Higher Baseline LDL-C Research Articles

Effect of biologic agents and inflammation on lipid levels and cardiovascular risk in rheumatoid arthritis patients

BackgroundCardiovascular disease (CVD) is the main cause of mortality in Rheumatoid Arthritis (RA). ObjectiveTo investigate the effect of biologic disease modifying anti-rheumatic drugs (bDMARDs) on lipids and CVD risk and evaluate associations with changes in systemic inflammation. MethodsPatients with RA initiating a bDMARD were evaluated at baseline, 3 and 6 months later. Longitudinal mixed effects models examined the association of individual biologics with changes in lipid levelsm Reynolds Risk Score (RRS) and Framingham risk score. Mediation by CRP, clinical disease activity index (CDAI) or swollen joint count on lipid changes were modeled using structural equation models. The correlation between CRP changes and LDL changes was estimated. Changes of LDL-C at 6 months among patients with low baseline LDL-C (<90 mg/dl) vs higher baseline LDL-C(90–130, and >130 mg/dl) were compared. The association between LDL-C changes across baseline LDL-C groups and disease activity improvement was evaluated. Results1698 bDMARD initiations were analyzed. Patients initiating tocilizumab had a significant increase in lipid levels but RRS at 3 and 6 months was similar across all biologics. Framingham risk score increased for patients treated with tocilizumab. Mediator analyses were statistically significant for the effects of CRP on lipid levels. Increases in LDL-C from baseline were independent of clinical response. An association of changes from baseline CRP and LDL-C were observed across all of the bDMARDs studied. ConclusionModerate increases in lipid levels on bDMARD treatment were not associated with an increased CVD risk by RRS regardless of the bDMARD initiated. Changes in CRP were significantly associated with changes in lipids in a mediator analysis.

Impact of conducting a genetic study on the management of familial hypercholesterolemia

Clinically diagnosed FH may require a genetic test (GT) to confirm diagnosis. GT availability/accessibility is resource-dependent and usually restricted to specialized clinics. While GT has a diagnostic value, it has not yet defined its impact on long-term management and prognosis of FH. The aim was to identify the clinical characteristics associated with the request for a GT in suspected heFH. Retrospective study including adult patients with clinically suspected to be FH. Positive GT (GT+) was defined as having a pathogenic/likely pathogenic variant. Patients were stratified in those conducted/not conducted a genetic study and within the former, those who had/did not have a GT+. From 4854 patients included, 3090 were performed a GT (GT+: 2113). Median follow-up: 6.2 years. A younger age, FH-related physical signs, premature coronary disease, higher LDLc and lower BMI and triglycerides, associated higher odds of being conducted a genetic study. These patients had higher baseline LDLc (252mg/dL vs. 211mg/dL among clinically diagnosed patients) and experienced larger reductions over the follow-up (157.7mg/dL, vs. 113.5mg/dL, respectively). A similar pattern was observed among patients with GT+ (vs. negative GT). LDLc target attainment was low but increased to 66-95% when a triple combination with statin/ezetimibe/PCSK9-inhibitor was used. Cardiovascular events occurred in 3.2% and 3.1% of patients who conducted/not conducted a genetic study. Patients conducted a genetic analysis and those with GT+ tended to present the events earlier. genetic study, vs. having a clinical-only diagnosis, impacts the management of FH. Cardiovascular prognosis was similar in both groups, perhaps as a result of the more intensive management of patients with a genetic study.

Novel Insights into the Management of Patients with Very High Cardiovascular Risk Eligible for PCSK9 Inhibitor Treatment: Baseline Findings from the PERI-DYS Study

AimThe PERI-DYS study aims to characterize two groups of patients with dyslipidaemia at very high CV risk: PCSK9i receivers and patients qualifying for but not receiving PCSK9i.MethodsThis is an observational study by office-based and clinic-based physicians, mainly cardiologists and other internists in Germany, with data extracted from patient charts. ClinicalTrials.gov identifier NCT03110432.ResultsA total of 1659 patients were enrolled across 70 sites. The majority of patients (91.0%) were reported as having mixed dyslipidaemia or non-familial or heterozygous familial hypercholesterolemia. At enrolment, 794 (47.9%) of patients were PCSK9i receivers (of these 65.9% ongoing, and 34.1% newly treated within 30 days before their baseline visit). Among PCSK9i receivers, the majority had evolocumab 140 mg (n = 632, 38.1% of total). PCSK9i receivers compared to non-receivers were about 2 years younger and had a lower proportion of males. In terms of comorbidities, they had (statistically significantly) more often CAD, and less often PAD, diabetes mellitus, arterial hypertension and chronic renal disease. The calculated untreated median LDL-C was 187 mg/dl (IQR 127; 270) in ongoing PCSK9i receivers, 212 mg/dl (IQR 132; 277) in newly treated PCSK9i receivers, and 179 mg/dl (IQR 129; 257) in non-receivers. Physician-reported statin intolerance was much more common in the two PCSK9i receiver groups as compared to non-receivers (67.3% versus 15.3%). Consequently, patients in the PCSK9i groups received fewer concomitant statins. Mean total cholesterol (143 vs. 172 mg/dl) and LDL-C (69 vs. 99 mg/dl) were considerably lower in ongoing PCSK9i receivers compared to non-receivers.ConclusionsPCSK9i receivers are characterized by higher baseline LDL-C and a higher portion of statin intolerance compared to those qualified for but not-receiving PCSK9i treatment. On-treatment, LDL-C was lower in PCSK9i receivers. Ongoing follow-up will determine the prognostic importance of these findings.

