full text of the sourcecites [32] Anami Y, Kobori S, Sakai M et al (1997) Human beta-migrating very low density lipoprotein induces foam cell formation in human mesangial cells. Atherosclerosis 135:225–234 source

In the paper

“ACE inhibitors increase creatinine through a true reduction in GFR secondary to reduced intraglomerular pressure, but are reno-protective because they decrease glomerular hyperfiltration and have anti-fibrogenic effects [26,27].”

What the sources say

• ?Not checked — no full text of the sourcecites [26] Taal MW, Brenner BM (2000) Renoprotective benefits of RAS inhibition: from ACEI to angiotensin II antagonists. Kidney Int 57:1803–1817 source
• ?Not checked — no full text of the sourcecites [27] Bakris GL, Weir MR (2000) Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine. Is this a cause for concern? Arch Intern Med 160:685–693 source

In the paper

“insulin resistance which is a risk factor for renal dysfunction [38].”

What the sources say

• ?Not checked — no full text of the sourcecites [38] Agrawal V, Shah A, Rice C, Franklin BA, McCullough PA (2009) Impact of treating the metabolic syndrome on chronic kidney disease. Nat Rev Nephrol 5:520–528 source

In the paper

“One strength of the FIELD study is that it is one of the largest type 2 diabetes randomised trials examining pre-specified renal outcomes.”

In the paper

“The arguably small absolute fall in estimated GFR in the placebo group (8% over 5 years) may reflect good control of blood pressure, glycaemia and dyslipidaemia [39].”

What the sources say

• ?Not checked — no full text of the sourcecites [39] Parving H-H, Lehnert H, Brochner-Mortensen J et al (2001) The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 345:870–878 source

In the paper

“We incorporated variables available in a usual-care context to ensure relevance to clinical practice.”

In the paper

“The observed relationships between both hypertriacylglycerolaemia and dyslipidaemia and renal function in the FIELD study may also reflect insulin resistance which is a risk factor for renal dysfunction [38].”

What the sources say

• ?Not checked — no full text of the sourcecites [38] Agrawal V, Shah A, Rice C, Franklin BA, McCullough PA (2009) Impact of treating the metabolic syndrome on chronic kidney disease. Nat Rev Nephrol 5:520–528 source

In the paper

“Serum cystatin C, an indicator of renal dysfunction in type 2 diabetes, also modestly increases in patients on fenofibrate without any change in inulin clearance [16] and reverts shortly after drug withdrawal (J.-C.Ansquer, Laboratoires Fournier SA, Dijon, France, personal communication), but has not yet been measured in FIELD.”

What the sources say

• ?Not checked — no full text of the sourcecites [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 source

In the paper

“Study sponsors had no role in data collection or analysis.”

In the paper

“This compares favourably with 66 to 100 for ACE inhibitor use in MICRO-HOPE [41].”

What the sources say

• ?Not checked — no full text of the sourcecites [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 source

In the paper

“The study was designed by an independent Management Committee and coordinated by the National Health and Medical Research Council (NHMRC) Clinical Trials Centre, University of Sydney, NSW, Australia.”

In the paper

“The authors had full access to all study data.”

In the paper

“The size and consistency of the estimated GFR and albuminuria benefits support use of fenofibrate in type 2 diabetes to reduce renal morbidity, especially in patients with dyslipidaemia.”

In the paper

“This appears to be independent of, and therefore additive to renin-angiotensin system blockade and glycaemic control.”