Percent Reduction In Low-density Lipoprotein Cholesterol Research Articles

A Comparative Analysis of Low-Density Lipoprotein Cholesterol (LDL-C)-Lowering Activities of Bempedoic Acid, Inclisiran, and PCSK9 Inhibitors: A Systematic Review.

Newer drugs, such as bempedoic acid, inclisiran, alirocumab, and evolocumab have recently been introduced for dyslipidemia. This systematic review aims to perform a comparative analysis of these drugs' low-density lipoprotein cholesterol (LDL-C)-lowering activities. The PubMed database was utilized to search for randomized controlled trials. Articles were screened and selected based on specific inclusion and exclusion criteria. The primary outcome of this review is to compare the percentage reduction of LDL-C and apolipoprotein-B, along with the number of reported serious adverse events (SAEs) in trials specific to each drug. A total of 14 studies were included, four for bempedoic acid and alirocumab and three for evolocumab and inclisiran. The maximum percentage reduction in LDL-C and apolipoprotein-B from baseline to 12 weeks was observed with alirocumab, administered at 150 mg subcutaneously twice weekly for 12 weeks, achieving reductions of 72.4% and 57.9%, respectively. Lesser reductions were observed with bempedoic acid, administered at 180 mg once daily orally for 12 weeks. The highest number of SAEs were reported with bempedoic acid (216, 10%) and inclisiran (181, 11%; 175, 11%). This systematic review showed that alirocumab achieved the greatest reductions in LDL-C and apolipoprotein-B and a better safety profile. Newer LDL-C-lowering drugs show promise in improving lipid profiles, patient compliance, and safety. However, these findings are not conclusive, as other factors also influence treatment choice.

Low-density lipoprotein cholesterol response to statins according to comorbidities and co-medications: A population-based study

The response of low-density lipoprotein cholesterol (LDL-C) to statin therapy is variable, and may be affected by the presence of co-morbid conditions or the use of concomitant medications. Systematic variation in the response to statins based on these factors could affect the selection of the statin treatment regimen in population subgroups. We investigated whether common comorbidities and co-medications had clinically important effects on statin responses in individual patients. This register-based cohort study included 89,006 simvastatin or atorvastatin initiators with measurements of pre-statin and on-statin LDL-C levels, in Denmark, 2008-2018. We defined statin response as the percentage reduction in LDL-C, and used linear regression to estimate percentage reduction differences (PRD) according to 175 chronic comorbidities and 99 co-medications. We evaluated both the statistical significance (P-values corrected for multiple testing) and the clinical importance (PRD of 5 percentage points or more) of the observed associations. Concomitant use of oral blood-glucose lowering drugs, which included metformin in 96% of treated individuals, was associated with a greater response to statin therapy that was both statistically significant and clinically important, with a PRD of 5.18 (95% confidence interval: 4.79 to 5.57). No other comorbidity or co-medication reached the prespecified thresholds for a significant, clinically important effect on statin response. Overall, comorbidities and co-medications had little effect on statin response, and altogether explained only 1.7% of the total observed population variance. Most of the studied comorbidities and co-medications did not have a clinically important effect on statin response, suggesting no need to modify treatment regimens. However, use of metformin was associated with a significantly enhanced LDL-C response to statins, suggesting that lower statin doses may be effective in patients taking metformin.

Moderate-Intensity Rosuvastatin/Ezetimibe Combination versus Quadruple-Dose Rosuvastatin Monotherapy: A Meta-Analysis and Systemic Review.

There are few studies in the literature on the dosage of statin that equivalently reduces low-density lipoprotein cholesterol (LDL-C) compared to an ezetimibe combination and whether such regimens have differences in safety. We compared the lipid-modifying efficacy and safety of 5 mg rosuvastatin/10 mg ezetimibe to those of 20 mg rosuvastatin. A literature search was conducted using the PubMed, EMBASE, Cochrane, Web of Sciences, and SCOPUS databases up to December 2021. Human studies investigating the two aforementioned regimens with a randomized controlled design were selected. Outcome variables included the percentage reduction in LDL-C and other lipid parameters and rates of composite adverse events (AEs), including muscle-related symptoms. A random-effects meta-analysis was performed after heterogeneity testing between studies. Seven studies were included in this meta-analysis. The percentage LDL-C reduction did not differ between the combination and monotherapy groups [standardized mean difference (SMD) 0.08; 95% confidence interval (CI) -0.09 to 0.26; p=0.35]. The risk of composite AEs (odds ratio 0.50; 95% CI 0.15 to 1.72; p=0.27) of the combination was not different compared to the monotherapy group. The percentage of total cholesterol reduction was greater in the combination group (SMD 0.22; p=0.02), whereas that of triglyceride reduction and high-density lipoprotein cholesterol elevation did not differ between the two groups. This meta-analysis showed that 5 mg rosuvastatin/10 mg ezetimibe had largely comparable lipid-modifying efficacy and tolerability as 20 mg rosuvastatin.

