Effect of fenofibrate on uric acid and gout in type 2 diabetes: a post-hoc analysis of the randomised, controlled FIELD study.

BACKGROUND: Gout is a painful disorder and is common in type 2 diabetes. Fenofibrate lowers uric acid and reduces gout attacks in small, short-term studies. Whether fenofibrate produces sustained reductions in uric acid and gout attacks is unknown. METHODS: In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, participants aged 50-75 years with type 2 diabetes were randomly assigned to receive either co-micronised fenofibrate 200 mg once per day or matching placebo for a median of 5 years follow-up. We did a post-hoc analysis of recorded on-study gout attacks and plasma uric acid concentrations according to treatment allocation. The outcomes of this analysis were change in uric acid concentrations and risk of on-study gout attacks. The FIELD study is registered with ISRCTN, number ISRCTN64783481. FINDINGS: Between Feb 23, 1998, and Nov 3, 2000, 9795 patients were randomly assigned to fenofibrate (n=4895) or placebo (n=4900) in the FIELD study. Uric acid concentrations fell by 20·2% (95% CI 19·9-20·5) during the 6-week active fenofibrate run-in period immediately pre-randomisation (a reduction of 0·06 mmol/L or 1 mg/dL) and remained -20·1% (18·5-21·7, p<0·0001) lower in patients taking fenofibrate than in those on placebo in a random subset re-measured at 1 year. With placebo allocation, there were 151 (3%) first gout events over 5 years, compared with 81 (2%) among those allocated fenofibrate (HR with treatment 0·54, 95% CI 0·41-0·70; p<0·0001). In the placebo group, the cumulative proportion of patients with first gout events was 7·7% in patients with baseline uric acid concentration higher than 0·36 mmol/L and 13·9% in those with baseline uric acid concentration higher than 0·42 mmol/L, compared with 3·4% and 5·7%, respectively, in the fenofibrate group. Risk reductions were similar among men and women and those with dyslipidaemia, on diuretics, and with elevated uric acid concentrations. For participants with elevated baseline uric acid concentrations despite taking allopurinol at study entry, there was no heterogeneity of the treatment effect of fenofibrate on gout risk. Taking account of all gout events, fenofibrate treatment halved the risk (HR 0·48, 95% CI 0·37-0·60; p<0·0001) compared with placebo. INTERPRETATION: Fenofibrate lowered uric acid concentrations by 20%, and almost halved first on-study gout events over 5 years of treatment. Fenofibrate could be a useful adjunct for preventing gout in diabetes. FUNDING: None.

Systematic literature review and meta-analysis of dual therapy with fenofibrate or fenofibric acid and a statin versus a double or equivalent dose of statin monotherapy.

OBJECTIVE: To assess the efficacy of fenofibrate and statin dual therapy versus a double or equivalent dose of statin monotherapy. METHODS: A systematic literature search and meta-analysis was performed for publications before 1 January 2014 in MEDLINE, Embase, and BIOSIS Previews, among others. RESULTS: The difference in percentage change from baseline was in favor of dual therapy versus a double dose of statin monotherapy for triglycerides (difference -20%; standard error [SE] 2.6%) and HDL-C (8.7%; SE 1.2%), but not for LDL-C (8.4%; SE 1.5%), non-HDL-C (2.8%; SE 1.1%), total cholesterol (4.5%; SE 1.0%) and apolipoprotein B (2.6%; SE 1.1%). For high intensity statins, the difference in percentage change from baseline was in favor of dual therapy versus equivalent statin monotherapy for triglycerides (-17%; SE 2.6%) and for HDL-C (8.7%; SE 1.9%). The difference in percentage change from baseline for LDL-C was 6% (SE 1.7%), implying a greater reduction in LDL-C with statin monotherapy. For moderate intensity statins, the difference in percentage change from baseline was in favor of dual therapy versus equivalent statin monotherapy for triglycerides (-24.2%; SE 1.2%) and HDL-C (8.2%; SE 0.9%). LDL-C decreased 2.2% (SE 1.4%) more with dual therapy. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: When aiming to change HDL-C or triglycerides, dual therapy is to be preferred to doubling the statin dose; conversely, doubling the statin dose is to be preferred when aiming to reduce LDL-C. If the aim is both to change HDL-C or triglycerides and to reduce LDL-C, the importance of the three outcomes may need to be weighed depending on the intensity of the statin. Combining high intensity statin therapy with fenofibrate improves the effect on HDL-C and triglycerides, but lowers the effect on LDL-C. Combining a moderate intensity statin with fenofibrate improves the effect on HDL-C and triglycerides without reducing the effect on LDL-C. There is a need for long-term randomized clinical trials to compare dual therapy versus doubling the statin dose to assess the importance of improvement in HDL-C and triglycerides versus improvement in LDL-C in terms of cardiovascular outcomes. Further, the addition of ezetimibe to statin/fenofibrate therapy may be of interest.

