Low-density Lipoprotein Cholesterol Variability Research Articles

Variability in Lipid Profiles During Young Adulthood and the Risk of Coronary Artery Calcium Incidence in Midlife: Insights From the CARDIA Study.

Intraindividual variability in lipid profiles is recognized as a potential predictor of cardiovascular events. However, the influence of early adulthood lipid profile variability along with mean lipid levels on future coronary artery calcium (CAC) incidence remains unclear. A total of 2395 participants (41.6% men; mean±SD age, 40.2±3.6 years) with initial CAC =0 from the CARDIA study (Coronary Artery Risk Development in Young Adults) were included. Serial lipid measurements were obtained to calculate mean levels and variability of total cholesterol, low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and triglycerides. CAC incidence was defined as CAC >0 at follow-up. During a mean follow-up of 9.0 years, 534 individuals (22.3%) exhibited CAC incidence. Higher mean levels of total cholesterol, LDL-C, and non-HDL-C were associated with a greater risk of future CAC incidence. Similarly, 1-SD increment of lipid variability, as assessed by variability independent of the mean, was associated with an increased risk of CAC incidence (LDL-C: hazard ratio, 1.139 [95% CI, 1.048-1.238]; P=0.002; non-HDL-C: hazard ratio, 1.102 [95% CI, 1.014-1.198]; P=0.022; and triglycerides: hazard ratio, 1.480 [95% CI, 1.384-1.582]; P<0.001). Combination analyses demonstrated that participants with both high lipid levels and high variability in lipid profiles (LDL-C and non-HDL-C) faced the greatest risk of CAC incidence. Specifically, elevated variability of LDL-C was associated with an additional risk of CAC incidence even in low mean levels of LDL-C (hazard ratio, 1.396 [95% CI, 1.106-1.763]; P=0.005). These findings remained robust across a series of sensitivity and subgroup analyses. Elevated variability in LDL-C and non-HDL-C during young adulthood was associated with an increased risk of CAC incidence in midlife, especially among those with high mean levels of atherogenic lipoproteins. These findings highlight the importance of maintaining consistently low levels of atherogenic lipids throughout early adulthood to reduce subclinical atherosclerosis in midlife. URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005130.

Evaluation of Single/Multiple Joint Effects of Lipid Profiles on Hypertension, Diabetes Mellitus and Obesity Accompanying Coronary Artery Disease

Objective: Although cardiovascular diseases are among the most prominent causes of mortality/morbidity in the world, they are even more important together with comorbidities. This study aims to reveal the single/multiple effects of total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and triglyceride (TG) on hypertension (HT), type 2 diabetes mellitus (T2DM) and obesity accompanying coronary artery disease (CAD). Method: The data were retrospectively achieved from the records of CAD patients undergoing coronary bypass surgery at the Department of Cardiovascular Surgery, Medical Center, University. The medical knowledge discovery process (MKDP) was applied to the data concerning HT, DM, obesity, TC, HDL-C, LDL-C, and TG variables. Different methods were used to determine the optimal cut-off points of lipid profiles. Logistic regression analysis (LRA) was examined the single/multiple effects of lipid profiles on HT, T2DM, and obesity. Results: TC, LDL-C, TG, and HDL-C lipid profiles categorized according to the cut-off points determined in the current study were analyzed with LRA models. LDL-C (&gt;117 mg/dL)*TC (&gt;191 mg/dL)*HDL-C (&gt;37.2 mg/dL) in HT and TC (&gt;190 mg/dL)*TG (&gt;197) mg/dL)*HDL-C (&gt;36.3 mg/dL) in T2DM interaction terms had a moderate effect size. LDL-C (&gt;115 mg/dL)*TG (&gt;197 mg/dL)*HDL-C (&gt;36.3 mg/dL) interaction terms in T2DM and TC (&gt;192 mg/dL)*LDL-C (&gt;117 mg/dL)*HDL-C (&gt;36.8 mg/dL), TK (&gt;192 mg/dL)*TG (&gt;193 mg/dL)*HDL-C (&gt;36.8 mg/dL) and LDL-C (&gt;117 mg/dL)*TG (&gt;193 mg/dL)*HDL-C (&gt;36.8 mg/dL) interaction terms in obesity were reported as having a high effect size. Conclusion: In conclusion, it is recommended to use the approach that analyzes the cut-off points proposed in this study for lipid profiles in predicting HT, T2DM, and obesity.

