Comparison of the efficacy of administering a combination of ezetimibe plus fenofibrate versus atorvastatin monotherapy in the treatment of dyslipidemia

<p>Abstract</p> <p>Background</p> <p>This trial compares the efficacy of administering a combination of ezetimibe plus fenofibrate as an alternative to statin monotherapy for the treatment of dyslipidemia. In this randomized, unblinded crossover study, 43 patients with documented hypercholesterolemia requiring pharmacotherapy were randomized to receive six weeks of either a combination of 10 mg of ezetimibe plus 160 mg of fenofibrate (combination) or 10 mg of atorvastatin monotherapy (atorvastatin). The primary endpoint was the percentage reduction of low-density lipoprotein cholesterol (LDL-C).</p> <p>Results</p> <p>LDL-C decreased by 34.6% with the combination therapy versus 36.7% with atorvastatin monotherapy. The difference between the two groups was not statistically significant (p = 0.46). Both study interventions provided similar improvements in total cholesterol (-25.1% with combination versus -24.6% with atorvastatin, p = 0.806) and high-density lipoproteins (+10.0% with combination versus +8.9% with atorvastatin, p = 0.778). Combination therapy showed a trend towards a greater reduction in triglycerides (-25.4% with combination versus -14.5% with atorvastatin, p = 0.079), although there was no significant difference between the two study interventions in terms of the improvement in the TC:HDL ratio (-29.0% with combination versus -28.7% with atorvastatin, p = 0.904).</p> <p>Conclusions</p> <p>The combination of ezetimibe plus fenofibrate appeared to produce nearly identical alterations in serum lipoprotein levels when compared to monotherapy with 10 mg of atorvastatin. Daily treatment with the combination of ezetimibe plus fenofibrate is an acceptable alternative to atorvastatin for the treatment of dyslipidemia in patients who are intolerant of statins.</p

Plasma PCSK9 levels are significantly modified by statins and fibrates in humans

<p>Abstract</p> <p>Background</p> <p>Proprotein convertase subtilisin kexin-like 9 (PCSK9) is a secreted glycoprotein that is transcriptionally regulated by cholesterol status. It modulates levels of circulating low density lipoprotein cholesterol (LDLC) by negatively regulating low density lipoprotein receptor (LDLR) levels. PCSK9 variants that result in 'gain of function' have been linked to autosomal dominant hypercholesterolemia, while significant protection from coronary artery disease has been documented in individuals who carry 'loss of function' PCSK9 variants. PCSK9 circulates in human plasma, and we previously reported that plasma PCSK9 is positively correlated with total cholesterol and LDLC in men.</p> <p>Results</p> <p>Herein, we report the effects of two lipid-modulating therapies, namely statins and fibrates, on PCSK9 plasma levels in human subjects. We also document their effects on endogenous PCSK9 and LDLR expression in a human hepatocyte cell line, HepG2, using immunoprecipitation and immunoblot analyses. Changes in plasma PCSK9 following fenofibrate or gemfibrozil treatments (fibric acid derivatives) were inversely correlated with changes in LDLC levels (r = -0.558, p = 0.013). Atorvastatin administration (HMGCoA reductase inhibitor) significantly increased plasma PCSK9 (7.40%, p = 0.033) and these changes were inversely correlated with changes in LDLC levels (r = -0.393, p = 0.012). Immunoblot analyses of endogenous PCSK9 and LDLR expression by HepG2 cells in response to statins and fibrates showed that LDLR is more upregulated than PCSK9 by simvastatin (2.6× vs 1.5×, respectively at 10 μM), while fenofibrate did not induce changes in either.</p> <p>Conclusion</p> <p>These results suggest that <it>in vivo </it>(1) statins directly increase PCSK9 expression while (2) fibrates affect PCSK9 expression indirectly through its modulation of cholesterol levels and (3) that these therapies could be improved by combination with a PCSK9 inhibitor, constituting a novel hypercholesterolemic therapy, since PCSK9 was significantly upregulated by both treatments.</p

L'Exposition municipale de Beaux-Arts. I

Exposition municipale des beaux-arts. Critique mitigée de "Guerrier furieux". Hodler a des qualités remarquables mais il manque de pondération. Talent inégal

Progression of atherosclerosis with carnitine supplementation: a randomized controlled trial in the metabolic syndrome