Effects of fenofibric acid on diabetic macular edema: the MacuFen study.

PURPOSE: Fenofibrate reduced progression of diabetic retinopathy in two large randomized studies. The effect of 135 mg fenofibric acid on diabetic macular edema (DME) was evaluated in subjects with existing DME. METHODS: In this double-blind, randomized, placebo-controlled study, 110 subjects with DME not requiring immediate photocoagulation or intraocular treatment with adequate diabetes and blood pressure control received either fenofibric acid or placebo once daily for 1 year. Total macula volume (TMV) and thickness were measured in the worse eye and all eligible eyes with time-domain optical coherence tomography at baseline and quarterly thereafter. RESULTS: TMV decreased by -0.35 mm(3) (within-group difference) after fenofibric acid treatment and by -0.11 mm(3) after placebo. The between-group comparison of the change was -0.25 mm(3) (95% confidence interval, CI, -0.645-0.155; p = 0.227, worse eye analysis). Weighted inner zone thickness and volume decreased by -18.7 µm and -0.13 mm(3), respectively, for within group difference after fenofibric acid and by -3.1 µm and -0.02 mm(3), respectively, after placebo. Considering all eligible eyes, thicknesses at central zone, mean inner zone, and entire retina decreased by -21.3 µm, -19.8 µm, and -20.4 µm, respectively, after fenofibric acid. No between-group difference in changes of these measurements was observed. Triglycerides decreased by 23% after fenofibric acid (vs 4% after placebo, p = 0.001) and high-density lipoprotein cholesterol increased by 8% (vs 0.3%, p = 0.014). No safety concern was identified. CONCLUSION: Subjects treated with fenofibric acid had a modest improvement in TMV, although the study was probably underpowered to detect a benefit over placebo after 1 year.

Pharmacokinetic interaction between simvastatin and fenofibrate with staggered and simultaneous dosing: Does it matter?

Simvastatin and fenofibrate are frequently co-prescribed at staggered intervals for the treatment of dyslipidemia. Since a drug-drug interaction has been reported when the two drugs are given simultaneously, it is of clinical interest to know whether the interaction differs between simultaneous and staggered combinations. A study, assessing the impact of both combinations on the interaction, was conducted with 7-day treatment regimens using simvastatin 40 mg and fenofibrate 145 mg: (A) simvastatin only (evening), (B) simvastatin and fenofibrate (both in evening), and (C) simvastatin (evening) and fenofibrate (morning). Eighty-five healthy subjects received the respective treatments in a randomized, 3-way cross-over study. The pharmacokinetics of simvastatin and the active metabolite simvastatin acid were determined. There was a limited reduction in the AUC0-24h of simvastatin acid of 21 and 29% for simultaneous and staggered combination, respectively. The geometric mean AUC0-24h ratio of simvastatin acid for the two combined dosing regimens (B/C) and 90% confidence interval were 111% (102-121). The interaction apparently had no impact on lipid markers. The findings imply that the observed pharmacokinetic interaction is unlikely clinically relevant, and support the combined use of simvastatin and fenofibrate not only given at staggered interval but also given simultaneously.

Effect of fenofibrate treatment on the low molecular weight urinary proteome of healthy volunteers.

