BACKGROUND:Lerodalcibep, a small binding anti-PCSK9 protein (adnectin), showed effective LDL cholesterol reduction in heterozygous familial hypercholesterolaemia. We aimed to assess the safety and efficacy of lerodalcibep and evolocumab in a globally diverse homozygous familial hypercholesterolaemia population. METHODS:This phase 3, randomised, open-label, crossover, non-inferiority study consisted of two 24-week treatment periods separated by an 8-week washout. The study was conducted in 12 lipid clinics in six countries (India, Israel, Norway, South Africa, Türkiye, and the USA). Patients aged 10 years or older with genetically confirmed homozygous familial hypercholesterolaemia were randomly assigned by computer-generated randomisation scheme performed centrally via interactive response technology to either monthly lerodalcibep 300 mg (1·2 mL subcutaneous injection) or monthly evolocumab 420 mg (subcutaneous 9 min infusion of 3·5 mL) for 24 weeks (period A) followed by an 8-week washout and then crossed over to the alternate therapy for the next 24 weeks (period B). The trial was open label, but all efficacy parameters were masked to patients, study staff, and the sponsor from randomisation. The primary efficacy endpoint was the percent change from baseline (day 1 of period A) in LDL cholesterol concentration to week 24 for period A and B. The intention-to-treat (ITT) population, defined as all randomly assigned patients, was used for the primary analysis. The safety population included all patients who received any study medication. The margin used to establish non-inferiority was 6%. The trial is registered with ClinicalTrials.gov (NCT04034485) and EudraCT (2019-003611-62), and has now finished. FINDINGS:Patients were enrolled from Nov 11, 2019, to July 2, 2021, and the final study visit took place on Aug 8, 2022. Of 82 patients screened, 66 entered period A (ITT population). The mean age was 28·7 years (SD 15·2); 20 (30%) of 66 were paediatric patients; 36 (55%) of 66 were female and 30 (45%) of 66 were male; and the mean baseline LDL cholesterol was 10·59 mmol/L (SD 4·37). Mean LDL cholesterol reduction by ITT analysis at week 24 was -4·9% (SE 3·5) on lerodalcibep compared with -10·3% (3·5) on evolocumab; the mean difference between treatments was 5·4% (95% CI -0·2 to 11·1), which did not show non-inferiority at the prespecified 6% margin. LDL cholesterol response varied considerably across the patient population but was generally similar in the same patients with both lerodalcibep and evolocumab. When averaged across all monthly visits, LDL cholesterol response was -9·1% (SE 3·2) on lerodalcibep and -10·8% (3·2) on evolocumab. Importantly, genotyping and free PCSK9 suppression were not predictive of response. Both drugs were well tolerated, with no treatment-related serious adverse events. Injection site reactions were reported in one (2%) of 65 patients on lerodalcibep and 15 (24%) of 62 patients on evolocumab. INTERPRETATION:The LDL cholesterol response was highly variable, but generally similar in patients treated with both lerodalcibep and evolocumab. Importantly, the study showed the inability to predict response based on genotyping, reinforcing the rationale for PCSK9 inhibition in all patients with homozygous familial hypercholesterolemia and continuing its use in responders. FUNDING:LIB Therapeutics.

