Low-density Lipoprotein Cholesterol Response Research Articles

Pharmacogenomics of CRP response to statins: a GIST consortium study

Abstract Introduction Statins are first line treatments in the primary and secondary prevention of cardiovascular disease. Prior clinical studies have shown that statins act independently of lipid lowering mechanisms to decrease C-reactive protein (CRP), a marker of inflammation. Purpose To elucidate genetic loci associated with CRP response to statins. Methods CRP response was specified as the change from baseline in log CRP after at least 4 weeks of statin therapy. Cohort level Genome-wide Association Studies (GWAS) of this CRP response was performed by linear regression analysis adjusted for baseline CRP, age, sex and BMI covariates using genetic data imputed to 1000 Genomes, testing ~10 million single nucleotide polymorphisms (SNPs) of minor allele frequency (MAF) >2%. Following quality control with EasyQC, a meta-analysis was conducted with METAL to combine GWAS results from six different cohorts of European ancestry (CARDS, FHS, JUPITER, MESA, PARC, PROSPER) within the GIST consortium. 1Mb loci regions were defined, centred +/-500kb around the lead SNP. Conditional analysis was performed using GCTA. Results There were 11,075 statin-treated individuals. The meta-analysis results revealed two loci achieving genome wide significance (P<5e-8): APOE (chr 19) and HNF1A (chr 12) (Figure 1). A signal at the CRP locus was highly suggestive (P=2.3e-7). All three loci are known to be associated with CRP levels in the absence of statin. Conditional analysis did not reveal secondary signals. The most associated variant at the APOE locus was the missense SNP rs429358, which contributes to the APOE E4 haplotype and is a risk locus for both dyslipidaemia and Alzheimer’s dementia. It is a C>T missense variant of MAF 0.12 leading to a R/C amino acid change, more common in African ancestry populations (MAF 0.27), and least common in Asian populations (MAF 0.09). A nominally significant association (P=0.09) for interaction with randomized allocation to statin v. placebo within samples derived from clinical trials supports this pharmacogenetic effect at APOE beyond genetic effects on baseline CRP levels. The most associated variant at the HNF1A locus was the intronic SNP rs11065384, which is in strong LD with the HNF1A missense SNP (rs1169288). The HNF1A locus is associated with diabetes, cholesterol levels, and coronary artery disease. There was no between-study heterogeneity at the top three loci (P>0.1), and forest plots show contribution to these signals from all 6 studies within the meta-analysis (Figure 2 A,B,C). Conclusions APOE and HNF1A are associated with CRP response to statins at the level of genome-wide significance. TheAPOE E4 signal is also known to be associated with LDL-Cholesterol response to statins, whereas the HNF1A locus is identified here for the first time as a pharmacogenetic determinant of statin response. The effect of this interindividual variability in CRP response on non-cardiovascular clinical outcomes should be elucidated.Figure 1Figure 2 A,B,C

Sex differences in LDL-C reduction response to evolocumab: A propensity score matching analysis.

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have been shown to improve cardiovascular outcomes by reducing low-density lipoprotein cholesterol (LDL-C). However, sex differences in the efficacy of evolocumab remain unclear. This study aimed to investigate sex differences in the efficacy of evolocumab using real-world data. Data were collected from the First Affiliated Hospital of Guangxi Medical University. A total of 416 eligible patients were selected from 1463 patients treated with evolocumab for secondary prevention. Clinical data, including individual characteristics and lipids profiles, were recorded. Propensity score matching (PSM) was used to control for potential confounders, with covariates including age, body mass index, smoking status, and diabetes. All eligible participants were propensity-matched 1:1 for female versus male with a match tolerance of 0.02. The efficacy of evolocumab in females and males was compared by PSM-adjusted analysis. In the PSM analysis, a significant difference was found in the relative percentage reduction of LDL-C between females and males (-42.7% vs. -54.4%, p < 0.001). In addition, the absolute LDL-C reduction was lower in females compared to males (interquartile range: -1.5 [-2.2, -0.8] mmol/L vs. -1.9 [-2.5, -1.0] mmol/L, p = 0.018). The rate of target LDL-C attainment was lower in females than in males after treatment with evolocumab (21.6% vs. 39.8%, p = 0.009). These results suggest that males have a better response to evolocumab in term of LDL-C reduction compared to females.

