Fibrate Therapy Research Articles

Association of Fenofibrate Therapy With Long-term Cardiovascular Risk in Statin-Treated Patients With Type 2 Diabetes

Patients with type 2 diabetes are at high risk of cardiovascular disease (CVD) in part owing to hypertriglyceridemia and low high-density lipoprotein cholesterol. It is unknown whether adding triglyceride-lowering treatment to statin reduces this risk. To determine whether fenofibrate reduces CVD risk in statin-treated patients with type 2 diabetes. Posttrial follow-up of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Study between July 2009 and October 2014; 5 years of follow-up were completed for a total of 9.7 years at general community and academic outpatient research clinics in the United States and Canada. Of the original 5518 ACCORD Lipid Trial participants, 4644 surviving participants were selected based on the presence of type 2 diabetes and either prevalent CVD or CVD risk factors and high-density lipoprotein levels less than 50 mg/dL (<55 mg/dL for women and African American individuals). Passive follow-up of study participants previously treated with fenofibrate or masked placebo. Occurrence of cardiovascular outcomes including primary composite outcome of fatal and nonfatal myocardial infarction and stroke in all participants and in prespecified subgroups. The 4644 follow-on study participants were broadly representative of the original ACCORD study population and included significant numbers of women (n = 1445; 31%), nonwhite individuals (n = 1094; 21%), and those with preexisting cardiovascular events (n = 1620; 35%). Only 4.3% of study participants continued treatment with fenofibrate following completion of ACCORD. High-density lipoprotein and triglyceride values rapidly equalized among participants originally randomized to fenofibrate or placebo. Over a median total postrandomization follow-up of 9.7 years, the hazard ratio (HR) for the primary study outcome among participants originally randomized to fenofibrate vs placebo (HR, 0.93; 95% CI, 0.83-1.05; P = .25) was comparable with that originally observed in ACCORD (HR, 0.92; 95% CI, 0.79-1,08; P = .32). Despite these overall neutral results, we continued to find evidence that fenofibrate therapy effectively reduced CVD in study participants with dyslipidemia, defined as triglyceride levels greater than 204 mg/dL and high-density lipoprotein cholesterol levels less than 34 mg/dL (HR, 0.73; 95% CI, 0.56-0.95). Extended follow-up of ACCORD-lipid trial participants confirms the original neutral effect of fenofibrate in the overall study cohort. The continued observation of heterogeneity of treatment response by baseline lipids suggests that fenofibrate therapy may reduce CVD in patients with diabetes with hypertriglyceridemia and low high-density lipoprotein cholesterol. A definitive trial of fibrate therapy in this patient population is needed to confirm these findings. clinicaltrials.gov Identifier: NCT00000620.

A Systematic Review and Meta-Analysis of Controlled Trials on the Effects of Statin and Fibrate Therapies on Plasma Homocysteine Levels.

Plasma homocysteine is an independent non-traditional risk factor for atherosclerotic cardiovascular disease. The impact of statin therapy on plasma homocysteine is not conclusive. To evaluate the effect of statin therapy on plasma homocysteine concentrations in a systematic review and meta-analysis of controlled clinical trials. The secondary aim was to assess the comparative effect of statins versus fibrates on plasma homocysteine levels in head-to-head trials. PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases were searched (from the first reports to March 07, 2016) to identify controlled trials evaluating the impact of statins on plasma homocysteine concentrations. A systematic assessment of bias in the included studies was performed using the Cochrane criteria. A random-effects model and generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. Random-effects meta-regression was performed using unrestricted maximum likelihood method to evaluate the impact of potential moderators. Meta-analysis of data from 7 studies did not suggest a significant alteration in plasma homocysteine concentrations following treatment with statins compared with the control group (WMD: -0.59 μmol/L, 95% CI: -1.66, 0.48, p=0.279; I2=52.53%). However, meta-analysis of 9 studies suggested a significantly greater reduction of plasma homocysteine concentrations with statins compared with fenofibrate (WMD: -4.81 μmol/L, 95% CI: -5.39, -4.23, p<0.001; I2=0%). Results of both analyses were robust in the sensitivity analysis. Statin therapy is not associated with a significant alteration of plasma homocysteine levels, while fenofibrate increases the homocysteine levels when compared with statins.

Fibrates for primary prevention of cardiovascular disease events.