Abstract Background and Aims Lerodalcibep, a novel small recombinant fusion protein of a proprotein convertase subtilisin/kexin type 9 gene–binding domain (adnectin) and human serum albumin, demonstrated highly effective low-density lipoprotein cholesterol (LDL-C) reduction with monthly 300 mg in 1.2 mL subcutaneous dosing in Phase 2. In this global Phase 3 trial, the safety and efficacy of lerodalcibep were evaluated in heterozygous familial hypercholesterolaemia patients requiring additional LDL-C lowering. Methods Patients were randomized 2:1 to monthly subcutaneous injections of either lerodalcibep 300 mg or placebo for 24 weeks. The primary efficacy endpoints were the per cent change from baseline in LDL-C at Week 24 and the mean of Weeks 22 and 24. Results In 478 randomized subjects [mean age (range); 53 (18–80) years, 51.7% female, mean (SD) baseline LDL-C 3.88 (1.66) mmol/L], lerodalcibep reduced LDL-C, compared with placebo by an absolute amount of 2.08 (0.11) mmol/L [LS mean (SE); 95% confidence interval −2.30 to −1.87] with a percentage difference of −58.61 (3.25)% at Week 24 and by 2.28 (0.10) mmol/L (95% confidence interval −2.47 to −2.09) with a percentage difference of −65.0 (2.87)% at the mean of Weeks 22 and 24 (P < .0001 for all). With lerodalcibep, 68% of subjects achieved both a reduction in LDL-C ≥ 50% and the recommended European Society of Cardiology LDL-C targets during the study. Except for mild injection site reactions, treatment-emergent adverse events were similar between lerodalcibep and placebo. Conclusions Lerodalcibep, a novel anti-proprotein convertase subtilisin/kexin type 9 gene small binding protein dosed monthly as an alternative to monoclonal antibodies, significantly reduced LDL-C in subjects with heterozygous familial hypercholesterolaemia with a safety profile similar to placebo.

IMPORTANCE Recent changes in national and international lipid guidelines for reducing cardiovascular events recommend additional drugs, greater reductions, and lower targets for low-density lipoprotein cholesterol (LDL-C) if not attained with statins. The achievement of these targets with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has not yet been evaluated in a randomized clinical trial. OBJECTIVE To evaluate the 52-week safety and efficacy of lerodalcibep, a small anti-PCSK9-binding protein, in patients with cardiovascular disease (CVD) or who are at very high or high risk of CVD and requiring addition LDL-C-lowering treatment. DESIGN, SETTING, AND PARTICIPANTS This was a randomized, double-blind, placebo-controlled phase 3 trial. The trial was conducted at 66 clinics in 11 countries between April 23, 2021, and November 15, 2023. Individuals 18 years and older taking maximally tolerated statin therapy with LDL-C of 70mg/dL or greater with CVD or 100mg/dL or greater if at high risk of CVD were included. INTERVENTIONS Patients were randomized 2:1 to monthly 1.2-mL subcutaneous lerodalcibep, 300mg, or placebo for 52 weeks. MAIN OUTCOMES AND MEASURES The safety analysis included all randomized patients. The co-primary efficacy end points were percent change from baseline in LDL-C at week 52 and the mean of weeks 50 and 52. Secondary efficacy outcomes included additional lipid apolipoprotein measures and achievement of guideline-recommended LDL-C targets. RESULTS Of 922 randomized participants (mean [range] age, 64.5 [27-87] years; 414 [44.9%] female; mean [SD] baseline LDL-C, 116.2 [43.5] mg/dL), 811 (88%) completed the trial. The mean (SE) placebo-adjusted reduction in LDL-C with lerodalcibep by modified intention-to-treat (mITT) analysis was 56.2%(2.2%) at week 52 and 62.7%(1.9%) for the mean of weeks 50 and 52; 49.7%(2.4%) and 55.3%(2.2%) by ITT with imputation using a washout model, and 60.3%(2.3%) and 65.9%(1.9%) by per-protocol analysis at week 52 and the mean of weeks 50 and 52, respectively (P <.001 for all). With lerodalcibep, 555 of 615 participants (90%) achieved both a reduction in LDL-C of 50% or greater and recommended LDL-C targets during the study. Treatment-emergent adverse events were similar between lerodalcibep and placebo, except for injection site reactions. These occurred in 42 of 613 participants receiving lerodalcibep (6.9%) compared to 1 of 307 receiving placebo (0.3%), were graded mild or moderate, and did not result in higher discontinuation of treatment, at 26 of 613 (4.2%) and 14 of 307 (4.6%), respectively. Sporadic in vitro antidrug antibodies were detected, which had no impact on free PCSK9 or LDL-C-lowering efficacy. CONCLUSIONS AND RELEVANCE In this trial, lerodalcibep, a novel anti-PCSK9 small binding protein, dosed monthly and stable at ambient temperatures significantly reduced LDL-C in patients with CVD or at high risk of atherosclerotic cardiovascular disease with a safety profile similar to placebo. These results support long-term use of lerodalcibep in patients with CVD or at high risk of CVD who are unable to achieve adequate LDL-C reduction while receiving maximal tolerated statins alone.

