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1.
Unmet Need for Adjunctive Dyslipidemia Therapy in Hypertriglyceridemia Management.
Ganda, OP, Bhatt, DL, Mason, RP, Miller, M, Boden, WE
Journal of the American College of Cardiology. 2018;(3):330-343
Abstract
Despite the important role of high-intensity statins in reducing atherosclerotic cardiovascular disease events in secondary and primary prevention, substantial residual risk persists, particularly among high-risk patients with type 2 diabetes mellitus, metabolic syndrome, and obesity. Considerable attention is currently directed to the role that elevated triglycerides (TGs) and non-high-density lipoprotein cholesterol levels play as important mediators of residual atherosclerotic cardiovascular disease risk, which is further strongly supported by genetic linkage studies. Previous trials with fibrates, niacin, and most cholesterol ester transfer protein inhibitors that targeted high-density lipoprotein cholesterol raising, and/or TG lowering, have failed to show conclusive evidence of incremental event reduction after low-density lipoprotein cholesterol levels were "optimally controlled" with statins. Although omega-3 fatty acids are efficacious in lowering TG levels and may have pleiotropic effects such as reducing plaque instability and proinflammatory mediators of atherogenesis, clinical outcomes data are currently lacking. Several ongoing randomized controlled trials of TG-lowering strategies with an optimal dosage of omega-3 fatty acids are nearing completion.
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2.
How to assess and manage cardiovascular risk associated with lipid alterations beyond LDL.
Averna, M, Stroes, E, ,
Atherosclerosis. Supplements. 2017;:16-24
Abstract
BACKGROUND AND AIMS The maintenance of clinically recommended levels of low-density lipoprotein cholesterol (LDL-C) through a statin therapy is a gold standard in the management of patients with dyslipidaemia and cardiovascular disease (CVD). However, even when LDL-C levels are at or below clinically recommended target levels, residual cardiovascular (CV) risk still remains. Therefore, assessing lipoproteins beyond LDL-C in managing CV risk is imperative. METHODS A working group of clinical experts have assessed the role of lipoproteins other than LDL-C in identifying the CV risk in patients with dyslipidaemia and CVD and in the management of atherogenic dyslipidaemia associated with a number of other diseases. The recommendations, in line with the European guidelines, are presented. RESULTS A thorough evaluation of clinical data by the expert working group resulted in recommendations to consider non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apoB), remnant cholesterol and lipoprotein(a) (Lp[a]) as biomarkers of residual CV risk in patients with CVD. Elevated Lp(a) levels were also suggested to be a causal factor. The experts highlighted the significance of non-HDL-C and triglycerides (TG) in atherogenic dyslipidaemia associated with type 2 diabetes, metabolic syndrome, chronic kidney disease (CKD) and familial combined hyperlipidaemia (FCH). The working group recommended combinatorial therapeutic approaches in high-risk patients, including agents impacting on TG and HDL-C levels. CONCLUSIONS Evaluation of a lipoprotein landscape when LDL-C levels remain low strongly supports the role of non-HDL-C, Lp(a) and TGs in identifying patients with increased residual risk of CV and in selecting their treatment strategy.
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3.
TRIGLYCERIDES, ATHEROSCLEROSIS, AND CARDIOVASCULAR OUTCOME STUDIES: FOCUS ON OMEGA-3 FATTY ACIDS.