Fibrates are effective for modifying atherogenic dyslipidaemia, and particularly for lowering serum triglycerides. However, evidence that fibrates reduce mortality and morbidity associated with cardiovascular disease (CVD), or overall mortality and morbidity, in the primary prevention of CVD is lacking. This Cochrane Review and meta-analysis aimed to evaluate the clinical benefits and harms of fibrates versus placebo or usual care or fibrates plus other lipid-modifying drugs versus other lipid-modifying drugs alone for the primary prevention of cardiovascular disease (CVD) morbidity and mortality. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCO), and Web of Science (all from inception to 19 May 2016). We searched four clinical trial registers (last searched on 3 August 2016) with the help of an experienced professional librarian. We searched the databases to identify randomised controlled trials (RCTs) evaluating the clinical effects of fibrate therapy in the primary prevention of CVD events. We did not impose any language restrictions. We aimed to include all RCTs comparing the effects of fibrate monotherapy versus placebo or usual care, or fibrates plus other lipid-modifying drugs versus other lipid-modifying drugs alone. Included studies had a follow-up of at least six months for the primary prevention of CVD events. We excluded trials with clofibrate, because it was withdrawn from the market in 2002. Two review authors independently screened titles and abstracts for potential study inclusion. Two review authors independently retrieved the full-text papers and extracted data. Disagreements were resolved by consensus. We calculated risk ratios (RRs) and accompanying 95% confidence intervals (CIs) for aggregate data on primary and secondary outcomes. We tested for heterogeneity with the Cochrane Q-test and used the I2 statistic to measure inconsistency of treatment effects across studies. Using the GRADE approach, we assessed the quality of the evidence and used the GRADE profiler software (GRADEpro GDT) to import data from Review Manager 5 to create 'Summary of findings' tables. We identified six eligible trials including 16,135 individuals. The mean age of trial populations varied across trials; between 47.3 and 62.3 years. Four trials included individuals with diabetes mellitus type 2 only. The mean treatment duration and follow-up of participants across trials was 4.8 years. We judged the risks of selection and performance bias to be low; risks of detection bias, attrition bias, and reporting bias were unclear. Reporting of adverse effects by included trials was very limited; that is why we used discontinuation of therapy due to adverse effects as a proxy for adverse effects. Patients treated with fibrates had a reduced risk for the combined primary outcome of CVD death, non-fatal myocardial infarction, or non-fatal stroke compared to patients on placebo (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.74 to 0.96; participants = 16,135; studies = 6; moderate-quality of evidence). For secondary outcomes we found RRs for fibrate therapy compared with placebo of 0.79 for combined coronary heart disease death or non-fatal myocardial infarction (95% CI 0.68 to 0.92; participants = 16,135; studies = 6; moderate-quality of evidence); 1.01 for overall mortality (95% CI 0.81 to 1.26; participants = 8471; studies = 5; low-quality of evidence); 1.01 for non-CVD mortality (95% CI 0.76 to 1.35; participants = 8471; studies = 5; low-quality of evidence); and 1.38 for discontinuation of therapy due to adverse effects (95% CI 0.71 to 2.68; participants = 4805; studies = 3; I2 = 74%; very low-quality of evidence). Data on quality of life were not available from any trial. Trials that evaluated fibrates in the background of statins (2 studies) showed no benefits in preventing cardiovascular events. Moderate-quality evidence suggests that fibrates lower the risk for cardiovascular and coronary events in primary prevention, but the absolute treatment effects in the primary prevention setting are modest (absolute risk reductions < 1%). There is low-quality evidence that fibrates have no effect on overall or non-CVD mortality. Very low-quality evidence suggests that fibrates are not associated with increased risk for adverse effects.

Frameshift mutation in the APOA5 gene causing hypertriglyceridemia in a Pakistani family: Management and considerations for cardiovascular risk

We report a novel homozygous apolipoprotein A5 (APOA5) frameshift mutation (c.G425del-C, p.Arg143AlafsTer57) identified in a 12-year-old boy of Pakistani origin with severe hypertriglyceridemia (up to 35 mmol/L) and type V hyperlipoproteinemia. The patient did not respond to fibrate therapy, but his condition improved under a very low fat diet, although compliance was suboptimal. Heterozygous status was detected in both parents (consanguineous union) and one sibling, all showing moderate hypertriglyceridemia (between 5 and 10 mmol/L). There was a significant family history of premature cardiovascular disease. The index case was also diagnosed with a coronary artery anomaly. Considering the recently reported association of rare mutations in APOA5 with the risk of early myocardial infarction, we discuss the implications of these findings for the young man and his family.

D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile.

Apolipoprotein C-III deficiency provides cardiovascular protection, but apolipoprotein C-III is not known to be associated with human amyloidosis. Here we report a form of amyloidosis characterized by renal insufficiency caused by a new apolipoprotein C-III variant, D25V. Despite their uremic state, the D25V-carriers exhibit low triglyceride (TG) and apolipoprotein C-III levels, and low very-low-density lipoprotein (VLDL)/high high-density lipoprotein (HDL) profile. Amyloid fibrils comprise the D25V-variant only, showing that wild-type apolipoprotein C-III does not contribute to amyloid deposition in vivo. The mutation profoundly impacts helical structure stability of D25V-variant, which is remarkably fibrillogenic under physiological conditions in vitro producing typical amyloid fibrils in its lipid-free form. D25V apolipoprotein C-III is a new human amyloidogenic protein and the first conferring cardioprotection even in the unfavourable context of renal failure, extending the evidence for an important cardiovascular protective role of apolipoprotein C-III deficiency. Thus, fibrate therapy, which reduces hepatic APOC3 transcription, may delay amyloid deposition in affected patients.