Implementation of inclisiran in United Kingdom primary care for patients with atherosclerotic cardiovascular disease or its-risk equivalents: rationale and design of Victorion-spirit, a pragmatic phase IIIb, randomised controlled study

Background: Translational gaps exist in implementing health innovations rapidly in clinical practice. Pragmatic effectiveness and implementation studies, therefore, play a pivotal role in understanding how high-value health innovations could be deployed and delivered in healthcare systems to reduce barriers to adoption and provide more rapid patient benefit. Victorion-spirit is an ongoing pragmatic, 9-month, phase IIIb, open-label, multicentre, randomised controlled study evaluating the implementation, patient experience, and delivery of the subcutaneous lipid-lowering therapy, inclisiran sodium 300 mg, in participants with elevated low-density lipoprotein cholesterol (LDL-C) who are on established lipid-lowering medication, or have been recommended lipid-lowering therapy, but are unable to tolerate treatment. Methods: Victorion-spirit utilises a type 1 hybrid effectiveness-implementation design, where the primary objective is to demonstrate superiority of inclisiran with or without (±) behavioural support versus standard of care (SOC; e.g., statin and/or other lipid-lowering therapies) + behavioural support in terms of percentage reduction in LDL-C from baseline to Day 270 in a primary care setting. Secondary objectives will evaluate implementation of inclisiran ± behavioural support versus SOC + behavioural support through assessment of patient satisfaction and patient activation/empowerment after treatment at Day 90; adherence to cardiovascular disease self-management; and serious adverse event profile. Additionally, a process evaluation ascertaining the views of patients, providers and national health service (NHS) commissioners will explore barriers and enablers to integrating inclisiran within primary care. Conclusions: The results of Victorion-spirit have potential to change our approach to lipid management and inform further implementation efforts in healthcare systems, such as the NHS. Trial registration: ClinicalTrials.gov NCT04087400.

How to bridge residual distance to target low-density-lipoprotein cholesterol in acute coronary syndrome patients after initial statin therapy?

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND Current guidelines recommend intensive low-density-lipoprotein cholesterol (LDL-C) lowering by ≥50% to target LDL-C <1.4mmol/L after acute coronary syndrome (ACS). Residual distance to LDL-C target can help select treatment strategy after initial statin therapy. PURPOSE We aimed to evaluate residual distance to guideline recommended target LDL-C and the proportion of ACS patients who are projected to reach target LDL-C by different statin and non-statin lipid lowering strategies. METHODS We retrospectively analyzed 46,114 patients admitted with ACS who survived 1 year from 18 acute hospitals in Hong Kong between Jan 2014 and Dec 2018. Patients were divided into (i) high potency (HP-S; rosuvastatin ≥20mg, atorvastatin ≥40mg or simvastatin ≥80mg); (ii) non-high potency (NHP-S; other statin doses) statin users and (iii) no statin therapy. We calculated the mean distance and percentage LDL-C reduction required to reach dual LDL-C targets (>50% reduction from baseline and <1.4mmol/L). We assumed up-titration from NHP-S to HP-S would further reduce LDL-C by approximately 5-10%; addition of ezetimibe 15-20% and PCSK-9 inhibitor 50-60%. RESULTS Of 46,114 patients (60.7% males, mean age 76.2 ± 13.3 years), 80.4% (n = 10945/13614) had LDL-C ≥1.4mmol/L at 12-months after index ACS with 60.2% (n = 18319/30450), 31.9% (n = 9726/30450) and 8.0% (2405/30450) of patients on no statin, NHP-S and HP-S, respectively. 86% of HP-S and 93% of NHP-S users did not reach dual LDL-C targets at 12-months. Among patients on NHP-S and HP-S, the mean LDL-C at 12-months was 2.0 ± 0.7 and2.1 ± 0.9 mmol/L; mean residual distance to target 0.64 ± 0.7 and0.66 ± 0.9 mmol/L; and mean percentage LDL-C reduction required to reach dual LDL-C targets was 22.4 ± 33% and 18.8 ± 36%, respectively. 13% of statin users required >50% further LDL-C reduction to reach targets. Projected proportion of NHP-S users to reach LDL-C targets is 11% (n = 430/3966) by up-titrating to HP-S, 21% (n = 828/3966) by up-titration to HP-S plus ezetimibe and 100% (n = 3966/3966) with PCSK-9 inhibitor plus HP-S and ezetimibe. Projected proportion of HP-S users to reach LDL-C targets is 13% (n = 143/1099) by ezetimibe and 100% (n = 1099/1099) with addition of PCSK-9 inhibitor. CONCLUSION The use of high-potency statin was low and almost all statin users did not reach dual LDL-C targets at 12-months after index ACS. High potency statin plus ezetimibe is projected to bridge about a fifth of these patients to target LDL-C. PCSK-9 inhibitor is likely needed in the majority of patients who have not achieved target LDL-C at 12-months after ACS to reach guideline recommendations.

