Lipoprotein Cholesterol Response Research Articles

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.

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.

Individualized dosing of evinacumab is predicted to yield reductions in drug expenses

Evinacumab is a first-in-class inhibitor of angiopoietin-like protein 3 (ANGPTL3) for treatment of the rare disease homozygous familial hypercholesterolemia (HoFH). With projected drug costs of $450,000 per person per year, the question rises if cost-efficacy of evinacumab can be further improved. To develop an individualized dosing regimen te reduce drug expenses. Using the clinical and pharmacological data as provided by the license holder, we developed an alternative dosing regimen in silico based on the principles of reduction of wastage by dosing based on weight bands rather than a linear milligram per kilogram body weight (mg/kg) dosing regimen, as well as dose individualization guided by low density lipoprotein cholesterol (LDL-C) response. We found that the average quantity of drug used for a dose could be reduced by 34% without predicted loss in efficacy (LDL-C reduction 24 weeks after treatment initiation). Dose reductions without compromising efficacy seem feasible. We call for implementation and prospective evaluation of this strategy to reduce treatment costs of HoFH.

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.

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.

A Head-to-Head Comparison of a Free Fatty Acid Formulation of Omega-3 Pentaenoic Acids Versus Icosapent Ethyl in Adults With Hypertriglyceridemia: The ENHANCE-IT Study.

BackgroundMAT9001 is an omega‐3 free fatty acid (FFA) formulation containing mainly eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA). Compared with icosapent ethyl (EPA‐ethyl esters [EE]), EPA+DPA‐FFA previously showed enhanced triglyceride lowering and higher plasma EPA when both were administered once daily with a very–low fat diet. This trial compared pharmacodynamic responses and plasma omega‐3 levels following twice daily dosing, with meals, of EPA+DPA‐FFA and EPA‐EE in hypertriglyceridemic subjects consuming a Therapeutic Lifestyle Changes diet.Methods and ResultsThis open‐label, randomized, 2‐way crossover trial, with 28‐day treatment periods separated by ≥28‐day washout, was conducted at 8 US centers and included 100 subjects with fasting triglycerides 1.70 to 5.64 mmol/L (150–499 mg/dL) (median 2.31 mmol/L [204 mg/dL]; 57% women, average age 60.3 years). The primary end point was least squares geometric mean percent change from baseline plasma triglycerides. In the 94 subjects with analyzable data for both treatment periods, EPA+DPA‐FFA and EPA‐EE reduced least squares geometric mean triglycerides from baseline: 20.9% and 18.3%, respectively (P=not significant). EPA+DPA‐FFA reduced least squares geometric mean high‐sensitivity C‐reactive protein by 5.8%; EPA‐EE increased high‐sensitivity C‐reactive protein by 8.5% (P=0.034). EPA+DPA‐FFA increased least squares geometric mean plasma EPA, DPA, and total omega‐3 (EPA+docosahexaenoic acid+DPA) concentrations by 848%, 177%, and 205%, respectively, compared with corresponding changes with EPA‐EE of 692%, 140%, and 165% (all P<0.001). EPA+DPA‐FFA increased docosahexaenoic acid by 1.7%; EPA‐EE decreased docosahexaenoic acid by 3.3% (P=0.011). Lipoprotein cholesterol and apolipoprotein responses did not differ between treatments.ConclusionsEPA+DPA‐FFA raised plasma EPA, DPA, and total omega‐3 significantly more than did EPA‐EE. EPA+DPA‐FFA also reduced triglycerides and high‐sensitivity C‐reactive protein without increasing low‐density lipoprotein cholesterol.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT04177680.

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.