Handelsman, Y, Shapiro, MD
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2017;(1):100-112
Abstract
OBJECTIVE To provide an overview of the roles of triglycerides and triglyceride-lowering agents in atherosclerosis in the context of cardiovascular outcomes studies. METHODS We reviewed the published literature as well as ClinicalTrials.gov entries for ongoing studies. RESULTS Despite improved atherosclerotic cardiovascular disease (ASCVD) outcomes with statin therapy, residual risk remains. Epidemiologic data and recent genetic insights provide compelling evidence that triglycerides are in the causal pathway for the development of atherosclerosis, thereby renewing interest in targeting triglycerides to improve ASCVD outcomes. Fibrates, niacin, and omega-3 fatty acids (OM3FAs) are three classes of triglyceride-lowering drugs. Outcome studies with triglyceride-lowering agents have been inconsistent. With regard to OM3FAs, the JELIS study showed that eicosapentaenoic acid (EPA) significantly reduced major coronary events in statin-treated hypercholesterolemic patients. Regarding other agents, extended-release niacin and fenofibrate are no longer recommended as statin add-on therapy (by some guidelines, though not all) because of the lack of convincing evidence from outcome studies. Notably, subgroup analyses from the outcome studies have generated the hypothesis that triglyceride lowering may provide benefit in statin-treated patients with persistent hypertriglyceridemia. Two ongoing OM3FA outcome studies (REDUCE-IT and STRENGTH) are testing this hypothesis in high-risk, statin-treated patients with triglyceride levels of 200 to 500 mg/dL. CONCLUSION There is consistent evidence that triglycerides are in the causal pathway of atherosclerosis but inconsistent evidence from cardiovascular outcomes studies as to whether triglyceride-lowering agents reduce cardiovascular risk. Ongoing outcomes studies will determine the role of triglyceride lowering in statin-treated patients with high-dose prescription OM3FAs in terms of improved ASCVD outcomes. ABBREVIATIONS AACE = American Association of Clinical Endocrinologists ACCORD = Action to Control Cardiovascular Risk in Diabetes AIM-HIGH = Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes apo = apolipoprotein ASCEND = A Study of Cardiovascular Events in Diabetes ASCVD = atherosclerotic cardiovascular disease BIP = Bezafibrate Infarction Prevention CHD = coronary heart disease CI = confidence interval CV = cardiovascular CVD = cardiovascular disease DHA = docosahexaenoic acid DO-IT = Diet and Omega-3 Intervention Trial EPA = eicosapentaenoic acid FIELD = Fenofibrate Intervention and Event Lowering in Diabetes GISSI-HF = GISSI-Heart Failure HDL-C = high-density-lipoprotein cholesterol HPS2-THRIVE = Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events HR = hazard ratio JELIS = Japan Eicosapentaenoic Acid Lipid Intervention Study LDL = low-density lipoprotein LDL-C = low-density-lipoprotein cholesterol MI = myocardial infarction OM3FAs = omega-3 fatty acids VITAL = Vitamin D and Omega-3 Trial.
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4.
Hypertriglyceridemia: the importance of identifying patients at risk.
Kushner, PA, Cobble, ME
Postgraduate medicine. 2016;(8):848-858
Abstract
This review aims to explain risk factors, consequences, and management strategies recommended for patients with hypertriglyceridemia. A search of PubMed was performed: 'Hypertriglyceridemia'[Majr], limited to English-language and published in the 5 years up to April 2016. Abstracts of the 680 results were screened for inclusion. Reference lists of publications included were also screened for inclusion. Approximately 25% of the United States population has elevated (≥150 mg/dL) triglycerides (TG) putting them at an increased risk of cardiovascular disease, non-alcoholic fatty liver disease, and pancreatitis. Risk factors for hypertriglyceridemia include genetics, lifestyle and diet, renal disease, endocrine disorders, and certain medications. Guidelines recommend that all patients with hypertriglyceridemia are advised on lifestyle modification to reduce TG to <150 mg/dL; a reduction in body weight of 5-10% can reduce TG by approximately 20%. For patients with TG <400 mg/dL, the primary goal is to reduce low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol, with most guidelines recommending statin therapy. When TG is ≥500 mg/dL the primary goal is to reduce TG levels to lower the risk of pancreatitis. Statin therapy (if LDL-C is elevated) in combination with a fibrate, or long-chain omega-3 fatty acid may be required. The Food and Drug Administration withdrew approval for niacin and some fibrates in combination with statins in April 2016 citing unfavorable benefit-risk profiles. With the increasing incidence of associated conditions (e.g. obesity, metabolic syndrome, and type 2 diabetes mellitus), it is likely that primary care physicians will encounter more patients with hypertriglyceridemia.
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5.
[Diabetic dyslipidaemia and the atherosclerosis].
