Use Of Fibrates Research Articles

A case of rhabdomyolysis complicated with acute renal failure after resumption of fenofibrate therapy: A first report

Adverse effects due to use of fibrates often relate to the skeletal muscle, kidneys, or liver. Rhabdomyolysis is a most serious potential adverse effect. We present a case of resumed fenofibrate induced rhabdomyolysis complicated with acute renal failure.

Lipid-Lowering Pharmacotherapy in Central and Eastern European Countries in Cardiovascular Prevention

The aims of this study were (1) to explore physicians' self-reported treatment of patients with dyslipidemia and (2) to identify intercountry differences and associations between physicians' characteristics and treatment patterns. A cross-sectional survey was performed in primary health care in 9 Central and Eastern European countries. An anonymous questionnaire, which included questions devoted to dyslipidemia treatment, was distributed. A total of 3000 physicians were randomly chosen and 867 responded. The mean percentage of physicians in all countries who reported regular use of statins in primary prevention of cardiovascular diseases (CVD) was 86.4 (range between 91.0% of Polish physicians and 75.7% of Czech physicians; P < .01). In secondary prevention, the mean percentage was only a little higher, 89.9. The use of fibrates for primary prevention was reported by 40.3% of the respondents from Bulgaria and by 2% of the respondents from Estonia (P < .01). Also, significant differences between countries were found in the use of fibrates and combination therapy in secondary prevention. Atorvastatin and simvastatin were the most prescribed drugs in everyday practice (the mean percentage of physicians in all countries was 72.5% and 68.0%, respectively). More than three-fourth of the respondents reported prescribing lifelong treatment with statins. Inconsistent associations were found between the characteristics of physicians and their treatment patterns. There are significant variations in the use of lipid-lowering drugs in Central and Eastern European countries; however, statin monotherapy predominates. Some physicians' decisions are made without supporting evidence from clinical trials. There is still scope to improve preventive care of CVD.

Use of fibrates and cancer risk: a systematic review and meta-analysis of 17 long-term randomized placebo-controlled trials.

BackgroundFibrates comprise a class of well-established antilipidemic agents that significantly reduce cardiovascular events. Given the concerns of cancer with fibrate therapy, we undertook a systematic review and meta-analysis to investigate the effects of fibrates on cancer outcomes.MethodsWe systematically searched Medline, Scopus, SCI Expanded, and the Cochrane Library for studies published up to 2012. We included randomized controlled trials (RCTs) that evaluated a fibrate therapy compared with placebo, had a minimum duration of two years, and reported data on the incidence of and/or deaths from cancer during the trial. Reviews of each study were performed and the relative data were abstracted. Pooled relative risk estimates (RR) and 95% confidence intervals (CIs) were calculated using the inverse variance weighted approach. Subgroup, sensitivity and meta-regression analyses were also conducted.ResultsSeventeen RCTs, involving 44,929 participants with an average follow-up of 5.2 years, contributed to the analysis. The degree of variability between trials was consistent with what would be expected to occur by chance alone. The quantitative synthesis of data retrieved from the RCTs was not indicative of a fibrate effect on cancer incidence (780 [fibrate] vs 814 [control]; RR = 1.02, 95% CI 0.92–1.12) or cancer death (385 [fibrate] vs 377 [control]; RR = 1.06, 95% CI: 0.92–1.22). When the analysis was restricted to major RCTs, the results did not substantially change. Similarly, we found no evidence of differential effects by length of follow-up or type of fibrate. Insignificant results were also obtained for the role of fibrates in cancers of the respiratory tract, breast, colon, gastrointestinal tract, prostate, genitourinary tract, or in melanoma.ConclusionOur findings demonstrate that fibrates have a neutral effect on cancer outcomes. However, it is important to continue monitoring their long-term safety profiles.