Combined ursodeoxycholic acid (UDCA) and fenofibrate in primary biliary cholangitis patients with incomplete UDCA response may improve outcomes.

Fibrates appear to improve biochemistry in patients with primary biliary cholangitis (PBC), but it is unclear which factors predict response and whether treatment improves transplant-free survival. To evaluate biochemical profiles, liver-related outcomes and adverse events following fenofibrate therapy in PBC patients with incomplete response to ursodeoxycholic acid (UDCA). A retrospective cohort study was performed at a tertiary centre. Cox regression was used to compare outcomes between patients treated with fibrates and UDCA (FF) or UDCA alone, adjusted for a propensity score to account for treatment selection bias. A total of 120 patients were included (FF group n = 46, UDCA group n = 74, median fenofibrate treatment 11 months); 41% vs. 7% met the Toronto criteria for biochemical response [alkaline phosphatase ≤1.67 times the upper limit of normal] in the FF and UDCA groups, respectively (P = 0.0001). Fenofibrate was also associated with improved decompensation-free and transplant-free survival [hazard ratio (HR) 0.09, 95% CI 0.03-0.32, P = 0.0002]. However, only fenofibrate use, not biochemical response, was independently associated with improved outcomes on multivariable analysis (HR 0.40, 95% CI 0.17-0.93, P = 0.03). Twenty-two percent discontinued fenofibrate due to adverse events (most common: abdominal pain and myalgias). In cirrhotic patients, bilirubin increased more rapidly in the FF group (P = 0.005). Fenofibrate therapy is associated with significant improvement in alkaline phosphatase, decompensation-free and transplant-free survival in PBC patients with incomplete UDCA response. However, fenofibrate should be used cautiously in cirrhosis, with close monitoring for clinical/biochemical decompensation. Additional studies are required to assess the validity of alkaline phosphatase as an appropriate response criteria for fibrate therapy.

Abstract 15997: The Effect of Combined Statin/Fibrate Therapy on Cardiovascular Disease is Influenced by Sex and Dyslipidemia: ACCORDION-Lipid Long-Term Follow-up

Introduction: In the long-term ACCORD-Lipid trial of 5,518 high risk patients with type 2 diabetes, combined statin+fibrate therapy failed to reduce the composite outcome of nonfatal myocardial infarction (MI), nonfatal stroke or cardiovascular (CV) death. Pre-specified subgroup analyses identified heterogeneity in treatment effect according to gender, with a benefit for men and possible harm for women, and possible benefit for patients with both high triglyceride and low HDL-C at baseline. At trial end, 4,644 ACCORD-Lipid Trial participants consented to be followed post-trial in the passive ACCORD Follow-On (ACCORDION) Study. Hypothesis: Does a therapeutic strategy that initially used a fibrate to raise HDL-C/lower triglyceride levels and a statin for treatment of LDL-C for a mean of almost 5 years reduce the long-term (mean 9+ years) risk of major CVD events after 4+ more years of follow-up compared to a strategy that only used a statin for treatment of LDL-C? Results: During about 9 years of follow-up (from ACCORD randomization to the end of ACCORDION), the hazard ratios between participants originally randomized to statin+fibrate versus statin alone were 0.93 (0.83-1.05 95%CI, p=0.25) for the primary outcome (nonfatal MI, nonfatal stroke or CV death); 0.94 (0.84 -1.06, p=0.32) for all-cause mortality, 0.93 (0.78-1.10, p=0.37) for nonfatal MI, and 0.84 (0.69-1.01, p=0.07) for cardiovascular mortality. These hazards are similar to those observed during the trial portion of follow-up. The heterogeneity of response for gender and presence of dyslipidemia observed in ACCORD-LIPID continued to be observed after the addition of post-trial events during the extended follow-up period with hazard ratios of 0.84 (0.73-0.96) for men and 1.30 (1.01-17) for women (interaction P=0.003) and 0.73 (0.56-0.95) for dyslipidemic and 0.99 (0.86-1.13) for non-dyslipidemic subgroups (interaction P=0.048). Conclusions: Additional post-trial follow-up of ACCORD participants for a total of about 9 years of total follow-up did not alter the original ACCORD findings that in people with type 2 diabetes and other cardiovascular risk factors, long-term treatment with a fibrate+statin (compared to a statin alone) did not reduce the rate of CV events or all-cause mortality.