Variation of LDL cholesterol in response to the replacement of saturated with unsaturated fatty acids: a nonrandomized, sequential dietary intervention; the Reading, Imperial, Surrey, Saturated fat Cholesterol Intervention (“RISSCI”-1) study

BackgroundSerum low density lipoprotein (LDL) cholesterol shows marked interindividual variation in response to the replacement of saturated fatty acids (SFAs) with unsaturated fatty acids (UFAs). ObjectivesTo demonstrate the efficacy of United Kingdom guidelines for exchanging dietary SFAs for UFAs, to reduce serum LDL cholesterol and other cardiovascular disease (CVD) risk factors, and to identify determinants of the variability in LDL cholesterol response. MethodsHealthy males (n = 109, mean ± SD age 48 ± 11 y; BMI 25.1 ± 3.3 kg/m2), consumed a higher-SFA/lower-UFA diet for 4 wk, followed by an isoenergetic, lower-SFA/higher-UFA diet for 4 wk (achieved intakes SFA:UFA as % total energy 19.1:14.8 and 8.9:24.5, respectively). Serum LDL cholesterol, CVD risk markers, peripheral blood mononuclear cell (PBMC) gene expression, and dietary intakes were assessed at baseline and the end of each diet. ResultsTransition from a higher-SFA/lower-UFA to a lower-SFA/higher-UFA diet significantly reduced fasting blood lipids: LDL cholesterol (−0.50 mmol/L; 95% confidence interval [CI]: −0.58, −0.42), high-density lipoprotein (HDL) cholesterol (−0.11 mmol/L; 95% CI: −0.14, −0.08), and total cholesterol (TC) (−0.65 mmol/L; 95% CI:−0.75, −0.55). The dietary exchange also reduced apolipoprotein (apo)B, TC:HDL cholesterol ratio, non-HDL cholesterol, E-selectin (P < 0.0001), and LDL subfraction composition (cholesterol [LDL-I and LDL-II], apoB100 [LDL-I and LDL-II], and TAG [LDL-II]) (P < 0.01). There was also an increase in plasma biomarkers of cholesterol intestinal absorption (β-sitosterol, campesterol, cholestanol), and synthesis (desmosterol) (P < 0.0001) and fold change in PBMC LDL-receptor mRNA expression relative to the higher-SFA/lower-UFA diet (P = 0.035). Marked interindividual variation in the change in serum LDL cholesterol response (−1.39 to +0.77 mmol/L) to this dietary exchange was observed, with 33.7% of this variation explained by serum LDL cholesterol before the lower-SFA/higher-UFA diet and reduction in dietary SFA intake (adjusted R2 27% and 6.7%, respectively). APOE genotype was unrelated to serum LDL cholesterol response to SFA. ConclusionsThese findings support the efficacy of United Kingdom SFA dietary guidelines for the overall lowering of serum LDL cholesterol but showed marked variation in LDL cholesterol response. Further identification of the determinants of this variation will facilitate targeting and increasing the efficacy of these guidelines.The RISSCI-1 study was registered with ClinicalTrials.Gov (No. NCT03270527).

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.

Predicted deleterious variants in ABCA1, LPL, LPA and KIF6 are associated with statin response and adverse events in patients with familial hypercholesterolemia and disturb protein structure and stability.

This study explored the association of deleterious variants in pharmacodynamics (PD) genes with statin response and adverse effects in patients with familial hypercholesterolemia (FH) and analyzed their potential effects on protein structure and stability. Clinical and laboratory data were obtained from 144 adult FH patients treated with statins. A panel of 32 PD genes was analyzed by exon-targeted gene sequencing. Deleterious variants were identified using prediction algorithms and their structural effects were analyzed by molecular modeling studies. A total of 102 variants were predicted as deleterious (83 missense, 8 stop-gain, 4 frameshift, 1 indel, 6 splicing). The variants ABCA1 rs769705621 (indel), LPA rs41267807 (p.Tyr2023Cys) and KIF6 rs20455 (p.Trp719Arg) were associated with reduced low-density lipoprotein cholesterol (LDLc) response to statins, and the LPL rs1801177 (p.Asp36Asn) with increased LDLc response (P < 0.05). LPA rs3124784 (p.Arg2016Cys) was predicted to increase statin response (P = 0.022), and ABCA1 rs769705621 to increase the risk of statin-related adverse events (SRAE) (P = 0.027). LPA p.Arg2016Cys and LPL p.Asn36Asp maintained interactions with solvent, LPA p.Tyr2023Cys reduced intramolecular interaction with Gln1987, and KIF6 p.Trp719Arg did not affect intramolecular interactions. DDMut analysis showed that LPA p.Arg2016Cys and p.Tyr2023Cys and LPL p.Asp36Asn caused energetically favorable changes, and KIF6 p.Trp719Arg resulted in unfavorable energetic changes, affecting protein stability. Deleterious variants in ABCA1, LPA, LPL and KIF6 are associated with variability in LDLc response to statins, and ABCA1 rs769705621 is associated with SRAE risk in FH patients. Molecular modeling studies suggest that LPA p.Tyr2023Cys and KIF6 p.Trp719Arg disturb protein conformational structure and stability.

