https://www.zora.uzh.ch/id/eprint/197950/1/%5B14374331_-_Clinical_Chemistry_and_Laboratory_Medicine_%28CCLM%29%5D_Quantifying_atherogenic_lipoproteins_for_lipid-lowering_strategies_consensus-based_recommendations_from_EAS_and_EFLM.pdf

Quantifying atherogenic lipoproteins for lipid-lowering strategies: consensus-based recommendations from EAS and EFLM

Background: The European Atherosclerosis Society–European Federation of Clinical Chemistry and Laboratory Medicine Consensus Panel aims to provide recommendations to optimize atherogenic lipoprotein quantification for cardiovascular risk management. Content: We critically examined LDL cholesterol, non-HDL cholesterol, apolipoprotein B (apoB), and LDL particle number assays based on key criteria for medical application of biomarkers. ( a ) Analytical performance: Discordant LDL cholesterol quantification occurs when LDL cholesterol is measured or calculated with different assays, especially in patients with hypertriglyceridemia >175 mg/dL (2 mmol/L) and low LDL cholesterol concentrations b ) Clinical performance: LDL cholesterol, non-HDL cholesterol, and apoB are comparable predictors of cardiovascular events in prospective population studies and clinical trials; however, discordance analysis of the markers improves risk prediction by adding remnant cholesterol (included in non-HDL cholesterol) and LDL particle number (with apoB) risk components to LDL cholesterol testing. ( c ) Clinical and cost-effectiveness: There is no consistent evidence yet that non-HDL cholesterol-, apoB-, or LDL particle-targeted treatment reduces the number of cardiovascular events and healthcare-related costs than treatment targeted to LDL cholesterol. Summary: Follow-up of pre- and on-treatment (measured or calculated) LDL cholesterol concentration in a patient should ideally be performed with the same documented test method. Non-HDL cholesterol (or apoB) should be the secondary treatment target in patients with mild to moderate hypertriglyceridemia, in whom LDL cholesterol measurement or calculation is less accurate and often less predictive of cardiovascular risk. Laboratories should report non-HDL cholesterol in all standard lipid panels.

/pdf/quantifying-atherogenic-lipoproteins-current-and-future-188sfw5car.pdf

Quantifying Atherogenic Lipoproteins : Current and Future Challenges in the Era of Personalized Medicine and Very Low Concentrations of LDL Cholesterol. A Consensus Statement from EAS and EFLM

Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases plasma low-density lipoprotein cholesterol (LDL-C) by decreasing expression of the LDL receptor on hepatic cells. Evolocumab is a human monoclonal immunoglobulin G2 that binds specifically to human PCSK9 to reduce LDL-C. Evolocumab exhibits nonlinear kinetics as a result of binding to PCSK9. Elimination is predominantly through saturable binding to PCSK9 at lower concentrations and a nonsaturable proteolytic pathway at higher concentrations. The effective half-life of evolocumab is 11–17 days. The pharmacodynamic effects of evolocumab on PCSK9 are rapid, with maximum suppression within 4 h. At steady state, peak reduction of LDL-C occurs approximately 1 week after a subcutaneous dose of 140 mg every 2 weeks (Q2W) and 2 weeks after a subcutaneous dose 420 mg once monthly (QM), and returns towards baseline over the dosing interval. In several clinical studies, these doses of evolocumab reduced LDL-C by approximately 55–75% compared with placebo. Evolocumab also reduced lipoprotein(a) [Lp(a)] levels and improved those of other lipids in clinical studies. No clinically meaningful differences in pharmacodynamic effects on LDL-C were observed in adult subjects regardless of mild/moderate hepatic impairment, renal impairment or renal failure, body weight, race, sex, or age. No clinically meaningful differences were observed for the pharmacodynamic effects of evolocumab on LDL-C between patients who received evolocumab alone or in combination with a statin, resulting in additional lowering of LDL-C when evolocumab was combined with a statin. No dose adjustment is necessary based on patient-specific factors or concomitant medication use.