Personalizing cholesterol treatment recommendations for primary cardiovascular disease prevention

Statin therapy is the cornerstone of preventing atherosclerotic cardiovascular disease (ASCVD), primarily by reducing low density lipoprotein cholesterol (LDL-C) levels. Optimal statin therapy decisions rely on shared decision making and may be uncertain for a given patient. In areas of clinical uncertainty, personalized approaches based on real-world data may help inform treatment decisions. We sought to develop a personalized statin recommendation approach for primary ASCVD prevention based on historical real-world outcomes in similar patients. Our retrospective cohort included adults from a large Northern California electronic health record (EHR) aged 40–79 years with no prior cardiovascular disease or statin use. The cohort was split into training and test sets. Weighted-K-nearest-neighbor (wKNN) regression models were used to identify historical EHR patients similar to a candidate patient. We modeled four statin decisions for each patient: none, low-intensity, moderate-intensity, and high-intensity. For each candidate patient, the algorithm recommended the statin decision that was associated with the greatest percentage reduction in LDL-C after 1 year in similar patients. The overall cohort consisted of 50,576 patients (age 54.6 ± 9.8 years) with 55% female, 48% non-Hispanic White, 32% Asian, and 7.4% Hispanic patients. Among 8383 test-set patients, 52%, 44%, and 4% were recommended high-, moderate-, and low-intensity statins, respectively, for a maximum predicted average 1-yr LDL-C reduction of 16.9%, 20.4%, and 14.9%, in each group, respectively. Overall, using aggregate EHR data, a personalized statin recommendation approach identified the statin intensity associated with the greatest LDL-C reduction in historical patients similar to a candidate patient. Recommendations included low- or moderate-intensity statins for maximum LDL-C lowering in nearly half the test set, which is discordant with their expected guideline-based efficacy. A data-driven personalized statin recommendation approach may inform shared decision making in areas of uncertainty, and highlight unexpected efficacy-effectiveness gaps.

Strategies to bridge therapeutic gap in low-density-lipoprotein cholesterol lowering among 90,590 Chinese population with atherosclerotic cardiovascular diseases on stable statin monotherapy

Abstract Background Current guideline recommends addition of PCSK9-inhibitor to achieve low-density-lipoprotein cholesterol (LDL-C) lowering by ≥50% to target LDL-C <1.4mmol/L for patients with established atherosclerotic cardiovascular disease (ASCVD) already on maximum tolerated dose of statin and ezetimibe. Purpose We aimed to evaluate the residual distance to target LDL-C (LDL-C lowered by ≥50% and <1.4mmol/L) in ASCVD patients on statin monotherapy and the proportion projected to reach target LDL-C by up-titration to high potency statin, addition of ezetimibe and PCSK9-inhibitor. Methods We retrospectively analyzed 90,590 patients with ASCVD on stable dose of statin monotherapy prior to lipid profile assessment from 43 public hospitals in Hong Kong between Aug 2016 and Jul 2020. Patients were divided into (i) high potency statin (HP-S; rosuvastatin ≥20mg, atorvastatin ≥40mg or simvastatin ≥80mg) and (ii) non-high potency statin (NHP-S; other statin doses) statin users. We calculated the mean percentage LDL-C reduction required to reach the target of LDL-C lowered by ≥50% and <1.4mmol/L. We assumed up-titration from NHP-S to HP-S would further reduce LDL-C by approximately 5–10%; addition of ezetimibe 15–20% and PCSK-9 inhibitor 50–60%. Results Of 90,590 patients (63.2% male, mean age 66.8±11.3), 80.5% had coronary artery, 1.6% had peripheral artery and 21% had cerebrovascular disease; 18.7% were on HP-S and 81.3% on NHP-S. LDL-C lowered by ≥50% and <1.4mmol/L were not achieved in 96.8% (n=71,333/73,655) patients on NHP-S and 93.9% (n=15,896/16,935) patients on HP-S. In these patients, mean LDL-C was 1.8±0.6 and 1.9±0.6mmol/L and mean percentage LDL-C reduction required to reach target LDL-C goal was 40.5±15.4% and 39.3±17.8%, respectively. The proportion of patients who required 5–10%, 10–30%, 30–60% and >60% further reduction to reach target LDL-C were 2.5%, 22.1%, 65.4% and 9%, respectively. Proportion of NHP-S patients projected to reach LDL-C goal by up-titrating to HP-S is 2.2% (n=1,569/71,333). Addition of ezetimibe is projected to achieve LDL-C target in 20.5% (n=17,519/85,660) patients on HP-S who are not at goal. Overall, 78.1% (n=68,141/87,229) of patients on HP-S and ezetimibe were expected to need PCSK-9 inhibitor and is projected to achieve LDL-C target in 98% of cases (n=66,806/68,141). Conclusion Our “real-world” study showed the use of HP-S in ASCVD patients was low and >90% did not reach LDL-C target. High potency statin plus ezetimibe was projected to bridge about one fifth of these patients to target LDL-C. PCSK-9 inhibitor is likely required in significant number of patients despite HP-S plus ezetimibe. Funding Acknowledgement Type of funding sources: None.