389 Real-Life Implementation of a LDL-C Treat-to-Target Strategy in the Management of Hyperlipidemia in High CVD Risk Patients in Québec

389 Real-Life Implementation of a LDL-C Treat-to-Target Strategy in the Management of Hyperlipidemia in High CVD Risk Patients in Québec

Use of fibrates in clinical practice: Queensland Lipid Group consensus recommendations

Fibrates have been prescribed for decades as 'broad-spectrum' lipid modifying agents that can improve plasma levels of triglycerides, high-density lipoprotein cholesterol, and triglyceride-rich lipoproteins, including very low- and intermediate-density lipoproteins. Fibrates are variably effective in lowering low-density cholesterol levels. Available fibrates include gemfibrozil, fenofibrate, bezafibrate, etiofibrate and ciprofobrate; only fenofibrate and gemfibrozil are available in Australia. Members of the Queensland Lipid Group provided consensus grades of recommendations for the clinical use of fibrates based on PubMed searches, product information, and personal clinical experience. Fibrates are well tolerated, and the combination of fenofibrate with statins appears to be safer than gemfibrozil, particularly with regard to adverse effects on muscle. Evidence has been provided recently for the efficacy of fenofibrate in reducing microvascular complications in diabetic patients, including progression of retinopathy, progression of microalbuminuria and nephropathy, development of sensory neuropathy, and leg amputation. Macrovascular benefits appear to be confined to those with reduced high-density lipoprotein cholesterol and/or increased triglyceride levels, and the relationship of microvascular benefits of fenofibrate to baseline lipid levels is variable and requires further assessment. Indications for fibrate therapy may be extended in the future to include protection from both macro- and micro-vascular disease, particularly in diabetic patients and patients with residual dyslipidaemia in spite of statin therapy. We provide recommendations on the use of fibrates in clinical practice to highlight these potential indications.

Postprandial dyslipidaemia and diabetes

There has been a resurgence of interest in the role of triglyceride-rich lipoproteins in the development of atherosclerosis and cardiovascular disease, and this is particularly relevant to diabetes mellitus and the postprandial state. Recent evidence suggests that insulin resistance in diabetes induces postprandial dyslipidemia by increasing the enterocytic production of chylomicrons and their remnant particles, but an impaired clearance capacity is also involved. Postprandial dyslipidaemia in diabetes induces oxidative stress, inflammation and endothelial dysfunction and this may be compounded by dysglycaemia. New guidelines for managing hypertriglyceridaemia in diabetes have been published, first-line therapies being improved glycaemic control, treatment of other secondary causes of dyslipidaemia and statin therapy, followed by judicious use of fibrates, n-3 fatty acids or niacin. A new role for incretin-based therapies in regulating dyslipidaemia has been identified. Postprandial dyslipidaemia is a pivotal mechanism whereby diabetes can induce and accelerate atherosclerosis. Regulating the plasma concentrations of triglyceride-rich lipoproteins may decrease the cardiovascular complications of diabetes. The mechanisms of action of incretin-based treatments on dyslipidaemia and endothelial dysfunction need further investigation. The efficacy of new therapies targeted at postprandial dysmetabolism in diabetes need to be confirmed, against best current levels of care, in clinical endpoint trials.

Abstract 141: APOA1, CETP, and CILP2 Variants Modify the Lipid Response to Fenofibrate: Genetics of Lipid Lowering and Diet Network