IMPORTANCE:Lipid management typically focuses on levels of low-density lipoprotein cholesterol (LDL-C) and, to a lesser extent, triglycerides (TG). However, animal models and genetic studies suggest that the atherogenic particle subpopulations (LDL and very-low-density lipoprotein [VLDL]) are both important and that the number of particles is more predictive of cardiac events than their lipid content. OBJECTIVE:To determine whether common measures of cholesterol concentration, TG concentration, or their ratio are associated with cardiovascular risk beyond the number of apolipoprotein B (apoB)-containing lipoproteins. DESIGN, SETTING, AND PARTICIPANTS:This prospective cohort analysis included individuals from the population-based UK Biobank and from 2 large international clinical trials, FOURIER and IMPROVE-IT. The median (IQR) follow-up was 11.1 (10.4-11.8) years in UK Biobank and 2.5 (2.0-4.7) years in the clinical trials. Two populations were studied in this analysis: 389 529 individuals in the primary prevention group who were not taking lipid-lowering therapy and 40 430 patients with established atherosclerosis who were receiving statin treatment. EXPOSURES:ApoB, non-high-density lipoprotein cholesterol (HDL-C), LDL-C, and TG. MAIN OUTCOME AND MEASURES:The primary study outcome was incident myocardial infarction (MI). RESULTS:Of the 389 529 individuals in the primary prevention group, 224 097 (58%) were female, and the median (IQR) age was 56.0 (49.5-62.5) years. Of the 40 430 patients with established atherosclerosis, 9647 (24%) were female, and the median (IQR) age was 63 (56.2-69.0) years. In the primary prevention cohort, apoB, non-HDL-C, and TG each individually were associated with incident MI. However, when assessed together, only apoB was associated (adjusted hazard ratio [aHR] per 1 SD, 1.27; 95% CI, 1.15-1.40; P < .001). Similarly, only apoB was associated with MI in the secondary prevention cohort. Adjusting for apoB, there was no association between the ratio of TG to LDL-C (a surrogate for the ratio of TG-rich lipoproteins to LDL) and risk of MI, implying that for a given concentration of apoB-containing lipoproteins, the relative proportions of particle subpopulations may no longer be a predictor of risk. CONCLUSIONS AND RELEVANCE:In this cohort study, risk of MI was best captured by the number of apoB-containing lipoproteins, independent from lipid content (cholesterol or TG) or type of lipoprotein (LDL or TG-rich). This suggests that apoB may be the primary driver of atherosclerosis and that lowering the concentration of all apoB-containing lipoproteins should be the focus of therapeutic strategies.

LDL-C is the pivotal risk factor for atherosclerotic cardiovascular disease, and the benefit from LDL-C lowering is proportional to the magnitude of reduction. Clinical trials demonstrate that evolocumab reduces LDL-C levels by approximately 60% when measured at the trough of drug effect, which may underestimate cumulative LDL-C reduction. We obtained a time-averaged estimate of LDLC lowering that included both peaks and troughs. Pooled analysis of 5 phase 2 trials included patients with hypercholesterolemia who received placebo or evolocumab (140 mg every 2 weeks [Q2W] or 420 mg monthly [QM]). Percent changes from baseline LDL-C and free serum PCSK9 were averaged across weeks 9-12. In 372 patients, time-averaged percent reduction from baseline in LDL-C with evolocumab vs placebo was 67.6% (95% CI: 63.9-71.3) with Q2W dosing and 65.0% (95% CI: 60.7-69.3) with QM dosing. The time-averaged measure yielded LDL-C reductions for evolocumab that exceeded measurements at the end of dosing intervals and may provide a better estimate of cardiovascular benefit during long-term therapy. (C) 2022 National Lipid Association. Published by Elsevier Inc.