Saturated fat and CVD: importance of inter-individual variation in the response of serum low-density lipoprotein cholesterol.

The aim of this review is to provide an overview of the history in support of the role of dietary saturated fatty acids (SFA) in the development of cardiovascular disease (CVD), and the controversy and consensus for the evidence in support of guidelines to remove and replace SFA with unsaturated fatty acids. The review will also examine the existence, origins, and implications for CVD risk of variability in serum LDL-cholesterol in response to these guidelines. While the quality of supporting evidence for the efficacy of restricting SFA on CVD risk has attracted controversy, this has helped to increase understanding of the inter-relationships between SFA, LDL-cholesterol and CVD, and reinforce confidence in this dietary recommendation. Nevertheless, there is significant inter-individual variation in serum LDL-C in response to this dietary change. The origins of this variation are multi-factorial and involve both dietary and metabolic traits. If serum biomarkers of more complex metabolic traits underlying LDL-responsiveness can be identified, this would have major implications for the targeting of these dietary guidelines to LDL-responders, to maximise the benefit to their cardiovascular health.

Sex X Time Interactions in Lp(a) and LDL-C Response to Evolocumab.

The aim of this study was to evaluate whether there were significant sex x time interactions in lipoprotein(a) (Lp(a)) and low-density lipoprotein cholesterol (LDL-C) response to treatment with the Proprotein Convertase Subtilisin/Kexin type 9 inhibitor (PCSK9i) Evolocumab, in a real-life clinical setting. For this purpose, we pooled data from 176 outpatients (Men: 93; Women: 83) clinically evaluated at baseline and every six months after starting Evolocumab. Individuals who had been on PCSK9i for less than 30 months and nonadherent patients were excluded from the analysis. Over time, absolute values of Lp(a) plasma concentrations significantly decreased in the entire cohort (p-value < 0.001) and by sex (p-value < 0.001 in men and p-value = 0.002 in and women). However, there were no sex-related significant differences. Absolute plasma concentrations of LDL-C significantly decreased over time in the entire cohort and by sex (p-value < 0.001 always), with greater improvements in men compared to women. The sex x time interaction was statistically significant in LDL-C (all p-values < 0.05), while absolute changes in Lp(a) were not influenced by either sex or time (all p-value > 0.05). Our data partially reinforce the presence of differences in response to treatment to PCSK9i between men and women and are essential to gain a better understanding of the relationship between LDL-C and Lp(a) lowering in response to PCSK9i. Further research will clarify whether these sex-related significant differences translate into a meaningful difference in the long-term risk of ASCVD.

Lipidomic analysis identified potential predictive biomarkers of statin response in subjects with Familial hypercholesterolemia

Familial hypercholesterolemia (FH) is a disorder of lipid metabolism that causes elevated low-density lipoprotein cholesterol (LDL-c) and increased premature atherosclerosis risk. Statins inhibit endogenous cholesterol biosynthesis, which reduces LDL-c plasma levels and prevent from cardiovascular events. This study aimed to explore the effects of statin treatment on serum lipidomic profile and to identify biomarkers of response in subjects with FH. Seventeen adult FH patients underwent a 6-week washout followed by 4-week treatment with atorvastatin (80 mg/day) or rosuvastatin (40 mg/day). LDL-c response was considered good (40–70 % reduction, n = 9) or poor (3–33 % reduction, n = 8). Serum lipidomic profile was analyzed by ultra-high-performance liquid chromatography combined with electrospray ionization tandem time-of-flight mass spectrometry, and data were analyzed using MetaboAnalyst v5.0. Lipidomic analysis identified 353 lipids grouped into 16 classes. Statin treatment reduced drastically 8 of 13 lipid classes, generating a characteristic lipidomic profile with a significant contribution of phosphatidylinositols (PI) 16:0/18:2, 18:0/18:1 and 18:0/18:2; and triacylglycerols (TAG) 18:2x2/18:3, 18:1/18:2/18:3, 16:1/18:2x2, 16:1/18:2/18:3 and 16:1/18:2/Arachidonic acid (p-adjusted <0.05). Biomarker analysis implemented in MetaboAnalyst subsequently identified PI 16:1/18:0, 16:0/18:2 and 18:0/18:2 as predictors of statin response with and receiver operating characteristic (ROC) areas under the curve of 0.98, 0.94 and 0.91, respectively. In conclusion, statins extensively modulate the overall serum lipid composition of FH individuals and these findings suggest that phosphatidyl-inositol molecules are potential predictive biomarkers of statin response.

