The need for a new classification of cholesterol lowering therapies

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The Potential Relevance of the Multiple Lipid-Independent (Pleiotropic) Effects of Statins in the Management of Acute Coronary Syndromes

Emerging data suggest that acute presentations of coronary artery disease may involve a complex interplay between the vessel wall, inflammatory cells, and the coagulation cascade. Although a culprit thrombotic lesion may be treated effectively by antithrombotic therapy and revascularization, this will have little effect on the global processes that determine recurrent events at non-culprit sites. Thus, additional systemic treatment is required to modulate the adverse biological features that are the hallmark of acute coronary syndromes (ACS). Statins possess multiple beneficial effects that are independent of low-density-lipoprotein cholesterol (LDL-C) lowering and that have favorable effects on inflammation, the endothelium, and the coagulation cascade. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, differences were seen based on achieved LDL-C that could be further discriminated by the achieved C-reactive protein level. Studies of non-vascular disease such as multiple sclerosis have shown that statins reduce inflammation, supporting the presence of lipid-independent effects of statins. This review focuses on the potential importance of these effects in the management of ACS

Non-antibody Approaches to Proprotein Convertase Subtilisin Kexin 9 Inhibition: siRNA, Antisense Oligonucleotides, Adnectins, Vaccination, and New Attempts at Small-Molecule Inhibitors Based on New Discoveries

Low-density lipoprotein (LDL) is one of the principal risk factors for atherosclerosis. Circulating LDL particles can penetrate into the sub-endothelial space of arterial walls. These particles undergo oxidation and promote an inflammatory response, resulting in injury to the vascular endothelial wall. Persistent elevation of LDL-cholesterol (LDL-C) is linked to the progression of fatty streaks to lipid-rich plaque and thus atherosclerosis. LDL-C is a causal factor for atherosclerotic cardiovascular disease and lowering it is beneficial across a range of conditions associated with high risk of cardiovascular events. Therefore, all guidelines-recommended initiations of statin therapy for patients at high cardiovascular risk is irrespective of LDL-C. In addition, intensive LDL-C lowering therapy with statins has been demonstrated to result in a greater reduction of cardiovascular event risk in large clinical trials. However, many high-risk patients receiving statins fail to achieve the guideline-recommended reduction in LDL-C levels in routine clinical practice. Moreover, low levels of adherence and often high rates of discontinuation demand the need for further therapies. Ezetimibe has typically been used as a complement to statins when further LDL-C reduction is required. More recently, proprotein convertase subtilisin kexin 9 (PCSK9) has emerged as a novel therapeutic target for lowering LDL-C levels, with PCSK9 inhibitors offering greater reductions than feasible through the addition of ezetimibe. PCSK9 monoclonal antibodies have been shown to not only considerably lower LDL-C levels but also cardiovascular events. However, PCSK9 monoclonal antibodies require once- or twice-monthly subcutaneous injections. Further, their manufacturing process is expensive, increasing the cost of therapy. Therefore, several non-antibody treatments to inhibit PCSK9 function are being developed as alternative approaches to monoclonal antibodies. These include gene-silencing or editing technologies, such as antisense oligonucleotides, small interfering RNA, and the clustered regularly interspaced short palindromic repeats/Cas9 platform; small-molecule inhibitors; mimetic peptides; adnectins; and vaccination. In this review, we summarize the current knowledge base on the role of PCSK9 in lipid metabolism and an overview of non-antibody approaches for PCSK9 inhibition and their limitations. The subsequent development of alternative approaches to PCSK9 inhibition may give us more affordable and convenient therapeutic options for the management of high-risk patients

Dietary food patterns and glucose/insulin homeostasis: a cross-sectional study involving 24,182 adult Americans

