Statins are effective drugs to reduce cardiovascular events secondary to dyslipidemia; however, they cause frequent undesirable side effects. The incidence of statin-induced myotoxicity (SIM) is ...presented by 7 to 29% of patients, depending upon the report. SIM may develop in presence of abnormally high concentrations of statins in the myocyte and/or in presence of muscular conditions that may predispose to SIM. High concentrations of statins in the myocyte may occur whenever the activity of liver influx membrane transporters, namely OATP1B1, of drug metabolizing enzymes, and of liver and muscular efflux transporters, MDR1 and BCRP, is reduced. In the muscle, conditions that may predispose to SIM include mitochondrial damage with disruption of the mitochondrial respiratory chain and decreased production of ATP, increase of ROS, and leak of cytochrome c and Ca
. In the sarcoplasma, statins activate MAPK and diminish the RhoA/AKT/mTOR/PGC-1α pathway. All these effects contribute to activate apoptosis, proteolysis, and muscle remodeling. Moreover, in the sarcoplasma, statins can reduce the resting chloride channel conductance, as well as lactate efflux. These changes will be responsible of fatigue, cramps, myalgia and elevation of serum CK. To date, besides avoiding drug-drug interactions and alcohol consumption, and correcting hypothyroidism, two strategies could be useful to prevent/diminish SIM, e.g. gradual dose titration with statins less prone to produce SIM, and high supplements of vitamin D in subjects with low plasma concentrations of 25(OH) D
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Summary Background Inhibition of proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) resulted in large reductions of low-density lipoprotein cholesterol (LDL-C) in phase 1 trials. ...We assessed the efficacy and safety of various doses and dosing intervals of REGN727, a monoclonal antibody to PCSK9, added to statins, to further lower LDL-C in patients with heterozygous familial hypercholesterolaemia. Methods This multicentre, randomised, placebo-controlled phase 2 trial was done at 16 lipid clinics in the USA and Canada. Between Jan 18, 2011, and Nov 7, 2011, we enrolled adults with heterozygous familial hypercholesterolaemia and LDL-C concentrations of 2·6 mmol/L or higher on stable diet and statin dose, with or without ezetimibe. Patients were randomly assigned to receive REGN727 150 mg, 200 mg, or 300 mg every 4 weeks, or 150 mg every 2 weeks, or placebo every 2 weeks (ratio 1:1:1:1:1). Randomisation was stratified by concomitant use of ezetimibe at baseline. Investigators, study staff, and patients were masked to treatment group. Blinding was maintained by administration of placebo alternating with REGN727 for the groups of 4 week dosing. The primary endpoint was mean percent reduction in LDL-C from baseline at week 12 and was analysed in the modified intention-to-treat population with an analysis of covariance (ANCOVA) model with treatment group. This trial is registered in ClinicalTrials.gov , number NCT 01266876. Findings 77 patients were randomly assigned to study groups (15–16 patients per group) and all were analysed. Least-squares (LS) mean LDL-C reduction from baseline to week 12 was 28·9% (SE 5·08) for 150 mg every 4 weeks (p=0·0113), 31·54% (4·91) for 200 mg every 4 weeks (p=0·0035), 42·53% (5·09) for 300 mg every 4 weeks (p<0·0001), and 67·90% (4·85) for 150 mg every 2 weeks (p<0·0001), compared with 10·65% (5·04) with placebo. One serious adverse event was reported with placebo and none with REGN727. No increases of more than three times the upper limit of normal were reported for hepatic transaminases or creatinine kinase. The most common adverse event was injection-site reaction with one patient in the group of 300 mg REGN727 terminating treatment. Interpretation REGN727 was well tolerated and achieved substantial further LDL-C reduction in patients with heterozygous familial hypercholesterolaemia and elevated LDL-C treated with high-dose statins, with or without ezetimibe. REGN727 has the potential to provide optimum control of LDL-C in patients with this disorder. Funding Sanofi US and Regeneron Pharmaceuticals Incorporated.