In The Lancet Diabetes & Endocrinology, Petr Ostadal and colleagues report a post-hoc subgroup analysis of the ODYSSEY OUTCOMES trial assessing the contribution of metabolic risk factors to future cardiovascular events in patients with recent acute coronary syndrome. 1 Ostadal P Steg PG Poulouin Y et al. Metabolic risk factors and effect of alirocumab on cardiovascular events after acute coronary syndrome: a post-hoc analysis of the ODYSSEY OUTCOMES randomised controlled trial. Lancet Diabetes Endocrinol. 2022; (published online April 1.)https://doi.org/10.1016/S2213-8587(22)00043-2 Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar This large cardiovascular outcome trial, describes the benefits of additional LDL cholesterol reduction with the PCSK9 inhibitor alirocumab, added to high intensity or maximally tolerated statin therapy. It is supportive of similar analyses over the past three decades in both primary and secondary prevention cardiovascular outcome trials with statin alone. 2 Robinson JG Stone NJ Identifying patients for aggressive cholesterol lowering: the risk curve concept. Am J Cardiol. 2006; 98: 1405-1408 Summary Full Text Full Text PDF PubMed Scopus (39) Google Scholar Although consistent with a similar analysis from the FOURIER trial 3 Deedwania P Murphy SA Scheen A et al. Efficacy and Safety of PCSK9 Inhibition With Evolocumab in Reducing Cardiovascular Events in Patients With Metabolic Syndrome Receiving Statin Therapy: Secondary Analysis From the FOURIER Randomized Clinical Trial. JAMA Cardiol. 2021; 6: 139-147 Crossref PubMed Scopus (15) Google Scholar with the PCSK9 inhibitor evolocumab, the new post-hoc analysis adds important further information and insight by stratifying residual cardiovascular risk by the number of metabolic risk factors. In combination, these two secondary prevention trials of more than 46 000 participants in total provide substantial evidence for the high residual risk—even after high intensity statin therapy—associated with diabetes and metabolic syndrome, either combined or separately. The analysis by Ostadal and colleagues 1 Ostadal P Steg PG Poulouin Y et al. Metabolic risk factors and effect of alirocumab on cardiovascular events after acute coronary syndrome: a post-hoc analysis of the ODYSSEY OUTCOMES randomised controlled trial. Lancet Diabetes Endocrinol. 2022; (published online April 1.)https://doi.org/10.1016/S2213-8587(22)00043-2 Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar highlights the additional overall cardiovascular benefit that patients with cardiovascular disease plus diabetes (with or without metabolic syndrome) derive from a further large reduction of up to 60% in LDL cholesterol with PCSK9 inhibition as well as larger absolute risk reduction in cardiovascular events compared with individuals without diabetes or metabolic syndrome. They show that every additional metabolic risk factor, other than low HDL cholesterol, identifies a population at greater and greater residual cardiovascular risk and for whom LDL cholesterol reduction results in greater absolute risk reduction. Therefore fewer patients need to be treated to prevent each cardiovascular event, resulting in greater cost effectiveness. Metabolic risk factors and effect of alirocumab on cardiovascular events after acute coronary syndrome: a post-hoc analysis of the ODYSSEY OUTCOMES randomised controlled trialAccumulation of metabolic risk factors was associated with higher risk of MACE in patients with recent acute coronary syndrome. Alirocumab reduced MACE consistently, but aRR increased with number of metabolic risk factors. Full-Text PDF

Background and aims: Trial evidence for the benefits of cholesterol-lowering is limited for familial hypercholesterolemia (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 stratified 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 nonsignificant. 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.