Márk, L, Dani, G
Orvosi hetilap. 2016;(19):746-52
Abstract
The incidence and the public health importance of diabetes mellitus are growing continuously. Despite the improvement observed in recent years, the leading cause of morbidity and mortality of diabetics are cardiovascular diseases. The diagnosis of diabetes mellitus constitutes such a high risk as the known presence of vascular disease. Diabetic dyslipidaemia is characterised by high fasting and postprandial triglyceride levels, low HDL level, and slightly elevated LDL-cholesterol with domination of atherogenic small dense LDL. These are not independent components of the atherogenic dyslipidaemia, but are closely linked to each other. Beside the known harmful effects of low HDL and small dense LDL, recent findings confirmed the atherogenicity of the triglyceride-rich lipoproteins and their remnants. It has been shown that the key of this process is the overproduction and delayed clearance of triglyceride-rich lipoproteins in the liver. In this metabolism the lipoprotein lipase has a determining role; its function is accelerated by ApoA5 and attenuated by ApoC3. The null mutations of the ApoC3 results in a reduced risk of myocardial infarction, the loss-of-function mutation of ApoA5 was associated with a 60% elevation of triglyceride level and 2.2-times increased risk of myocardial infarction. In case of diabetes mellitus, insulin resistance, obesity, metabolic syndrome and chronic kidney disease the non-HDL-cholesterol is a better marker of the risk than the LDL-cholesterol. Its value can be calculated by subtraction of HDL-cholesterol from total cholesterol. Target values of non-HDL-cholesterol can be obtained by adding 0.8 mmol/L to the LDL-cholesterol targets (this means 3.3 mmol/L in high, and 2.6 mmol/L in very high risk patients). The drugs of first choice in the treatment of diabetic dyslipidaemia are statins. Nevertheless, it is known that even if statin therapy is optimal (treated to target), a considerable residual (lipid) risk remains. For its reduction treatment of low HDL-cholesterol and high triglyceride levels is obvious by the administration of fibrates. In addition to statin therapy, fenofibrate can be recommended.
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6.
Molecular sources of residual cardiovascular risk, clinical signals, and innovative solutions: relationship with subclinical disease, undertreatment, and poor adherence: implications of new evidence upon optimizing cardiovascular patient outcomes.
Kones, R
Vascular health and risk management. 2013;:617-70
Abstract
Residual risk, the ongoing appreciable risk of major cardiovascular events (MCVE) in statin-treated patients who have achieved evidence-based lipid goals, remains a concern among cardiologists. Factors that contribute to this continuing risk are atherogenic non-low-density lipoprotein (LDL) particles and atherogenic processes unrelated to LDL cholesterol, including other risk factors, the inherent properties of statin drugs, and patient characteristics, ie, genetics and behaviors. In addition, providers, health care systems, the community, public policies, and the environment play a role. Major statin studies suggest an average 28% reduction in LDL cholesterol and a 31% reduction in relative risk, leaving a residual risk of about 69%. Incomplete reductions in risk, and failure to improve conditions that create risk, may result in ongoing progression of atherosclerosis, with new and recurring lesions in original and distant culprit sites, remodeling, arrhythmias, rehospitalizations, invasive procedures, and terminal disability. As a result, identification of additional agents to reduce residual risk, particularly administered together with statin drugs, has been an ongoing quest. The current model of atherosclerosis involves many steps during which disease may progress independently of guideline-defined elevations in LDL cholesterol. Differences in genetic responsiveness to statin therapy, differences in ability of the endothelium to regenerate and repair, and differences in susceptibility to nonlipid risk factors, such as tobacco smoking, hypertension, and molecular changes associated with obesity and diabetes, may all create residual risk. A large number of inflammatory and metabolic processes may also provide eventual therapeutic targets to lower residual risk. Classically, epidemiologic and other evidence suggested that raising high-density lipoprotein (HDL) cholesterol would be cardioprotective. When LDL cholesterol is aggressively lowered to targets, low HDL cholesterol levels are still inversely related to MCVE. The efflux capacity, or ability to relocate cholesterol out of macrophages, is believed to be a major antiatherogenic mechanism responsible for reduction in MCVE mediated in part by healthy HDL. HDL cholesterol is a complex molecule with antioxidative, anti-inflammatory, anti-thrombotic, antiplatelet, and