Introduction: Despite the widespread use of fibrates in treatment of dyslipidemia, the observed response is highly heterogeneous, suggesting a role for genetic determinants. Whether replicated variants associated with blood lipids identified by genome wide association studies (GWAS) are also associated with lipid response to fenofibrate is unknown. Objectives: To test if 95 genome-wide significant loci identified in a recent meta-analysis of blood lipids are associated with changes in high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-HDL-C, and triglycerides (TG) following 3 weeks of therapy with 160 mg of micronized fenofibrate. Methods: Using data from 861 European American Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) participants, we fit mixed linear models with baseline blood lipids and the post-to-pre fenofibrate treatment ratio of blood lipid levels as outcomes, the corresponding genetic markers from the published meta-analysis as predictors, and age, sex, pedigree, and ancestry as assessed by principal components as covariates. A Bonferroni correction was applied to adjust for multiple comparisons. Least square means were used to report the direction of fenofibrate-induced changes by genotype. Results: We observed statistically significant associations between rs964184 , a variant near the APOA1 gene, and baseline HDL-C (P&lt;0.0001) and baseline TG (P&lt;0.0001), as well as with diminished response to fenofibrate as evidenced by a smaller increase in HDL-C (P&lt;0.0001) and a smaller decrease in TG (P=0.0001) per each copy of the variant allele. Additionally, we report suggestive associations of rs3764261 locus in the CETP gene and the rs10401969 locus in the CILP2 gene with decreased fenofibrate response as measured by changes in LDL-C (P=0.0003 and 0.02, respectively) and non-HDL-C (P=0.004 and 0.005, respectively). Conclusions: We have identified several novel biologically relevant loci associated with baseline blood lipids and fenofibrate-induced changes in blood lipids.

Fibrate use increases serum creatinine level in elderly adults

Fibrate use increases serum creatinine level in elderly adults

Inviting Patients to Read Doctors' Notes

Fibric acid derivatives (fibrates) have been shown to increase serum creatinine level in randomized trials. To assess renal outcomes in elderly adults within 90 days of a new fibrate prescription. Population-based cohort study. Ontario, Canada. Patients aged 66 years or older with a new outpatient prescription for a fibrate or ezetimibe (comparator drug) between January 2004 and December 2008. Hospitalization for an increase in serum creatinine level (primary outcome) and consultation with a nephrologist, receipt of dialysis for severe acute kidney injury, all-cause mortality, and increases in serum creatinine level (secondary outcomes). All outcomes were assessed within 90 days of a new prescription for ezetimibe or a fibrate. Compared with ezetimibe users (n = 61,831), fibrate users (n = 19,072) were more likely to be hospitalized for an increase in serum creatinine level (adjusted odds ratio, 2.4 [95% CI, 1.7 to 3.3]) and were more likely to consult a nephrologist (absolute risk difference, 0.15% [CI, 0.01% to 0.29%]; adjusted odds ratio, 1.3 [CI, 1.0 to 1.6]). There were no differences between groups in the risk for all-cause mortality or receiving dialysis for severe acute kidney injury. In a subpopulation of 1110 patients (fibrates, n = 220; ezetimibe, n = 890), 9.1% of fibrate users and 0.3% of ezetimibe users had an increase in serum creatinine level of 50% or more (absolute difference, 8.8% [CI, 4.5% to 13.1%]; odds ratio, 29.6 [CI, 8.7 to 100.5]). Risks were greater among fibrate users with chronic kidney disease. Because hospitalizations for an increase in serum creatinine level were underestimated, absolute differences may be misleading. Most patients (91%) were prescribed fenofibrate. Serum creatinine levels were measured as part of routine care and were not available for everyone or at predefined times. New fibrate use in elderly adults was associated with an increase in serum creatinine level and a small 90-day absolute increase in hospitalizations and nephrologist consultations. There was no detectable effect on dialysis for severe acute kidney injury or on mortality. The mechanism and clinical significance of the increase in serum creatinine level with fibrates is unclear. Ontario Ministry of Health and Long-Term Care Drug Innovation Fund.

Diagnosis and treatment of severe hypertriglyceridemia

Severe hypertriglyceridemia is associated with acute pancreatitis and can be a manifestation of lipoprotein lipase (LPL) deficiency. It is associated with a spectrum of disorders, ranging from heterozygous LPL deficiency allied with environmental factors to rare severe cases of homozygous LPL deficiency. The genes associated with reduced LPL activity include LPL, its cofactor apoC-2, a controlling protein apoA-5 and the LPL receptor GPI-HBP1. The effects of mutations are exacerbated by environmental factors such as diet, pregnancy and insulin resistance. Treatment of clinical LPL deficiency is by ultra-low-fat diet along with the use of fibrates, omega-3 fatty acids, niacin, statins and insulin-sensitizing therapies, depending on the extent of residual LPL activity. Novel therapies that target lipoprotein particle assembly through the antisense oligonucleotides or by interference with triglyceride-loading microsomal transport protein inhibitors offer new potential options for treating hypertriglyceridemia.