AIM: To investigate the association of major dietary patterns with glucose and insulin homeostasis parameters in a large American sample. The association between dietary patterns (DP) derived via principal components analysis (PCA), with glucose/insulin homeostasis parameters was assessed. The likelihood of insulin resistance (IR) across the DPs quarters was also explored. METHOD: The United States National Health and Nutrition Examination Survey (NHANES) participants during 2005-2012 were included if they underwent measurement of dietary intake as well as glucose and insulin homeostasis parameters. Analysis of covariance (ANCOVA) and adjusted logistic and linear regression models were employed to account for the complex survey design and sample weights. RESULTS: A total of 24,182 participants were included; 48.9% (n = 11,815) were men. Applying PCA revealed three DP (56.8% of variance): the first was comprised mainly of saturated fat (SFA), total fat, mono-unsaturated fatty acids (MUFA) and carbohydrate (CHO); the second is highly enriched with vitamins, trace elements and dietary fiber; and the third was composed of polyunsaturated fatty acids (PUFA), cholesterol and protein. Among the total population, after adjustment for age, sex, race, C-reactive protein, smoking, and physical activity, glucose homeostasis factors, visceral adiposity index and lipid accumulation product improved across the quarters of the first and third DP; and a reverse pattern with the second DP. The same trend was observed for the non-diabetic subjects. Moreover, subjects with higher adherence to the first and third DP had higher likelihood for developing IR, whereas there was a lower likelihood for the second DP. CONCLUSION: This study shows that the DP heavily loaded with CHO, SFA, PUFA, protein, total fat and MUFA as well as high-cholesterol-load foods is associated with impaired glucose tolerance; in contrast, the healthy pattern which is high in vitamins, minerals and fiber may have favourable effects on insulin sensitivity and glucose tolerance

'Highest risk-highest benefit' strategy: a pragmatic, cost-effective approach to targeting use of PCSK9 inhibitor therapies.

No abstract available

Retrospective examination of lipid-lowering treatment patterns in a real-world high-risk cohort in the UK in 2014:comparison with the National Institute for Health and Care Excellence (NICE) 2014 lipid modification guidelines

BACKGROUND: In 2014, guidelines from the National Institute for Health and Care Excellence (NICE) provided updated recommendations on lipid-modifying therapy (LMT). We assessed clinical practice contemporaneous to release of these guidelines in a UK general practice setting for secondary and high-risk primary-prevention populations, and extrapolated the findings to UK nation level. METHODS: Patients from The Health Improvement Network database with the following criteria were included: lipid profile in 2014 (index date); ≥20 years of age; ≥2 years representation in database prior to index; ≥1 statin indication either for atherosclerotic cardiovascular disease (ASCVD) or the non-ASCVD conditions high-risk diabetes mellitus and/or chronic kidney disease. RESULTS: Overall, 183 565 patients met the inclusion criteria (n=91 479 for ASCVD, 92 086 for non-ASCVD). In those with ASCVD, 79% received statin treatment and 31% received high-intensity statin. In the non-ASCVD group, 62% were on a statin and 57% received medium-intensity or high-intensity statin. In the ASCVD and non-ASCVD cohorts, 6% and 15%, respectively, were already treated according to dosing recommendations as per updated NICE guidelines. Extrapolation to the 2014 UK population indicated that, of the 3.3 million individuals with ASCVD, 2.4 million would require statin uptitration and 680 000 would require statin initiation (31% de novo initiation, 60% reinitiation, 9% addition to non-statin LMT) to achieve full concordance with updated guidelines. Of the 3.5 million high-risk non-ASCVD individuals, 1.6 million would require statin uptitration and 1.4 million would require statin initiation (59% de novo initiation, 36% reinitiation, 5% addition to non-statin LMT). CONCLUSIONS: A large proportion of UK individuals with ASCVD and high-risk non-ASCVD received statin treatment (79% and 62%, respectively) during the year of NICE 2014 guidelines release. Up to 94% of patients with ASCVD and 85% of high-risk non-ASCVD individuals, representing ∼3 million individuals in each group, would require statin uptitration or initiation to achieve full concordance with updated guidelines

A meta‐analysis of published studies of endothelial dysfunction does not support its routine clinical use