vasodilatory properties, among which is protection of LDL from oxidation. HDL-associated paraoxonase-1 has a major effect on endothelial function. Further, HDL promotes endothelial repair and progenitor cell health, and supports production of nitric oxide. HDL from patients with cardiovascular disease, diabetes, and autoimmune disease may fail to protect or even become proinflammatory or pro-oxidant. Mendelian randomization and other clinical studies in which raising HDL cholesterol has not been beneficial suggest that high plasma levels do not necessarily reduce cardiovascular risk. These data, coupled with extensive preclinical information about the functional heterogeneity of HDL, challenge the "HDL hypothesis", ie, raising HDL cholesterol per se will reduce MCVE. After the equivocal AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) study and withdrawal of two major cholesteryl ester transfer protein compounds, one for off-target adverse effects and the other for lack of efficacy, development continues for two other agents, ie, anacetrapib and evacetrapib, both of which lower LDL cholesterol substantially. The negative but controversial HPS2-THRIVE (the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) trial casts further doubt on the HDL cholesterol hypothesis. The growing impression that HDL functionality, rather than abundance, is clinically important is supported by experimental evidence highlighting the conditional pleiotropic actions of HDL. Non-HDL cholesterol reflects the cholesterol in all atherogenic particles containing apolipoprotein B, and has outperformed LDL cholesterol as a lipid marker of cardiovascular risk and future mortality. In addition to including a measure of residual risk, the advantages of using non-HDL cholesterol as a primary lipid target are now compelling. Reinterpretation of data from the Treating to New Targets study suggests that better control of smoking, body weight, hypertension, and diabetes will help lower residual risk. Although much improved, control of risk factors other than LDL cholesterol currently remains inadequate due to shortfalls in compliance with guidelines and poor patient adherence. More efficient and greater use of proven simple therapies, such as aspirin, beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, combined with statin therapy, may be more fruitful in improving outcomes than using other complex therapies. Comprehensive, intensive, multimechanistic, global, and national programs using primordial, primary, and secondary prevention to lower the total level of cardiovascular risk are necessary.
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7.
Demystifying the management of hypertriglyceridaemia.
Watts, GF, Ooi, EM, Chan, DC
Nature reviews. Cardiology. 2013;(11):648-61
Abstract
Hypertriglyceridaemia (typical triglyceride level 1.7-5.0 mmol/l) is caused by interactions between many genetic and nongenetic factors, and is a common risk factor for atherosclerotic cardiovascular disease (CVD). Patients with hypertriglyceridaemia usually present with obesity, insulin resistance, hepatic steatosis, ectopic fat deposition, and diabetes mellitus. Hypertriglyceridaemia reflects the accumulation in plasma of proatherogenic lipoproteins, triglyceride-rich lipoprotein (TRL) remnants, and small, dense LDL particles. Mendelian randomization studies and research on inherited dyslipidaemias, such as type III dysbetalipoproteinaemia, testify that TRLs are causally related to atherosclerotic CVD. Extreme hypertriglyceridaemia (a triglyceride level >20 mmol/l) is rare, often monogenic in aetiology, and frequently causes pancreatitis. Treatment of hypertriglyceridaemia relies on correcting secondary factors and unhealthy lifestyle habits, particularly poor diet and lack of exercise. Pharmacotherapy is indicated for patients with established CVD or individuals at moderate-to-high risk of CVD, primarily those with metabolic syndrome or diabetes. Statins are the cornerstone of treatment, followed by fibrates and n-3 fatty acids, to achieve recommended therapeutic levels of plasma LDL cholesterol, non-HDL cholesterol, and apolipoprotein (apo) B-100. The case for using niacin has been weakened by the results of clinical trials, but needs further investigation. Extreme hypertriglyceridaemia requires strict dietary measures, and patients with a diagnosis of genetic lipoprotein lipase deficiency might benefit from LPL gene replacement therapy. Several therapies for regulating TRL metabolism, including inhibitors of diacylglycerol O-acyltransferase and microsomal triglyceride transfer protein, and apoC-III antisense oligonucleotides, merit further investigation in patients with hypertriglyceridaemia.
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8.
Selective peroxisome proliferator-activated receptor α modulators (SPPARMα): the next generation of peroxisome proliferator-activated receptor α-agonists.