Optimized Treatment of Refractory Hypercholesterolemia in Patients With Atherosclerotic Cardiovascular Disease or Heterozygous Familial Hypercholesterolemia With Alirocumab (OPTIMIZE)

BackgroundLow-density lipoprotein cholesterol (LDL-C) is a major risk factor for atherosclerotic cardiovascular disease (ASCVD). In confirmatory trials, proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab substantially lowered LDL-C and reduced cardiovascular morbidity and mortality. However, the routine clinical use of alirocumab in Switzerland has not yet been studied.MethodsIn this prospective nation-wide cohort study, we aimed to investigate the patient profile and routine clinical efficacy and safety of alirocumab in 207 patients with ASCVD or heterozygous familial hypercholesterolemia and increased LDL-C despite maximally tolerated statin therapy. LDL-C was measured at baseline and after 3-months follow-up.ResultsOverall, mean age was 63 ± 11 years, 138 (67%) were men, and 168 (81%) had statin intolerance (SI). Patients with SI had a higher baseline LDL-C (4.3 ± 1.4 vs. 3.3 ± 1.4 mmol/l; p < 0.001) and less frequently ASCVD (71% vs. 95%; p = 0.002). After 3 months of treatment with alirocumab, LDL-C was reduced from 4.1 ± 1.5 to 2.0 ± 1.2 mmol/l (50.5%; p < 0.001). Mean absolute and relative reductions in LDL-C were similar in patients with vs. without SI (2.2 ± 1.2 vs. 1.9 ± 1.3 mmol/l; p = 0.24 and 49.0 vs. 56.6%; p = 0.11, respectively). In total, adverse events were recorded in 25 (12%) patients, with no new safety signals.ConclusionsIn routine clinical practice, alirocumab was predominantly used in patients with SI suggesting that the great majority of patients with insufficient LDL-C control who would be candidates for alirocumab are not receiving this therapeutic option in Switzerland. LDL-C lowering was potent and similar in patients with and without SI, replicating the favorable efficacy-safety profile of alirocumab from randomized trials.

Familial Hypercholesterolemia: Real-World Data of 1236 Patients Attending a Czech Lipid Clinic. A Retrospective Analysis of Experience in More than 50 years. Part II. Clinical Characteristics

Introduction: Patients with familial hypercholesterolemia (FH) are at increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Aim of study: To perform a retrospective analysis of data to assess the effects of individual lipoproteins and other risk factors (RFs) on the development of ASCVD and to compare these parameters in individuals with versus without ASCVD. Patients and methods: Our study group included a total of 1,236 patients with FH (395 men and 841 women with a mean age of 44.8 ± 16.7 years) attending a single lipid clinic. The diagnosis of FH was established using the Dutch Lipid Clinic Network score (DLCN). Among the 1236 FH patients, 1,008 of them [854 suspected with LDL receptor-mediated FH and 154 with familial defective apolipoprotein B-100 (FDB)] were genetically analysed. Their RFs were assessed based on the patients’ clinical characteristics. Results: While patients with ASCVD had higher baseline LDL-C, TC, TG and Lp(a) compared with patients without this diagnosis, this ratio was just the opposite by the follow-up. The highest statistically significant differences were seen in the baseline levels of Lp(a) and, quite surprisingly, TG. Except for Lp(a), the levels of all lipid parameters declined significantly over time. While the incidence of diabetes and arterial hypertension was not higher in our group compared with the general population, these patients were at a more significant risk of ASCVD. Conclusion: Familial hypercholesterolemia is a major RF for the development of ASCVD. While our analysis confirmed the important role of LDL-C, it also corroborated a strong correlation between ASCVD and other lipid parameters, and Lp(a) and TG in particular. Familial hypercholesterolemia is not the only RF and, to reduce cardiovascular risk of their patients, physicians have to search for other potential RFs. Patients diagnosed to have FH benefit from attending a specialized lipid clinic perse.