PURPOSE: Urinary peptidome changes and discrimination for potential renal glomerular and tubular damage after 6 wk of fenofibrate treatment were evaluated in 26 healthy subjects. EXPERIMENTAL DESIGN: Peptide profiling was performed in urine samples before and after treatment using high-resolution capillary electrophoresis coupled with electrospray ionization mass spectrometry. RESULTS: A panel of 88 fenofibrate-sensitive peptides was detected with a frequency of ≥50% before and after treatment. This was reduced to 36 peptides by repeating the comparison ten times by randomly excluding samples at each time-point. Nineteen peptides were consistent and reliable biomarkers after an additional comparison with an age and sex-matched subject control group. Levels of peptides identified as fragments of Collagen α-1 (I), Collagen α-1 (XVII), Collagen α-2 (VIII) or sodium/potassium-transporting ATPase subunit gamma were reduced after fenofibrate treatment. Classification scores for renal tubular and glomerular damages determined by support vector machine based biomarker models increased after treatment but remained below pathological score cutoff values. CONCLUSIONS AND CLINICAL RELEVANCE: Fenofibrate treatment led to minor modifications of the urinary proteomic profile in a way that does not create safety issues affecting glomerular and tubular functions. Urinary peptide profiling proved to be appropriate to monitor drug pharmacological effects in a clinical setting.

Fibrates and statins in the treatment of diabetic retinopathy.

Diabetic retinopathy (DR) is one of the leading risk factors and causes of blindness worldwide. Tight glucose and blood pressure control has been shown to significantly decrease the risk of development as well as the progression of retinopathy and represents the cornerstone of medical management of DR. The two most threatening complications of DR are diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). Photocoagulation is standard treatment for both DME and PDR. However, some patients suffer permanent visual loss despite therapy. Treatment with fibrates first showed reduction in hard exudates, an effect subsequently shown with statins in short term studies, in particular two randomized studies in patients with macular edema. In the FIELD study which pre-specified microvascular outcomes, fenofibrate reduced laser treatment for DME or PDR by 31%:164 (3.4%) patients on fenofibrate vs. 238 (4.9%) on placebo (p<0.001). In the ophthalmology sub-study of FIELD, the composite exploratory endpoint of 2-step progression of ETDRS retinopathy grade, macular edema or laser treatment was significantly reduced by 34%: 53 (11.1%) patients on fenofibrate vs. 75 (16.1%) on placebo (p=0.022). Conversely, there was no reduction in laser treatment or reduced progression of retinopathy in two large scale studies of statins where cardiovascular events were significantly reduced. Neither class of lipid-lowering drugs consistently improved visual acuity. In the ACCORD-EYE study, the combination of fenofibrate and simvastatin reduced by 40% the rate of progression of diabetic retinopathy compared with simvastatin alone. Other studies are needed to establish the place of lipid lowering drugs in the treatment of macular edema and the prevention of vision loss.

Fenofibrate, homocysteine and renal function.

Fibrates or PPAR alpha agonists, in particular fenofibrate, are known to increase homocysteine levels (Hcy). A 3 to 5 micromol/L increase in Hcy is commonly observed within the first few weeks of fenofibrate treatment; it then persists in plateau when treatment is continued and is reversible upon its cessation. Since its description in 1999, this pharmacological effect attracted a great deal of attention as epidemiological studies in most populations have shown that elevated Hcy levels i.e.Hcy> or =15 micromol/L are associated with an increased risk of cardiovascular events (CVD), venous thromboembolic events (VTE) and possibly cognitive disorders and bone fractures. Chronic kidney disease is also associated with elevated Hcy levels and since fenofibrate increases creatinine levels by about 10-12 micromol/L, a relationship between Hcy and creatinine was postulated. Animal studies have shown that the Hcy increase is PPARalpha dependent but to date animal or human studies have not provided a clear mechanism. In particular, fenofibrate treatment does not change vitamin B levels; however, vitamin B supplements reduce fenofibrate-induced Hcy elevation but not the concomitant cysteine elevation. Similarly, the increase in creatinine with fenofibrate only partially accounted for by a reduction in glomerular filtration rate (GFR) since creatinine production is also increased by 5-10%. In the FIELD study, a placebo-controlled study in 9795 patients with type 2 diabetes, fenofibrate over 5 years reduced non-fatal cardiovascular events and microvascular events such as albuminuria, the need for laser treatment for proliferative retinopathy or maculopathy and amputations but did not reduce fatal events. The increase in Hcy was indeed much larger that what would be explained by creatinine elevation and independent from baseline kidney function. Although baseline Hcy and creatinine levels were associated with subsequent risk of CVD, as suggested by epidemiology, their respective elevation was not. Of interest, after withdrawal of fenofibrate, a potential renoprotective effect was unmasked, as estimated GFR was 5 ml/min/1.73 m2 higher in previous fenofibrate-allocated patients than in previous placebo-allocated patients. There was no suggestion that Hcy elevation was associated with VTE (which were increased by an unknown mechanism) or bone disorders. In conclusion, the discrepancy between the role of baseline Hcy levels in epidemiology and the absence of effect when altering its levels by either decreasing them with vitamin B supplements or increasing them with fenofibrate, suggests that the risk factor(s) behind homocysteine should be found. Nevertheless, other studies are also needed to understand the mechanism and the implications of the moderate homocysteine and creatinine elevations with fenofibrate and other PPARalpha agonists.