Fruchart, JC
Cardiovascular diabetology. 2013;:82
Abstract
Dyslipidemia is a major risk factor for cardiovascular (CV) disease - the primary cause of death, worldwide. Although reducing levels of low-density lipoprotein-cholesterol can significantly reduce CV risk, a high level of residual risk persists, especially in people with obesity-related conditions, such as metabolic syndrome and type 2 diabetes mellitus. Peroxisome proliferator-activated receptor alpha- (PPARα-) agonists (e.g. fibrates), play a central role in the reduction of macro- and microvascular risk in these patients. However, the currently available fibrates are weak (PPARα-agonists) with limited efficacy due to dose-related adverse effects. To address this problem, a new generation of highly potent and selective PPARα-modulators (SPPARMα) is being developed that separate the benefits of the PPARα-agonists from their unwanted side effects. Among these, aleglitazar (a dual PPARα/γ agonist) and GFT505 (a dual PPAR α/δ agonist) have recently entered late-phase development. Although both compounds are more potent PPARα-activators than fenofibrate in vitro, only aleglitezar is more effective in lowering triglycerides and raising high-density lipoprotein-cholesterol (HDL-C) in humans. However, it is also associated with a potential risk of adverse effects. More recently, a highly potent, specific PPARα-agonist (K-877) has emerged with SPPARMα characteristics. Compared to fenofibrate, K-877 has more potent PPARα-activating efficacy in vitro, greater effects on triglycerides- and HDL-C levels in humans, and a reduced risk of adverse effects. If successful, K-877 has the potential to supersede the fibrates as the treatment of choice for patients with residual CV risk associated with metabolic syndrome and type 2 diabetes.
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9.
Dyslipidemia in obesity: mechanisms and potential targets.
Klop, B, Elte, JW, Cabezas, MC
Nutrients. 2013;(4):1218-40
Abstract
Obesity has become a major worldwide health problem. In every single country in the world, the incidence of obesity is rising continuously and therefore, the associated morbidity, mortality and both medical and economical costs are expected to increase as well. The majority of these complications are related to co-morbid conditions that include coronary artery disease, hypertension, type 2 diabetes mellitus, respiratory disorders and dyslipidemia. Obesity increases cardiovascular risk through risk factors such as increased fasting plasma triglycerides, high LDL cholesterol, low HDL cholesterol, elevated blood glucose and insulin levels and high blood pressure. Novel lipid dependent, metabolic risk factors associated to obesity are the presence of the small dense LDL phenotype, postprandial hyperlipidemia with accumulation of atherogenic remnants and hepatic overproduction of apoB containing lipoproteins. All these lipid abnormalities are typical features of the metabolic syndrome and may be associated to a pro-inflammatory gradient which in part may originate in the adipose tissue itself and directly affect the endothelium. An important link between obesity, the metabolic syndrome and dyslipidemia, seems to be the development of insulin resistance in peripheral tissues leading to an enhanced hepatic flux of fatty acids from dietary sources, intravascular lipolysis and from adipose tissue resistant to the antilipolytic effects of insulin. The current review will focus on these aspects of lipid metabolism in obesity and potential interventions to treat the obesity related dyslipidemia.
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10.
Recent clinical trials evaluating benefit of drug therapy for modification of HDL cholesterol.
Wright, RS
Current opinion in cardiology. 2013;(4):389-98
Abstract
PURPOSE OF REVIEW To highlight the recent data evaluating pharmacological manipulation of HDL cholesterol (HDL-C) and examine whether medication-induced changes were associated with improved clinical outcomes and reduced short-term and long-term cardiovascular risks. The review focuses on the studies with niacin and the new cholesteryl ester transfer protein (CETP) inhibitors torcetrapib, dalcetrapib, anacetrapib and evacetrapib. RECENT FINDINGS Several large randomized clinical trials have evaluated drug therapy on HDL-C and cardiovascular outcomes. Two studies have evaluated the clinical outcomes following HDL-C raising with niacin. Data from the Heart Protection 2 Treatment of HDL to Reduce the Incidence of Vascular Events and The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health trials both demonstrated no clinical benefit from use of niacin therapy when added to background statin therapy with regard to short-term and long-term cardiovascular risk reduction. Both studies demonstrated excess side-effects from use of niacin. A number of clinical trials have evaluated HDL-C modification from use of a CETP inhibitor. All of the studies have demonstrated significant increases in HDL-C. To date, the outcome data are not favorable. Use of torcetrapib was associated with excess mortality. Use of dalcetrapib had no effect on short-term and long-term cardiovascular events. Two outcome studies with anacetrapib and evacetrapib are ongoing and will report out in a few years' time. SUMMARY Pharmacological manipulation of HDL-C has not improved the cardiovascular outcomes. Several agents have caused harm or unacceptable side-effects. Further studies are needed before one can recommend the use of additional lipid-modifying therapies beyond statins.