The Effects of Endocrine Therapies on Lipid Profiles in Chinese Young Women With Early Breast Cancer.

This study aimed to evaluate and compare the effects of various endocrine therapies on lipid profiles in young patients with breast cancer. A retrospective, single-center study was performed to investigate the effects of tamoxifen (TAM), tamoxifen plus ovarian function suppression (TAM+OFS), and aromatase inhibitors plus ovarian function suppression (AI+OFS) on lipid profiles during the 60 months of endocrine therapy in hormone receptor-positive patients aged <40 with early breast cancer. The primary endpoint was the cumulative incidence of lipid events, and the secondary endpoints were the changes in lipid profiles. A total of 230 young patients were included with the mean age of 35.7 years old. The patients in TAM group had significantly lower incidence of 5-year lipid events than those in TAM+OFS group (7.4% versus 21.3%; P=0.016) and AI+OFS group (7.4% versus 21.6%; P=0.009). The incidence of fatty liver was significantly higher in TAM+OFS group than TAM group (52.5%versus 30.9%; P=0.043). Lipid events were associated with younger age (odds ratio (OR)=0.865, 95% confidence interval (CI): 0.780-0960; P=0.006), higher baseline LDL-C (OR=14.959, 95% CI: 4.379-51.105; P<0.001), and use of OFS (OR=3.557, 95% CI: 1.151-10.989; P=0.027). Therefore, application of OFS, with younger age and higher baseline LDL-C, may increase the incidence of lipid events in premenopausal breast cancer. More care should be taken for lipid profiles during the endocrine therapy for young breast cancer patients.

Lipid biomarkers and Cancer risk - a population-based prospective cohort study in Taiwan

BackgroundBlood lipids are essential components for cellular growth. An inverse association between serum lipid levels and risk of cancer has led to a controversy among previous studies. The aim of this prospective cohort study was to investigate the association between blood lipids change and risk of cancer incidence.MethodsA cohort of 4130 Taiwanese adults from the Taiwanese Survey on the Prevalence of Hypertension, Hyperglycemia, and Hyperlipidemia database underwent repeated examinations in 2002 and 2007. Six groups were established based on the combined baseline (lower/higher) and interval change (decreasing/stable/increasing) in plasma lipid levels. Multivariable Cox proportional hazard model was used to investigate the relationship between lipids change and all-cause cancer incidence.ResultsTwo hundred and forty cancer events developed over a median follow-up of 13.4 years. Comparing these with individuals with decreasing lower-baseline lipid levels, cancer risk reduction was demonstrated in those with increasing lower-baseline total cholesterol (adjusted hazard ratio [aHR], 0.48; 95% confidence interval [CI], 0.27 to 0.85), low-density lipoprotein cholesterol (LDL-C; aHR, 0.56; 95% CI, 0.35 to 0.92), and non–high-density lipoprotein cholesterol (non-HDL-C) (aHR, 0.54; 95% CI, 0.31 to 0.92) levels. A decreased risk for cancer incidence also presented in participants with stable lower-baseline, decreasing and increasing higher-baseline LDL-C levels, and with decreasing and stable higher-baseline non-HDL-C levels.ConclusionsThe interval decline in lower-baseline total cholesterol, LDL-C, and non-HDL-C levels was linked to a higher risk for all-cause cancer incidence. More attention to a potential cancer risk may be warranted for an unexplained fall in serum lipids.

Heterogeneous long-term trajectories of glycaemic control in type 1 diabetes.

We aimed to identify long-term HbA1c trajectories and examine associated characteristics in an observational, childhood-onset (<17years) type 1 diabetes cohort. Data are from the Epidemiology of Diabetes Complications study, comprising 405 participants with ≥2 of seven possible HbA1c measurements over follow-up (1988-2013) and available DNA (baseline mean diabetes duration 21years, 53% men). HbA1c trajectories were estimated using latent class growth models. Baseline and change in participant characteristics were compared across trajectories. Five HbA1c trajectories were identified: low (51%), intermediate stable (22%), improved (19%), high stable (6%), and worsened (2%; not included in analyses). Age, diabetes duration, diabetes onset age, and sex did not differ across trajectories. Characteristics did not differ significantly between intermediate stable and low trajectories at baseline, though albumin excretion rate (AER, p=0.0002) and estimated glomerular filtration rate (eGFR, p=0.001) worsened slightly more in intermediate stable over time. Improved and high stable trajectories had higher baseline LDL-c (p=0.002 and 0.003, respectively). Improved trajectory increased median self-monitoring of blood glucose from <1 to 3.5 times/day (p<0.0001) and had larger LDL-c improvement (p=0.004) but greater worsening of AER (p<0.0001) and eGFR (p<0.0001) than low. The A allele of rs12970134 (near MC4R) was associated with improved (p=0.0003) or high stable (p=0.001) HbA1c trajectory, both patterns with high baseline HbA1c. Long-term HbA1c trajectories were primarily associated with modifiable factors in this type 1 diabetes cohort. The intermediate stable pattern had a risk factor profile that suggests some protection against adverse metabolic effects of chronic hyperglycaemia, warranting further study.

