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Effect of PCSK9 Evolocumab on Non-High-Density Lipoprotein Cholesterol, Apolipoprotein B, and Lipoprotein(a): A Pooled Analysis of Phase 2 and Phase 3 Studies
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Discussion
ApoB, non-HDL-C, and Lp(a) are important measures of risk for ASCVD. The incorporation of these apoprotein and lipoprotein measures into guidelines makes risk assessment more comprehensive and helps to identify more patients likely to benefit from lipid-lowering therapies. Herein we demonstrate that evolocumab provides substantial reductions in ApoB, non-HDL-C, and Lp(a) when used either as monotherapy or when used as adjuvant therapy to statins or ezetimibe. Moreover, the administration of evolocumab in a broad range of patients at high cardiovascular risk or unable to receive high-intensity statin therapy (eg, patients with primary dyslipidemia, HeFH, diabetes mellitus, or statin intolerance) substantially increases the likelihood of attaining risk-stratified goals of therapy for ApoB and non-HDL-C in these subgroups. The reductions in ApoB, non-HDL-C, and Lp(a) are durable for up to 5 years of continuous therapy. We also demonstrate substantive reductions in VLDL-C in these patients. In total these changes represent significant, broad-spectrum incremental reductions in total atherogenic lipoprotein burden in serum that no other currently available drug class can achieve.
Lp(a) is a covalent conjugate of an LDL-like lipoprotein particle and apolipoprotein(a). Prospective longitudinal cohort and Mendelian randomization studies confirm that elevated levels of Lp(a) are causally associated with risk for ASCVD-related events.1, 5, 6, 21, 22 Neither statins nor ezetimibe impact serum levels of Lp(a). Nicotinic acid was long heralded as a therapy that reduced Lp(a).23 In a post hoc analysis of the AIM HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial, there was no demonstrable impact of the limited extent of Lp(a) lowering with nicotinic acid on risk for cardiovascular events.24 In a recent kinetic analysis by Watts et al, it was shown that evolocumab therapy decreases hepatic production of Lp(a) when used as monotherapy and increases the clearance of Lp(a) when used in combination with a statin,25 likely via a LDL receptor–dependent pathway.26, 27 In the FOURIER trial, evolocumab reduced Lp(a) by a median of 26.9%, consistent with our findings herein.28 This analysis of FOURIER also demonstrated that higher baseline Lp(a) concentration helped to identify individuals with greater clinical efficacy with evolocumab, raising the possibility that in addition to LDL lowering, concurrent reduction in Lp(a) by evolocumab may have provided incremental risk reduction.
Substantial arguments have been advanced that ApoB is the optimal lipid-related ASCVD risk marker.29, 30 All atherogenic lipoproteins (VLDL remnants, intermediate-density lipoprotein, LDL, and Lp(a)) contain ApoB. The capacity of evolocumab to reduce ApoB is significantly larger than that of statins and ezetimibe; in addition, the effect of evolocumab on ApoB is additive to that of statins and ezetimibe in patients with primary dyslipidemia or HeFH. In patients in whom evolocumab is indicated, the ability of evolocumab to further reduce ApoB when added to statins, ezetimibe, or the combination of the 2 affords clinicians therapeutic opportunity to target a potential contributor to residual ASCVD risk. This is especially important in patients such as those with statin intolerance or HeFH, where substantial atherogenic lipoprotein reductions can be difficult to achieve.31 Our findings are particularly relevant now that the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) lipid guidelines recommend measuring ApoB (especially in patients with high triglycerides, obesity, diabetes mellitus, and metabolic syndrome) and Lp(a), the latter at least once in each adult person's lifetime.