Association between visit-to-visit lipid variability and risk of ischemic heart disease: a cohort study in China.

To explore the associations between visit-to-visit lipid variability and risk of ischemic heart disease (IHD) in a population-based cohort in China. We evaluated lipid variability in 30,217 individuals from the Yinzhou Health Information System who had ≥3 recorded lipid measurements during 2010-2014. We used various indicators including standard deviation (SD), coefficient of variation (CV), variability independent of the mean (VIM), and average real variability (ARV) to quantify the variability in triglycerides, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Overall, a total of 1305 participants with IHD were identified during the follow-up of 194,421 person-years. Subjects in Q4 had a 21% elevated risk of IHD (HR = 1.21, 95% CI: 1.03-1.41) for LDL-C variability (CV) compared with the reference (Q1). The HRs for Q4 vs Q1 were 1.21 (95% CI: 1.04-1.42) for HDL-C variability, and 1.28 (95% CI: 1.10-1.50) for TC variability. However, no association was observed between triglycerides variability and risk of IHD. Higher variability in LDL-C, HDL-C, and TC levels was associated with an elevated risk of IHD, suggesting that lipid variability could be considered as an independent risk factor of IHD.

LDL Cholesterol Variability Impacts the Prognosis of Patients with Chronic Ischemic Heart Disease: A Real-World Italian Experience.

Epidemiologic, genetic, and clinical intervention studies have indisputably shown that low-density lipoprotein cholesterol (LDL-C) is causal in the development of atherosclerotic cardiovascular disease (ASCVD). However, LDL-C variability could be related to increased ASCVD risk in patients already treated with statins. The aim of the present retrospective real-life study was to assess the prognostic impact of LDL-C variability on all-cause mortality and cardiovascular hospitalizations in patients with stable cardiovascular artery disease. A total of 3398 patients were enrolled and followed up for a median of 56 months. Considering LDL-C < 70 mg/dL as the therapeutical target, during follow-up, the percentage of patients who achieved this goal raised from 20.7% to 31.9%. In total, 1988 events were recorded, of which 428 were all-cause deaths and 1560 were cardiovascular hospitalizations. At the last medical examination, each increase in LDL-C levels of 20 mg/dL corresponded to a 6% raise in the risk of any event (HR 1.06; 95%CI, 1.03 to 1.09). In conclusion, our real-world study supports the hypothesis that a continuous and progressive downward trend in LDL-C levels is needed to achieve and maintain a cardiovascular benefit, at least in secondary prevention.

1432-P: Lipid Profile and Visit-to-Visit Variability of LDL Cholesterol, the Association with Risk of Young-Onset Type 2 Diabetes—Nationwide Retrospective Cohort Study

Background: It is reported that the prevalence of young-onset type 2 diabetes (YOD) is increasing in recent. YOD usually defined that it diagnosis at age &amp;lt;40 year. However, the underlying pathophysiology of YOD is still unknown. Previous studies suggested that lipid level and its variability associated with various health outcome. Aim: We aimed to examine the effect of lipid profile and variability of low-density lipoprotein cholesterol (LDL-C) on the risk of young-onset type 2 diabetes in Participants with 20 to 40 Years Methods: We examined the General Health Check-up sub-dataset of the Korean National Health Insurance Service (NHIS) of 1,376,416 participants with 20 to 40 year who had at least three health check-ups between 2012 and 2017, and were not reported to have diabetes during that time. The visit to visit variability of LDL-C was measured using variability independent of the mean (VIM), standard deviation (SD), average successive variability (ASV), and coefficient of variation (CV),. Results: During a median of 5 years of follow up, 19,706 subjects (1.5%) developed YOD. Risk of incident YOD increased with quartiles 2, 3 and 4 versus quartile 1 in Total cholesterol (TC), LDL-C, triglyceride (TC) whereas, inversely associated with high density lipoprotein cholesterol (HDL-C) in multivariate analysis. Compare with the lowest quartile, the highest quartile of VIM, SD, ASV and CV of LDL-C was associated with 1.22-1.43 fold risk of YOD (VIM HR, 1.292; SD HR 1.428; ASV HR 1.364; CV HR 1.218, P for trend &amp;lt;0.0001) in the multivariable adjusted model. When calculating variability of TC, LDL and HDL-C index, we did not observe that consistent results were obtained. Conclusion: Risk of incident YOD is increased with increasing lipid profile. High visit to visit LDL-C variability and level of LDL-C per se, were independent predictors of YOD. Both lowering and stabilizing LDL-C can be beneficial for reducing diabetes risk in young population. Disclosure M.Seo: None. S.Park: None. E.Rhee: None. W.Lee: None.