Trends in the Use of Nonstatin Lipid-Lowering Therapy Among Patients With Coronary Heart Disease: A Retrospective Cohort Study in the Medicare Population 2007 to 2011

BackgroundNonstatin lipid-lowering therapy is adjunctive therapy for high-risk individuals on statins or monotherapy among those who cannot tolerate statins. ObjectivesThis study determined time trends between 2007 and 2011 for statin and nonstatin lipid-lowering therapy (niacin, fibrates, bile acid sequestrants, and ezetimibe) use among Medicare beneficiaries with coronary heart disease (CHD) in light of emerging clinical trial evidence. MethodsWe conducted a retrospective cohort study using the national 5% random sample of Medicare beneficiaries (n = 310,091). We created 20 cohorts of individuals with CHD, representing calendar quarters from 2007 through 2011, to assess trends in use of statins and nonstatin lipid-lowering medications. ResultsStatin use increased from 53.1% to 58.8% between 2007 and 2011. Ezetimibe use peaked at 12.1% and declined to 4.6% by the end of 2011, declining among both patients on statins (18.4% to 6.2%) and not on statins (5.0% to 2.4%). Fibrate use increased from 4.2% to 5.0%, bile acid sequestrants did not change significantly, and niacin use increased from 1.5% to 2.4% and then declined in late 2011. Use of nonstatin lipid-lowering therapy was less common at older age, among African Americans, patients with heart failure, and patients with a higher Charlson comorbidity score. Nonstatin lipid-lowering therapy use was more common among men and patients with diabetes, those who had cardiologist visits, and among those taking statins. ConclusionsDeclining ezetimibe and niacin use but not fibrate therapy among Medicare beneficiaries with CHD coincides with negative clinical trial results for these agents.

Research in brief

In a phase 2, dose-ranging study, researchers assessed patiromer twice a day for treating hyperkalaemia in people with type 2 diabetes and chronic kidney disease who were already receiving renin-angiotensin-aldosterone system inhibitors (n=306). After about 4 weeks, investigators noted a reduction in serum potassium concentration compared with baseline in participants with mild hyperkalaemia (starting dose 8·4 g: least squares mean reduction 0·35 mmol/L [95% CI 0·22–0·48]; 16·8 g group: 0·51 mmol/L [0·38–0·64]; 25·2 g group: 0·55 mmol/L [0·42–0·68]). Across the various dose groups, serum potassium also decreased in participants with moderate hyperkalaemia (p<0·001 for comparisons with baseline across the different groups and doses). Risk of cancer with pioglitazone use was assessed in a diabetes registry study by Lewis and colleagues. Researchers included a cohort of 193 099 individuals for the bladder cancer analysis, 18% (34 181) of whom had used pioglitazone for a median of 2·8 years (range 0·2–13·2). Bladder cancer occurred in 1261 individuals, with adjusted analysis indicative of no significant association between pioglitazone and bladder cancer (adjusted hazard ratio [aHR] for ever-use of pioglitazone 1·06, 95% CI 0·89–1·26); these results were supported in a case-control analysis. In the cohort of 236 507 individuals included in the analysis of ten other cancers, an association between pioglitazone ever-use and prostate cancer (aHR 1·13, 95% CI 1·02–1·26) and pancreatic cancer (1·41, 1·16–1·71) was noted; the researchers concluded that these results, “…merit further investigation to assess whether the observed associations are causal or due to chance, residual confounding, or reverse causality”. Results from a phase 2, dose-ranging study pave the way for a phase 3 trial of ISIS 304801. In the double-blind trial, researchers randomly allocated patients with hypertriglyceridaemia to receive either weekly ISIS 304801 or placebo for 13 weeks. Participants who received placebo monotherapy (n=16) showed an increase in plasma APOC3 concentration from baseline (mean change 4·2% [SD 41·7]), whereas participants who received active treatment (n=35) showed reductions in APOC3 concentration (100 mg: −40·0% [32·0]; p<0·05 compared with placebo; 200 mg: −63·8% [22·3]; p<0·001; 300 mg: −79·6% [9·3]; p<0·001). Participants who received active treatment in addition to continued fibrate therapy (n=18) also had greater reductions in APOC3 concentrations than the eight participants who received placebo plus fibrate (p<0·001). APOC3 lowering was associated with reductions in triglycerides. As part of a prospective observational study, Olsen and colleagues have described the baseline characteristics of a cohort of young people with gender dysphoria. Participants were aged 12–24 years and were seen in a transgender youth clinic in Los Angeles, CA, USA. 51 (50%) of 101 participants were of female gender at birth (transmasculine). Baseline mean testosterone in the transmasculine cohort was 1·48 nmol/L (SD 1·43; normal female range 0·07–1·56); one (2%) participant had a virilising disorder, and four (8%) had polycystic ovarian syndrome. In transfeminine youth, baseline mean estradiol was 101 pmol/L (SD 46; normal male range <106), and prolactin was 0·35 nmol/L (0·17; normal range 0·09–0·78). Extension of the 2-year DATA trial provides insight into the effect of switching between teriparatide and denosumab treatment in women with postmenopausal osteoporosis. Women who were originally assigned to teriparatide (20 mg per day) were switched to denosumab (n=27), those who had received denosumab (60 mg every 6 months) were switched to teriparatide (n=27), and women who had received combination therapy were transitioned to denosumab (n=23). At the end of the 2-year extension, mean spine bone mineral density (BMD) continued to increase in all treatment groups, although switching from denosumab to teriparatide led to a transient decrease before BMD increased. Switching to teriparatide led to initial decreased hip BMD, whereas BMD continued to increase in the other groups, with greatest increases in the group originally receiving combination therapy (p<0·05). In an ongoing extension study of postmenopausal osteoporosis, the effect of long-term denosumab treatment was assessed. After completion of the 3-year placebo versus denosumab FREEDOM study, all women received denosumab for an additional 5 years (denosumab continuation, n=2343; placebo crossover, n=2207). In participants originally allocated to denosumab, BMD continued to increase relative to extension baseline at the hip (8·3%), femoral neck (7·8%), lumbar spine (18·4%), and radius (3·5%; p<0·05 for all). Women who switched from placebo to denosumab had increases in BMD at hip (6·2%), femoral neck (5·7%), lumbar spine (18·4%), and radius (1·5%; p<0·05 for all). During the extension phase, eight cases of osteonecrosis of the jaw and two atypical femoral fractures were reported.

Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia

BackgroundApolipoprotein C-III (APOC3) is a key regulator of plasma triglyceride levels. Elevated triglyceride levels are associated with a risk of adverse cardiovascular events and pancreatitis. ISIS 304801 is a second-generation antisense inhibitor of APOC3 synthesis.MethodsWe conducted a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 study to evaluate ISIS 304801 in untreated patients with fasting triglyceride levels between 350 mg per deciliter (4.0 mmol per liter) and 2000 mg per deciliter (22.6 mmol per liter) (ISIS 304801 monotherapy cohort), as well as in patients receiving stable fibrate therapy who had fasting triglyceride levels between 225 mg per deciliter (2.5 mmol per liter) and 2000 mg per deciliter (ISIS 304801–fibrate cohort). Eligible patients were randomly assigned to receive either ISIS 304801, at doses ranging from 100 to 300 mg, or placebo, once weekly for 13 weeks. The primary outcome was the percentage change in APOC3 level from baseline.ResultsA total of 57 patients were treated in the ISIS 304801 monotherapy cohort (41 received active agent, and 16 received placebo), and 28 patients were treated in the ISIS 304801–fibrate cohort (20 received active agent, and 8 received placebo). The mean (±SD) baseline triglyceride levels in the two cohorts were 581±291 mg per deciliter (6.6±3.3 mmol per liter) and 376±188 mg per deciliter (4.2±2.1 mmol per liter), respectively. Treatment with ISIS 304801 resulted in dose-dependent and prolonged decreases in plasma APOC3 levels when the drug was administered as a single agent (decreases of 40.0±32.0% in the 100-mg group, 63.8±22.3% in the 200-mg group, and 79.6±9.3% in the 300-mg group, vs. an increase of 4.2±41.7% in the placebo group) and when it was administered as an add-on to fibrates (decreases of 60.2±12.5% in the 200-mg group and 70.9±13.0% in the 300-mg group, vs. a decrease of 2.2±25.2% in the placebo group). Concordant reductions of 31.3 to 70.9% were observed in triglyceride levels. No safety concerns were identified in this short-term study.ConclusionsWe found that treatment with ISIS 304801 was associated with significant lowering of triglyceride levels, among patients with a broad range of baseline levels, through selective antisense inhibition of APOC3 synthesis. (Funded by Isis Pharmaceuticals; ClinicalTrials.gov number, NCT01529424.)

Rhabdomyolysis probably induced by influenza vaccine and fibrate therapy.

Rhabdomyolysis probably induced by influenza vaccine and fibrate therapy.

Fibrate therapy predispose to influenza vaccine-induced rabdomyolysis

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Pleiotropic effects of fenofibrate therapy on rats with hypertriglycemia.