Historically, risk-stratified goal attainment rates for such measures as LDL-C, non-HDL-C, and ApoB have been relatively low, especially among high-risk patients and those with statin intolerance.32, 33 Evolocumab dramatically increases the percentage of patients reaching their non-HDL-C and ApoB goals compared with both placebo and ezetimibe, with or without a statin background. This has important direct consequences on risk for ASCVD events and their associated economic burden in terms of long-term physical and physiological function, poorer quality of life, and costs because of myocardial infarction, stroke, and need for revascularization procedures.34, 35
In the FOURIER trial, evolocumab was shown to provide stable reductions in atherogenic lipoprotein for a median of 26 months.18 We extend these findings with results from the Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) -2 and -1 trials. These trials demonstrate that the therapeutic effect of evolocumab is durable over 3 and 5 years of follow-up, respectively. The lack of attenuation in lipid-lowering efficacy suggests there is no tachyphylaxis with chronic, long-term use of this monoclonal antibody. Stable reductions were observed with ApoB, non-HDL-C, and Lp(a).
Also, of note, diabetic dyslipidemia is multifactorial and is frequently accompanied by elevated VLDL and triglycerides. In patients with diabetes mellitus and impaired triglyceride clearance, remnant lipoprotein levels (small VLDLs and intermediate-density lipoproteins) are increased. It is now widely accepted that remnant lipoproteins are atherogenic and proinflammatory.36, 37, 38 In previous work, we have demonstrated reduction in remnant lipoproteins by evolocumab.39 Herein we demonstrate a substantial reduction of VLDL-C, the direct precursor to remnant lipoprotein formation. For diabetic patients with hypertriglyceridemia, ApoB and non-HDL-C reductions are important. The diabetic patients in this analysis experienced marked reductions in both ApoB and non-HDL-C, with notable improvements in goal attainment for these risk markers when compared with either placebo or ezetimibe, with or without a statin background.
Limitations of the analysis include the 12-week duration of most studies and the between-study heterogeneity, which was minimized by the use of highly consistent procedures across studies for randomization, blinding, and lipid measurement.
Additionally, LDL-C and VLDL-C were calculated by the Friedewald equation and not directly measured, with VLDL-C estimated as the difference between LDL-C and non-HDL-C. As such, LDL may have been underestimated at low LDL levels and higher triglyceride levels.
In this pooled analysis of 15 studies, evolocumab treatment demonstrated consistent and stable reductions in non-HDL-C, ApoB, and Lp(a) across all patient populations studied.
Both non-HDL-C and ApoB are well-validated measures of cardiovascular risk, particularly for patients with elevated triglyceride levels, diabetes mellitus, or metabolic syndrome.1, 2, 8 For patients at very high total cardiovascular risk, guidelines recommend lowering of non-HDL-C (<100 mg/dL) for which treatment intensification on top of statin therapy may be needed.1, 2 A treatment goal for ApoB <80 mg/dL has also been recommended for these patients.1 It has been suggested that in patients at cardiovascular risk with Lp(a) ≥50 mg/dL or ≥125 nmol/L, intensification of treatment directed to modifiable risk factors, including LDL-C, is a reasonable strategy.1, 2 Another recommendation suggests that levels of Lp(a) >75 nmol/L are associated with an increased risk of cardiovascular events.9
Meta-analyses present conflicting results as to whether ApoB or non-HDL-C provide enhanced predictive value of cardiovascular risk over LDL-C, suggesting these markers be measured in complement rather than in place of LDL-C until further evidence emerges.10, 11
Apolipoprotein B is the primary apolipoprotein of chylomicrons, VLDL, Lp(a), IDL, and LDL particles (LDL-commonly known as "bad cholesterol" when in reference to both heart disease and vascular disease in general), which is responsible for carrying fat molecules (lipids), including cholesterol, around the body to all cells within all tissues. While all the functional roles of ApoB within the LDL (and all larger) particles remain somewhat unclear, it is the primary organizing protein (of the entire complex shell enclosing/carrying fat molecules within) component of the particles and is absolutely required for the formation of these particles. What is also clear is that the ApoB on the LDL particle acts as a ligand for LDL receptors in various cells throughout the body (i.e., less formally, ApoB indicates fat carrying particles are ready to enter any cells with ApoB receptors and deliver fats carried within into the cells).