Proof of concept study: does fenofibrate have a role in sleep apnoea syndrome?

OBJECTIVE: To investigate the effect of fenofibrate on sleep apnoea indices. METHODS: Proof-of-concept study comprising a placebo run-in period (1 week, 5 weeks if fibrate washout was required) and a 4-week randomized, double-blind treatment period. Thirty-four subjects (mean age 55 years, body mass index 34 kg/m 2 , fasting triglycerides 3.5 mmol/L) with diagnosed sleep apnoea syndrome not treated with continuous positive airways pressure were enrolled and randomized to once daily treatment with fenofibrate (145 mg NanoCrystal(R) tablet) or placebo. Overnight polysomnography, computerized attention/vigilance tests and blood sampling for measurement of lipids, insulin, fasting plasma glucose and fibrinogen were performed at the end of each study period. CLINICAL TRIAL REGISTRATION: NCT00816829. MAIN OUTCOME MEASURES: As this was an exploratory study, a range of sleep variables were evaluated. The apnoea/hypopnoea index (AHI) and percentage of time spent with arterial oxygen saturation (SpO(2)) <90% were relevant as they have been evaluated in other clinical trials. Other variables included total apnoeas, hypopnoeas and oxygen desaturations, and non-cortical micro-awakenings related to respiratory events per hour. RESULTS: Fenofibrate treatment significantly reduced the percentage of time with SpO(2) <90% (from 9.0% to 3.5% vs. 10.0% to 11.5% with placebo, p = 0.007), although there was no significant change in the AHI (reduction vs. control 14% (95%CI -47 to 40%, p = 0.533). Treatment reduced obstructive apnoeas (by 44%, from 18.5 at baseline to 15.0 at end of treatment vs. 29.0 to 30.5 on placebo, p = 0.048), and non-cortical micro-awakenings per hour (from 23.5 to 18.0 vs. 24.0 to 25.0 with placebo, p = 0.004). Other sleep variables were not significantly influenced by fenofibrate. KEY LIMITATIONS: Exploratory study in patients with mild to moderate sleep apnoea, limited treatment duration; concomitant hypnotic treatment (35%); lack of correction for multiplicity of testing. CONCLUSIONS: The consistent direction of change in sleep indices in this proof-of-concept study may support further investigation of fenofibrate in moderate to severe sleep apnoea syndrome.

Comparison of the gastrointestinal absorption and bioavailability of fenofibrate and fenofibric acid in humans.

This study compared the gastrointestinal (GI) absorption characteristics and absolute bioavailability of fenofibric acid and fenofibrate (which is converted to fenofibric acid in vivo) in healthy volunteers. Treatments were delivered to the proximal small bowel, distal small bowel, and colon using a site-specific delivery system (Enterion capsule) and to the stomach by oral administration of equimolar doses. Serial blood samples were collected for 120 hours postdose and assayed for plasma fenofibric acid concentrations. The absolute bioavailability of each treatment was determined relative to 50 mg of fenofibric acid administered intravenously. Plasma exposure to fenofibric acid following fenofibric acid administration was approximately 1.5 times higher than that following fenofibrate administration for delivery to the proximal and distal small bowel and following oral administration, and it was approximately 5 times higher following colon delivery. The absolute bioavailability in the stomach, proximal small bowel, distal small bowel, and colon was approximately 81%, 88%, 84%, and 78%, respectively, for fenofibric acid and 69%, 73%, 66%, and 22%, respectively, for fenofibrate (P < .0001 and P = .033 for fenofibric acid vs fenofibrate in the colon and distal small bowel, respectively). In conclusion, fenofibric acid is well absorbed throughout the GI tract and has greater bioavailability than fenofibrate in all GI regions.