LDL-cholesterol decrease by anti-PCSK9 monoclonal antibodies: systematic review, meta-analysis and meta-regression of randomized controlled trials

Abstract Background PCSK9 antibodies are novel potent and expansive lipid lowering agents that demonstrated clinical benefit in high risk patients. We hypothesized that optimization of dose and administration schedule, ideally adapted to the target population, could reduce costs while maintaining the clinical benefit. Objective To explore the relationship between LDL-Cholesterol (LDL-C) decrease by anti-PCSK9 monoclonal antibodies and several covariates such as drug dose, administration schedule, baseline LDL-C, population and statins. Methods We performed systematic review, meta-analysis and meta-regression of randomized controlled trials that compared alirocumab or evolocumab to placebo or no treatment and reported LDL-C decrease, with a minimum follow-up of 12 weeks and with a sample size of 30 patients or more. Electronic searches of MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov from inception to March 2019. We evaluated the quality of included studies and extracted aggregate data. We used random effect models and multivariate multilevel meta-regression to explore factors influencing LDL-C decrease. All analyses were performed with R. Results From 1479 references identified and screened on title/abstract, the full texts of 72 articles were screened. We included 32 studies (31 references.) Anti-PCSK9 mAbs decreased LDL-C by 53%, 95% CI (−56% to −50%), with no significant difference between the two drugs (p=0.07). In univariate meta-regressions, higher baseline LDL-C level, monthly administration, higher percentage of patients with high-dose statins were associated with a lower LDL-C decrease (p&amp;lt;0.0001, p=0.02 and p=0.006 respectively). Drug dose and population did not influence LDL-C decrease in univariate analysis, but with a significant statistical interaction between drug dose and administration schedule (p=0.03). In multivariate meta-regression, LDL-C decrease remained significantly and negatively influenced by baseline LDL-C level (p&amp;lt;0.0001) and the percentage of patients with high-dose statins (p=0.0009), and was significantly and positively influenced by drug dose (p&amp;lt;0.0001). Conclusion Alirocumab and evolocumab showed substantial LDL-C reductions in clinical trials, without significant differences in their biological efficacies. A higher baseline LDL-C, higher intensity of statin co-treatment and a lower dose seemed to negatively influence LDL-C decrease. Funding Acknowledgement Type of funding source: None

Higher responsiveness to rosuvastatin in polygenic versus monogenic hypercholesterolaemia: a propensity score analysis

Abstract Background The underlying monogenic defect in familial hypercholesterolemia (FH) can be detected in ∼40% of cases. The majority of mutation-negative patients have a polygenic cause of high LDL-cholesterol (LDL-C) due to having inherited a greater than average number of common LDL-C raising single nucleotide polymorphisms (SNPs). Purpose We sought to investigate, whether the monogenic or polygenic defect in FH is associated with the response to rosuvastatin. Methods Individuals with a clinical diagnosis of FH were tested for mutations in LDLR and APOB genes. A previously established LDL-C-specific polygenic risk score (PRS) was used to examine the possibility of polygenic hypercholesterolemia in mutation negative patients. The propensity score analysis was performed to evaluate the variables associated with the response to rosuvastatin. The type of hypercholesterolemia (polygenic or monogenic) and following variables: age, gender, LDL-baseline, statin intolerance, ezetimibe use, rosuvastatin dose, diabetes and cardiovascular disease (CVD), were examined to minimize the bias of this observational study. Results LDLR/APOB mutation was found in 47 (42%) patients, whereas polygenic hypercholesterolemia was diagnosed in 65 (58%) of patients. Mean age was comparable in both groups (54±13 vs 51±13, p=0.134). CVD was diagnosed in ≈26% of individuals in both cohorts (p=0.343). There was no difference in the distribution of CV risk factors, such as arterial hypertension, smoking, diabetes, body mass index and in rate of statin intolerance. Monogenic subjects had higher baseline LDL-C compared to polygenic (Table 1). Adjusted model showed a lower percentage of change in LDL-C after rosuvastatin treatment in monogenic vs. polygenic subjects (46% vs 55%, p&amp;lt;0.001) (Figure 1). The probability of achieving LDL-C targets in monogenic FH was lower than in polygenic subjects (0.075 vs. 0.245, p=0.004). Polygenic patients were more likely to achieve LDL-C goals, compared to mutation-positive patients (OR 3.28; 95% CI:1.23–8.72). Conclusion Our findings indicate an essentially higher responsiveness to rosuvastatin in patients with a polygenic cause, as compared to those carrying monogenic mutations. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): 1. Polish Ministry of Science and Higher Education European Regional Development Fund under the Programme Innovative Economy 2007–2013 (POIG.01.01.02-22-079/09). 2. British Heart Foundation (PG 08/008). 3. The National Institute for Health Research, University College London Hospitals, Biomedical Research Centre. 4. The Foundation Leducq Transatlantic Networks of Excellence Program grant (no. 14 CVD03)