Through mechanisms only partially understood, high levels of ApoB, especially associated with the higher LDL particle concentrations, are the primary driver of plaques that cause vascular disease (atherosclerosis), commonly first becoming obviously symptomatic as heart disease, stroke and many other body wide complications after decades of progression. There is considerable evidence that concentrations of ApoB[5][6] and especially the NMR assay[7] (specific for LDL-particle concentrations) are superior indicators of vascular/heart disease driving physiology than either total cholesterol or LDL-cholesterol (as long promoted by the NIH starting in the early 1970s). However, primarily for historic cost/complexity reasons, cholesterol, and estimated LDL-cholesterol by calculation, remains the most commonly promoted lipid test for the risk factor of atherosclerosis. ApoB is routinely measured using immunoassays such as ELISA or nephelometry. Refined and automated NMR methods allow measurement distinctions between the many different ApoB particles. https://en.wikipedia.org/wiki/Apolipoprotein_B
Results are given in milligrams per deciliter (mg/dL). Normal levels of ApoB-100 in adults are less than 100 mg/dL. Your risk is high if you have a result greater than 110 mg/dL.
High levels of ApoB may mean that you have a higher than normal risk of developing cardiovascular disease. An ApoA test (linked with "good" cholesterol) may also be done with the ApoB test. The ratio of the ApoA results and the ApoB results is sometimes used as an alternative to a total cholesterol ratio to evaluate your risk of developing cardiovascular disease.
https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=167&contentid=apolipoprotein_b100
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2 Mar 2020
Abstract
Background
Dyslipidemia guidelines recommend non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (ApoB) as additional targets of therapy and consider lipoprotein(a) a significant cardiovascular risk marker. The current analysis evaluates the effects of evolocumab on these parameters in various patient populations over time.
Methods and Results
Data from 7690 patients, 4943 of whom received at least 1 dose of evolocumab, in 15 phase 2 and phase 3 studies with a duration ranging from 12 weeks to 5 years were pooled based on study length, patient population, and ezetimibe or placebo comparator groups. Patients could receive intensive statin therapy but not in the statin intolerance and monotherapy studies.
The effects of evolocumab on percent change from baseline for non-HDL-C, ApoB, and lipoprotein(a) and achievement of treatment goals for non-HDL-C and ApoB were examined. Compared with placebo, evolocumab at both approved dosing regimens substantially reduced mean non-HDL-C (Q2W dose: -49% to -56%, monthly dose: -48% to -52%), mean ApoB (Q2W dose: -46% to -52%, monthly dose: -40% to -48%), and median lipoprotein(a) (Q2W dose: -22% to -38%, monthly dose: -20% to -33%) at 12 weeks. Effects on all 3 parameters persisted over 5 years. Lipid-lowering effects were consistent among the patient populations examined (hypercholesterolemia/mixed dyslipidemia, statin intolerance, heterozygous familial hypercholesterolemia, and type 2 diabetes mellitus).
Conclusions
In this pooled analysis, evolocumab substantially reduced non-HDL-C, ApoB, and lipoprotein(a) compared with placebo. The effect was consistent and maintained in various patient populations over 5 years.