BackgroundCardio-protective effect of fibrate therapy is controversial and current research is to evaluate the effect of fenofibrate therapy on rats with hypertriglycemia.MethodsRats with hypertriglycemia were produced by 10% fructose administration (10 ml daily) for 4 weeks. After model has been successfully produced as reflected by increased triglyceride level, different doses of fenofibrate, namely low dose (50 mg/kg body weight) and high dose (100 mg/kg body weight), were orally prescribed for 2 weeks. At baseline, 4 weeks of fructose administration and 2 weeks of fenofibrate therapy, parameters of interest were evaluated and compared.ResultsAt baseline, no significant differences of parameter were observed between groups. After 4 weeks of fructose prescription, triglyceride level increased in company with high density lipoprotein cholesterol (HDL-C) and apoprotein A1 (ApoA1) decreased. C-reactive protein (CRP) and malondialdehyde (MDA) levels were also elevated. Endothelial function was impaired as reflected by reduced nitric oxide (NO) production and elevated serum asymmetric dimethylarginine (ADMA) level. All these changes were significant as compared to the control group (P < 0.05), suggesting that short-term of triglyceride elevation could potently initiate atherosclerosis. With 2 weeks of fenofibrate therapy, in comparison to un-treated group, triglyceride level was significantly reduced in parallel with HDL-C and ApoA1 elevation. Inflammation and oxidation were also profoundly ameliorated as reflected by CRP and MDA reduction. Notably, NO production was enhanced in company with serum ADMA level decrease. Overall, these improvements manifested in a dose-dependent manner, which was supported by multivariate regression analysis showing that after adjusted to other variables, the dose of fenofibrate therapy remained significantly associated with NO production and serum ADMA level, with OR of 1.042 (high-dose versus low-dose, 95% CI 1.028-1.055, P < 0.05).ConclusionsFenofibrate therapy not only could reduce triglyceride level but also confer pleiotropic effects in terms of endothelium-protection and amelioration of inflammation and oxidation in a dose-dependent manner.

Over-the-counter fish oil use in a county hospital: Medication use evaluation and efficacy analysis

Little is known about the use and effectiveness of over-the-counter (OTC) fish oil supplements for triglyceride (TG) lowering. To (1) perform a medication-use evaluation (MUE) and (2) assess the efficacy of OTC fish oil. Retrospective, observational cohort study using electronic medical records and the pharmacy database from Parkland Health and Hospital System in Dallas, Texas. Parkland is a tax-supported county institution that provides patients with single-brand OTC fish oil. Two separate analyses were conducted. Six hundred seventeen patients (prescribed fish oil between July 1, 2012, and August 31, 2012) were included in the MUE analysis and 235 patients (109 fish oil, 72 fenofibrate, and 54 gemfibrozil, prescribed between January 1, 2012, and July 31, 2013) were included in the efficacy analysis. The main outcome measure for the MUE was fish oil prescribing habits including dosages and patient adherence, as defined by medication possession ratio. The main outcome measure for the efficacy analysis was change in lipids measured using the last value before fish oil treatment and the first value after fish oil treatment. MUE: 617 patients received prescriptions for OTC fish oil. Sixty-four percent were prescribed a total daily dose of 2000mg. Only 25% of patients were adherent. Efficacy analysis: despite being prescribed suboptimal doses, fish oil reduced TGs by 29% (95% confidence interval, 34.3-22.7). Compared with fish oil therapy, fibrate therapy resulted in a greater TG reduction: 48.5% (55.1-41.0) with fenofibrate and 49.8% (57.6-40.5) with gemfibrozil (P<.0001, both medications compared with fish oil). Health care providers prescribe suboptimal doses of fish oil, and adherence is poor. Even at low doses (2g/d), though, fish oil lowers TGs by 29%.

Circulating Levels of Proprotein Convertase Subtilisin Kexin Type 9 are Elevated by Fibrate Therapy

Proprotein convertase subtilisin kexin type 9 (PCSK9) affects lipid metabolism through modulation of low-density lipoprotein (LDL) receptor degradation. Circulating PCSK9 status is an important determinant of LDL-cholesterol levels and is thus implicated in atherogenesis. The present study aimed to resolve inconsistencies in clinical findings on the impact of fibrate therapy on circulating PCSK9 concentrations using a meta-analysis of all published studies. A comprehensive literature search in Medline and Scopus was carried out to identify clinical reports on the impact of treatment with fibrates on circulating concentrations of PCSK9. A meta-analysis of eligible studies was performed using a random-effects model. A weighed mean difference (WMD) with 95% confidence interval (CI) was used to assess the magnitude of fibrates' effect on PCSK9 concentrations. Six studies comprising 218 subjects fulfilled the eligibility criteria and were included for systematic review and quantitative data synthesis. A meta-analysis indicated a significant elevation of circulating PCSK9 concentrations following fibrate therapy (WMD: +60.37; 95% CI: 11.04-109.71; P = 0.02). The PCSK9-elevating effect of fibrates remained significant after comparison with a control group receiving either placebo or a statin (WMD: +23.97; 95% CI: 5.68-42.26; P = 0.01). Meta-regression analysis indicated that the effect size of fibrates in modulating circulating PCSK9 levels is not dependent on the duration of treatment (point estimate for slope = 0.59, SE = 4.56; 95% CI = -8.34 to 9.53; z = 0.130, P = 0.897). Fibrate therapy is associated with a significant increase in circulating PCSK9 concentrations. Such a PCSK9 elevation may partly explain the modest efficacy of fibrates on LDL-C.