BACKGROUND Proprotein convertase subtilisin/kexin type 9 inhibitor therapy is a treatment option for patients with familial hypercholesterolemia (FH) who are unable to reach low-density lipoprotein cholesterol (LDL-C) goals. OBJECTIVES The aim of this study was to provide long-term safety and efficacy data for evolocumab in patients with homozygous FH (HoFH) and severe heterozygous FH (HeFH). METHODS In this open-label, single-arm study, patients with HoFH or severe HeFH >= 12 years of age and on stable lipid-lowering therapy began subcutaneous evolocumab 420 mg monthly or 420 mg every 2 weeks if on lipoprotein apheresis. After 12 weeks, those not on apheresis could be up-titrated to 420 mg every 2 weeks. The primary endpoint was the incidence of treatment-emergent adverse events; secondary endpoints were changes in LDL-C and other lipids. RESULTS In total, 300 patients (106 with HoFH, including 14 <18 years of age at enrollment) received evolocumab for a median of 4.1 years. Adverse events occurred in 89.3% of patients, the most common of which were nasopharyngitis, influenza, upper respiratory tract infection, and headache. Mean change in LDL-C from baseline to week 12 was -21.2% (-59.8 mg/dl) in patients with HoFH and -54.9% (-104.4 mg/dl) in those with severe HeFH and was sustained over time. Of 48 patients with HoFH who were up-titrated, mean change in LDL-C improved from -19.6% at week 12 to -29.7% after 12 weeks of 420 mg every 2 weeks. The adjudicated cardiovascular event rate was 2.7% per year. Of 61 patients receiving apheresis at enrollment, 16 discontinued apheresis. CONCLUSIONS Evolocumab was well tolerated and effectively reduced plasma LDL-C levels in patients with HoFH and severe HeFH over a median of 4.1 years. (C) 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated plasma low-density lipoprotein-cholesterol (LDL-C), and premature atherosclerotic cardiovascular disease. Depending on residual LDL receptor (LDLR) function, most HoFH patients respond modestly to statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. However, LDL-C typically remains markedly elevated necessitating additional therapies, including apheresis. Gemcabene is a novel lipid-lowering agent with a mechanism of action independent of the LDLR, which has previously demonstrated the ability to reduce levels of LDL-C on top of maximally tolerated statins. The present study (COBALT-1) assessed efficacy, tolerability, and safety of gemcabene as an adjunctive therapy to current lipid-lowering treatment for familial hypercholesterolemia patients. Eight patients with either a clinical or genetic diagnosis of HoFH on stable standard of care, including statins, ezetimibe, and PCSK9 inhibitors, were treated with gemcabene in an open-label study for 12 weeks. DNA analysis for mutations in the LDLR, apolipoprotein B, and PCSK9 genes was performed. Patients received 300 mg gemcabene for the first 4 weeks, 600 mg for the next 4 weeks, and 900 mg for the final 4 weeks. All patients completed the 12-week study. Mean change from baseline in LDL-C was 26% (p = 0.004) at Week 4 (300 mg), -30% (p = 0.001) at Week 8 (600 mg), and -29% (p = 0.001) at Week 12 (900 mg). In conclusion, the COBALT-1 study demonstrates gemcabene has potential to significantly reduce LDL-C levels when used as an adjunctive therapy to current lipid-lowering treatment for familial hypercholesterolemia patients. (C) 2019 Elsevier Inc. All rights reserved.

Introduction: LIB003 (LIB) is a recombinant fusion protein of a PCSK9-binding domain (adnectin) and human serum albumin which offers small injection volumes for monthly (Q4W) dosing. We evaluated l...