Anti-drug Antibody Magnitude and Clinical Relevance Using Signal to Noise (S/N): Bococizumab Case Study.

Historically, the biopharmaceutical industry has used titer to characterize the magnitude of an anti-drug antibody (ADA) response. While reporting levels of antibodies in terms of titer is generally understood and accepted by regulatory and medical communities, titer values are inherently variable given the multiple serial dilutions and reporting a value either directly before or interpolated at the assay cut point on the lower plateau of the assay curve range. Using S/N is an appealing alternative approach to titer as it simplifies analysis with less dilutions, significantly reducing testing, time, and resources and provides a more precise value potentially differentiating low-level ADA responses. Current bridging electrochemiluminescence (ECL) ADA assays using Meso Scale Discovery (MSD) platform are also significantly more sensitive and drug tolerant with wider assay ranges compared to historic ELISA platforms; therefore, ADA response based on S/N may help differentiate and identify those ADA samples that are more likely to be clinically relevant. Bococizumab is a humanized monoclonal antibody targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), which reduces plasma levels of low-density lipoprotein (LDL) cholesterol. Bococizumab was discontinued during Phase 3 clinical development based in part on the high rate of ADA and wide variation in LDL cholesterol responses among patients. The impact of anti-bococizumab antibodies on pharmacokinetic (PK) and pharmacodynamic (PD) endpoints was originally assessed using titer. Retrospective analysis of anti-bococizumab ADA responses using S/N ratios illustrates that S/N is an acceptable alternative to titer for characterizing the magnitude of ADA response and interpretation of clinically relevant ADA.

Association Between Age and Low-Density Lipoprotein Cholesterol Response to Statins : A Danish Nationwide Cohort Study.

There is large patient-to-patient variability in the low-density lipoprotein cholesterol (LDL-C) response to statin treatment. The reduction in LDL-C may depend on the age of the patient treated-particularly in older adults, who have been substantially underrepresented in randomized controlled trials. To investigate the association between age and the LDL-C reduction by statins. Nationwide, register-based cohort study. Denmark, 2008 to 2018. 82 958 simvastatin or atorvastatin initiators with LDL-C measurements before and during statin use. Statin response, defined as percentage reduction in prestatin LDL-C level, and percentage reduction differences (PRDs) according to age and simvastatin or atorvastatin dose based on a longitudinal model for LDL-C. Among 82 958 statin initiators, 10 388 (13%) were aged 75 years or older. With low- to moderate-intensity statins, initiators aged 75 years or older had greater mean LDL-C percentage reductions than initiators younger than 50 years-for example, 39.0% versus 33.8% for simvastatin, 20 mg, and 44.2% versus 40.2% for atorvastatin, 20 mg. The adjusted PRD for initiators aged 75 years compared with initiators aged 50 years was 2.62 percentage points. This association was consistent for primary prevention (2.54 percentage points) and secondary prevention (2.32 percentage points) but smaller for initiators of high-intensity statins (atorvastatin, 40 mg: 1.36 percentage points; atorvastatin, 80 mg: -0.58 percentage point). Use of administrative data, observational pre-post comparison with a moderately high proportion of missing data, lack of information on body mass index, and the mainly White study population may limit generalizability. Low- to moderate-intensity statins were associated with a greater reduction in LDL-C levels in older persons than younger persons and may be more appealing as initial treatment in older adults who are at increased risk for adverse events. The Independent Research Fund Denmark, Brødrene Hartmanns Fond, and Fonden til Lægevidenskabens Fremme.