4115Effect of alirocumab on recurrent cardiovascular events after acute coronary syndrome, according to the intensity of background statin treatment

Abstract Background Statins are a cornerstone of therapy for coronary heart disease. We describe the effects of alirocumab (ALI) in patients (pts) with recent acute coronary syndrome (ACS) and dyslipidaemia per category of statin use. Methods ODYSSEY OUTCOMES compared ALI with placebo (PBO) in 18,924 pts with recent ACS and dyslipidaemia despite high-intensity/maximum tolerated statin (atorvastatin 40–80 mg/d or rosuvastatin 20–40 mg/d). Lower doses could be used if there were symptoms, laboratory abnormalities, or contraindications with higher doses. In cases of documented intolerance to ≥2 statins, pts could qualify on no statin treatment. Pts were randomized to ALI (75 mg SC Q2W, with possible uptitration to 150 mg Q2W) or PBO. Median follow-up was 2.8 years. Primary endpoint was major adverse cardiovascular events (MACE: CHD death, non-fatal MI, ischaemic stroke, or unstable angina requiring hospitalization). Pts were categorized by statin therapy at baseline: high intensity (88.8%), low or moderate intensity (8.7%), or no statin use (2.4%). In each category we determined the relative (hazard ratio [HR]) and absolute risk reductions (ARR) for MACE with ALI. Results Overall, ALI reduced MACE (HR 0.85, 95% CI 0.78–0.93; P&lt;0.001). HRs were consistent across statin categories (Table). Baseline LDL-C increased across high-intensity, low/moderate-intensity, and no statin categories. Correspondingly, there was a gradient of the risk of MACE in the PBO group across these categories (10.8%, 10.7%, and 26%). With ALI treatment, the mean reduction in LDL-C from baseline to Month 4 increased across the 3 statin categories and correspondingly the ARRs for MACE were 1.3%, 3.2%, and 8.0% (P interaction &lt;.001). LDL-C values and MACE events All patients High-intensity statin Low-/moderate-intensity statin No statin Interaction P-value N=18,924 (100%) N=16,811 (88.8%) N=1653 (8.7%) N=460 (2.4%) (treatment x statin category) PBO (N=9462) ALI (N=9462) PBO (N=8431) ALI (N=8380) PBO (N=804) ALI (N=849) PBO (N=227) ALI (N=233) LDL-C at baseline, mmol/L, mean (SE)* 2.39 (0.01) 2.39 (0.01) 2.35 (0.01) 2.35 (0.01) 2.41 (0.03) 2.43 (0.03) 3.76 (0.08) 3.82 (0.08) Change in LDL-C from baseline to Month 4, mmol/L, mean (SE) 0.03 (0.01) −1.4 (0.01) 0.03 (0.01) −1.37 (0.01) 0.01 (0.02) −1.47 (0.02) −0.004 (0.06) −2.27 (0.06) &lt;0.001 MACE, n (%)* 1052 (11.1) 903 (9.5) 907 (10.8) 797 (9.5) 86 (10.7) 64 (7.5) 59 (26.0) 42 (18.0) HR (95% CI) 0.85 (0.78−0.93) 0.88 (0.80−0.96) 0.69 (0.50−0.95) 0.65 (0.43−0.96) 0.14 ARR (%) (95% CI) 1.6 (0.7−2.4) 1.3 (0.3−2.2) 3.2 (0.4−5.9) 8.0 (0.4−15.5) &lt;0.001 *P&lt;0.001 for difference among statin categories. Conclusions In ODYSSEY OUTCOMES, patients unable to receive high-intensity statin treatment showed greater ARRs with ALI, consistent with higher baseline LDL-C concentration and greater absolute LDL-C reduction. Patients unable to receive high-intensity statin treatment are an important group to consider for treatment with ALI after ACS. Acknowledgement/Funding Funded by Sanofi and Regeneron Pharmaceuticals