Abstract 123: Replicating the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial in Real-World Claims Data

Background: The ACCORD-Lipid Trial’s finding that statin-fibrate combination therapy (CT) provides no incremental cardiovascular risk reduction in type 2 diabetese over statin monotherapy (MT) prompted FDA to issue a public communication on 11/9/2011 stating that fenofibrate may not reduce risk of heart attack or stroke. Yet, fibrate use continues unabated with over $1 billion in sales in the US that raises concern regarding the inconsistency in diffusion of scientific evidence into clinical practice. Critics of ACCORD findings maintain that ACCORD trial adopted flexible thresholds for qualifying HDL and triglyceride levels and that it left unanswered whether the effects of non-ACCORD statins or fibrates or combinations thereof will be different. By replicating the ACCORD-Lipid trial as closely as possible using 16-year longitudinal claims database from a large national health plan, our study seeks to compare the following ACCORD outcomes between CT and MT cohorts: (i) primary composite outcome of nonfatal MI, nonfatal stroke and cardiovascular death; (ii) secondary outcomes of all-cause mortality, expanded macrovascular outcome, major CAD events and CHF. Methods (Research Design, Data Source and Data Analysis Methods) : Retrospective claims analysis that included patients enrolled between 1995 and 2010 using ACCORD inclusion/exclusion criteria including type 2 diabetes patients aged 40 to 79 with baseline A1C≥7.5 and on statin. Patients in the two study cohorts, CT and MT, were required to have minimum of 1-year baseline and 90-day follow-up periods. Propensity score (PS) matching was used to adjust for patient baseline characteristics. T- and Chi-squared tests were used to assess differences in continuous and categorical covariates and Cox proportional hazard model was used to assess the hazard of study events. Results: The study included 6765 patients (CT=954; MT=5811) with a mean follow-up of 2.4 years. An average patient in the sample was a White male aged 57 years from the South. The two study cohorts differed in demographics (age, female, ethnicity, income categories), baseline lipids (HDL, LDL, triglyceride and HbA1c), and in numerous comorbid conditions. After 1-to-1 PS matching, baseline LDL, triglycerides and total cholesterol were similar but HDL (HbA1c) was higher (lower) in CT than in MT cohort (n=943 in each cohort). Most other baseline covariates were balanced. Unadjusted results showed that compared to MT, CT cohort had higher primary composite outcomes (62 vs 45), all-cause deaths (113 vs 105), macrovascular events (16 vs 9), major CAD (84 vs 59), nonfatal stroke (35 vs 33) and CHF (60 vs 51). Adjusted results show no difference in the rate of primary composite outcome (hazard rate or HR=1.44, p=0.09) and in secondary outcomes of macrovascular events (HR=1.61), all-cause mortality (HR=1.22), major CAD (HR=1.45), CHF (HR=1.24) and non-fatal stroke (HR=0.98) [all p&gt;.05] Conclusion: The study results appear to confirm the non-significance of CT over MT in cardiovascular risk reduction among type 2 diabetes patients in a large US commercial health plan.

