BACKGROUND:Lipoprotein(a) Lp(a) may play a causal role in atherosclerosis. PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors have been shown to significantly reduce plasma Lp(a) ...concentration. However, the relationship between Lp(a) levels, PCSK9 inhibition, and cardiovascular risk reduction remains undefined.
METHODS:Lp(a) was measured in 25 096 patients in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a randomized trial of evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease (median follow-up, 2.2 years). Cox models were used to assess the independent prognostic value of Lp(a) and the efficacy of evolocumab for coronary risk reduction by baseline Lp(a) concentration.
RESULTS:The median (interquartile range) baseline Lp(a) concentration was 37 (13–165) nmol/L. In the placebo arm, patients with baseline Lp(a) in the highest quartile had a higher risk of coronary heart disease death, myocardial infarction, or urgent revascularization (adjusted hazard ratio quartile 4quartile 1, 1.22; 95% CI, 1.01–1.48) independent of low-density lipoprotein cholesterol. At 48 weeks, evolocumab significantly reduced Lp(a) by a median (interquartile range) of 26.9% (6.2%–46.7%). The percent change in Lp(a) and low-density lipoprotein cholesterol at 48 weeks in patients taking evolocumab was moderately positively correlated (r=0.37; 95% CI, 0.36–0.39; P<0.001). Evolocumab reduced the risk of coronary heart disease death, myocardial infarction, or urgent revascularization by 23% (hazard ratio, 0.77; 95% CI, 0.67–0.88) in patients with a baseline Lp(a) >median, and by 7% (hazard ratio, 0.93; 95% CI, 0.80–1.08; P interaction=0.07) in those ≤median. Coupled with the higher baseline risk, the absolute risk reductions, and number needed to treat over 3 years were 2.49% and 40 versus 0.95% and 105, respectively.
CONCLUSIONS:Higher levels of Lp(a) are associated with an increased risk of cardiovascular events in patients with established cardiovascular disease irrespective of low-density lipoprotein cholesterol. Evolocumab significantly reduced Lp(a) levels, and patients with higher baseline Lp(a) levels experienced greater absolute reductions in Lp(a) and tended to derive greater coronary benefit from PCSK9 inhibition.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT01764633.
The kinetics of elimination of various dicarbonyl-modified low-density lipoproteins from the bloodstream of
monkeys were investigated. The low-density lipoproteins (LDL) in the monkey blood plasma ...were isolated by density gradient ultracentrifugation and labeled in vitro with the fluorescent dye FITC; thereupon, they were modified with different natural low molecular-weight dicarbonyls: malondialdehyde (MDA), glyoxal, or methylglyoxal. The control native FITC-labeled LDL and dicarbonyl-modified FITC-labeled LDL were injected into the monkey's ulnar vein; thereafter, blood samples were taken at fixed time intervals during 24 h. The plasma level of FITC-labeled LDL was determined with spectrofluorimetry. The study established that glyoxal- and monkeysglyoxal-labeled LDL circulated in monkey virtually at the same time as native (non-modified) LDL. In contrast, MDA-modified LDL disappeared from the blood extremely rapidly. Administration of the PCSK9 inhibitor involocumab (which increases LDL utilization) to patients with coronary heart disease (CHD) was found to significantly reduce levels of MDA-modified LDL.
The 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) dyslipidaemia guidelines recommend achievement of low-density lipoprotein cholestrol (LDL-C) goals based on an ...individual's risk. We aimed to evaluate the impact of guideline adoption with statin, ezetimibe, and statin plus ezetimibe fixed-dose combination (FDC) on LDL-C goal achievement and incidence of major adverse cardiovascular events (MACE) across six countries.
A simulation model with a five-year horizon (2020-2024) was developed based on Institute for Health Metrics and Evaluation Global Burden of Disease Study database with a business-as-usual (BAU) scenario representing status quo, intervention scenario-1 representing treatment with statin and ezetimibe as separate agents, and intervention scenario-2 representing treatment with statin or statin plus ezetimibe FDC. MACE was defined as the composite of myocardial infarction, ischaemic stroke, and cardiovascular death. The mean population LDL-C was reduced from 4.25 mmol/L in the BAU scenario, to 3.65 mmol/L and 3.59 mmol/L in intervention scenarios-1 and -2, respectively. Compared with BAU, intervention scenarios-1 and-2 resulted in relative reduction of MACE by 5.4% and 6.4% representing ∼3.7 and 4.4 million MACE averted, respectively, across six countries over 5 years. The absolute benefit in terms of MACE averted was highest for China, whereas France had highest relative reduction in MACE with both intervention scenarios compared with BAU.
The 2019 ESC/EAS guideline-based treatment intensification with strategies based on statin, ezetimibe, and statin plus ezetimibe FDC is estimated to result in a substantial population-level benefit in terms of MACE averted compared with BAU.