Summary Background Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature ...cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the effect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder. Methods This multicentre, randomised, double-blind, placebo-controlled trial was undertaken at 39 sites (most of which were specialised lipid clinics, mainly attached to academic institutions) in Australia, Asia, Europe, New Zealand, North America, and South Africa between Feb 7 and Dec 19, 2013. 331 eligible patients (18–80 years of age), who met clinical criteria for heterozygous familial hypercholesterolaemia and were on stable lipid-lowering therapy for at least 4 weeks, with a fasting LDL cholesterol concentration of 2·6 mmol/L or higher, were randomly allocated in a 2:2:1:1 ratio to receive subcutaneous evolocumab 140 mg every 2 weeks, evolocumab 420 mg monthly, or subcutaneous placebo every 2 weeks or monthly for 12 weeks. Randomisation was computer generated by the study sponsor, implemented by a computerised voice interactive system, and stratified by LDL cholesterol concentration at screening (higher or lower than 4·1 mmol/L) and by baseline ezetimibe use (yes/no). Patients, study personnel, investigators, and Amgen study staff were masked to treatment assignments within dosing frequency groups. The coprimary endpoints were percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov , number NCT01763918. Findings Of 415 screened patients, 331 were eligible and were randomly assigned to the four treatment groups: evolocumab 140 mg every 2 weeks (n=111), evolocumab 420 mg monthly (n=110), placebo every 2 weeks (n=55), or placebo monthly (n=55). 329 patients received at least one dose of study drug. Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59·2% reduction 95% CI 53·4–65·1, monthly dose: 61·3% reduction 53·6–69·0; both p<0·0001) and at the mean of weeks 10 and 12 (60·2% reduction 95% CI 54·5–65·8 and 65·6% reduction 59·8–71·3; both p<0·0001). Evolocumab was well tolerated, with rates of adverse events similar to placebo. The most common adverse events occurring more frequently in the evolocumab-treated patients than in the placebo groups were nasopharyngitis (in 19 patients 9% vs five 5% in the placebo group) and muscle-related adverse events (ten patients 5% vs 1 1%). Interpretation In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo. Funding Amgen Inc.
Background Familial hypercholesterolemia (FH) is characterized by extremely high low-density lipoprotein cholesterol (LDL-C) concentration and premature cardiovascular disease (CVD). Not all FH ...patients present the same CVD risk, and currently, there is no clinical tool to assess this risk. Objective The objectives of this cross-sectional cohort study are twofold: to identify the strongest predictors of CVD in patients with FH and to develop a new score to identify FH patients at very high CVD risk. Methods We screened 20,434 patients with dyslipidemia to identify carriers of an FH-causing mutation. A total of 670 adult subjects with a causal mutation in the LDL receptor ( LDLR ) gene were included in the present study. Results Age (β = 0.75), HDL-C (β = −0.27), male gender (β = 0.25), hypertension (β = 0.19), and smoking (β = 0.12) were independent predictors of CVD risk in FH subjects (n = 638). The Montreal-FH-SCORE significantly predicted CVD better than each individual variable (AUC of 0.840 0.808–0.872, P < .0001). FH subjects with a high Montreal-FH-SCORE score (above 20) presented a significant 10.3-fold higher odds of presenting CVD events compared to subjects in the lower score group (95% CI, 6.7–15.7, P < .0001). Conclusion Cardiovascular risk in FH can be stratified with a combination of simple clinical variables, independently of LDL-C value. The Montreal-FH-SCORE score is strongly associated with CVD events in FH and could be useful to select FH subjects who would benefit from further CVD risk reduction.
OBJECTIVESTo assess the contribution of the rs3846662 polymorphism of HMGCR on serum lipid levels and statin efficacy, we measured in vivo HMGCR mRNA and lipid levels in French Canadian individuals ...affected by heterozygous familial hypercholesterolemia due to the deletion of more than 15 kb of the LDLR gene.