LDL Cholesterol Reduction Variability with Different Types and Doses of Statins in Monotherapy or Combined with Ezetimibe. Results from the Spanish Arteriosclerosis Society Dyslipidaemia Registry.

Low-density lipoprotein (LDL) cholesterol reduction by statin therapy is dose-dependent, varies among different statins, and has wide inter-individual variability. The present study aimed to compare mean LDL cholesterol reduction and its variability achieved with different doses of the three statins most frequently used in monotherapy or combined with ezetimibe in a real clinical setting. Of 5620 cases with primary hypercholesterolemia on the Spanish Arteriosclerosis Society Registry, 1004 with non-familial hypercholesterolemia and complete information on drug therapy and lipid profile were included. The lowest mean percentage LDL cholesterol reduction was observed with simvastatin 10mg (32.5 ± 18.5%), while the highest mean percentage LDL reduction was obtained with rosuvastatin 40mg (58.7 ± 18.8%). As to combined treatment, the lowest and highest mean percentage LDL cholesterol reductions were obtained with simvastatin 10mg combined with ezetimibe (50.6 ± 24.6%) and rosuvastatin 40mg combined with ezetimibe (71.6 ± 11.1%), respectively. Factors associated with a suboptimal response were male sex, lower age, body mass index, and baseline LDL cholesterol levels. Combined treatment was associated with less variability in LDL cholesterol reduction (OR 0.603, p < 0.001). In a real clinical setting, rosuvastatin was superior to the other statins in lowering LDL cholesterol, both as monotherapy or combined with ezetimibe. Factors associated with a suboptimal response in LDL cholesterol decline were male sex, age, body mass index, and baseline LDL cholesterol levels. Combined treatment was associated with less variability in LDL cholesterol improvement.

Abstract 13200: Relationship Between Baseline Low-Density Lipoprotein Cholesterol and Percent Low-Density Lipoprotein Cholesterol Reduction With Evolocumab in the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) Trial

Introduction: The FOURIER trial demonstrated that the PCSK9 inhibitor evolocumab robustly reduced LDL-C amongst patients on moderate or high intensity statins. We investigated whether the magnitude of the percentage LDL-C reduction is consistent across baseline LDL-C levels. Methods: FOURIER enrolled 27,564 patients with ASCVD and an LDL-C ≥70 mg/dl or a non-HDL-C ≥100 mg/dl on optimized statin therapy at the time of enrollment. The % LDL-C reduction from baseline to 12 wks was examined in patients on study drug through 12 wks (N=25,847) using a quadratic regression model including terms for treatment (evolocumab vs. placebo), baseline LDL-C and [LDL-C] 2 , and interaction terms. Stratified analyses were done for patients on high vs. moderate intensity statin. Results: Overall, compared with placebo, evolocumab reduced LDL-C by 61% (95% CI 61-62%). Patients with lower baseline LDL-C had significantly greater % LDL-C reductions (Figure top; P&lt;0.001 for interaction between baseline LDL-C and % LDL-C reduction with evolocumab). Among patients with a baseline LDL-C of 70 mg/dL, LDL-C reduction was 68% (95% CI 67-69%) vs. 54% (95% CI 53-55%) in patients with a baseline LDL-C of 130 mg/dl. When stratified by concomitant statin intensity, similar relationships were observed (Figure middle &amp; bottom). Conclusions: The magnitude of % LDL-C reduction with evolocumab is greater in patients with lower baseline LDL-C levels. These data are encouraging for the use of PCSK9 inhibition even for patients at the lower end of LDL-C.

Drug related metabolites and genetic polymorphisms predict low low-density lipoprotein cholesterol response to atorvastatin treatment in patients with coronary heart disease

Abstract Background There is considerable individual variation in the low-density lipoprotein cholesterol (LDL-C) reduction at all classes and doses of statins. Knowledge of the determinants of individual variation LDL-C response upon statin treatment may pave the way for personalized and optimized statin treatment. Purpose We aimed to determine clinical and drug related predictors of variability of LDL-C response to atorvastatin 40 mg in patients with coronary heart disease. Methods This is an explorative study among 70 patients enrolled in the MUscle Side-Effects of atorvastatin in coronary patients (MUSE) randomized double blinded cross-over trial. Absolute and relative changes in LDL-C after 7 weeks treatment with atorvastatin 40 mg/day and 7 weeks treatment with placebo, were calculated for each patient. Linear regression analyses were applied to investigate the association between clinical (10 variables) and drug related (atorvastatin and/or metabolites, 18 variables) predictors and changes in LDL-C. Results Adherence to allocated treatment was high as confirmed by atorvastatin levels in blood and a mean proportion of days covered of 99% (range 91–100%). Mean reduction in LDL-C on atorvastatin treatment (LDL-C atorvastatin – LDL-C placebo) was 2.1 (SD 0.7, range 0.3 to 3.4) mmol/L. Mean percentage reduction in LDL-C was 51.1 (SD 11.2, range 29 to 60)%, and 37 patients (52.9%) had &amp;lt;50% LDL-C reduction. Genetic polymorphisms in SLCO1B1 or CYP3A (B 0.06, 95% CI 0.01 to 0.12, p=0.026), increasing number of coronary events (B 0.06, 95% CI 0.002 to 0.10, p=0.005), increasing trough concentration of 4-OH atorvastatin lactone (B 0.05, 95% CI 0.01 to 0.08, p=0.005) and increasing trough concentration of 4-OH atorvastatin acid (B 0.05, 95% CI 0.01 to 0.08, p=0.006) were the significant determinants of lower relative change (%) in LDL-C, in adjusted analyses. Age, gender, somatic comorbidity, cardiovascular risk factors, statin dependent muscle side-effects and other clinical and drug related determinants were not associated with changes in LDL-C. Conclusions There is considerable inter-individual variation in the LDL-C response upon treatment with atorvastatin despite confirmed high statin adherence. This is the first study reporting that genetic polymorphisms involved in the metabolism of statins and atorvastatin metabolites predict lower LDL-C response. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): National Association of Health, Grant/Award