Abstract
In recent years, there has been growing interest in the possible use of nutraceuticals to improve and optimize dyslipidemia control and therapy. Based on the data from available studies, ...nutraceuticals might help patients obtain theraputic lipid goals and reduce cardiovascular residual risk. Some nutraceuticals have essential lipid-lowering properties confirmed in studies; some might also have possible positive effects on nonlipid cardiovascular risk factors and have been shown to improve early markers of vascular health such as endothelial function and pulse wave velocity. However, the clinical evidence supporting the use of a single lipid-lowering nutraceutical or a combination of them is largely variable and, for many of the nutraceuticals, the evidence is very limited and, therefore, often debatable. The purpose of this position paper is to provide consensus-based recommendations for the optimal use of lipid-lowering nutraceuticals to manage dyslipidemia in patients who are still not on statin therapy, patients who are on statin or combination therapy but have not achieved lipid goals, and patients with statin intolerance. This statement is intended for physicians and other healthcare professionals engaged in the diagnosis and management of patients with lipid disorders, especially in the primary care setting.
Background Omega-3 fatty acids in free fatty acid form have enhanced bioavailability, and plasma levels are less influenced by food than for ethyl ester forms. Objective The aim was to evaluate the ...safety and lipid-altering efficacy in subjects with severe hypertriglyceridemia of an investigational pharmaceutical omega-3 free fatty acid (OM3-FFA) containing eicosapentaenoic acid and docosahexaenoic acid. Methods This was a multinational, double-blind, randomized, out-patient study. Men and women with triglycerides (TGs) ≥500 mg/dL, but <2000 mg/dL, took control (olive oil OO 4 g/d; n = 99), OM3-FFA 2 g/d (plus OO 2 g/d; n = 100), OM3-FFA 3 g/d (plus OO 1 g/d; n = 101), or OM3-FFA 4 g/d (n = 99) capsules for 12 weeks in combination with the National Cholesterol Education Program Therapeutic Lifestyle Changes diet. Results Fasting serum TGs changed from baseline by −25.9% ( P < .01 vs OO), −25.5% ( P < .01 vs OO), and −30.9% ( P < .001 vs OO) with 2, 3, and 4 g/d OM3-FFA, respectively, compared with −4.3% with OO. Non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol-to-HDL-C ratio, very low-density lipoprotein cholesterol, remnant-like particle cholesterol, apolipoprotein CIII, lipoprotein-associated phospholipase A2 , and arachidonic acid were significantly lowered ( P < .05 at each OM3-FFA dosage vs OO); and plasma eicosapentaenoic acid and docosahexaenoic acid were significantly elevated ( P < .001 at each OM3-FFA dosage vs OO). With OM3-FFA 2 and 4 g/d (but not 3 g/d), low-density lipoprotein cholesterol was significantly increased compared with OO ( P < .05 vs OO). High-sensitivity C-reactive protein responses with OM3-FFA did not differ significantly from the OO response at any dosage. Fewer subjects reported any adverse event with OO vs OM3-FFA, but frequencies across dosage groups were similar. Discontinuation due to adverse event, primarily gastrointestinal, ranged from 5% to 7% across OM3-FFA dosage groups vs 0% for OO. Conclusions OM3-FFA achieved the primary end point for TG lowering and secondary end point of non-HDL-C lowering at 2, 3, and 4 g/d in persons with severe hypertriglyceridemia. This trial was registered at www.clinicaltrials.gov as NCT01242527.
Background: Multiple trials have demonstrated the efficacy of fenofibrate for the management of dyslipidemia. Real-world evidence may provide important insights into the effectiveness and safety of ...fenofibrate in patients with metabolic syndrome and elevated triglyceride (TG) levels, but such evidence is currently scarce. Materials and Methods: A non-interventional study was conducted among routine healthcare providers. Patients with TG levels of >2.3 mmol/L on stable statin therapy starting fenofibrate treatment were enrolled. Data on medical history, fenofibrate treatment, change in lipid levels, and C-reactive protein (CRP) were collected from medical records every 3 months for 6 to 7 months of observation. Results: Overall, 988 patients receiving fenofibrate were enrolled (median age 95% CI 60 26.0–86.0 years), and 46.4% of the participants were females. Most patients had concomitant cardiovascular disease. A baseline TG level of 3.6 ± 1.5 mmol/L was reduced by 50.1% to 1.7 ± 0.58 mmol/L at 6 months of treatment (p < 0.001). Baseline non-high-density lipoprotein cholesterol (non-HDL-C) levels decreased by 33.7% at 6 months. Total cholesterol and low-density lipoprotein levels by the end of follow-up were reduced by 24.7 and 25.5% (p < 0.001 for both). C-reactive protein level decreased more than 39% from baseline. Conclusions: Fenofibrate in a real-world setting significantly reduced TG, LDL-C, and non-HDL-C levels. In addition, a C-reactive protein level reduction of 39% was achieved.