Abstract P336: Predictors of High Intensity Statin Initiation for Primary Prevention in Veterans With Familial Hypercholesterolemia Phenotype

Introduction: Familial hypercholesterolemia (FH) phenotype, defined in part by LDL-Cholesterol (LDL-C) ≥190mg/dL, is a strong risk factor for cardiovascular disease (CVD). The 2013 ACC/AHA cholesterol guidelines recommend high intensity statins for primary prevention irrespective of global risk assessment. We sought to determine predictors of high intensity statin initiation in patients with FH phenotype in the Veteran’s Health Administration (VHA). Methods: Inclusion criteria consisted of VHA care (2002-2014), age ≥21 years, absence of prevalent CVD, baseline maximum LDL-C ≥190 mg/dL, no prior statin use, and statin initiation within 90 days of outpatient LDL-C measurement. Baseline characteristics were obtained from the electronic health record. We defined baseline LDL-C using quartile cutoffs. High intensity statin definitions were based on the 2013 cholesterol guidelines plus high dose simvastatin when it was available. Multivariable logistic regression models were constructed to determine the odds of high intensity statin initiation versus low or moderate intensity. Results: A total of 88,878 Veterans (age=53.7±11.6, men=91%; white race=74%, LDL-C mean=209.5±23.9, Q1=195, median=202, Q3=215) met inclusion criteria. High intensity statin was initiated in 29,533 (33%) of patients. Comorbidities included smoking history (80%), hypertension (39%), diabetes (10%), and chronic kidney disease (3%). Significant predictors were age &gt;40 years, male sex, diabetes, hypertension, black race, smoking, higher baseline LDL-C quartile, and recent calendar year. Veterans with cancer and white race had lower odds of statin initiation. Conclusion: Nearly 1/3 of the Veteran population with the FH phenotype was started on high intensity statins. They were more likely to be older, black, smokers, hypertensive, diabetic, and have a higher baseline LDL-C. The odds of high intensity statin initiation increased in recent years, which may partly reflect practice changes concordant with recent cholesterol guidelines.

More Intensive LDL-C Lowering Reduces Major Vascular Events Beyond Current Recommendations: Systematic Review and Meta-Analysis

Aims: To determine the relationship between more intensive low-density lipoprotein (LDL-C) lowering therapy and relative risk of major vascular events (MVEs) across different LDL-C levels. Methods: Randomised trials of statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors that reported rates of MVEs were included. Random-effects and network meta-analyses evaluated associations between baseline LDL-C, achieved LDL-C, degree of LDL-C lowering and 10-year risk of cardiovascular (CVD) death with the relative risk (RR) of MVEs. Results: Fifty studies, totalling 316,605 patients with mean follow-up 3.6 ± 1.6 years were included. Although more intensive LDL-C lowering was associated with greater reductions in MVEs in patients with higher baseline LDL-C (p < 0.001), there was benefit in further lowering LDL-C amongst subgroups of patients with all baseline LDL-C <2.07 mmol/l (RR, 0.89; 95% CI, 0.82–0.96). In a network meta-analysis, patients with achieved LDL-C <1.50 mmol/l were most likely free from MVEs (surface under the cumulative ranking curve, 0.98), followed by 1.50–1.79, 1.80–2.59, 2.60–3.39, 3.40–4.09 and ≥4.10 mmol/l respectively. In meta-regression of primary prevention trials, LDL-C lowering therapy provided greater RR reductions in MVEs in populations with lower 10-year risk of CVD death (p = 0.030). Patients aged >75 years who received intensive LDL-C lowering therapy had significantly less MVEs. There was significantly more adverse drug reactions in the intensive LDL-C lowering arm (RR, 1.18; 95% CI, 1.10–1.27), but no significant difference in serious adverse effects. Conclusions: This meta-analysis provides new evidence that further lowering LDL-C is associated with greater reductions in MVEs beyond current recommendations.

Type of LDLR mutation and the pharmacogenetics of familial hypercholesterolemia treatment.

Familial hypercholesterolemia (FH) is an autosomal dominant disease mainly caused by mutations in the low-density lipoprotein receptor (LDLR) gene. FH patients present a wide variability regarding response to drugs and they are usually undertreated. Here, we review studies that evaluated the association between the type of LDLR mutation and the response to lipid-lowering therapy. The main findings were that patients with a null LDLR mutation had: higher baseline LDL-C, higher LDL-C after drug therapy, lower proportion of patients within the LDL-C target value and higher frequencies of CVD. Thus, we conclude that FH patients harboring a null mutation have a trend to an increased risk, even if diagnosis is early established and lipid-lowering treatment instituted. It is suggested that these individuals may benefit from the use of newly approved lipid-lowering agents.