New Fibrate Use and Acute Renal Outcomes in Elderly Adults

Background: Fibric acid derivatives (fibrates) have been shown to increase serum creatinine level in randomized trials. Objective: To assess renal outcomes in elderly adults within 90 days of a new fibrate prescription. Design: Population-based cohort study. Setting: Ontario, Canada. Patients: Patients aged 66 years or older with a new outpatient prescription for a fibrate or ezetimibe (comparator drug) between January 2004 and December 2008. Measurements: Hospitalization for an increase in serum creatinine level (primary outcome) and consultation with a nephrologist, receipt of dialysis for severe acute kidney injury, all-cause mortality, and increases in serum creatinine level (secondary outcomes). All outcomes were assessed within 90 days of a new prescription for ezetimibe or a fibrate. Results: Compared with ezetimibe users (n = 61 831), fibrate users (n = 19 072) were more likely to be hospitalized for an increase in serum creatinine level (adjusted odds ratio, 2.4 [95% CI, 1.7 to 3.3]) and were more likely to consult a nephrologist (absolute risk difference, 0.15% [CI, 0.01% to 0.29%]; adjusted odds ratio, 1.3 [CI, 1.0 to 1.6]). There were no differences between groups in the risk for all-cause mortality or receiving dialysis for severe acute kidney injury. In a subpopulation of 1110 patients (fibrates, n = 220; ezetimibe, n = 890), 9.1% of fibrate users and 0.3% of ezetimibe users had an increase in serum creatinine level of 50% or more (absolute difference, 8.8% [CI, 4.5% to 13.1%]; odds ratio, 29.6 [CI, 8.7 to 100.5]). Risks were greater among fibrate users with chronic kidney disease. Limitations: Because hospitalizations for an increase in serum creatinine level were underestimated, absolute differences may be misleading. Most patients (91%) were prescribed fenofibrate. Serum creatinine levels were measured as part of routine care and were not available for everyone or at predefined times. Conclusion: New fibrate use in elderly adults was associated with an increase in serum creatinine level and a small 90-day absolute increase in hospitalizations and nephrologist consultations. There was no detectable effect on dialysis for severe acute kidney injury or on mortality. The mechanism and clinical significance of the increase in serum creatinine level with fibrates is unclear. Primary Funding Source: Ontario Ministry of Health and Long-Term Care Drug Innovation Fund.

Use of Fenofibrate During the First Trimester of Unplanned Pregnancy in a Patient with Hypertriglyceridemia

To describe a successful pregnancy in a patient who used fenofibrate during the first trimester. A 30-year-old female with a history of polycystic ovarian syndrome was referred to our department for evaluation of hypertriglyceridemia, and fenofibrate treatment was initiated. After 1 year of therapy, a gynecologic visit for menstrual cycle abnormalities revealed an unplanned pregnancy at 8 weeks of gestation (dating from the first day of the last menstrual period). Fenofibrate was discontinued and the pregnancy was continued despite the potential risks involved with the use of fibrates during early pregnancy. Fetal ultrasound performed routinely during each trimester showed normal fetal growth with no malformation. The patient delivered a healthy male infant at 36 weeks of gestation. No congenital malformation was recorded. The baby was healthy on pediatrician examination at 1 year. Fibrates have good efficacy in lowering fasting triglyceride (TG) levels as well as postprandial TG and TG-rich lipoprotein remnant particles. Previous reports showed that fibrates have been administered cautiously in pregnant women after embryogenesis if their use is necessary; however, in our case, the embryo had been exposed to fenofibrate from the beginning of fertilization. Nevertheless, fenofibrate did not cause significant damage, such as external, skeletal, and visceral abnormalities, to the developing embryo. In this case, no harmful effects on fetal development were observed after exposure to fenofibrate during organogenesis.

A Neutral Risk on the Development of New-Onset Diabetes Mellitus (NODM) in Taiwanese Patients with Dyslipidaemia Treated with Fibrates