A Novel Functional Refined Olive Oil, Enhanced with Orange Peel Extract, Modulates Postprandial LDL-Cholesterol Responses in Individuals at Cardiometabolic Risk: A Pilot Randomized, Controlled, Cross-Over Nutritional Intervention

Olive oil, as the main source of polyphenols in the Mediterranean diet pattern, is mentioned to show remarkable postprandial bioactivity, contributing to the reduction of cardiometabolic risk factors. In recent years, the consumption of refined olive oil, instead of other olive oil classes, led to a reduced intake of polyphenols from the usual diet. This controlled, human nutritional intervention investigated whether the enhancement of refined olive oil with orange peel extract may modulate postprandial lipemia, glycemia, and oxidative stress in individuals at cardiometabolic risk. In a cross-over framework, 21 participants aged 30–65 years, who met the eligibility criteria, received a fat and carbohydrate meal of mashed potatoes, homogenized with refined olive oil (50 mL) or the functional olive oil, enhanced with 10% orange peel extract, intervening a washout week. Blood draws were performed in fasting, 30 min, 1.5 h, and 3 h after the meal intake. Plasma lipids, glucose, uric acid, and total plasma antioxidant capacity, according to the FRAP method, were measured at each timepoint. A significant reduction of LDL-cholesterol was observed, 1.5 h and 3 h after the functional meal intake, compared to non-significant changes after the control meal (p &lt; 0.05). No other statistically significant interactions were detected to the remaining biomarkers (p &gt; 0.05). Further investigation is needed for safer conclusions about the postprandial modulation of cardiometabolic risk factors by the functional olive oil enhanced with orange peel extract.

Efficacy, safety and clinical outcome associated with statin use for primary prevention in Korean patients with low-density lipoprotein cholesterol level ≥ 190 mg/dL: A retrospective cohort study.

Although the current guideline recommends the use of high-intensity statin to reduce the low-density lipoprotein cholesterol (LDL-C) level by 50% in patients with baseline value of ≥ 190 mg/dL, direct application of this recommendation to Asian populations is still questionable. This study was performed to investigate the statin response of LDL-C in Korean patients with LDL-C ≥ 190 mg/dL. A total of 1,075 Korean patients (age 60.7 ± 12.2 years, women 68%) with baseline LDL-C ≥ 190 mg/dL without cardiovascular disease was retrospectively reviewed. Lipid profiles at 6 months, side effects and clinical outcomes during the follow-up period after statin treatment were assessed according to statin intensity. Most of the patients (76.3%) were treated with moderate-intensity statins, 11.4% with high-intensity statins, and 12.3% with a statin + ezetimibe. The reductions in LDL-C percentage at 6 months were 48.0%, 56.0% and 53.3% in patients treated with moderate-intensity statins, high-intensity statins and statin + ezetimibe, respectively (P < 0.001). Side effects requiring dose reduction, medication switch or drug interruption were observed in 1.3%, 4.9% and 2.3% of patients treated with moderate-intensity statin, high-intensity statin and statin + ezetimibe, respectively (P = 0.024). During the median follow-duration of 815 days (interquartile range, 408-1,361 days), the incidences of cardiovascular events were not different among the 3 groups (log-rank P = 0.823). Compared to high-intensity statin, moderate-intensity statin was effective enough in reaching target goal of LDL-C without increase in cardiovascular risk and with fewer side effects in Korean patients with LDL-C ≥ 190 mg/dL.

Mendelian Randomization Analysis Reveals Statins Potentially Increase Amyotrophic Lateral Sclerosis Risk Independent of Peripheral Cholesterol-Lowering Effects.

Observational studies suggest that statins may affect amyotrophic lateral sclerosis (ALS). However, they are limited by confounding and reverse causality biases. Therefore, we aimed to investigate the potential causal associations between statins and ALS using a mendelian randomization (MR) approach. Two-sample MR and drug-target MR were performed. Exposure sources included GWAS summary statistics of statin use, low-density-lipoprotein cholesterol (LDL-C), HMGCR-mediated LDL-C and LDL-C response to statins. Genetic predisposition to statin medication was associated with increased ALS risk (OR = 1.085, 95% CI = 1.025-1.148, p = 0.005). After removing SNPs significantly associated with statin use from the instrumental variables (IVs), LDL-C-related higher ALS risk was absent (before removing: OR = 1.075, 95% CI = 1.013-1.141, p = 0.017; after removing: OR = 1.036, 95% CI = 0.949-1.131, p = 0.432). HMGCR-mediated LDL-C (OR = 1.033, 95% CI = 0.823-1.296, p = 0.779) and blood LDL-C response to statins (OR = 0.998, 95% CI = 0.991-1.005, p = 0.538) had no association with ALS. Here, we show that statins may be a risky exposure that increases ALS risk independent of the lowering effect of LDL-C in peripheral circulation. This provides insights into ALS development and prevention.