Summary Background Endothelial dysfunction is a marker of future cardiovascular disease (CVD) risk, yet epidemiological studies have yielded inconsistent results. We therefore studied the association between endothelial dysfunction and CVD under diverse circumstances. Methods and results Literature-based meta-analysis of prospective observational studies with ≥ 12 months of follow-up published in Medline and having information on endothelial function and CVD outcomes. Tabular data on participant characteristics, endothelial function assessments and incident CVD outcomes were abstracted from individual studies. Random-effects meta-analysis was used to quantify pooled associations, and I2 statistic to evaluate between-study heterogeneity. Potential sources of heterogeneity were explored by subgroup analyses and meta-regression. Thirty five studies involving 17,206 participants met the inclusion criteria. During more than 80,000 person-years of observation, up to 2755 CVD events were accrued, yielding a pooled relative risk (RR) of 1.25 (95% confidence interval 1.15–1.35) for CVD comparing top (i.e. more severe) vs. bottom (less severe) third of endothelial dysfunction. There was significant between-study heterogeneity and evidence of publication bias. RRs varied importantly according to the method used to ascertain endothelial function, and were higher among older individuals and among participants with risk factors for CVD or established CVD at baseline. Conclusions Although endothelial dysfunction is an important determinant of cardiovascular outcomes in people with pre-existing CVD, current evidence base does not support its use as a potentially useful measurement for risk stratification in people at lower risk of CVD

LDL-cholesterol lowering and clinical outcomes in hypercholesterolemic subjects with and without a familial hypercholesterolemia phenotype: Analysis from the secondary prevention 4S trial

Background and aims: Trial evidence for the benefits of cholesterol-lowering is limited for familial hypercho lesterolemia (FH) patients, since they have not been the focus of large outcome trials. We assess statin use in coronary artery disease (CAD) subjects with low-density lipoprotein cholesterol (LDL-C) ≥4.9 mmol/L with or without an FH phenotype. Methods: The 4S trial randomized hypercholesterolemic CAD patients to simvastatin or placebo. We first strat ified participants into baseline LDL-C <4.9 and ≥ 4.9 mmol/L; next, based on the DLCN criteria for FH, the latter group was stratified into four subgroups by presence of none, one or both of “premature CAD” and “family history of CAD”. Participants having both are defined as having an FH phenotype. Results: 2267 and 2164 participants had LDL-C <4.9 and ≥ 4.9 mmol/L, respectively. Mortality endpoints and major coronary events (MCE) were significantly reduced with simvastatin versus placebo in both groups over 5.4 years, but the latter derived greater absolute risk reductions (ARR) (4.1–4.3% for mortality endpoints, versus 2.5–2.8%). LDL-C reductions were similar among the 4 subgroups with levels ≥4.9 mmol/L. Participants with FH phenotype (n = 152) appeared to derive greater relative benefits with simvastatin than the other three subgroups (all-cause death: 84% relative risk reduction, p = 0.046; MCE: 55% reduction, p = 0.0297); statistical interaction was non significant. Participants with FH phenotype derived greater ARR than any other group with simvastatin versus placebo (all-cause mortality: 6.6% ARR; MCE 13.2%; versus 3.8% and 8.3%, respectively, among participants with LDL-C ≥4.9 mmol/L but without features suggestive of FH). Conclusions: The FH phenotype appeared to be associated with greater clinical benefits from a given magnitude of LDL-C reduction as compared to individuals without FH phenotype

INTERASPIRE:an International Survey of Coronary Patients; Their Cardiometabolic, Renal and Biomarker Status; and the Quality of Preventive Care Delivered in All WHO Regions: In Partnership with the World Heart Federation, European Society of Cardiology, Asia Pacific Society of Cardiology, InterAmerican Society of Cardiology, and PanAfrican Society of Cardiology.

Purpose of Review To describe the INTERASPIRE scientific protocol-an international survey of secondary prevention of coronary heart disease (CHD). Recent Findings This international survey is being conducted through National Societies of Cardiology in selected countries from each of the six WHO regions and has the following overall aims: (i) describe prevalence of cardiometabolic and renal risk factors together with biomarkers in CHD patients; (ii) describe current risk factor management through lifestyle changes and cardioprotective drug therapies; (iii) provide an objective assessment of clinical implementation of preventive care by comparison with the lifestyle and risk factor targets defined in international and national guidelines; (iv) investigate the reasons for variation in preventive cardiology practice between regions and countries; and (v) promote the principles of best preventive cardiology practice. This international survey will provide a unique picture of CHD patients; their cardiometabolic, renal and biomarker status; lifestyle and therapeutic management; and the quality of preventive care provided in all WHO regions