Abstract P334: Gender Disparities in Cholesterol Control Among Patients with Diabetes

Background: It has been reported that women often receive less aggressive primary and secondary prevention for cardiovascular disease. Diabetes decreases the cardiovascular protection that women experience, and is considered a coronary heart disease equivalent. National diabetes guidelines thus recommend similar LDL-cholesterol (LDL-c), blood pressure, and hemoglobin A1c (HbA1c) goals for men and women. Methods: We conducted a retrospective, longitudinal study in a cohort of 6,573 patients with incident type 2 diabetes at Kaiser Permanente Colorado (2000-2008). We examined LDL-c, blood pressure, and HbA1c at the time of diagnosis (baseline) and after one year follow-up. We identified baseline coronary artery disease (CAD) via diagnosis codes. Results: Women and men had similar age and race distributions. Women were more likely to be never smokers and had higher BMI (34.0 vs. 31.9 kg/m 2 ), while men were more likely to be former smokers and have CAD (20.9% vs. 9.8%). Men had slightly higher baseline HbA1c, but the difference disappeared at follow-up. No gender differences were seen for blood pressure. Women had higher baseline LDL-c ( Table , p-value &lt;0.0001), with 79% of the initial difference persisting after one year (p-value &lt;0.0001). Women were less likely to have LDL-c &lt; 100 mg/dL at one year follow-up (50.7% vs. 57.2%). In both genders, LDL-c was lower among individuals with CAD than those without CAD. Baseline CAD accounted for 35% of the follow-up LDL-c gender difference. At follow-up, women were slightly less likely to be taking a statin (40% vs. 38%). Conclusions: Even with population-based case-management programs aimed at cholesterol management, fewer women than men met the recommended LDL-c goal of &lt; 100 mg/dL one year after diabetes diagnosis. Some of the difference can be attributed to differences in CAD prevalence. These findings suggest that diabetes is often not treated as a CAD equivalent in clinical care, and greater emphasis should be placed on primary CAD prevention among both men and women with diabetes. Table LDL-c (mg/dL) by gender and baseline CAD status Women Men Mean difference Mean (SD) Median Mean (SD) Median Baseline No CAD 121.5 (37.0) 119.0 117.4 (36.4) 115.0 4.1 CAD 94.0 (35.0) 88.0 89.1 (29.1) 86.0 4.9 Total 118.8 (37.7) 116.0 111.5 (36.8) 109.0 7.3 Follow-up No CAD 106.0 (33.7) 102.0 102.2 (31.1) 100.0 3.8 CAD 86.5 (32.8) 82.0 82.9 (26.5) 79.0 3.6 Total 104.0 (34.1) 100.0 98.2 (31.2) 95.0 5.8

Abstract 9649: Lipid-modifying Effects of Anacetrapib in Patients with Lower versus Higher Baseline Levels Of HDL-C, LDL-C, And TG: Pre-Specified Subgroup Analyses of the DEFINE (Determining the Efficacy and Tolerability of CETP INhibition with AnacEtrapib) Trial

Purpose : Low HDL-C is a risk factor for coronary heart disease which partly accounts for residual risk despite statin therapy. After 24 weeks of treatment, the addition of anacetrapib (ANA), a cholesteryl ester transfer protein (CETP) inhibitor to statin therapy increased HDL-C by 138% and reduced LDL-C by 40% in a 1623 patient safety and lipid efficacy Phase III trial (DEFINE). Sub-group analyses were performed to determine the degree to which ANA raises HDL-C and lowers LDL-C in patients with low baseline HDL-C and in patients with diabetes and other subgroups. Methods: Percent placebo-corrected HDL-C increases and LDL-C decreases from baseline after 24 weeks of ANA, 100 mg/day, were compared among patients according to baseline HDL-C, LDL-C, and TG levels above or below the median and in patients with diabetes. Results: Median baseline HDL-C, LDL-C, and TG were 40 mg/dL, 81 mg/dL, and 128 mg/dL, respectively. ANA produced robust increases in HDL-C in patients with baseline HDL-C below (152%) and above (127%) the median. In the lowest baseline quartile of HDL-C (15 to 34 mg/dL) levels also increased to a mean on-treatment HDL-C of 85 mg/dL. The percent increase in HDL-C was similar in patients with lower vs. higher baseline TG levels. ANA increased HDL-C similarly in diabetics compared to non-diabetics (130% vs 150%) with a mean on-treatment HDL-C of 100 vs. 102 respectively. The percent reduction in LDL-C with ANA was generally similar in patients with lower vs higher baseline LDL-C, HDL-C or TG levels and in patients with or without diabetes. Conclusion: ANA robustly increased HDL-C in all patients especially those with low HDL-C. Reductions in LDL-C with ANA were independent of baseline LDL-C, HDL-C, or TG levels. The clinical impact of these lipid-modifying effects of ANA in these sub-groups will be assessed in REVEAL-HPS3/TIMI55, a 30,000 patient clinical outcomes trial.