Effects of statin response on cardiovascular outcomes in patients with ST-segment elevation myocardial infarction

SUMMARYOBJECTIVE:This study aimed to evaluate the effects of statin response on cardiovascular outcomes in patients with ST-segment elevation myocardial infarction.METHODS:A total of 1029 ST-segment elevation myocardial infarction patients were enrolled in the study. The patients who failed to achieve >40% reduction in baseline low-density lipoprotein cholesterol levels within 30 days to 12 months after statin initiation were defined as suboptimal statin responders. The adjusted hazard ratios for cardiovascular outcomes for low-density lipoprotein cholesterol response to statins were estimated via the Cox proportional regression model. The relationship between the statin response and cardiovascular outcomes was also evaluated in a subgroup of on-treatment low-density lipoprotein cholesterol levels below 55 mg/dL.RESULTS:Among the study population, 573 (55.6%) patients demonstrated suboptimal low-density lipoprotein cholesterol response to statin therapy. These patients showed a significantly higher incidence of the composite of major adverse cardiovascular events, including cardiovascular death, reinfarction, recurrent myocardial infarction, and target vessel revascularization during the follow-up compared with optimal responders (adjusted hazard ratios 3.99; 95%CI 2.66–6.01; p<0.001). In a subgroup of patients with on-treatment low-density lipoprotein cholesterol levels below 55 mg/dL, suboptimal statin responders also showed unfavorable cardiovascular outcomes (adjusted hazard ratios 8.73; 95%CI 2.81–27.1; p<0.001).CONCLUSIONS:The present study showed that over half of the patients with ST-segment elevation myocardial infarction did not exhibit optimal low-density lipoprotein cholesterol response to statin. These patients have an increased risk of future major adverse cardiovascular events.

Low-density lipoprotein cholesterol increased significantly after short-term discontinuation of atorvastatin, but did not correlate with plasma drug concentrations

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The Dam foundation Introduction Statin non-adherence remains a prevalent challenge in cardiovascular disease prevention and robust methods to monitor adherence are needed. Large variations in low-density-lipoprotein cholesterol (LDL-C) response to a given type and dose of statin have been reported. The LDL-C response to short-term discontinuation of statins is not well defined. Moreover, the relationship between the blood concentrations of statin metabolites and LDL-C, and how clinical factors interact, are unknown. Purpose To determine changes in LDL-C at an individual and group level during four-day discontinuation of atorvastatin, and to investigate whether clinical factors and atorvastatin metabolites concentration correlate with changes in LDL-C. Methods This clinical pharmacokinetic adherence study conducted in 2021, included 60 adult participants treated with atorvastatin 20 mg (n=20), 40 mg (n=20) or 80 mg (n=20). The participants were instructed to take atorvastatin daily between 07 and 10 am the week before study start, to ensure steady state drug concentrations. The last dose of atorvastatin was taken 24 hours prior to the first blood sampling (day zero). Atorvastatin doses were omitted until after blood sampling on the fourth day. The concentrations of atorvastatin metabolites (acid and lactone forms, including 2-OH- and 4-OH metabolite) were measured by a liquid chromatography–tandem mass spectrometry assay. Paired-samples T-tests, Spearman rank correlations and linear regression analyses were performed with SPSS. Results Mean age was 65 (SD 11) years, 18 (30%) were female, 45 (75%) had cardiovascular disease and 11 (18%) had diabetes mellitus. Mean LDL-C at steady state on day zero was 1.9 (SD 0.6) mmol/L. LDL-C increased on average by 0.5 (SD 0.3) mmol/L (30%) from day zero to day four, during the period with atorvastatin discontinuation. The increase of LDL-C was significant already after the first omitted dose (day one) (Figure 1). LDL-C increased from day zero to day four in 78 out of the 80 patients (97.5%). Higher Body Mass Index was significantly associated with lager increase in LDL-C during the four-day discontinuation (B 0.02, 95% CI 0.01 to 0.04, p=0.028), whereas age, sex, kidney function, cardiovascular disease and diabetes were not. Changes in atorvastatin plus metabolites concentration from day zero to day four were not associated with changes in LDL-C during discontinuation (Figure 2). This also applied if we assessed the individual atorvastatin metabolites. Conclusion Atorvastatin discontinuation for only four days resulted in a statistically significant 30% increase of LDL-C. Atorvastatin pharmacokinetics did not correlate with change in LDL-C during the discontinuation. Even short-term non-adherence may have unfavourable consequences, and deserves further attention.