/pdf/clinical-pharmacokinetics-and-pharmacodynamics-of-evolocumab-2qj8640dph.pdf

Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor.

Aims
Individuals with type 2 diabetes (T2DM) and mixed dyslipidaemia represent a high-risk and difficult-to-treat population. ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) compared alirocumab, a proprotein convertase subtilisin-kexin type 9 inhibitor, with usual care (UC) in individuals with T2DM and mixed dyslipidaemia not optimally managed by maximally-tolerated statins.

Materials and Methods
UC options (no additional lipid-lowering therapy; fenofibrate; ezetimibe; omega-3 fatty acid; nicotinic acid) were selected prior to stratified randomization to open-label alirocumab 75 mg every 2 weeks (Q2W; with increase to 150 mg Q2W at Week [W]12 if W8 non-high-density lipoprotein cholesterol [non-HDL-C] was ≥2.59 mmol/L [100 mg/dL]) or UC for 24 weeks. Primary efficacy endpoint was percentage change in non-HDL-C from baseline to W24.

Results
The randomized population comprised 413 individuals (409 intention-to-treat; 412 safety). At W24, mean non-HDL-C reductions were superior with alirocumab (-32.5% difference vs UC; 97.5% confidence interval: -38.1 to -27.0; P<.0001). Overall, 63.6% of alirocumab-treated individuals were maintained on 75 mg Q2W. Alirocumab also reduced low-density lipoprotein cholesterol (-43.0%), apolipoprotein B (-32.3%), total cholesterol (-24.6%), and LDL particle number (-37.8%) at W24 vs UC (all P<.0001). Consistent with the overall trial comparison, alirocumab reduced non-HDL-C to a greater degree within each UC stratum at W24. Incidence of treatment-emergent adverse events was 68.4% (alirocumab) and 66.4% (UC). No clinically meaningful effect on glycated hemoglobin, or change in number of glucose-lowering agents, was seen.

Conclusions
In individuals with T2DM and mixed dyslipidaemia on maximally tolerated statin, alirocumab showed superiority in non-HDL-C reduction vs UC and was generally well tolerated.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/dom.13257

Alirocumab vs usual lipid-lowering care as add-on to statin therapy in individuals with type 2 diabetes and mixed dyslipidaemia: The ODYSSEY DM-DYSLIPIDEMIA randomized trial.

Guidelines propose using non-HDL cholesterol or apolipoprotein (apo) B as a secondary treatment target to reduce residual cardiovascular risk of LDL-targeted therapies This review summarizes the strengths, weaknesses, opportunities, and threats (SWOT) of using apoB compared with non-HDL cholesterol Non-HDL cholesterol, calculated as total-HDL cholesterol, includes the assessment of remnant lipoprotein cholesterol, an additional risk factor independent of LDL cholesterol ApoB is a direct measure of circulating numbers of atherogenic lipoproteins, and its measurement can be standardized across laboratories worldwide Discordance analysis of non-HDL cholesterol versus apoB demonstrates that apoB is the more accurate marker of cardiovascular risk Baseline and on-treatment apoB can identify elevated numbers of small cholesterol-depleted LDL particles that are not reflected by LDL and non-HDL cholesterol ApoB is superior to non-HDL cholesterol as a secondary target in patients with mild-to-moderate hypertriglyceridemia (175–880 mg/dL), diabetes, obesity or metabolic syndrome, or very low LDL cholesterol < 70 mg/dL When apoB is not available, non-HDL cholesterol should be used to supplement LDLC

Non-HDL Cholesterol or apoB: Which to Prefer as a Target for the Prevention of Atherosclerotic Cardiovascular Disease?

Efficacy and safety of the pcsk9 inhibitor evolocumab in patients with mixed hyperlipidemia

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Efficacy and safety of the pcsk9 inhibitor evolocumab in patients with mixed hyperlipidemia