LIB003 is a 77 kDa recombinant fusion protein consisting of an adnectin, derived from the 10th type III domain of human fibronectin and targeted with high affinity to proprotein convertase subtilisin/kexin type 9 (PCSK9), and human serum albumin. We evaluated safety, tolerability, pharmacokinetics

Familial hypercholesterolemia (FH) is a major contributor to premature cardiovascular disease in South Africans of Afrikaner, Jewish and Indian descent due to gene founder effects. However, no systematic program exists to detect these families. Additionally, information regarding prevalence of FH in

Evolocumab reduced low-density lipoprotein cholesterol (LDL-C) in 12-week trials in statin-intolerant patients (GAUSS-1 and GAUSS-2); however, the persistence of efficacy during longer-term treatment is unknown. This subset analysis of the open-label extension studies (OSLER-1 and OSLER-2) aimed to evaluate the safety and efficacy of evolocumab up to 2 years in statin-intolerant patients.

Aims To objectively appraise evidence for possible adverse effects of long-term statin therapy on glucose homeostasis, cognitive, renal and hepatic function, and risk for haemorrhagic stroke or cataract. Methods and results A literature search covering 2000-2017 was performed. The Panel critically appraised the data and agreed by consensus on the categorization of reported adverse effects. Randomized controlled trials (RCTs) and genetic studies show that statin therapy is associated with a modest increase in the risk of new-onset diabetes mellitus (about one per thousand patient-years), generally defined by laboratory findings (glycated haemoglobin >= 6.5); this risk is significantly higher in the metabolic syndrome or prediabetes. Statin treatment does not adversely affect cognitive function, even at very low levels of low-density lipoprotein cholesterol and is not associated with clinically significant deterioration of renal function, or development of cataract. Transient increases in liver enzymes occur in 0.5-2% of patients taking statins but are not clinically relevant; idiosyncratic liver injury due to statins is very rare and causality difficult to prove. The evidence base does not support an increased risk of haemorrhagic stroke in individuals without cerebrovascular disease; a small increase in risk was suggested by the Stroke Prevention by Aggressive Reduction of Cholesterol Levels study in subjects with prior stroke but has not been confirmed in the substantive evidence base of RCTs, cohort studies and case-control studies. Conclusion Long-term statin treatment is remarkably safe with a low risk of clinically relevant adverse effects as defined above; statin-associated muscle symptoms were discussed in a previous Consensus Statement. Importantly, the established cardiovascular benefits of statin therapy far outweigh the risk of adverse effects.

Importance:Recent studies have shown that Friedewald underestimates low-density lipoprotein cholesterol (LDL-C) at lower levels, which could result in undertreatment of high-risk patients. A novel method (Martin/Hopkins) using a patient-specific conversion factor provides more accurate LDL-C levels. However, this method has not been tested in proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor-treated patients. Objective:To investigate accuracy of 2 different methods for estimating LDL-C levels (Martin/Hopkins and Friedewald) compared with gold standard preparative ultracentrifugation (PUC) in patients with low LDL-C levels in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk (FOURIER) trial. Design, Setting, and Participants:The FOURIER trial was a randomized clinical trial of evolocumab vs placebo added to statin therapy in 27 564 patients with stable atherosclerotic cardiovascular disease. The patients' LDL-C levels were assessed at baseline, 4 weeks, 12 weeks, 24 weeks, and every 24 weeks thereafter, and measured directly by PUC when the level was less than 40 mg/dL per the Friedewald method (calculated as non-HDL-C level - triglycerides/5). In the Martin/Hopkins method, patient-specific ratios of triglycerides to very low-density lipoprotein cholesterol (VLDL-C) ratios were determined and used to estimate VLDL-C, which was subtracted from the non-HDL-C level to obtain the LDL-C level. Main Outcomes and Measures:Low-density lipoprotein cholesterol calculated by the Friedewald and Martin/Hopkins methods, with PUC as the reference method. Results:For this analysis, the mean (SD) age was 62.7 (9.0) years; 2885 of the 12 742 patients were women (22.6%). A total of 56 624 observations from 12 742 patients had Friedewald, Martin/Hopkins, and PUC LDL-C measurements. The median difference from PUC LDL-C levels for Martin/Hopkins LDL-C levels was -2 mg/dL (interquartile range [IQR], -4 to 1 mg/dL) and for Friedewald LDL-C levels was -4 mg/dL (IQR, -8 to -1 mg/dL; P < .001). Overall, 22.9% of Martin/Hopkins LDL-C values were more than 5 mg/dL different than PUC values, and 2.6% were more than 10 mg/dL different than PUC levels. These were significantly less than respective proportions with Friedewald estimation (40.1% and 13.3%; P < .001), mainly because of underestimation by the Friedewald method. The correlation with PUC LDL-C was significantly higher for Martin/Hopkins vs Friedewald (ρ, 0.918 [95% CI 0.916-0.919] vs ρ, 0.867 [0.865-0.869], P < .001). Conclusions and Relevance:In patients achieving low LDL-C with PCSK9 inhibition, the Martin/Hopkins method for LDL-C estimation more closely approximates gold standard PUC than Friedewald estimation does. The Martin/Hopkins method may prevent undertreatment because of LDL-C underestimation by the Friedewald method. Trial Registration:ClinicalTrials.gov Identifier: NCT01764633.