Long-term visit-to-visit variability in low-density lipoprotein cholesterol is associated with poor cardiovascular and kidney outcomes in patients with primary nephrotic syndrome.

It is unclear whether long-term variability in low-density lipoprotein cholesterol (LDL-C) is associated with clinical outcomes in patients with nephrotic syndrome (NS). A large cohort of 1100 patients with primary NS underwent treatment and regular follow-up. Long-term variability in LDL-C was assessed by calculating its weighted standard deviation (w-SD). The primary endpoints of this study were the occurrence of arteriosclerotic cardiovascular disease (ASCVD) or kidney dysfunction. Factors associated with the w-SD of LDL-C were evaluated by linear regression. Associations of the w-SD of LDL-C with clinical outcomes were evaluated by Cox proportional hazards regression. Over a median follow-up of 44.8 (interquartile range, 26.8, 70.1) months, 198 patients developed ASCVD (45.9 cases per 1,000 patient-years), and 84 patients developed kidney dysfunction (17.6 cases per 1,000 patient-years). The incidence rates of the primary outcomes increased across the quartiles of the w-SD of LDL-C (log-rank, P < 0.001). Multivariate Cox regression analysis showed that higher LDL-C variability was associated with an increased risk of ASCVD [hazard ratio (HR), 2.236; 95% confidence interval (CI), 1.684-2.969, P < 0.001] and an increased risk of kidney dysfunction (HR, 3.047; 95% CI 2.240-4.144, P < 0.001). The results were similar after adjusting the w-SD of LDL-C by its related parameters (baseline and mean LDL-C as well as mean total cholesterol), although the mean LDL-C was also an independent risk factor for ASCVD and kidney dysfunction. Long-term variability in LDL-C was independently associated with the risk of ASCVD and kidney dysfunction in NS patients.

A Randomized Study to Evaluate the Effect of an Inclisiran First Implementation Strategy vs Usual Care in Patients with ASCVD and Elevated Low-density Lipoprotein Cholesterol: Rationale and Design of the VICTORION-INITIATE Trial

Lead Author's Financial Disclosures Nothing to disclose. Study Funding Novartis Pharmaceuticals Corporation, East Hanover, NJ. Background/Synopsis Most patients with atherosclerotic cardiovascular disease (ASCVD) have elevated low-density lipoprotein cholesterol (LDL-C). Compared to placebo, inclisiran has been shown to be safe, tolerable, and effective at reducing LDL-C in patients with ASCVD. It is unknown whether an inclisiran first strategy compared to usual care (allowing for changes in lipid-lowering therapy to mimic routine clinical decision-making) can improve LDL-C control in patients with ASCVD when inclisiran is added to statin therapy. Objective/Purpose Describe the rationale and design of the ongoing VICTORION-INITIATE (NCT04929249) trial. Methods VICTORION-INITIATE is a phase 3, randomized, 2-arm, parallel-group, open-label, U.S.-based trial assessing the efficacy of an inclisiran first strategy vs usual care to treat ASCVD. Patients in the inclisiran arm will receive both inclisiran and maximally tolerated statin therapy immediately upon failure to reach LDL-C less than 70 mg/dL with statins alone. Patients in the usual care arm will continue to receive maximally tolerated statin therapy and may receive other non-statin therapies per usual care. Sites were selected based on geography, population, and lipid management practices. The trial will enroll ∼444 patients (aged greater than or equal to 18 years) with established ASCVD and elevated LDL-C (greater than or equal to 70 mg/dL) or non-high-density lipoprotein cholesterol (greater than or equal to 100 mg/dL) despite receiving maximally tolerated statin therapy, fasting triglycerides less than 500 mg/dL, and an estimated glomerular filtration rate greater than 30 mL/min. The study has 6 planned visits over 330 days from screening to completion. Results Primary outcomes are percent change from baseline in LDL-C and proportion of patients discontinuing statins during the 330-day trial. Key secondary outcomes include the proportion of patients achieving prespecified LDL-C targets, proportion of patients achieving greater than or equal to 50% LDL-C reductions, absolute and time-averaged changes in LDL-C, changes in other lipids, changes in and adherence to ongoing lipid-lowering therapy, visit-to-visit variability in LDL-C, and inclisiran safety and tolerability. Conclusions VICTORION-INITIATE is ongoing and planned to complete in early 2023. This trial aims to determine the efficacy of adding inclisiran first when maximally tolerated statin therapy fails to achieve LDL-C less than 70 mg/dL in those with ASCVD. Nothing to disclose.