Background: L-carnitine (L-C), a ubiquitous nutritional supplement, has been investigated as a potential therapy for cardiovascular disease, but its effects on human atherosclerosis are unknown. Clinical studies suggest improvement of some cardiovascular risk factors, whereas others show increased plasma levels of pro-atherogenic trimethylamine N-oxide. The primary aim was to determine whether L-C therapy led to progression or regression of carotid total plaque volume (TPV) in participants with metabolic syndrome (MetS). Methods: This was a phase 2, prospective, double blinded, randomized, placebo-controlled, two-center trial. MetS was defined as ≥ 3/5 cardiac risk factors: elevated waist circumference; elevated triglycerides; reduced HDL-cholesterol; elevated blood pressure; elevated glucose or HbA1c; or on treatment. Participants with a baseline TPV ≥ 50 mm3 were randomized to placebo or 2 g L-C daily for 6 months. Results: The primary outcome was the percent change in TPV over 6 months. In 157 participants (L-C N = 76, placebo N = 81), no difference in TPV change between arms was found. The L-C group had a greater increase in carotid atherosclerotic stenosis of 9.3% (p = 0.02) than the placebo group. There was a greater increase in total cholesterol and LDL-C levels in the L-C arm. Conclusions: Though total carotid plaque volume did not change in MetS participants taking L-C over 6-months, there was a concerning progression of carotid plaque stenosis. The potential harm of L-C in MetS and its association with pro-atherogenic metabolites raises concerns for its further use as a potential therapy and its widespread availability as a nutritional supplement. Trial registration: ClinicalTrials.gov, NCT02117661, Registered April 21, 2014, https://clinicaltrials.gov/ct2/show/NCT02117661

TbPIF5 Is a Trypanosoma brucei Mitochondrial DNA Helicase Involved in Processing of Minicircle Okazaki Fragments

Trypanosoma brucei's mitochondrial genome, kinetoplast DNA (kDNA), is a giant network of catenated DNA rings. The network consists of a few thousand 1 kb minicircles and several dozen 23 kb maxicircles. Here we report that TbPIF5, one of T. brucei's six mitochondrial proteins related to Saccharomyces cerevisiae mitochondrial DNA helicase ScPIF1, is involved in minicircle lagging strand synthesis. Like its yeast homolog, TbPIF5 is a 5′ to 3′ DNA helicase. Together with other enzymes thought to be involved in Okazaki fragment processing, TbPIF5 localizes in vivo to the antipodal sites flanking the kDNA. Minicircles in wild type cells replicate unidirectionally as theta-structures and are unusual in that Okazaki fragments are not joined until after the progeny minicircles have segregated. We now report that overexpression of TbPIF5 causes premature removal of RNA primers and joining of Okazaki fragments on theta structures. Further elongation of the lagging strand is blocked, but the leading strand is completed and the minicircle progeny, one with a truncated H strand (ranging from 0.1 to 1 kb), are segregated. The minicircles with a truncated H strand electrophorese on an agarose gel as a smear. This replication defect is associated with kinetoplast shrinkage and eventual slowing of cell growth. We propose that TbPIF5 unwinds RNA primers after lagging strand synthesis, thus facilitating processing of Okazaki fragments

Performance of the “CCS Algorithm” in real world patients

Background: With the publication of the 2014 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation, the Canadian Cardiovascular Society Atrial Fibrillation Guidelines Committee has introduced a new triage and management algorithm; the so-called “CCS Algorithm”. The CCS Algorithm is based upon expert opinion of the best available evidence; however, the CCS Algorithm has not yet been validated. Accordingly, the purpose of this study is to evaluate the performance of the CCS Algorithm in a cohort of real world patients. Methods: We compared the CCS Algorithm with the European Society of Cardiology (ESC) Algorithm in 172 hospital inpatients who are at risk of stroke due to non-valvular atrial fibrillation in whom anticoagulant therapy was being considered. Results: The CCS Algorithm and the ESC Algorithm were concordant in 170/172 patients (99% of the time). There were two patients (1%) with vascular disease, but no other thromboembolic risk factors, which were classified as requiring oral anticoagulant therapy using the ESC Algorithm, but for whom ASA was recommended by the CCS Algorithm. Conclusions: The CCS Algorithm appears to be unnecessarily complicated in so far as it does not appear to provide any additional discriminatory value above and beyond the use of the ESC Algorithm, and its use could result in under treatment of patients, specifically female patients with vascular disease, whose real risk of stroke has been understated by the Guidelines

Performance of the “CCS Algorithm” in real world patients

With the publication of the 2014 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation, the Canadian Cardiovascular Society Atrial Fibrillation Guidelines Committee has introduced a new triage and management algorithm, the so-called “CCS Algorithm”. The CCS Algorithm is based upon expert opinion of the best available evidence, however, the CCS Algorithm has not yet been validated. Accordingly, the purpose of this study is to evaluate the performance of the CCS Algorithm in a cohort of real world patients. We compared the CCS Algorithm with the European Society of Cardiology (ESC) Algorithm in 172 hospital inpatients who are at risk of stroke due to non-valvular atrial fibrillation in whom anticoagulant therapy was being considered. The CCS Algorithm and the ESC Algorithm were concordant in 170/172 patients (99% of the time). There were two patients (1%) with vascular disease, but no other thromboembolic risk factors, which were classified as requiring oral anticoagulant therapy using the ESC Algorithm, but for whom ASA was recommended by the CCS Algorithm. The CCS Algorithm appears to be unnecessarily complicated in so far as it does not appear to provide any additional discriminatory value above and beyond the use of the ESC Algorithm, and its use could result in under treatment of patients, specifically female patients with vascular disease, whose real risk of stroke has been understated by the Guidelines