LDL-Cholesterin in der Sekundärprävention: Zielwert-Erreichung unter Lipidsenkern in Praxis und Spital in Österreich (ZIEL)

A hospital-based screening project (HSP) in Austria found 47% of high-risk patients (LDL-C < 100 mg/dl) and 24% of very high-risk patients (LDL-C < 70 mg/dl) at goal. Separate data for the sexes were not reported. We analyze whether LDL-C goal attainment in patients with manifest atherosclerosis and/or diabetes on stable lipid-lowering treatment differs between private practice and hospital and between men and women. From September to November 2007, 49 Austrian centers (36 private practice, 13 hospitals) documented vascular morbidity, lipid levels, and lipid lowering treatment in patients with high risk (atherosclerosis or diabetes, n = 978) and very high risk (coronary heart disease and diabetes or acute coronary syndrome, n = 322). 75% and 25% of the 1300 patients were high and very high risk, respectively. LDL-C goals of < 100 and < 70 mg/dl, respectively, were attained by 45.4% and 26.4% of patients (p < 0.001). A similar percentage of patients with very high risk was found in men and women (26.4% vs. 22.9%, NS) and goal attainment was not influenced by sex (high risk: 47.2% (m) vs. 43.8% (w), NS and very high risk: 29.1% (m) vs. 22.4% (w), NS). In patients with high risk, 41.6% treated in private practice vs. 57.9% treated in the hospital were at goal (p < 0.001). In patients with very high risk, 15.9% treated in private practice vs. 45.2% treated in the hospital were at goal (p < 0.001). Lower goal-attainment in private practice occurred despite significantly more intensive lipid intervention and probably reflects higher baseline LDL-C. LDL-C > 100 mg/dl leads to a more aggressive lipid lowering in approx. 70% of patients, irrespective of whether they are treated in private practice or in the hospital. LDL-C between 70 and 100 mg/dl, however, leads to a more aggressive lipid lowering in < 5% of patients, irrespective of whether they are high or very high risk. As observed in EUROASPIRE III for other European countries, there is substantial potential for improvement in lipid control in Austrian cardiovascular high-risk patients, irrespective of whether they are treated in private practice or in the hospital.

Effects of Fish and Walnuts on LDL‐C and Triglycerides: Influence of BMI and Baseline Lipids

Consumption of n3 fatty acids has been shown to produce cardiovascular benefits, but in some published studies, fish oil supplementation resulted in a paradoxical increase in LDL-cholesterol (LDL-C). We used mixed linear models to investigate how BMI and baseline serum lipids influence the effects of 2 sources of n3 fatty acids, fish and walnuts, on serum LDL-C and triglyceride (TAG) levels in a randomized crossover metabolic trial. 25 subjects received 3 eucaloric diets for 4 wk each in random order. The diets conformed to the Dietary Guidelines for Americans and differed primarily in source and type of polyunsaturated fat: Walnut (42.5 g, 6 d/wk), Fish (113 g salmon, 2 d/wk), and Control (no fish or nuts). Compared with Control, we observed an LDL-C-increasing effect of Fish that was magnified in subjects with higher baseline LDL-C (mean change ± SE: 3.2 ± 1.9 mg/dL for a baseline LDL-C of 110 mg/dL vs 8.1 ± 2.0 for a baseline LDL-C of 170; P value for diet-baseline interaction 0.04). In contrast, we observed an LDL-C-lowering effect of Walnut that was uninfluenced by subjects’ baseline LDL-C level. After controlling for baseline TAG, we observed a TAG-lowering effect of Fish that attenuated with increasing BMI, reversed, and became a TAG-increasing effect among the 3 subjects with the highest BMI (>30kg/m2) (−23.2 ± 5.5 mg/dL at BMI of 22, −0.6 ± 6.4 at BMI of 27.5, 25.4 ± 17.1 at BMI of 33; P value for diet-BMI interaction 0.02). We observed no effect on TAG for Walnut. In summary, high baseline LDL-C magnified an LDL-C-increasing effect of Fish, but did not influence an LDL-C-lowering effect of Walnut; and high BMI attenuated a TAG-lowering effect of Fish. Funding: California Walnut Commission