Efficacy and Safety of Alirocumab in Patients With Autosomal Dominant Hypercholesterolemia Associated With Proprotein Convertase Subtilisin/Kexin Type 9 Gain-of-Function or Apolipoprotein B Loss-of-Function Mutations

Autosomal dominant hypercholesterolemia results from mutations affecting the low-density lipoprotein receptor pathway, including proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GoFm) and apolipoprotein B (APOB) loss-of-function mutations (LoFm). This study examined the long-term efficacy and safety of alirocumab in patients with PCSK9 GoFm and APOB LoFm who participated in the open-label extension to a Phase 2 double-blind study (NCT01604824). Of the 23 patients who completed the 14-week double-blind period and 8-week follow-up, 21 opted to continue in the open-label extension (PCSK9 GoFm, n = 15; APOB LoFm, n = 6). Patients received alirocumab 150 mg every 2 weeks from week 32 up to 3 years for PCSK9 GoFm and 2 years for APOB LoFm. Mean duration of alirocumab exposure was 129 weeks (median: 144 weeks). After initiation of alirocumab treatment, low-density lipoprotein cholesterol (LDL-C) decreased in both groups. At week 80, mean percent reduction in LDL-C from baseline was 58.0% and 47.1% for PCSK9 GoFm and APOB LoFm groups, respectively. Treatment-emergent adverse events were reported in 19 patients (90.5%); no patients discontinued treatment due to treatment-emergent adverse events. In patients with autosomal dominant hypercholesterolemia and elevated LDL-C levels despite receiving maximally tolerated lipid-lowering therapies, alirocumab 150 mg every 2 weeks resulted in clinically meaningful reductions in LDL-C, sustained through to 3 years and 2 years for patients with PCSK9 GoFm and APOB LoFm, respectively. Alirocumab was generally well tolerated with no unexpected safety concerns.

Pharmacokinetic and pharmacodynamic assessment of alirocumab in patients with familial hypercholesterolemia associated with proprotein convertase subtilisin/kexin type 9 gain-of-function or apolipoprotein B loss-of-function mutations

Familial hypercholesterolemia is characterized by high levels of low-density lipoprotein cholesterol (LDL-C), and causes of familial hypercholesterolemia include apolipoprotein B (APOB) loss-of-function mutations (LOFm) and proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GOFm). The aim of this study was to compare the pharmacokinetics and pharmacodynamics of alirocumab between patients with APOB LOFm vs PCSK9 GOFm. Patients (6 APOB LOFm and 17 PCSK9 GOFm carriers) with LDL-C ≥70mg/dL on maximally tolerated lipid-lowering therapies received alirocumab 150mg at Weeks 0, 2, 4, and 6, placebo at Week 8, alirocumab at Week 10, placebo at Weeks 12 and 14, then completed a follow-up period at Week22. At Week 8, mean±standard error (SE) alirocumab concentration was lower in APOB LOFm carriers compared with PCSK9 GOFm carriers (12.12±1.81 vs 16.74±2.53mg/L). APOB LOFm carriers had higher mean±SE total PCSK9 (6.56±0.73mg/L) and lower mean±SE free PCSK9 (0.025±0.016mg/L) at Week 8 compared with PCSK9 GOFm carriers (4.21±0.35 and 0.11±0.035mg/L for total and free PCSK9, respectively). Despite this observed greater PCSK9 suppression, mean±SE percent LDL-C reduction was lower in APOB LOFm (55.3±1.0%) compared with PCSK9 GOFm carriers (73.1±0.9%). Treatment-emergent adverse events occurred in 16 patients (94.1%) in the PCSK9 GOFm group and 5 patients (83.3%) in the APOB LOFm group. Overall, PCSK9 inhibition with alirocumab results in clinically meaningful reductions in LDL-C in both APOB LOFm and PCSK9 GOFm carriers, although reductions were greater in the PCSK9 GOFm carriers. The results indicate a possible underlying contributor to hypercholesterolemia other than PCSK9 in patients with APOB LOFm. NCT01604824; clinicaltrials.gov.