Efficacy and safety of coadministration of fenofibrate and ezetimibe compared with each as monotherapy in patients with type IIb dyslipidemia and features of the metabolic syndrome: a prospective, randomized, double-blind, three-parallel arm, multicenter, comparative study.

BACKGROUND: Patients with type IIb, or mixed, dyslipidemia have high levels of low-density lipoprotein cholesterol (LDL-C) with predominance of small dense LDL particles, high levels of triglycerides (TG), and low levels of high-density lipoprotein cholesterol (HDL-C). Fenofibrate significantly reduces TG and, more moderately, LDL-C, increases HDL-C and produces a shift from small to large LDL particle size; the main effect of ezetimibe is a reduction in LDL-C levels. Combined treatment with fenofibrate and ezetimibe may correct all the abnormalities of type IIb dyslipidemia. OBJECTIVE: To assess the efficacy and safety of coadministration of fenofibrate (NanoCrystal(R)) and ezetimibe in patients with type IIb dyslipidemia and the metabolic syndrome compared with administration of fenofibrate and ezetimibe alone (ClinicalTrials.gov Identifier: NCT00349284; Study ID: CLF178P 04 01). METHODS: This was a prospective, randomized, double-blind, three-parallel arm, multicenter, comparative study. Sixty ambulatory patients (mean age 56 years; 50% women, 50% men) were treated in each group. For inclusion in the study, patients were required to have LDL-C >or=4.13 mmol/L (>or=160 mg/dL), TG >or=1.71 mmol/L and or=150 mg/dL and

Effects of atorvastatin 10 mg and fenofibrate 200 mg on the low-density lipoprotein profile in dyslipidemic patients: A 12-week, multicenter, randomized, open-label, parallel-group study.

BACKGROUND: Elevated plasma low-density lipoprotein cholesterol (LDL-C) concentrations are highly atherogenic, especially the small, dense LDL (sdLDL) species. Fenofibrate has been reported to shift the LDL profile by decreasing the sdLDL subfraction and increasing larger LDL subclasses. Atorvastatin, anantihyperlipidemic agent, has been reported to reduce plasma total cholesterol (TC) and triglyceride (TG) concentrations and thus could modify the LDL profile. OBJECTIVE: The aim of this study was to compare the effects of fenofi brate and atorvastatin on standard lipid concentrations and the LDL profile. METHODS: In this randomized, open-label, parallel-group study, men and women aged 18 to 79 years with type II primary dyslipidemia, defined as LDL-C ≥160 and TG 150 to 400 mg/dL, after a 4- to 6-week washout period while eating an appropriate diet, were randomized to receive either atorvastatin 10 mg once daily or fenofi-brate 200 mg once daily. Plasma lipid concentrations and cholesterol and apolipoprotein (apo) B (reflecting the LDL particle number) in each LDL subfraction prepared by ultracentrifiigation were determined at baseline and after 12 weeks of treatment. Tolerability was assessed using adverse events (AEs) obtained on laboratory analysis and vital sign measurement. Adherence was assessed by counting unused drug supplies. RESULTS: A total of 165 patients (117 men, 48 women; mean [SD] age, 50.1 [10.7] years; mean TC concentration, 289 mg/dL) were randomized to receive atorvastatin (n = 81) or fenofibrate (n = 84). Compared with fenofibrate, atorvastatin was associated with a significantly greater mean (SD) percentage decrease in TC (27.0% [12.3%] vs 16.5% [12.9%]; P < 0.001), calculated LDL-C (35.4% [15.8%] vs 17.3% [17.2%]; P < 0.001), TC/high-density lipoprotein cholesterol (HDL-C) ratio (29.1% [16.3%] vs 22.9% [15.9%]; P = 0.001), and apoB (30.3% [12.7%] vs 19.6% [15.5%]; P < 0.001). Compared with atorvastatin, fenofibrate was associated with a significantly greater decrease in TG (37.2% [25.9%] vs 20.2% [27.3%]; P < 0.001) and a significantly greater increase in HDL-C concentration (10.4% [15.7%] vs 4.6% [12.1%]; P = 0.017). Fibrinogen concentration was significantly different between the 2 groups (P = 0.002); it was decreased with fenofibrate use (4.6% [23.7%]) and was increased with atorvastatin use (5.7% [23.5%]). Atorvastatin did not markedly affect the LDL distribution; it was associated with a homogeneous decrease in cholesterol and apoB concentrations in all subfractions, whereas fenofibrate was associated with a marked movement toward a normalized LDL profile, shifting the sdLDL subfractions toward larger and less atherogenic particles, particularly in those patients with baseline TG ≥200 mg/dL. No serious AEs related to the study treatments were reported. A total of 5 AEs were observed in 8 patients, including: abdominal pain, 3 patients (2 in the atorvastatin group and 1 in the fenofibrate group); abnormal liver function test results, 1 (fenofibrate); increased creatine Phosphokinase activity, 2 (atorvastatin); gastrointestinal disorders, 1 (fenofibrate); and vertigo, 1 (fenofibrate). CONCLUSION: In these dyslipidemic patients, fenofibrate treatment was associated with an improved LDL subfraction profile beyond reduction in LDL-C, particularly in patients with elevated TG concentration, whereas atorvastatin was associated with equally reduced concentrations of cholesterol and apoB in all LDL subfractions independent of TG concentrations.