Genetic Variant ABCC1 rs45511401 Is Associated with Increased Response to Statins in Patients with Familial Hypercholesterolemia.

Statins are the first-line treatment for familial hypercholesterolemia (FH), but response is highly variable due to genetic and nongenetic factors. Here, we explored the association between response and genetic variability in 114 Brazilian adult FH patients. Specifically, a panel of 84 genes was analyzed by exon-targeted gene sequencing (ETGS), and the functional impact of variants in pharmacokinetic (PK) genes was assessed using an array of functionality prediction methods. Low-density lipoprotein cholesterol (LDL-c) response to statins (reduction ≥ 50%) and statin-related adverse event (SRAE) risk were assessed in carriers of deleterious variants in PK-related genes using multivariate linear regression analyses. Fifty-eight (50.8%) FH patients responded to statins, and 24 (21.0%) had SRAE. Results of the multivariate regression analysis revealed that ABCC1 rs45511401 significantly increased LDL-c reduction after statin treatment (p < 0.05). In silico analysis of the amino-acid change using molecular docking showed that ABCC1 rs45511401 possibly impairs statin efflux. Deleterious variants in PK genes were not associated with an increased risk of SRAE. In conclusion, the deleterious variant ABCC1 rs45511401 enhanced LDL-c response in Brazilian FH patients. As such, this variant might be a promising candidate for the individualization of statin therapy.

Elevated LDL Cholesterol with a Carbohydrate-Restricted Diet: Evidence for a “Lean Mass Hyper-Responder” Phenotype

ABSTRACTBackgroundPeople commencing a carbohydrate-restricted diet (CRD) experience markedly heterogenous responses in LDL cholesterol, ranging from extreme elevations to reductions.ObjectivesThe aim was to elucidate possible sources of heterogeneity in LDL cholesterol response to a CRD and thereby identify individuals who may be at risk for LDL cholesterol elevation.MethodsHypothesis-naive analyses were conducted on web survey data from 548 adults consuming a CRD. Univariate and multivariate regression models and regression trees were built to evaluate the interaction between body mass index (BMI) and baseline lipid markers. Data were also collected from a case series of five clinical patients with extremely high LDL cholesterol consuming a CRD.ResultsBMI was inversely associated with LDL cholesterol change. Low triglyceride (TG) to HDL cholesterol ratio, a marker of good metabolic health, predicted larger LDL cholesterol increases. A subgroup of respondents with LDL cholesterol ≥200 mg/dL, HDL cholesterol ≥80 mg/dL, and TG ≤70 mg/dL were characterized as “lean mass hyper-responders.” Respondents with this phenotype (n = 100) had a lower BMI and, remarkably, similar prior LDL cholesterol versus other respondents. In the case series, moderate reintroduction of carbohydrate produced a marked decrease in LDL cholesterol.ConclusionsThese data suggest that, in contrast to the typical pattern of dyslipidemia, greater LDL cholesterol elevation on a CRD tends to occur in the context of otherwise low cardiometabolic risk.

Determining propensity for sub-optimal low-density lipoprotein cholesterol response to statins and future risk of cardiovascular disease.

Variability in low-density lipoprotein cholesterol (LDL-C) response to statins is underappreciated. We characterised patients by their statin response (SR), baseline risk of cardiovascular disease (CVD) and 10-year CVD outcomes. A multivariable model was developed using 183,213 United Kingdom (UK) patients without CVD to predict probability of sub-optimal SR, defined by guidelines as <40% reduction in LDL-C. We externally validated the model in a Hong Kong (HK) cohort (n = 170,904). Patients were stratified into four groups by predicted SR and 10-year CVD risk score: [SR1] optimal SR & low risk; [SR2] sub-optimal SR & low risk; [SR3] optimal SR & high risk; [SR4] sub-optimal SR & high risk; and 10-year hazard ratios (HR) determined for first major adverse cardiovascular event (MACE). Our SR model included 12 characteristics, with an area under the curve of 0.70 (95% confidence interval [CI] 0.70-0.71; UK) and 0.68 (95% CI 0.67-0.68; HK). HRs for MACE in predicted sub-optimal SR with low CVD risk groups (SR2 to SR1) were 1.39 (95% CI 1.35-1.43, p<0.001; UK) and 1.14 (95% CI 1.11-1.17, p<0.001; HK). In both cohorts, patients with predicted sub-optimal SR with high CVD risk (SR4 to SR3) had elevated risk of MACE (UK HR 1.36, 95% CI 1.32-1.40, p<0.001: HK HR 1.25, 95% CI 1.21-1.28, p<0.001). Patients with sub-optimal response to statins experienced significantly more MACE, regardless of baseline CVD risk. To enhance cholesterol management for primary prevention, statin response should be considered alongside risk assessment.