P5328Clinical and demographic predictors of attenuated LDL-C response to PCSK9 inhibition with bococizumab: Insights from the SPIRE trials

Abstract Background While there exists significant inter-individual variability in low density lipoprotein cholesterol (LDL-C) response to proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, predictors of this response remain uncertain. The Studies of PCSK9 Inhibition and the Reduction of Vascular Events (SPIRE) randomized control trials evaluated the efficacy of bococizumab, a humanized murine PCSK9 antibody, in patients at high cardiovascular risk. Purpose This study's purpose is to determine predictors of attenuated LDL-C response to bococizumab. Methods SPIRE 1 and 2 trial subjects allocated to bococizumab (n=13,675) were included. Subjects with an increase in LDL-C or non-compliance to bococizumab, or development of anti-drug or neutralizing antibodies were excluded. The remaining 8281 subjects were divided into quintiles of percent LDL-C reduction from baseline to 14 weeks. The first quintile (Q1) was considered an attenuated response. Multivariate logistic regression was used to discern significant predictors of attenuated response (Q1) compared to robust response (Q5). Results Q1 included 1657 subjects with median 35% LDL-C reduction (range 0.4% - 48%), whereas Q5 included 1658 subjects with median 83% LDL-C reduction (range 78% - 99%). Female sex, diabetes, white race, younger age, higher baseline non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein (a) [Lp(a)] and high-sensitivity C-reactive protein (hsCRP) were significantly associated with an attenuated response compared to a robust response (each p&lt;0.05, Table). Multivariate logistic regression for attenuated percent LDL-C response to bococizumab from baseline to 14 week Baseline characteristic Adjusted odds ratio (95% confidence interval) P-value Female 3.30 (2.72, 4.00) &lt;0.0001 Diabetes 1.57 (1.32, 1.86) &lt;0.0001 White race 1.44 (1.07, 1.93) 0.016 BMI (per 1kg/m2) 1.09 (1.07, 1.11) &lt;0.0001 Age (per year) 0.98 (0.98, 0.99) 0.0005 Ln hs-CRP (per 1mg/L) 1.19 (1.11, 1.29) &lt;0.0001 Lp (a) (per 10mg/dL) 1.11 (1.09, 1.14) &lt;0.0001 Non-HDL-C (per 10mg/dL) 1.05 (1.02, 1.07) &lt;0.0001 Odds ratios mutually adjusted for the listed variables. Conclusions In the SPIRE 1 and 2 trials, excluding subjects with anti-drug and neutralizing antibodies, significant predictors of an attenuated LDL-C response to PCSK9 inhibition with bococizumab included female sex, diabetes, younger age and white race. Acknowledgement/Funding Pfizer

P2781How to bridge residual distance to target low-density-lipoprotein cholesterol in stroke patients after initial statin therapy?

Abstract Background Current guidelines recommend intensive low-density-lipoprotein cholesterol (LDL-C) lowering to target LDL-C &lt;1.8mmol/L after ischemic stroke (IS). Residual distance to LDL-C target can help select further treatment options after initial statin therapy. Purpose We aimed to evaluate residual distance to target LDL-C and the proportion of IS patients who are projected to reach target LDL-C by different statin and non-statin lipid lowering strategies. Methods We retrospectively analyzed 5,025 patients admitted with IS or transient ischemic attack who survived 1 year from an academic institution in Hong Kong between Jan 2005 and Sep 2017. Patients were divided into (i) high potency (HP-S; rosuvastatin ≥20mg, atorvastatin ≥40mg or simvastatin ≥80mg); (ii) non-high potency (NHP-S; other statin doses) statin users and (iii) no statin therapy. We calculated the mean distance and percentage LDL-C reduction required to reach target LDL-C. We assumed up-titration from NHP-S to HP-S would further reduce LDL-C by 5–15%; addition of ezetimibe 15–25%; up-titrate to HP-S plus ezetimibe 20–40% and combine statin with proprotein convertase subtilsin-kexin type 9 inhibitor (PCSK-9) 40–60%. Results Of 5,025 patients (56.3% males, mean age 69.1±11.5 years), 62.4% (3134/5025) had LDL-C ≥1.8mmol/L at 12-months after index stroke with 16.7% (839/5025), 80.9% (4064/5025) and 2.4% (122/5025) of patients on no statin, NHP-S and HP-S, respectively. 58.1% (2362/4064) of NHP-S and 60.7% (74/122) of HP-S users did not reach LDL-C target. Among these patients, the mean LDL-C was 2.5±0.6 and 2.8±1.0mmol/L; mean residual distance to target 0.7±0.6 and 1.0±1.0mmol/L; and mean percentage LDL-C reduction required to reach target LDL-C goal was 23.3±15.1% and 29.5±18.1%, respectively. The proportion of NHP-S users projected to reach target LDL-C is 34.9% (824/2362) by up-titrating/switching to HP-S, 57.2% (n=1352/2362) by addition of ezetimibe, 84.5% (n=1997/2362) by up-titration to HP-S plus ezetimibe and 98.6% (2330/2362) with PCSK-9 inhibitor (Figure 1). The proportion of HP-S users projected to reach target LDL-C is 43.2% (32/74) by addition of ezetimibe and 94.6% (70/74) with PCSK-9 inhibitor (Figure 1). Conclusion The use of high-potency statin is low and more than 50% of statin users did not reach target LDL-C at 12-months after index stroke. Combined up-titration to high-potency statin plus addition of ezetimibe is expected to bridge residual distance to target LDL-C in majority of stroke patients. Acknowledgement/Funding Supported in part by a research grant from Investigator-Initiated Studies Program of Merck Sharp &amp; Dohme (Asia) Ltd.