Lipid Variability and Risk of Cardiovascular Diseases and All-Cause Mortality: A Systematic Review and Meta-Analysis of Cohort Studies.

No consensus has yet been reached on the associations of lipid variability (LV) with cardiovascular diseases (CVDs) and all-cause mortality. We aimed to quantify the associations of different types and metrics of LV with CVDs and all-cause mortality. PubMed, Medline, and Embase databases were searched for eligible cohort studies published until 14 December 2021. Lipids included total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). Metrics of variability included standard deviation (SD), coefficient of variation (CV), and variation independent of the mean (VIM). The primary outcomes were CVDs and all-cause mortality. Random-effects meta-analysis was used to generate a summary of the relative risks (SRRs). Sources of heterogeneity were explored by subgroup analysis and meta-regression. A total of 11 articles based on seven cohorts were included. Participants in the top quartile of TC variability had an increased risk of CVDs (vs. bottom quartile: TC-CV: SRR 1.29, 95% CI 1.15-1.45; TC-SD: 1.28, 1.15–1.43; TC-VIM: 1.26, 1.13–1.41, respectively) and all-cause mortality (vs. bottom quartile: TC-CV: 1.28, 1.15–1.42; TC-SD: 1.32, 1.22–1.44; TC-VIM: 1.32, 1.25–1.40, respectively). Participants in the top quartile of HDL-C variability had an increased risk of CVDs (vs. bottom quartile: HDL-C-CV: 1.11, 1.07–1.15; HDL-C-SD: 1.18, 1.02–1.38; HDL-C-VIM: 1.18, 1.09–1.27, respectively) and all-cause mortality (vs. bottom quartile: HDL-C-CV: 1.29, 1.27–1.31; HDL-C-SD: 1.24, 1.09–1.41; HDL-C-VIM: 1.25, 1.22–1.27, respectively). LDL-C variability was also associated with an increased risk of CVDs (for top vs. bottom quartile; LDL-C-SD: 1.09, 1.02–1.17; LDL-C-VIM: 1.16, 1.02–1.32, respectively) and all-cause mortality (for top vs. bottom quartile; LDL-C-CV: 1.19, 1.04–1.36; LDL-C-SD: 1.17, 1.09–1.26, respectively). The relationships of TG variability with the risk of CVDs and all-cause mortality were inconclusive across different metrics. The effects of SRR became stronger when analyses were restricted to studies that adjusted for lipid-lowering medication and unadjusted for mean lipid levels. These findings indicate that the measurement and surveillance of lipid variability might have important clinical implications for risk assessment of CVDs and all-cause mortality.