There are no data on the incidence of new-onset diabetes mellitus (NODM ) in nondiabetic dyslipidaemia patients treated with fibrates. The aim of our study was to clarify these issues, to investigate the relationship between NODM and fibrate and whether the fibrates lead to increased risk for developing NODM. A retrospective cohort study was conducted by analyzing the Longitudinal Health Insurance Database (LHID 2005) of the National Health Insurance Research Database (NHIRD) from 2005 to 2010 to investigate all fibrate prescriptions for patients with dyslipidaemia. We estimated the hazard ratios (HRs) of NODM associated with fibrate use. We identified 145 NODM patients among 3,815 dyslipidaemic patients in the database for the study period. The risk estimates for NODM for users of fenofibrate (HR 1.30; 95% CI 0.82, 2.05) and gemfibrozil (HR 0.771; 95% CI 0.49, 1.22) were not associated with an increased risk of developing NODM (P > 0.05). Our results revealed that patients with dyslipidaemia who took fenofibrate and gemfibrozil had a neutral risk of NODM. The reasons may be associated with the fibrates have the properties that activate PPARα and in some cases also activated PPARγ, leading to showing a neutral risk of NODM.

Elevation of fasting morning glucose relative to hemoglobin A1c in normoglycemic patients treated with niacin and with statins

Niacin increases fasting glucose levels, and statins modestly increase the rate of new-onset diabetes. The clinical importance and mechanisms of these effects are not fully explored. On the basis of anecdotal observations, we hypothesized that elevated morning fasting glucose may be accompanied by relatively normal hemoglobin A1c (HbA1c) in patients treated with niacin and other lipid-modifying drugs. We conducted a retrospective cohort analysis to test this hypothesis. The Duke Lipid Clinic database (1994-2007) was screened for simultaneous determinations of fasting morning glucose and HbA1c, yielding 1483 data pairs among 554 subjects. Subjects with diabetes, by clinical diagnosis, medication, or any HbA1c ≥6.5%, or nondiabetes were analyzed separately. Repeated-measures linear regression featured glucose as dependent variable and included terms for HbA1c, drug(s), and their interaction. Regression lines for glucose on HbA1c had altered slopes in the presence of niacin and/or statin use in normoglycemic subjects. The corresponding interaction terms (drug and HbA1c) were significant (niacin P= .026, statin P= .013). Fibrate use had no effect (interaction P= .49). When modeled together, niacin and statin effects were independent. Regression curves in diabetic patients were not affected by lipid medications. Elevated fasting glucose may be accompanied by relatively normal HbA1c in niacin- and statin-treated patients. HbA1c reflects average daily glucose levels and is likely a better measure of the glycemic effect of lipid medications. Because our data were retrospective, confirmation from randomized trials is needed.

N-002 FACTORS RELATED WITH DISCORCODANCE BETWEEN LONGITUDINAL CHANGES OF ALBUMINURIA AND ESTIMATED GLOMERULAR FILTRATION RATE

Background Albuminuria (AU) and estimated glomerular filtration rate (eGFR) are two important parameters to predict cardiovascular and renal events for the hypertensives. However, recent interventional trials show longitudinally disconcordant changes between AU and eGFR. We investigated which factors are associated with the disconcordance in a hypertension cohort. Method We prospectively recruited 482 hypertension patients from a tertiary hospital clinic. The eGFR was calculated with 4-item Modification of Diet in Renal Disease (MDRD) Study equation. The albuminuria is calculated as ratio of urine albumin to urine creatinine. Depend on the changes of two parameters at one year we categorized patients into 4 groups, with or without worsening of albuminuria (AU+ or AU-) and eGFR (eGFR+ or eGFR-). We further stratified subjects into concordant (CC, AU+/eGFR+ and AU-/eGFR-) and disconcordant changes groups (DC, AU+/eGFR- and AU-/eGFR+). Result Age was 60.8 ± 12.0 years old. Among the 4 groups, baseline age, albuminuria, fasting glucose and HbA1C were different. Patients in the DC group had higher CRP, albuminuria and fibrate use at baseline. Binary logistic regression analysis showed only baseline albuminuria level is the independent predictor for patients in the DC group (OR = 1.003, CI: 1.001–1.006, p = 0.019). Conclusion This study showed that those with higher baseline albuminuria level might have longitudinally disconcordant changes between albuminuria and eGFR in the hypertensives.