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

Cholesterol and Graves’ Orbitopathy (GO): ‘A new decision-making algorithm based on baseline low density lipoprotein cholesterol (LDLc) and early GO clinical response to parenteral corticosteroids’

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The impact of adjusting for baseline in pharmacogenomic genome-wide association studies of quantitative change

In pharmacogenomic studies of quantitative change, any association between genetic variants and the pretreatment (baseline) measurement can bias the estimate of effect between those variants and drug response. A putative solution is to adjust for baseline. We conducted a series of genome-wide association studies (GWASs) for low-density lipoprotein cholesterol (LDL-C) response to statin therapy in 34,874 participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort as a case study to investigate the impact of baseline adjustment on results generated from pharmacogenomic studies of quantitative change. Across phenotypes of statin-induced LDL-C change, baseline adjustment identified variants from six loci meeting genome-wide significance (SORT/CELSR2/PSRC1, LPA, SLCO1B1, APOE, APOB, and SMARCA4/LDLR). In contrast, baseline-unadjusted analyses yielded variants from three loci meeting the criteria for genome-wide significance (LPA, APOE, and SLCO1B1). A genome-wide heterogeneity test of baseline versus statin on-treatment LDL-C levels was performed as the definitive test for the true effect of genetic variants on statin-induced LDL-C change. These findings were generally consistent with the models not adjusting for baseline signifying that genome-wide significant hits generated only from baseline-adjusted analyses (SORT/CELSR2/PSRC1, APOB, SMARCA4/LDLR) were likely biased. We then comprehensively reviewed published GWASs of drug-induced quantitative change and discovered that more than half (59%) inappropriately adjusted for baseline. Altogether, we demonstrate that (1) baseline adjustment introduces bias in pharmacogenomic studies of quantitative change and (2) this erroneous methodology is highly prevalent. We conclude that it is critical to avoid this common statistical approach in future pharmacogenomic studies of quantitative change.

Plasma high-density lipoprotein cholesterol responses to endurance exercise training: A meta-analysis of randomized controlled trials

Background: Endurance exercise improves lipid and lipoproteins levels, while low high-density lipoprotein cholesterol (HDL-C) levels are risk factors for cardiovascular disease. There is a lack of evidence for the exercise characteristics in increasing lipids level, irrespective of the fact that endurance exercise increases lipids and lipoproteins level. The aim of this study was to clarify the effect and characteristics of endurance exercise in increasing HDL-C in randomized controlled trials. Methods: A search was performed for published studies between 1999 and 2014. Studies that assessed endurance exercise for ≥8 weeks and also reported the HDL-C levels pre- and post-training were included. The random effects model was used to measure the association between exercise and net change of HDL-C. Univariate regression analyses investigated the correlation of exercise characteristics. Subgroup and sensitivity analyses were performed to explore the sources of heterogeneity and the effect of potential confounders. The influence of pre-exercise lipid profile was assessed by meta-regression. Data were analyzed using Stata SE (12.0). Results: Fourteen studies with a total of 777 subjects were included. The mean HDL-C was reported to be increased and was statistically significant (weighted mean difference: 4.41 mg/dL; 95% confidence interval [CI]: 2.16–6.66 mg/dL, P < 0.001; I2 = 87.4%, P < 0.001). Univariate analysis indicated that exercise length was significantly associated with a net change of HDL-C (r = 0.56, P = 0.01). Nevertheless, there was no significant association between exercise frequency, duration, and total minutes. By subgroup analysis, exercise increased HDL-C level in Asia, Europe, and Africa and among all body mass index groups (P < 0.05). None of the studies omitted, in turn, seemed to substantially influence the effect of exercise on HDL-C by sensitivity analysis. Meta-regression showed that pre-exercise total cholesterol (TC) negatively correlated with net change of HDL-C (95% CI: 0.127, −0.018, r = −0073, P = 0.012). However, pre-exercise triglycerides, low-density lipoprotein cholesterol, and HDL-C did not correlate with a net change of HDL-C. Conclusions: Regular endurance exercise increases HDL-C level in any weight population. Exercise length of more than 8 weeks was the most important element of an exercise prescription. Among all lipid profiles, only the initial lower TC level responded better to exercise training and was more effective in increasing HDL-C level.

Determination of variability in serum low density lipoprotein cholesterol response to the replacement of dietary saturated fat with unsaturated fat, in the Reading, Imperial, Surrey Saturated fat Cholesterol Intervention (‘RISSCI’) project

Determination of variability in serum low density lipoprotein cholesterol response to the replacement of dietary saturated fat with unsaturated fat, in the Reading, Imperial, Surrey Saturated fat Cholesterol Intervention (‘RISSCI’) project - Volume 79 Issue OCE1

Incorporating healthy dietary changes in addition to an increase in fruit and vegetable intake further improves the status of cardiovascular disease risk factors: A systematic review, meta-regression, and meta-analysis of randomized controlled trials.