RESULTSMen and women carrying the AA genotype at rs3846662, and no APOE4 allele, had higher levels of total cholesterol (5.43 vs. 4.58 mmol/l, P<0.05) and LDL-cholesterol (5.20 vs. 4.39 mmol/l, P<0.05) at baseline. However, with regard to statin efficacy, the penetrance of the AA genotype was sex dependent. Indeed, the percentage reduction in LDL-cholesterol upon statin treatment was significantly decreased in women with the AA genotype compared with women without it (38.4 vs. 46.2%, P<0.05), whereas this was not observed in men. Although both men and women bearing the AA genotype showed a higher ratio of full-length HMGCR mRNA/total HMGCR mRNA compared with individuals without it (n=37, P<0.05), overall transcription of HMGCR was decreased and increased in men and women carrying this genotype, respectively (n=37, P<0.01 and P<0.05). Finally, in our familial hypercholesterolemia cohort, HMGCR alternative splicing explained between 22 and 55% of the variance in statin response.
CONCLUSIONrs3846662 polymorphism and the alternative splicing of HMGCR mRNA significantly impact women’s response to statin therapy.
Purpose Multiparametric magnetic resonance imaging can be used to guide prostate biopsy by targeting biopsies to areas in the prostate at high risk for cancer. We compared the detection of clinically ...significant and insignificant cancer by transperineal magnetic resonance imaging targeted biopsy and transperineal template guided prostate biopsy. Materials and Methods A total of 182 men with a lesion suspicious for cancer on multiparametric magnetic resonance imaging underwent transperineal magnetic resonance imaging targeted biopsy using a cognitive registration technique, followed by systematic transperineal template guided prostate biopsy. The primary outcome was the detection rate of clinically significant prostate cancer. Clinical significance was defined using maximum cancer core length 4 mm or greater and/or Gleason grade 3 + 4 or greater (University College London definition 2). We secondarily evaluated other commonly used thresholds of clinically significant disease, including maximum cancer core length 6 mm or greater and/or Gleason grade 4 + 3 or greater, maximum cancer core length 3 mm or greater and/or Gleason grade 3 + 4 or greater, and maximum cancer core length 2 or greater mm and/or Gleason grade 3 + 4 or greater. Strategies were statistically compared with the McNemar test. Results Mean ± SD patient age was 63.3 ± 7.2 years. Median prostate specific antigen was 6.7 ng/ml (IQR 4.7–10.0). Clinically significant cancer was detected by magnetic resonance imaging targeted biopsy and template guided prostate biopsy in 103 (57%) and 113 of the 182 men (62%) (p = 0.174), and clinically insignificant cancer was detected in 17 (9.3%) and 31 (17.0%), respectively (p = 0.024). Conclusions Prostate biopsy targeted to suspicious lesions on multiparametric magnetic resonance imaging has encouraging rates of detection of clinically significant cancer while also decreasing the detection rate of clinically insignificant cancer. This is achieved with fewer biopsy cores than for systematic template guided biopsy. Further prospective, multicenter, comparative trials of the performance of targeting strategies are needed to consider magnetic resonance imaging targeted biopsy an alternative to conventional systematic biopsy.
Abstract Many developments have occurred since the publication of the widely-used 2009 Canadian Cardiovascular Society (CCS) Dyslipidemia guidelines. Here, we present an updated version of the ...guidelines, incorporating new recommendations based on recent findings and harmonizing CCS guidelines with those from other Societies. The G rading of R ecommendations A ssessment, D evelopment and E valuation (GRADE) system was used, per present standards of the CCS. The total cardiovascular disease Framingham Risk Score (FRS), modified for a family history of premature coronary disease, is recommended for risk assessment. Low-density lipoprotein cholesterol remains the primary target of therapy. However, non-high density lipoprotein cholesterol has been added to apolipoprotein B as an alternate target. There is an increased emphasis on treatment of higher risk patients, including those with chronic kidney disease and high risk hypertension. The primary panel has recommended a judicious use of secondary testing for subjects in whom the need for statin therapy is unclear. Expanded information on health behaviours is presented and is the backbone of risk reduction in all subjects. Finally, a systematic approach to statin intolerance is advocated to maximize appropriate use of lipid-lowering therapy. This document presents the recommendations and principal conclusions of this process. Along with associated Supplementary Material that can be accessed online, this document will be part of a program of knowledge translation. The goal is to increase the appropriate use of evidence-based cardiovascular disease event risk assessment in the management of dyslipidemia as a fundamental means of reducing global risk in the Canadian population.