Incidence of Hospitalized Rhabdomyolysis with Statin and Fibrate Use in an Insured US Population

The incidence of hospitalized rhabdomyolysis is not well characterized among patients taking statin-fibrate combination therapies. To estimate and compare the rates of hospitalized rhabdomyolysis during periods of exposure to different statins and fibrates. We retrospectively identified a cohort of patients who initiated a statin or fibrate between January 1, 1998, and December 31, 2007, using a database of a large US health insurer. Patients were followed for the occurrence of hospitalized rhabdomyolysis, determined by clinical review of medical records. Exposure status during the study period was determined by electronic records of statin and fibrate dispensing. Incidence rates (IRs) and incidence rate ratios (IRRs) for various combinations of fibrate and statin exposure were modeled, using Poisson regression. There were 1,116,805 patients who initiated statin and/or fibrate therapy, with 2.4 million person-years of observation. Seventy cases of hospitalized rhabdomyolysis were confirmed. Adjusted analyses showed a persistent increased risk of rhabdomyolysis with combination therapy, while statin and fibrate therapy alone showed similar, nonsignificant increases in risk. The adjusted IRR for a statin and fenofibrate was 3.26 (95% CI 1.21 to 8.80), while the adjusted IRR for a statin and gemfibrozil was 11.93 (95% CI 3.96 to 35.93) versus statin therapy alone. The individual IRs for statin monotherapy ranged from 0.00 to 3.34 per 100,000 person-years. The number needed to harm was lower for combination statin-gemfibrozil therapy (2753) compared with that for statin therapy alone (454,545). The incidence of hospitalized rhabdomyolysis is rare, but higher in patients with concomitant statin-fibrate treatment than in patients on statin therapy alone. The rate found in this study is consistent with the known profile of the statin-fibrate treatment option for mixed dyslipidemia.

No more pilots, a phase III trial of fibrates in primary biliary cirrhosis is long overdue!

No more pilots, a phase III trial of fibrates in primary biliary cirrhosis is long overdue!

The mitochondrial carnitine/acylcarnitine carrier: Function, structure and physiopathology

The carnitine/acylcarnitine carrier (CAC) is a transport protein of the inner mitochondrial membrane that belongs to the mitochondrial carrier protein family. In its cytosolic conformation the carrier consists of a bundle of six transmembrane α-helices, which delimit a water filled cavity opened towards the cytosol and closed towards the matrix by a network of interacting charged residues. Most of the functional data on this transporter come from studies performed with the protein purified from rat liver mitochondria or recombinant proteins from different sources incorporated into phospholipid vesicles (liposomes). The carnitine/acylcarnitine carrier transports carnitine and acylcarnitines with acyl chains of various lengths from 2 to 18 carbon atoms. The mammalian transporter exhibits higher affinity for acylcarnitines with longer carbon chains. The functional data indicate that CAC plays the important function of catalyzing transport of acylcarnitines into the mitochondria in exchange for intramitochondrial free carnitine. This results in net transport of fatty acyl units into the mitochondrial matrix where they are oxidized by the β-oxidation enzymes. The essential role of the transporter in cell metabolism is demonstrated by the fact that alterations of the human gene SLC25A20 coding for CAC are associated with a severe disease known as carnitine carrier deficiency. This autosomal recessive disorder is characterized by life-threatening episodes of coma induced by fasting, cardiomyopathy, liver dysfunction, muscle weakness, respiratory distress and seizures. Until now 35 different mutations of CAC gene have been identified in carnitine carrier deficient patients. Some missense mutations concern residues of the signature motif present in all mitochondrial carriers. Diagnosis of carnitine carrier deficiency requires biochemical and genetic tests; treatment is essentially limited to important dietetic measures. Recently, a pharmacological approach based on the use of statins and/or fibrates for the treatment of CAC-deficient patients with mild phenotype has been proposed.

Fibrate Use in the United States and Canada

Fibrate Use in the United States and Canada