Lipoprotein(a) (Lp(a)) is recognized as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). The aim of this study was to estimate the distribution of Lp(a) levels in ...working age adults from the Russian population and to assess its association with ischemic heart disease (IHD), myocardial infarction (MI), stroke, diabetes mellitus (DM), and arterial hypertension (AH).
This substudy of the population-based study "Epidemiology of Cardiovascular Diseases and their Risk Factors in Some Regions of the Russian Federation" (ESSE-RF) included 8461 subjects aged 25-64 years (63.7% women) without lipid-lowering drugs. Atherosclerotic cardiovascular disease was self-reported. Lp(a), apolipoproteins AI and B, and lipid and glucose levels in blood serum were determined.
The prevalence of Lp(a) ≥ 30 mg/dl was 20.5% and 23.0%, and prevalence of Lp(a) ≥ 50 mg/dl was 13.3% and 15.2%, in men and women, respectively. An association of Lp(a) with IHD, MI, and AH, but not with stroke and DM, was shown. A cut-off level of Lp(a) of 9 mg/dl was determined, above which there was increased frequency of MI (by 59.2%,
= 0.02), IHD (by 33.4%,
< 0.001), and AH (by 11.6%,
< 0.001). In the multivariate analysis only the association of Lp(a) with IHD (1.19 (1.01-1.41),
= 0.038) and MI (1.57 (1.06-2.38),
= 0.028) remained significant.
Lipoprotein(a) level ≥ 30 mg/dl was detected in every fifth adult aged 25-64 years. Increased risk of MI and IHD starts at an Lp(a) serum level above 9 mg/dl.
Statins are one of the most commonly prescribed drugs in clinical practice. They are usually well tolerated and effectively prevent cardiovascular events. Most adverse effects associated with statin ...therapy are muscle-related. The recent statement of the European Atherosclerosis Society (EAS) has focused on statin associated muscle symptoms (SAMS), and avoided the use of the term 'statin intolerance'. Although muscle syndromes are the most common adverse effects observed after statin therapy, excluding other side effects might underestimate the number of patients with statin intolerance, which might be observed in 10-15% of patients. In clinical practice, statin intolerance limits effective treatment of patients at risk of, or with, cardiovascular disease. Knowledge of the most common adverse effects of statin therapy that might cause statin intolerance and the clear definition of this phenomenon is crucial to effectively treat patients with lipid disorders. Therefore, the aim of this position paper was to suggest a unified definition of statin intolerance, and to complement the recent EAS statement on SAMS, where the pathophysiology, diagnosis and the management were comprehensively presented.
Purpose of Review
High lipoprotein(a) (Lp(a)) level is an independent cardiovascular risk factor with higher prevalence among patients with atherosclerotic cardiovascular disease (ASCVD). The actual ...problem is that most currently available lipid-lowering drugs are unable to abolish Lp(a) pathogenicity. Lipoprotein apheresis (LA) is an effective method for elimination of atherogenic lipoproteins, but it is approved only in some countries for treatment of elevated Lp(a) level in the presence of progressive ASCVD. In recent years, new studies on LA were published and the purpose of this review is to present the information on optimal management of Lp(a) hyperlipoproteinemia by LA in the modern era.
Recent Findings
Most clinical studies designed to treat Lp(a) hyperlipoproteinemia with different LA systems are small in size but demonstrate that the elimination of Lp(a) from bloodstream leads to reduction of inflammatory and prothrombotic process in a few months and to atherosclerotic plaques regression in 1.5 years. Treatment with LA for 2 to 5 years in terms of clinical trials and in real-world setting provides further evidence that Lp(a) reduction by 60–80% is associated with proportional decreasing of rate and risk of cardiovascular events.
Summary
Specific Lp(a) apheresis is the only possible method that solely targets Lp(a). In most countries, non-specific LA is used for treatment Lp(a) hyperlipoproteinemia in very high-risk subjects with progressive ASCVD. PCSK9 inhibitors have only modest effect on significantly elevated Lp(a), whereas large population-based studies requested sustained and prolonged reduction of Lp(a) levels by 50–100 mg/dL to gain proportional decreasing of major adverse cardiovascular events.
Familial hypercholesterolemia (FH) is a monogenic disease, leading to atherosclerosis due to a high level of low-density lipoprotein cholesterol. Most cases of the disease are based on pathological ...variants in the LDLR gene. Hepatocyte-like and endothelial cells derived from individual iPSCs are a good model for developing new approaches to therapy. We obtained an iPSC line from peripheral blood mononuclear cells of the patient with compound heterozygous p.Ser177Leu/p.Cys352Arg mutation in LDLR using non-integrating vectors. The iPSCs with a confirmed patient-specific mutation demonstrate pluripotency markers, normal karyotype, and the ability to differentiate into derivatives of three germ layers.
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