HomeCirculationVol. 137, No. 6Letter by Koh Regarding Article, "Effect of Rosuvastatin on Carotid Intima-Media Thickness in Children With Heterozygous Familial Hypercholesterolemia: The CHARON Study (Hypercholesterolemia in Children and Adolescents Taking Rosuvastatin Open Label)" Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Koh Regarding Article, "Effect of Rosuvastatin on Carotid Intima-Media Thickness in Children With Heterozygous Familial Hypercholesterolemia: The CHARON Study (Hypercholesterolemia in Children and Adolescents Taking Rosuvastatin Open Label)" Kwang Kon Koh, MD, PhD Kwang Kon KohKwang Kon Koh Department of Cardiovascular Medicine, Heart Center, Gachon University, Gil Medical Center, and Gachon Cardiovascular Research Institute, Incheon, Korea. Originally published6 Feb 2018https://doi.org/10.1161/CIRCULATIONAHA.117.030934Circulation. 2018;137:639–640To the Editor:Dr Braamskamp and colleagues1 assessed the effect of 2-year treatment with rosuvastatin on carotid intima-media thickness (IMT) in children with heterozygous familial hypercholesterolemia. In children with heterozygous familial hypercholesterolemia who were ≥6 years of age, carotid IMT was significantly greater at baseline in comparison with unaffected siblings. Rosuvastatin treatment for 2 years resulted in significantly less progression of increased carotid IMT in children with heterozygous familial hypercholesterolemia than in untreated unaffected siblings. As a result, no difference in carotid IMT could be detected between the 2 groups after 2 years of rosuvastatin.The combined thickness of carotid IMT is associated with the prevalence of cardiovascular disease. Increases in the thickness of carotid IMT are directly associated with an increased risk of myocardial infarction and stroke in older adults without a history of cardiovascular disease.2 Measuring carotid IMT is noninvasive and can be repeated, and thus it is widely used as a surrogate marker of atherosclerosis and cardiovascular events. Therefore, the present study clearly demonstrated that early initiation of statin treatment will prevent the rapid development of atherosclerosis and cardiovascular events. They assumed it was because of low-density lipoprotein (LDL)–cholesterol reduction.Most believe that statins reduce cardiovascular risk by lowering LDL-cholesterol levels, but some believe that statins reduce risk through multiple actions called pleiotropic effects.3,4 Statins may exert cardiovascular protective effects that are independent of LDL-cholesterol lowering. The relative contributions of statin pleiotropy to clinical outcomes, however, remain a matter of debate and are hard to quantify despite the many randomized controlled trials denying pleiotropic effects, because the degree of isoprenoid inhibition by statins correlates to some extent with the amount of LDL-cholesterol reduction. Indeed, this hypothesis is difficult to prove despite its clinical importance. This issue has been disputed recently. Namely, the primary mechanism of its effect is to reduce LDL-cholesterol and atherogenic lipoproteins. Recent metaregression analysis showed that lower achieved LDL-cholesterol levels were associated with lower rates of major coronary events. Statins are like other LDL-lowering agents and are not unique except in LDL-lowering potency.5However, statins alone are sometimes not sufficient to lower LDL-cholesterol levels in children with heterozygous familial hypercholesterolemia. Combination