Effects of Niacin, Statin, and Fenofibrate on Circulating Proprotein Convertase Subtilisin/Kexin Type 9 Levels in Patients With Dyslipidemia

Recent trials demonstrated substantial improvement in lipid parameters with inhibition of proprotein convertase subtilisin-like/kexin type 9 (PCSK9). Although statins and fibrates have been reported to increase plasma PCSK9 levels, the effect of niacin on PCSK9 is unknown. We investigated the impact of niacin, atorvastatin, and fenofibrate on PCSK9 levels in 3 distinct studies. A statin-only study randomized 74 hypercholesterolemic patients to placebo, atorvastatin 10 mg/day, or atorvastatin 80 mg/day for 16 weeks. A dose-related increase in PCSK9 was noted such that atorvastatin 80 mg increased PCSK9 by a mean +27% (95% confidence interval [CI] +12 to +42), confirming the effect of statin therapy on raising PCSK9. A second study randomized 70 patients with carotid atherosclerosis to simvastatin 20 mg/day, simvastatin 80 mg/day, or simvastatin 20 mg/extended-release (ER) niacin 2 g/day. PCSK9 levels were increased with statin therapy, but decreased with the simvastatin 20 mg/ER niacin combination (mean -13%, CI -3 to -23). A final study involved 19 dyslipidemic participants on atorvastatin 10 mg with serial addition of fenofibric acid 135 mg followed by ER niacin 2 g/day. Fenofibric acid led to a +23% (CI +10 to +36, p = 0.001) increase in PCSK9; the addition of niacin resulted in a subsequent -17% decrease (CI -19 to -5, p = 0.004). A positive association was noted between change in PCSK9 and low-density lipoprotein cholesterol levels (r = 0.62, p = 0.006) with the addition of niacin. In conclusion, niacin therapy offsets the increase in PCSK9 levels noted with statin and fibrate therapy. A portion of the low-density lipoprotein cholesterol reduction seen with niacin therapy may be due to reduction in PCSK9.

Association between triglyceride and high-density lipoprotein cholesterol change following fibrate therapy

BackgroundDebate surrounding the role of fibrates has followed mixed outcomes from several randomised controlled trials. Subgroup analysis of even the negative trials reveals significant reduction in cardiovascular risk amongst patients with low HDL-C and high TG. We previously described factors associated with HDL-C change following fibrates. As fibrates influence both HDL-C and TG levels via their action on PPAR-α, we now wished to study TG change following fibrate therapy and any associations with baseline and change in HDL-C and TC levels. MethodsData was collected from case notes of patients started on fibrates (n=248) between 2002 and 2008 in the lipid clinics at Heart of England NHS Foundation Trust. Regression analyses were carried out to determine factors associated with changes in TG. ResultsMultiple regression analysis revealed that TG change was associated with pre-treatment TG (p<0.001) and TC levels (p=0.029). The association between TG change and pre-treatment TG remained significant when all factors including gender, concurrent statin treatment, diabetes and baseline HDL-C were entered into the regression model. Our previous study demonstrated significant post-fibrate HDL-C change in the group with baseline HDL-C values <1.0mmol/l. In our present study significant TG reduction was observed regardless of the baseline patient characteristics including HDL-C levels. ConclusionsThe actions of fibrates are considered to be mediated via PPAR-α, but our data suggest that the effects on TG and HDL-C are different. Thus, the mechanisms mediating the changes of these lipids following fibrate treatment may vary.

Rare LPL gene variants attenuate triglyceride reduction and HDL cholesterol increase in response to fenofibric acid therapy in individuals with mixed dyslipidemia