Association between dietary saturated fat with cardiovascular disease risk markers and body composition in healthy adults: findings from the cross-sectional BODYCON study

BackgroundDiets high in saturated fatty acids (SFAs) and greater abdominal obesity are both associated with raised low-density lipoprotein cholesterol (LDL-C) concentrations, an independent cardiovascular disease (CVD) risk marker. Although reducing SFA intake is a public health strategy for CVD prevention, the role of body fat distribution on the relationship between SFA and LDL-C is unclear. Therefore, our objective was to investigate whether the association between dietary SFAs and LDL-C concentrations is related to body composition.MethodsIn the BODYCON (impact of physiological and lifestyle factors on body composition) study, 409 adults [mean age 42 ± 16 years and median BMI of 23.5 (21.5–25.9) kg/m2] underwent a measure of body composition by dual energy x-ray absorptiometry, assessment of habitual dietary intake using a 4-day weighed food diary and physical activity level using a tri-axial accelerometer. Blood pressure was measured, and a fasting blood sample was collected to determine cardiometabolic disease risk markers. Correlations between body composition, circulating risk markers and dietary macronutrients were assessed prior to multivariate regression analysis. The effect of increasing intakes of dietary SFA on outcome measures was assessed using ANCOVA after adjusting for covariates.ResultsAbdominal visceral adipose tissue (VAT) mass was moderately positively correlated with total cholesterol (TC), LDL-C, systolic blood pressure (SBP), diastolic blood pressure and HOMA-IR (rs = 0.25–0.44, p < 0.01). In multiple regression analysis, 18.3% of the variability in LDL-C was explained by SFA intake [% total energy (TE)], abdominal VAT mass, carbohydrate%TE and fat%TE intakes. When data were stratified according to increasing SFA%TE intakes, fasting TC, LDL-C and non-high-density lipoprotein-cholesterol were higher in Q4 compared with Q2 (p ≤ 0.03). SBP was higher in Q4 versus Q3 (p = 0.01). Android lean mass was also higher in Q3 versus Q1 (p = 0.02). Other anthropometric and CVD risk markers were not different across quartile groups.ConclusionsAlthough dietary SFA was found to explain 9% of the variability in LDL-C, stratification of data according to quartiles of SFA intake did not reveal a dose-dependent relationship with LDL-C concentration. Furthermore, this association appeared to be independent of abdominal obesity in this cohort.Clinical Trail registration: Trial registration: clinicaltrials.gov as NCT02658539. Registered 20 January 2016, https://clinicaltrials.gov/ct2/show/NCT02658539.

Genetic Determinants of Visit-to-Visit Lipid Variability: Genome-Wide Association Study in Statin-Naïve Korean Population.

Background and AimThere is a growing evidence that fluctuation in lipid profiles is important in cardiovascular outcomes. We aimed to identify single nucleotide polymorphism (SNP) variants associated with low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) variability in statin-naïve Korean subjects and evaluate their associations with coronary atherosclerosis.MethodsIn statin-naïve subjects from Gene-Environment of Interaction and phenotype cohort, we performed genome-wide association studies of lipid variability; the discovery (first) and replication (second) sets included 4,287 and 1,086 subjects, respectively. Coronary artery calcium (CAC) score and degree of coronary artery stenosis were used as outcome measures. Cholesterol variability was determined by standard deviation and average successive variability, and significant coronary atherosclerosis was defined as CAC score ≥400 or coronary stenosis ≥70%.ResultsMean HDL-C and LDL-C level were 54 ± 12 and 123 ± 30 mg/dL in the first set and 53 ± 12 and 126 ± 29 mg/dL in the second set. APOA5 rs662799 and APOA5 rs2266788 were associated with LDL-C variability and PXDNL rs80056520, ALDH2 rs671, HECTD4 rs2074356, and CETP rs2303790 were SNPs associated for HDL-C variability. APOA5 rs662799 passed Bonferroni correction with p-value of 1.789 × 10−9. Among the SNPs associated with cholesterol variability, rs80056520 and rs2266788 variants were associated with CACS ≥400 and coronary stenosis ≥70% and rs662799 variant was associated with coronary stenosis ≥70%.ConclusionTwo SNPs associated with LDL-C variability (APOA5 rs662799 and rs2266788) and one SNP associated with HDL-C variability (PXDNL rs80056520) were significantly associated with advanced coronary artery stenosis. Combining GWAS results with imaging parameters, our study may provide a deeper understanding of underlying pathogenic basis of the link between lipid variability and coronary atherosclerosis.

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.

Mean and Variability of Lipid Measurements and Risk for Development of Subclinical Left Ventricular Diastolic Dysfunction.