therapy with statins and other classes of drugs such as ezetimibe, PCSK9 (proprotein convertase subtilisin kexin 9) inhibitors, inclisiran, or angiopoietin-like 3 antisense oligonucleotides is a promising approach to maximize therapeutic benefit while reducing the inherent metabolic risks of potent statins.Kwang Kon Koh, MD, PhDDisclosuresDr Koh holds certificate of patent no. 10-1579656 (pravastatin + valsartan).FootnotesCirculation is available at http://circ.ahajournals.org.References1. Braamskamp MJAM, Langslet G, McCrindle BW, Cassiman D, Francis GA, Gagne C, Gaudet D, Morrison KM, Wiegman A, Turner T, Miller E, Kusters DM, Raichlen JS, Martin PD, Stein EA, Kastelein JJP, Hutten BA. Effect of rosuvastatin on carotid intima-media thickness in children with heterozygous familial hypercholesterolemia: the CHARON Study (Hypercholesterolemia in Children and Adolescents Taking Rosuvastatin Open Label).Circulation. 2017; 136:359–366. doi: 10.1161/CIRCULATIONAHA.116.025158.LinkGoogle Scholar2. O'Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SKCarotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group.N Engl J Med. 1999; 340:14–22. doi: 10.1056/NEJM199901073400103.CrossrefMedlineGoogle Scholar3. Koh KK. Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability.Cardiovasc Res. 2000; 47:648–657.CrossrefMedlineGoogle Scholar4. Oesterle A, Laufs U, Liao JK. Pleiotropic effects of statins on the cardiovascular system.Circ Res. 2017; 120:229–243. doi: 10.1161/CIRCRESAHA.116.308537.LinkGoogle Scholar5. Silverman MG, Ference BA, Im K, Wiviott SD, Giugliano RP, Grundy SM, Braunwald E, Sabatine MS. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis.JAMA. 2016; 316:1289–1297. doi: 10.1001/jama.2016.13985.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails February 6, 2018Vol 137, Issue 6 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.117.030934PMID: 29431666 Originally publishedFebruary 6, 2018 PDF download Advertisement SubjectsCardiovascular DiseaseLipids and CholesterolPediatrics

This article provides an updated review of the LDL-cholesterol efficacy, safety, and cardiovascular benefits of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. It focuses on evidence from numerous clinical trials and provides clinicians with a basis for understanding, assessing, and selecting these agents for clinical practice. It also provides some perspective on other potential agents in development that target PCSK9.

Since the initial publication in 2012 of the first human studies showing dramatic reductions in low density lipoprotein cholesterol (LDL-C) by inhibiting PCSK9 with a monoclonal antibody, speculati...

Diabetes mellitus (DM) is associated with an increased risk of cardiovascular disease (CVD). Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) have emerged as effective low-density lipoprotein cholesterol-lowering compounds. Although the results of available epidemiological, preclinical, and clinical studies suggest a positive association of plasma PCSK9 levels with glycemic parameters and risk of type 2 DM (T2DM), genetic findings have shown contradictory results. Overall, the impact of PCSK9 inhibitors on glycemic control parameters in patients with DM remains unclear. Here, we assess the available evidence for the association of PCSK9 status with the incidence and control of DM in preclinical and clinical studies, and identify molecular mechanisms regulating PCSK9 expression in the diabetic state.