Effect of fenofibrate on kidney function: a 6-week randomized crossover trial in healthy people.

BACKGROUND: Fenofibrate was associated with increases in serum creatinine concentrations. The effect of short-term fenofibrate treatment on kidney function was investigated in subjects with normal kidney function. STUDY DESIGN: Double-blind, crossover, placebo-controlled. SETTING AND PARTICIPANTS: 24 middle-aged subjects with normal kidney function (estimated creatinine clearance > or = 80 mL/min). INTERVENTION: Subjects were treated with fenofibrate (160-mg/d tablet) and placebo in two 6-week periods separated by a washout. OUTCOMES AND MEASUREMENTS: The primary outcome measure was glomerular filtration rate measured by means of inulin clearance, with a test of noninferiority to rule out a change in the 95% confidence interval (CI) greater than 20%. Secondary outcomes included effective renal plasma flow measured by means of para-aminohippurate (PAH) clearance, creatinine clearance, creatinine secretion (ratio of creatinine to inulin clearance), serum cystatin C and uric acid, and urinary excretion of creatinine. Glomerular and tubular damage was evaluated by using albumin and retinol-binding protein levels and N-acetyl-beta-d-glucosaminidase activity. RESULTS: Inulin clearance was unchanged after fenofibrate (change [Delta] between treatments on 6-week values, 0.8 mL/min; 95% CI, -10.5 to 12.2; P = 0.9), but PAH clearance decreased (Delta, -33; 95% CI, -66 to -1; P = 0.05). Changes in inulin and PAH clearances were not greater than 20%. Plasma creatinine level increased (Delta, 0.11 mg/dL; 95% CI, 0.05 to 0.18; P < 0.05), and creatinine clearance decreased (Delta, -9.5 mL/min; 95% CI, -14.4 to -4.7; P < 0.001). Creatinine secretion and urinary creatinine excretion were unchanged (Delta, -0.05; 95% CI, -0.11 to 0.02; P = 0.2; Delta, 0.37 g/24 h; 95% CI, -0.13 to 0.88; P = 0.1, respectively). Plasma cystatin C level increased (Delta, 0.18 mg/L; 95% CI, 0.03 to 0.34; P = 0.02) and serum uric acid level decreased (Delta, -0.7 mg/dL; 95% CI, -1.2 to -0.3; P = 0.1). Urinary albumin and retinol-binding protein levels were unchanged, but urinary N-acetyl-beta-d-glucosaminidase activity increased (Delta, 20.0 mumol/h/mmol creatinine; 95% CI, 9.3 to 30.7; P = 0.001). LIMITATIONS: Short treatment duration and inclusion of healthy subjects precludes conclusions about effects of longer term use in patients with kidney disease. Small changes in glomerular filtration rate may be difficult to detect by using clearance methods. Interference with the creatinine assay cannot be excluded. CONCLUSION: Short-term fenofibrate treatment did not alter glomerular filtration rate by more than 20% in subjects with normal kidney function, but a smaller decrease cannot be ruled out. Increased serum creatinine levels may be caused by decreased creatinine clearance. The explanation for decreased creatinine clearance and increased serum creatinine levels in this study is not clear.