Fruit and vegetable (FV) intake has been associated with a reduced risk of cardiovascular disease (CVD). Beyond increasing FV intake, the incorporation of other healthy dietary changes may help to further attenuate CVD risk. A systematic review and meta-analysis was conducted to determine the effect of increasing FV intake to > 3 servings daily as well as incorporating other healthy dietary changes on classical CVD risk factors through a systematic review, meta-regression, and meta-analysis of randomized controlled trials. The following databases were searched: PubMed, CINAHL Plus with Full Text, Medline (ProQuest), and Cochrane Library. 82, 24, and 10 articles were selected for the systematic review, meta-regression, and meta-analysis, respectively. Meta-regression analysis showed a dose-dependent response between the number of FV servings consumed in each intervention group and the blood triglyceride change value. Pooled weighted mean differences from the meta-analysis suggested that increasing FV intake to > 3 servings daily contributes to significant decreases in triglyceride (-0.10 mmol/L; 95%CI, -0.18 to -0.01) and diastolic blood pressure (-1.99 mmHg; 95%CI, -2.28 to -1.70) as well as marginal decreases in total cholesterol and low-density lipoprotein cholesterol. While improvements were observed in the triglyceride and high-density lipoprotein cholesterol response following the incorporation of other healthy dietary changes, no additional cardiovascular benefits were observed when FV intake was increased from > 3 to > 5 servings daily. Increasing FV intake to > 3 servings daily improves CVD risk factors, most distinctly triglyceride, especially when complemented with other healthy dietary changes.

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

Percentage low-density lipoprotein-cholesterol response to a given statin dose is not fixed across the pre-treatment range: Real world evidence from clinical practice: Data from the ESC-EORP EUROASPIRE V Study.

Recent European guidelines recommend in patients with atherosclerotic cardiovascular disease to achieve a reduction of low-density lipoprotein-cholesterol of at least 50% if the baseline low-density lipoprotein-cholesterol level is between 1.8 and 3.5 mmol/L. Systematic reviews have associated a given statin/dose combination with a fixed percentage low-density lipoprotein-cholesterol response. Algorithms for detecting cases and estimating the prevalence of familial hypercholesterolaemia often rely on such fixed percentage reductions. We used data from 915 coronary patients participating in the EUROASPIRE V study in whom atorvastatin or rosuvastatin therapy was initiated at hospital discharge and who were still using these drugs at the same dose at a follow-up visit 6 or more months later. Pre and on-treatment low-density lipoprotein-cholesterol levels were compared across the full low-density lipoprotein-cholesterol range. The prevalence of FH was estimated using the Dutch Lipid Clinic Network criteria, once using observed pre-treatment low-density lipoprotein-cholesterol and once using imputed pre-treatment low-density lipoprotein-cholesterol by following the common strategy of applying fixed correction factors to on-treatment low-density lipoprotein-cholesterol. Inter-individual variation in the low-density lipoprotein-cholesterol response to a fixed statin and dose was considerable, with a strong inverse relation of percentage reductions to pre-treatment low-density lipoprotein-cholesterol. The percentage low-density lipoprotein-cholesterol response was markedly lower at the left end of the pre-treatment low-density lipoprotein-cholesterol range especially for levels less than 3 mmol/L. The estimated prevalence of familial hypercholesterolaemia was 2% if using observed pre-treatment low-density lipoprotein-cholesterol and 10% when using imputed low-density lipoprotein-cholesterol. The inter-individual variation in the percentage low-density lipoprotein-cholesterol response to a given dose of a statin is largely dependent on the pre-treatment level: the lower the pre-treatment low-density lipoprotein-cholesterol level the smaller the percentage low-density lipoprotein-cholesterol reduction. The use of uniform correction factors to estimate pre-treatment low-density lipoprotein-cholesterol is not justified.

A dietary exchange model to study inter-individual variation in serum low-density lipoprotein cholesterol response to dietary saturated fat intake

A dietary exchange model to study inter-individual variation in serum low-density lipoprotein cholesterol response to dietary saturated fat intake