BackgroundSubclinical left ventricular diastolic dysfunction (LVDD) is an emerging consequence of increased insulin resistance, and dyslipidemia is one of the few correctable risk factors of LVDD. This study evaluated the role of mean and visit-to-visit variability of lipid measurements in risk of LVDD in a healthy population.MethodsThis was a 3.7-year (interquartile range, 2.1 to 4.9) longitudinal cohort study including 2,817 adults (median age 55 years) with left ventricular ejection fraction >50% who underwent an annual or biannual health screening between January 2008 and July 2016. The mean, standard deviation (SD), coefficient of variation (CV), variability independent of the mean (VIM), and average real variability of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (apoB), non-HDL-C, and triglycerides were obtained from three to six measurements during the 5 years preceding the first echocardiogram.ResultsAmong the 2,817 patients, 560 (19.9%) developed LVDD. The mean of no component of lipid measurements was associated with risk of LVDD. CV (hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.10 to 1.67), SD (HR, 1.27; 95% CI, 1.03 to 1.57), and VIM (HR, 1.26; 95% CI, 1.03 to 1.55) of LDL-C and all the variability parameters of apoB were significantly associated with development of LVDD. The association between CV-LDL and risk of LVDD did not have significant interaction with sex, increasing/decreasing trend at baseline, or use of stain and/or lipid-modifying agents.ConclusionThe variability of LDL-C and apoB, rather than their mean, was associated with risk for LVDD.

Association Between Cumulative Low-Density Lipoprotein Cholesterol Exposure During Young Adulthood and Middle Age and Risk of Cardiovascular Events

Low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease (CVD). Most observational studies on the association between LDL-C and CVD have focused on LDL-C level at a single time point (usually in middle or older age), and few studies have characterized long-term exposures to LDL-C and their role in CVD risk. To evaluate the associations of cumulative exposure to LDL-C, time-weighted average (TWA) LDL-C, and the LDL-C slope change during young adulthood and middle age with incident CVD later in life. This cohort study analyzed pooled data from 4 prospective cohort studies in the US (Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Framingham Heart Study Offspring Cohort, and Multi-Ethnic Study of Atherosclerosis). Participants were included if they had 2 or more LDL-C measures that were at least 2 years apart between ages 18 and 60 years, with at least 1 of the LDL-C measures occurring during middle age at 40 to 60 years. Data from 1971 to 2017 were collected and analyzed from September 25, 2020, to January 10, 2021. Cumulative exposure to LDL-C, TWA LDL-C, and LDL-C slope from age 18 to 60 years. Incident coronary heart disease (CHD), ischemic stroke, and heart failure (HF). A total of 18 288 participants were included in this study. These participants had a mean (SD) age of 56.4 (3.7) years and consisted of 10 309 women (56.4%). During a median follow-up of 16 years, 1165 CHD, 599 ischemic stroke, and 1145 HF events occurred. In multivariable Cox proportional hazards regression models that adjusted for the most recent LDL-C level measured during middle age and for other CVD risk factors, the hazard ratios for CHD were as follows: 1.57 (95% CI, 1.10-2.23; P for trend = .01) for cumulative LDL-C level, 1.69 (95% CI, 1.23-2.31; P for trend <.001) for TWA LDL-C level, and 0.88 (95% CI, 0.69-1.12; P for trend = .28) for LDL-C slope. No association was found between any of the LDL-C variables and ischemic stroke or HF. This cohort study showed that cumulative LDL-C and TWA LDL-C during young adulthood and middle age were associated with the risk of incident CHD, independent of midlife LDL-C level. These findings suggest that past levels of LDL-C may inform strategies for primary prevention of CHD and that maintaining optimal LDL-C levels at an earlier age may reduce the lifetime risk of developing atherosclerotic CVD.

Risk stratification of cardiac arrhythmias and sudden cardiac death in type 2 diabetes mellitus patients receiving insulin therapy: A population-based cohort study.