Gene-diet interaction in plasma lipid response to plant sterols and stanols: A review of clinical trials

• PS reduce plasma LDL-C levels by 6–12%. • LDL-C response to PS intake modulated by variants in cholesterol metabolism genes. • Only CYP7A1 c. −204C > A variant offered an hypocholesterolemic effect. • Standardization of clinical trials evaluating gene-diet interaction is necessary. Plant sterols and stanols (PS) are well known for their cholesterol-lowering effect by reducing intestinal absorption of cholesterol. However, genetic factors modulate the low-density lipoprotein cholesterol (LDL-C) response to PS therapy. This review examines clinical trials evaluating the impact of the main genes associated with response of plasma lipid concentrations to PS intake: APOE, CYP7A1, ABCG5/G8, NPC1L1, CETP, APOA4/A5, SCARBI, HMGCR, PPARα, LIPC, MTHFR and LPA. Evidence indicates that carriers of mutant allele of the CYP7A1 c. −204 A > C variant experience a greater plasma cholesterol reduction after PS intake, although there is discrepancy for the rest of genetic variants studied. Thus, it is necessary to standardize the design of these studies to validate the use of genetic information as a predictor marker of the response to the intervention with PS, to scientifically validate the use of these data in the personalized dietary advice.

Diet-Responsive Hypercholesterolemia With Cardiofaciocutaneous Syndrome Type 3

Background: Molecular basis of diet responsive hypercholesterolemia remains unclear. We report diet-responsive severe hypercholesterolemia in a young female with cardiofaciocutaneous syndrome type 3 (CFC3) due to a heterozygous pathogenic MAP2K1 variant, suggesting a role of common MAPK variants in LDL-cholesterol (LDL-C) response to diet. Clinical case: A 3-year-old Caucasian female with CFC3 (macrocephaly, frontal bossing, wide nasal root with depressed bridge, anteverted nares, low set fleshy ears, congenital pulmonic valve stenosis, postnatal growth deficiency, hypotonia, and neurocognitive impairment) due to a de novo heterozygous c.389A>G, p.Tyr130Cys pathogenic variant in MAP2K1, presented with extremely elevated serum total cholesterol of 446 mg/dL, triglycerides of 239 mg/dL, HDL-cholesterol of 53 mg/dL, LDL-C of 335 mg/dL (normal range < 110 mg/dL) and serum apolipoprotein B level 219 mg/dL (normal range < 90 mg/dL). Her LDL-C was 252 mg/dL a year ago and 215 mg/dL one month prior to presentation. Reducing total dietary fat to 20–25% of total energy and saturated fat to <6% of total energy over the next 4 months lowered LDL-C to 104 mg/dL. However, her weight decreased by 0.5 kg and liberalization of fat intake again increased LDL-C to 222 mg/dL. Her father has mildly elevated LDL-C of 160 mg/dL and her mother had normal LDL-C of 80 mg/dL. Her plasma phytosterol levels were normal and she had ApoE3/E3 genotype. Targeted genetic testing of the patient and parents showed a benign heterozygous LDL receptor (LDLR) variant c.2242G>A; p.Asp748Asn, (Minor allele frequency 0.00008) in the patient and her father. Whole exome sequencing of the patient and both parents showed no known disease-causing variants in LDLR, APOB, PCSK9, LDLRAP1, APOE, STAP1, LIPA, ABCG5, ABCG8 and other known hyperlipidemia-related genes. There are no previous reports of hypercholesterolemia in patients with CFC3. MAP2K1 stimulates various MAP kinases upon wide variety of extra- and intracellular signal and is involved in cell proliferation, differentiation, transcription regulation and development. Previous studies of the relationship between p42/44MAPK activation and LDLR expression in human hepatoma HepG2-derived cell line showed that that activation of the Raf-1/MEK/p42/44MAPK cascade induces LDLR expression and modulation of the Raf-1 kinase signal strength can determine LDLR expression levels. Thus, extent of MAPK activation can alter signaling of LDLR, resulting in hypercholesterolemia. Conclusion: Our case report suggests that MAP2K1 may play a significant role in LDLR signaling, and some MAP2K1 variants may be associated with diet-responsive hypercholesterolemia. Larger studies are required to assess dietary response to LDL-C in subjects with MAP2K1 variants.