Compared with placebo or ezetimibe, a higher percentage of patients treated with evolocumab achieved non-HDL-C and ApoB recommended treatment goals. At 12 weeks, non-HDL-C <100 mg/dL was achieved in 84.3% to 87.9% of patients with hypercholesterolemia or mixed dyslipidemia receiving evolocumab versus 28.5% receiving ezetimibe versus 11.5% receiving placebo. Of those statin-intolerant patients not receiving background intensive statin therapy, this was achieved by 43.4% of patients receiving evolocumab versus 0.8% receiving ezetimibe. In patients with HeFH or type 2 diabetes mellitus, 73.7% to 86.3% of patients receiving evolocumab versus 0.7% to 25.5% receiving placebo were within recommended levels. In the 1-year study, this was achieved by 85.0% with evolocumab versus 14.8% with placebo (Figure 2A). In longer-term (OSLER studies), 62.2% to 66.9% of patients receiving evolocumab reached goal levels. At 12 weeks, ApoB <80 mg/dL was achieved in ≈94% of patients with hypercholesterolemia or mixed dyslipidemia receiving evolocumab versus 45.4% receiving ezetimibe versus 24.4% receiving placebo, and 60.6% of statin-intolerant patients receiving evolocumab versus 4.8% receiving ezetimibe. In patients with HeFH or type 2 diabetes mellitus, 83% to 87% receiving evolocumab versus 4% to 24% receiving placebo were within recommended levels. In the 1-year study, this was achieved by 90.7% with evolocumab versus 40.7% with placebo (Figure 2B). Longer-term, 73.9% to 82.0% of patients receiving evolocumab in long-term studies achieved goal levels.
Introduction
Low-density lipoprotein (LDL) is the primary lipid treatment target to reduce atherosclerotic risk.1, 2, 3, 4 Non-high-density lipoprotein cholesterol (non-HDL-C) is considered to be a co-primary3 or secondary treatment target,1, 2, 4 while apolipoprotein B (ApoB) can be considered as a secondary target2, 3 or an alternative to LDL cholesterol (LDL-C) as the primary measurement, and may be preferred over non-HDL-C in patients with high triglycerides, diabetes mellitus, obesity, or very low LDL-C.1 Lipoprotein(a) (Lp(a)) is recognized as a risk factor, based on Mendelian randomization, for atherosclerotic disease1 and cardiovascular events,5, 6 and its measurement can help improve cardiovascular risk classification under certain conditions.1, 2 Non-HDL-C levels are an estimate of the concentration of atherogenic cholesterol in low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) particles.7 ApoB is a direct measure of non-HDL atherogenic lipoprotein particle concentration.8
Both non-HDL-C and ApoB are well-validated measures of cardiovascular risk, particularly for patients with elevated triglyceride levels, diabetes mellitus, or metabolic syndrome.1, 2, 8 For patients at very high total cardiovascular risk, guidelines recommend lowering of non-HDL-C (<100 mg/dL) for which treatment intensification on top of statin therapy may be needed.1, 2 A treatment goal for ApoB <80 mg/dL has also been recommended for these patients.1 It has been suggested that in patients at cardiovascular risk with Lp(a) ≥50 mg/dL or ≥125 nmol/L, intensification of treatment directed to modifiable risk factors, including LDL-C, is a reasonable strategy.1, 2Another recommendation suggests that levels of Lp(a) >75 nmol/L are associated with an increased risk of cardiovascular events.9
Meta-analyses present conflicting results as to whether ApoB or non-HDL-C provide enhanced predictive value of cardiovascular risk over LDL-C, suggesting these markers be measured in complement rather than in place of LDL-C until further evidence emerges.10, 11
Evolocumab, a monoclonal antibody that binds to proprotein convertase subtilisin/kexin type 9, substantially and consistently reduces LDL-C levels in a broad range of patients12, 13, 14, 15, 16, 17 and significantly reduces the risk of such cardiovascular events as myocardial infarction, ischemic stroke, and coronary revascularization in patients with stable atherosclerotic cardiovascular disease (ASCVD).18 When considering the clinical outcome of major vascular events (coronary heart death, nonfatal myocardial infarction, stroke, or coronary revascularization) used by the CTTC (Cholesterol Treatment Trialists' Collaboration), each 1 mmol/L reduction in LDL-C with evolocumab treatment in the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial18 had an associated risk reduction in major vascular events of 10% during year 1 and 17% during year 2.
The primary objective of this pooled analysis of phase 2 and phase 3 global evolocumab studies is to characterize the effects of evolocumab on non-HDL-C, ApoB, and Lp(a) across a range of patient populations and for up to 5 years of treatment
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