Micronized fenofibrate: a useful choice for the correction of dyslipidemia in metabolic syndrome and Type 2 diabetes.

Cardiovascular disease is the principal cause of illness and disability in patients with diabetes, and is also the most common cause of death worldwide in adults. Fenofibrate, a member of the fibrate class of lipid-modifying drugs, is a potent triglyceride-lowering and high-density lipoprotein cholesterol-raising agent and has a variable effect on low-density lipoprotein cholesterol. Fenofibrate administration also leads to a modified, less atherogenic low-density lipoprotein profile, with a consistent effect toward increased low-density lipoprotein particle size and a reduction in the low-density lipoprotein particle density. Maximal clinical efficacy in fibrates has been demonstrated in subjects with dyslipidemia, particularly in populations with features of the metabolic syndrome and in patients with Type 2 diabetes. Angiographic data from the Diabetes Atherosclerosis Intervention Study (DAIS) support a similar effect of fenofibrate. However, in the recent Fenofibrate Intervention and Event Lowering in Diabetes trial (FIELD; 9795 patients with Type 2 diabetes), the rate of nonfatal macrovascular events, after adjustment for the use of other lipid-lowering agents and significant reductions in microvascular complications, was lower for the fenofibrate treatment group. These results and those from a current large trial, ACtion to COntrol cardiovascular Risk in Diabetes (ACCORD), will provide valuable evidence for the likely future use of this drug in combination with statins for reducing cardiovascular disease risk in the metabolic syndrome and in Type 2 diabetes.

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).

BACKGROUND: Microalbuminuria is an early marker of diabetic nephropathy and an independent risk factor for cardiovascular disease. In the Diabetes Atherosclerosis Intervention Study (DAIS), treatment of people with type 2 diabetes with micronized fenofibrate for an average of 38 months reduced the progression of angiographically evaluated coronary artery disease and improved lipoprotein level abnormalities compared with placebo. The aim of this analysis is to study the influence of the treatment on changes in urinary albumin excretion. METHODS: Microalbuminuria was measured on 2 to 3 occasions by using timed overnight samples at baseline and yearly thereafter in 314 DAIS participants (77 women, 237 men; average age, 56 years); all except 3 participants had either a normal albumin excretion rate (<20 microg/min; n = 214) or microalbuminuria (albumin, 20 to 200 microg/min; n = 97) before randomization. Tabulated shifts (between normal, microalbuminuria, and macroalbuminuria) from baseline to last observed values were compared between treatment groups by means of chi-square or Fisher's exact test. RESULTS: Fenofibrate significantly reduced the worsening of albumin excretion (fenofibrate, 8% versus placebo, 18%; P < 0.05). This effect was caused mostly by reduced progression from normal albumin excretion to microalbuminuria: 3 of 101 participants in the fenofibrate group versus 20 of 113 participants in the placebo group (P < 0.001). Overall, changes in albumin excretion were independent of age or changes in lipid or creatinine levels, weight, or blood pressure. CONCLUSION: Improvement in lipid profiles with fenofibrate in patients with type 2 diabetes was associated with reduced progression from normal albumin excretion to microalbuminuria.

Response to micronized fenofibrate treatment is associated with the peroxisome-proliferator-activated receptors alpha G/C intron7 polymorphism in subjects with type 2 diabetes.