ObjectiveIndividuals with mixed dyslipidemia have elevated triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), and increased risk for coronary disease. Fibrate therapy is commonly used to lower TG and increase HDL-C. Common genetic variants are known to affect the response to fibrate therapy. We sought to identify rare genetic variants (frequency ≤ 1%) in genes involved in TG and HDL-C metabolism that affect the response to fenofibric acid (FA) therapy. MethodsFour genes with a major role in HDL-C and TG metabolism APOA1, APOC2, APOC-III and LPL were sequenced in 2385 participants with mixed dyslipidemia in a randomized, double-blind, active-controlled study comparing therapy with FA alone, in combination with statins, or statin alone. Rare variants collapsing or SKAT methods were used for the analysis. ResultsSynonymous rare variants in the LPL gene were significantly associated with absolute HDL-C change (P = 9 × 10−4) and TG percent change (P = 6.76 × 10−4) in those treated with FA only. Participants with these rare variants had a 2 mg/dL increase in HDL-C and 39 mg/dL decrease in TG as compared to 6.2 mg/dL increase in HDL-C and 100 mg/dL decrease in TG in those without these variants. Rare variants in the APOC-III gene were associated with a modest 3 mg/dL less reduction in APOB (P = 8.72 × 10−4) in those receiving FA and statin. ConclusionIn individuals with mixed dyslipidemia rare synonymous variants within LPL gene were associated with attenuated response to FA therapy while APOCIII rare variants were associated with a modest effect on APOB response to FA-statin therapy. These results should be replicated in a similar clinical trial for further confirmation.

Cognitive Function and Brain Structure in Persons With Type 2 Diabetes Mellitus After Intensive Lowering of Blood Pressure and Lipid Levels

Persons with type 2 diabetes mellitus (T2DM) are at increased risk for decline in cognitive function, reduced brain volume, and increased white matter lesions in the brain. Poor control of blood pressure (BP) and lipid levels are risk factors for T2DM-related cognitive decline, but the effect of intensive treatment on brain function and structure is unknown. To examine whether intensive therapy for hypertension and combination therapy with a statin plus a fibrate reduces the risk of decline in cognitive function and total brain volume (TBV) in patients with T2DM. A North American multicenter clinical trial including 2977 participants without baseline clinical evidence of cognitive impairment or dementia and with hemoglobin A1c (HbA1c) levels less than 7.5% randomized to a systolic BP goal of less than 120 vs less than 140 mm Hg (n = 1439) or to a fibrate vs placebo in patients with low-density lipoprotein cholesterol levels less than 100 mg/dL (n = 1538). Participants were recruited from August 1, 2003, through October 31, 2005, with the final follow-up visit by June 30, 2009. Cognition was assessed at baseline and 20 and 40 months. A subset of 503 participants underwent baseline and 40-month brain magnetic resonance imaging to assess for change in TBV and other structural measures of brain health. Baseline mean HbA1c level was 8.3%; mean age, 62 years; and mean duration of T2DM, 10 years. At 40 months, no differences in cognitive function were found in the intensive BP-lowering trial or in the fibrate trial. At 40 months, TBV had declined more in the intensive vs standard BP-lowering group (difference, -4.4 [95% CI, -7.8 to -1.1] cm(3); P = .01). Fibrate therapy had no effect on TBV compared with placebo. In participants with long-standing T2DM and at high risk for cardiovascular events, intensive BP control and fibrate therapy in the presence of controlled low-density lipoprotein cholesterol levels did not produce a measurable effect on cognitive decline at 40 months of follow-up. Intensive BP control was associated with greater decline in TBV at 40 months relative to standard therapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00000620.

Effect of fibrate treatment on liver function tests in patients with the metabolic syndrome

BackgroundFibrates are used especially in patients with hypertriglyceridaemia, a feature of the metabolic syndrome. Elevated LFTs are often observed in these patients perhaps related to fatty infiltration.AimWe wished to study changes seen in LFTs (GGT, ALT and ALP) following fibrate therapy and then determine associated factors.MethodsThis was a retrospective observational study in which data was collected from case notes of patients started on fibrates (n = 118, 2002–2008) in the lipid clinic at Good Hope Hospital and pre/post-fibrate lipid and LFT values were obtained. All biochemistry was performed on the Roche P-Unit using supplied reagents. Statistical analyses included t tests and regression analyses (factorised when quartiles were compared).ResultsOf the study population 106 patients were on fenofibrate; the remaining on bezafibrate. Significant lowering of GGT (p < 0.0001), ALT (p = 0.0014) and ALP (p < 0.0001) levels were observed following fibrate treatment. Baseline lipid (cholesterol, triglycerides and HDL) concentrations, alcohol intake, length of treatment, gender, concurrent statin treatment and diabetes did not correlate with these changes in LFT in a multiple regression analysis. Higher pre-fibrate GGT (p < 0.0001), ALT (p < 0.0001) and ALP (p < 0.0001) concentrations were associated with larger decreases in each of these tests respectively with the highest 2 quartiles (GGT > 57 IU/l, ALT > 34 IU/l and ALP > 94 IU/l) significantly different to the lowest quartile. The above associations remained significant even when the regression analyses were corrected for changes in lipid values (which did not show an association).ConclusionsFibrate treatment led to improvements in LFT, the greatest benefit seen in patients with higher baseline LFT values. It appears that baseline and changes in lipid values post fibrate treatment were not associated with change in LFT.