Disease-associated blood biomarkers exist in exceedingly low concentrations within complex mixtures of high-abundance proteins such as albumin. We have introduced an affinity bait molecule into ...N-isopropylacrylamide to produce a particle that will perform three independent functions within minutes, in one step, in solution: (a) molecular size sieving, (b) affinity capture of all solution-phase target molecules, and (c) complete protection of harvested proteins from enzymatic degradation. The captured analytes can be readily electroeluted for analysis.
Abstract Familial hypercholesterolemia (FH) is the most common genetic disorder causing premature cardiovascular disease and death. Heterozygous FH conservatively affects approximately 1:500 ...Canadians, and the more serious homozygous form affects approximately 1:1,000,000 Canadians, although these numbers might be underestimated. Of approximately 83,500 Canadians estimated to have FH, most are undiagnosed, which represents a simultaneous public health deficit and opportunity, because early treatment of heterozygous FH can normalize life expectancy. Diagnostic algorithms for FH incorporate increased plasma low-density lipoprotein cholesterol, pathognomonic clinical features, and family history of early cardiovascular disease and hyperlipidemia. DNA-based detection of causative mutations in FH-related genes can help with diagnosis. Maximizing diagnosis and treatment of FH in Canada will involve a multipronged approach, including: (1) increasing awareness of FH among health care providers and patients; (2) creating a national registry for FH individuals; (3) setting standards for screening, including cascade screening in affected families; (4) ensuring availability of standard-of-care therapies, in particular optimization of plasma low-density lipoprotein cholesterol levels and timely access to future validated therapies; (5) promoting patient-based support and advocacy groups; and (6) forming alliances with international colleagues, resources, and initiatives that focus on FH. This document aims to raise awareness of FH nationally, and to mobilize knowledge translation, patient support, and availability of treatment and health care resources for this underrecognized, but important medical condition.
Familial hypercholesterolemia (FH) is a disease characterized by increased low-density lipoprotein cholesterol and premature cardiovascular disease (CVD) but there is marked individuality in the ...occurrence of CVD events. Recently, the Montreal-FH-SCORE (MFHS) has been shown to stratify CVD frequency in FH subjects, but this score has not yet been validated.
The aims of the present study were to conduct an independent external validation of the MFHS in a retrospective cohort of heterozygous FH and to identify additional variables that could significantly improve the prediction of prevalent CVD.
The MFHS calculation is based on 5 variables: age, high-density lipoprotein cholesterol, gender, hypertension, and smoking status. This score was validated in a cohort of 718 adult FH using receiver operating characteristic (ROC) curves analysis to determine the discriminatory ability of the MFHS. The performance of the MFHS was compared to a novel Combined-FH-SCORE in 1388 FH.
The MFHS had an excellent discrimination for prevalent CVD events in the validation cohort, with an area under the receiver operating characteristic curve of 0.799 (0.766–0.832, P < .0001). Patients with a high MFHS score presented a significant 8.8-fold increased odd of CVD events compared with patients with a low score (95% confidence interval 5.8–13.3, P < .0001). The addition of lipoprotein(a) to the score did not improve the prediction of CVD events (area under the receiver operating characteristic curve 0.823 vs 0.817, P = .11).
This study confirmed that the MFHS is a strong predictor of prevalent CVD in FH and that the addition of lipoprotein(a) offers a minor improvement in the discrimination of the score.
•Not all patients with familial hypercholesterolemia (FH) present the same cardiovascular disease (CVD) risk.•Age, high-density lipoprotein cholesterol, gender, hypertension, and smoking are predictors of prevalent CVD in FH.•This study provides an external validation of the Montreal-FH-SCORE.•The Montreal-FH-SCORE had an excellent discrimination for prevalent CVD in the validation cohort.•The addition of lipoprotein(a) to the score did not improve prediction.
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