Familial Hypercholesterolemia Among Young Adults With Myocardial Infarction

BackgroundThere are limited data on the prevalence and treatment of familial hypercholesterolemia (FH) among U.S. adults who experience a myocardial infarction (MI) at a young age. ObjectivesThis study aimed to evaluate the prevalence of clinically defined FH and examine the rates of statin utilization and low-density lipoprotein cholesterol (LDL-C) achieved 1-year post MI. MethodsThe YOUNG-MI registry is a retrospective cohort study that includes patients who experience an MI at or below age 50 years between 2000 and 2016 at 2 academic centers. Probable or definite FH was defined by the Dutch Lipid Clinic criteria. Outcomes included the proportion of patients classified as probable or definite FH, use of lipid-lowering therapy, and LDL-C achieved 1-year post MI. ResultsThe cohort consisted of 1,996 adults with a median age of 45 years; 19% were women, and 54% had ST-segment elevation MI. Probable/definite FH was present in 180 (9%) of whom 42.8% were not on statins prior to their MI. Of the 1,966 patients surviving until hospital discharge, 89.4% of FH patients and 89.9% of non-FH patients were discharged on statin therapy (p = 0.82). Among FH patients, 63.3% were discharged on high-intensity statin compared with 48.4% for non-FH patients (p < 0.001). At 1-year follow-up, the percent reduction in LDL-C among FH patients was −44.4% compared with −34.5% (p = 0.006) in non-FH patients. The proportion of patients with LDL-C ≥70 mg/dl was higher among FH patients (82.2%) compared with non-FH patients (64.5%; p < 0.001). ConclusionsClinically defined FH was present in nearly 1 of 10 patients with MI at a young age. Only two-thirds of FH patients were discharged on high-intensity statin therapy, and the vast majority had elevated LDL-C at 1 year. These findings reinforce the need for more aggressive lipid-lowering therapy in young FH and non-FH patients post-MI.

Efficacy of Evolocumab in Monogenic vs Polygenic Hypercholesterolemia

BackgroundInhibitors of proprotein convertase subtilisin kexin 9 are indicated in Canada for treatment of patients with familial hypercholesterolemia (FH). Classically, FH is considered to be a monogenic condition caused by rare pathogenic mutations; however, some patients have hypercholesterolemia on a polygenic basis. Whether the effect of proprotein convertase subtilisin kexin 9 inhibitor treatment differs between patients with monogenic hypercholesterolemia and patients with polygenic hypercholesterolemia is unclear. MethodsWe performed retrospective chart reviews on patients treated with evolocumab 140 mg subcutaneously biweekly from the Lipid Genetics Clinic, London Health Sciences Centre. Evolocumab-treated patients with hypercholesterolemia were grouped into monogenic or polygenic categories on the basis of their genotype determined by targeted next-generation sequencing. Absolute and relative changes in low-density lipoprotein cholesterol (LDL-C) levels before and after evolocumab treatment were studied. ResultsIn 32 patients with monogenic heterozygous FH and 7 patients with polygenic hypercholesterolemia treated with evolocumab, absolute incremental reductions in LDL-C were 2.94 ± 1.22 mmol/L and 3.15 ± 0.90 mmol/L, respectively (P = not significant), whereas percent reductions in LDL-C were 63.9% ± 16.0% and 67.7% ± 20.7%, respectively (P = not significant). ConclusionAlthough the sample size is small, the findings suggest comparable biochemical responsiveness to evolocumab in both monogenic (heterozygous) and polygenic hypercholesterolemia.

Statins: Then and Now.