OBJECTIVE: The association between polymorphisms in candidate genes related to lipoprotein metabolism and the reduction in plasma triglyceride (TG) in response to fenofibrate treatment was evaluated in subjects with type 2 diabetes treated with micronized fenofibrate (200 mg/day) for at least 3 years in the Diabetes Atherosclerosis Intervention Study. METHODS: The cholesteryl ester transfer protein Taq1B, LPL S447X, hepatic lipase -514 C-->T, peroxisome-proliferator-activated receptors alpha (PPARA) L162V and G/C intron 7 polymorphisms and the apolipoprotein E2/E3/E4 alleles were genotyped using PCR and restriction enzyme digestion. Subjects were divided into high TG-responders (with > 30% TG relative reduction after treatment) and low TG-responders. RESULTS: The frequency of the PPARA intron 7 G/G genotype was higher in high TG-responders than in low TG-responders (85% vs. 69%, P < 0.05). There was no significant difference between the percentage of high TG-responders and low TG-responders for any of the other genetic polymorphisms examined. In stepwise logistic regression, baseline TG and only the PPARA intron 7 polymorphism among the others were selected in the model as significant predictors of TG-response (odds ratio: 3.10, 95% CI: 1.28-7.52, P = 0.012 for PPARA polymorphism). With age, gender, body mass index, smoking status and HbA1c as additional factors, baseline TG (P< 0.0001), intron 7 (P = 0.013), body mass index (P = 0.040) and LPL-S447X (P = 0.084) were significant predictors of TG-response. CONCLUSION: These results indicate that elevated baseline TG levels and PPARA gene intron 7 G/G genotype were associated with TG reduction > 30% after fenofibrate treatment in patients with type 2 diabetes.

Relationships between low-density lipoprotein particle size, plasma lipoproteins, and progression of coronary artery disease: the Diabetes Atherosclerosis Intervention Study (DAIS).

BACKGROUND: The Diabetes Atherosclerosis Intervention Study showed that treatment with fenofibrate decreases progression of coronary atherosclerosis in subjects with type 2 diabetes. We determined whether on-treatment plasma lipid concentrations and LDL particle size contribute to the favorable effect of fenofibrate on the progression of coronary artery disease (CAD). METHODS AND RESULTS: A total of 418 subjects with type 2 diabetes were randomly assigned to 200 mg micronized fenofibrate daily or placebo. The mean follow-up time was 39.6 months. LDL peak particle diameter (LDL size) was determined by polyacrylamide gradient gel electrophoresis from 405 subjects at baseline and at the end of the study. Progression of CAD was measured with quantitative coronary angiography. LDL size increased significantly more in the fenofibrate group than in the placebo group (0.98+/-1.04 versus 0.32+/-0.92 nm, P<0.001). In the combined group, small LDL size was significantly associated with progression of CAD measured as the increase of percentage diameter stenosis (r=-0.16, P=0.002) and decreases in minimum (r=-0.11, P=0.030) and mean (r=-0.10, P=0.045) lumen diameter. High on-treatment LDL cholesterol, apolipoprotein B, and triglyceride concentrations were also associated with the progression of CAD. In regression analyses, small LDL size added to the effect of LDL cholesterol and apolipoprotein B on the progression of CAD. Similar associations were observed in the fenofibrate group, whereas in the placebo group, lipoprotein variables were not significantly correlated with the progression of CAD. CONCLUSIONS: Changes in LDL size and plasma lipid levels account for part of the antiatherogenic effect of fenofibrate in type 2 diabetes.

Micronized fenofibrate normalizes the enhanced lipidemic response to a fat load in patients with type 2 diabetes and optimal glucose control.

This study evaluated the postprandial (PP) response to an oral fat load in 28 male patients with type 2 diabetes (mean HbA1c of 5.1%), all receiving metformin and performing physical exercise, compared with healthy subjects. The effects of micronized fenofibrate (200 mg once daily) on triglycerides (TG) and retinyl palmitate (RP) responses, lipoprotein mass concentrations, post-heparin lipase activities and coagulation factors were investigated after a 16-week double-blind, placebo-controlled period. Higher and delayed TG response after the oral fat load (P<0.001) corresponding to increases in both intestinally and endogenous TG-rich lipoproteins and lower lipoprotein lipase (LPL) activity 30 and 60 min post-heparin injection (P<0.05) were observed in the patients as compared with controls. Fasting PAI-1 activity, 6 h PP Factor VII and PAI-1 activities were higher in patients (P=0.036, P=0.032 and P=0.017, respectively). After fenofibrate treatment, TG and RP responses and peak LPL activity were no more significantly different from controls at baseline. Compared with placebo, fasting TG-rich lipoproteins and HDL(3) mass concentrations were significantly lower and higher, respectively; PP chylomicrons and very low density lipoprotein (VLDL) mass concentrations were lower; fasting and PP fibrinogen levels were significantly reduced after fenofibrate treatment. Diabetes control was unchanged throughout the study. Fenofibrate normalized the abnormal PP response and improved the fasting lipoprotein abnormalities in patients with type 2 diabetes and optimal glucose control.