The discovery of statins (3-hydroxy-3-methylglutaryl CoA reductase inhibitors) is a consequence of the highly targeted, arduous search for naturally occurring compounds that inhibit cholesterol biosynthesis. An enormous amount of basic scientific, genetic, and clinical research substantiated the role of lipoprotein-derived cholesterol in atherogenesis. Quantifying the impact of lipid lowering on cardiovascular event rates became an issue of utmost urgency. Although a variety of nonstatin drugs had been tested in clinical trials, they found limited utility in the clinical setting due to lack of mortality reduction or tolerability issues. As multiple prospective randomized statin trials began publishing their results, it became clear that reducing atherogenic lipoprotein burden with these drugs was highly efficacious, safe, and generally well tolerated. Statins have been shown to reduce risk for nonfatal MI, ischemic stroke, need for revascularization, and cardiovascular and all-cause mortality. They have also been shown to stabilize and even regress established atherosclerotic plaque. For the first 2 decades of their use, statin dosing was largely determined by risk-stratified low-density lipoprotein cholesterol (LDL-C) goals. More recently, there has been a transition away from LDL-C goal attainment with a focus more on cardiovascular risk and percent LDL-C reduction. Unfortunately, long-term adherence rates with statin therapy remain low and, even when used, they tend to be underdosed.

Effect of SLCO1B1 T521C on statin-induced reduction in low-density lipoprotein cholesterol: a systematic review and meta-analysis

Increasing number of studies have examined the effect of SLCO1B1 T521C polymorphism on lipid-lowering efficacy of statin. This study was conducted to clarify the effect of SLCO1B1 T521C on the rate of statin-induced reduction in low-density lipoprotein cholesterol (LDL-C). The databases of PubMed, Embase, Ovid, and Cochrane Library were searched for all published studies from inception to April 2018. Using the Review Manager 5, the pooled estimates of the weighted mean difference (WMD) of the percent changes of LDL-C and corresponding 95% confidence intervals (CIs) were calculated. A total of 17 cohort studies were included in this meta-analysis. The percent reduction in LDL-C was slightly higher in the statin users carrying 521TT than in the users carrying 521CC (WMD: 2.41; 95% CI: 0.15, 4.67; p=0.04). Sim-ilarly, the carriers of 521TC achieved slightly higher reduction in LDL-C than the carriers of 521CC (WMD: 2.07; 95% CI: 0.79, 3.35; p=0.002). However, no significant difference in percent reduction was found between the carriers and non-carriers of the 521C allele (TC+CC vs TT, WMD: 0.87; 95% CI: -0.67, 2.41; p=0.27). These results imply that the SLCO1B1 T521C polymorphism has little or no effect on the rate of reduction in LDL-C following statin therapy.

Phenotyping of Korean patients with better-than-expected efficacy of moderate-intensity statins using tensor factorization.

Several studies have been conducted to evaluate the efficacy of statins in Korean and Asian patients. However, most previous studies only observed the percent reduction in low-density lipoprotein cholesterol (LDL-C) and did not consider the effects of various patient conditions simultaneously, such as abnormal test results, patient demographics, and prescribed drugs before taking a statin. Moreover, the characteristics of the patients whose percent reduction in LDL-C was higher than expected were not provided. Therefore, in this study, we aimed to derive meaningful phenotypes by using tensor factorization to observe the characteristics of the patients whose percent reduction in LDL-C was higher than expected among patients taking moderate-intensity statins. In addition, we used the derived phenotypes to predict how much the LDL-C levels of new patients decreased. We consequently identified eight phenotypes that represented the characteristics of the patients whose percent reduction in LDL-C was higher than expected. Moreover, the latent representations of the derived phenotypes achieved prediction performance similar to that obtained using the raw data. These results demonstrate that the derived phenotypes and latent representations are useful tools for observing the characteristics of patients and predicting LDL-C levels. Additionally, our findings provide direction on how to conduct clinical studies in the future.

Glucagon-like peptide-1 receptor agonists reduced the low-density lipoprotein cholesterol in Japanese patients with type 2 diabetes mellitus treated with statins

Patients with type 2 diabetes mellitus (T2DM) often have hypercholesterolemia, and their serum low-density lipoprotein cholesterol (LDL-C) levels are not always well-controlled even by statin treatment. The glucose-lowering glucagon-like peptide-1 receptor agonists (GLP-1RAs) are reported to change the lipid profiles in T2DM patients, but their effects have been unclear. We examined whether GLP-1RAs affect serum cholesterol levels in T2DM patients with/without statin treatment. We retrospectively assessed the baseline and follow-up (median 119days) levels of serum lipids, HbA1c, and body mass index (BMI) in 103 and 214 Japanese patients with T2DM in whom GLP-1RAs were initiated (GLP-1RA group) and not initiated (control group), stratified by the use of statins. In the GLP-1RA group, the LDL-C, HbA1c, and BMI significantly decreased; high-density lipoprotein cholesterol and triglycerides did not decrease during follow-up. In the control group, these did not decrease. Among the statin users, the percentage change in LDL-C during follow-up was significantly greater in the GLP-1RA group than that in the control group (-6.5% vs -1.0%, P=.040). In the GLP-1RA group, the percentage reduction in LDL-C was not associated with that in BMI but was associated with that in HbA1c only among the statin users. Our findings demonstrated that GLP-1RAs reduced the serum LDL-C in Japanese patients with T2DM treated with statins. The percentage reduction in LDL-C by GLP-1RAs was associated with that in HbA1c, but not associated with that in BMI. The combination of GLP-1RAs and statins may be a reasonable therapeutic option in T2DM with dyslipidemia.