IntroductionMetabolic abnormalities may exacerbate the risk of adverse outcomes in patients with type 2 diabetes mellitus. The present study aims to assess the predictive value of HbA1c and lipid variability on the risks of sudden cardiac death (SCD) and incident atrial fibrillation (AF).MethodsThe retrospective observational study consists of type 2 diabetic patients prescribed with insulin, who went to publicly funded clinics and hospitals in Hong Kong between January 1, 2009 and December 31, 2009. Variability in total cholesterol, low‐density lipoprotein‐cholesterol (LDL‐C), high‐density lipoprotein‐cholesterol (HDL‐C), triglyceride, and HbA1c were assessed through their SD and coefficient of variation. The primary outcomes were incident (1) ventricular tachycardia/ventricular fibrillation, actual or aborted SCD and (2) AF.ResultsA total of 23 329 patients (mean ± SD age: 64 ± 14 years old; 51% male; mean HbA1c 8.6 ± 1.3%) were included. On multivariable analysis, HbA1c, total cholesterol, LDL‐C and triglyceride variability were found to be predictors of SCD (p < .05).ConclusionHbA1c and lipid variability were predictive of SCD. Therefore, poor glucose control and variability in lipid parameters in diabetic patients are associated with aborted or actual SCD. These observations suggest the need to re‐evaluate the extent of glycemic control required for outcome optimization.

Association Between Visit-to-Visit Variability in Low-Density Lipoprotein Cholesterol and Plaque Rupture That Leads to Acute Coronary Syndrome

Background: The effect of intraindividual variability in lipid levels on the onset of acute coronary syndrome (ACS) remains uncertain. We evaluated the relationship between intraindividual variability in lipid levels and culprit lesion morphologies by optical coherence tomography (OCT).Methods and Results: Seventy-four consecutive patients with ACS whose cholesterol levels were assessed ≥3 times during outpatient visits before the onset of ACS were enrolled in the study; 222 patients without significant stenotic lesions were used as a control group. Based on OCT findings of culprit lesions, ACS patients were categorized into a plaque rupture ACS (PR-ACS) group (n=44) or a non-plaque rupture ACS (NPR-ACS) group (erosion or calcified nodule; n=30). Visit-to-visit variability in lipid levels was evaluated using the corrected variability independent of the mean (cVIM). Patients with ACS had significantly higher low-density lipoprotein cholesterol (LDL-C) levels and cVIM in LDL-C than the control group. The PR-ACS group had significantly higher mean LDL-C levels and greater cVIM in LDL-C than the control group. The PR-ACS group had a significantly higher cVIM than the NPR-ACS group, despite similar mean LDL-C levels. Multivariate analysis revealed that higher cVIM of LDL-C was an independent predictor of PR-ACS (odds ratio 1.06; P=0.018).Conclusions: In addition to the LDL-C level, greater visit-to-visit variability in LDL-C levels may be associated with the onset of ACS induced by plaque rupture.

Abstract P102: Variability In Lipid Levels And Risk For Cardiovascular Disease: An Electronic Health Record-based Population Cohort Study

Background: Larger within-patient variability of lipid levels has been associated with an increased risk of cardiovascular disease (CVD). However, measures of lipid variability are not currently used clinically. We investigated the feasibility of calculating lipid variability within a large electronic health record (EHR)-based population cohort and assessed associations with incident CVD. Methods: We identified all individuals ≥40 years of age who resided in Olmsted County, MN on 1/1/2006 (index date) without prior CVD. CVD was defined as myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary intervention or stroke. Patients with ≥3 measurements of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and/or triglycerides during the 5 years before the index date were retained in the analyses. Lipid variability was calculated using variability independent of the mean (VIM). Patients were followed through 9/30/2017 for incident CVD (including CVD death). Cox regression was used to investigate the association between quintiles of lipid VIMs and incident CVD. Results: We identified 18,642 individuals (mean age 60; 55% female) who were free of CVD at baseline and VIM calculated for at least one lipid measurement. After adjustment, those in the highest VIM quintiles of total cholesterol had a 25% increased risk of CVD (Q5 vs. Q1 HR: 1.25, 95% CI: 1.08-1.45; Table). We observed similar results for LDL-C (Q5 vs. Q1 HR: 1.20, 95% CI: 1.04-1.39) and HDL-C (Q5 vs. Q1 HR: 1.25, 95% CI: 1.09-1.43). There was no association between triglyceride variability quintiles and CVD risk. Conclusion: In a large EHR-based population cohort, high variability in total cholesterol, HDL-C and LDL-C was associated with an increased risk of CVD, independently of traditional risk factors, suggesting it may be a target for intervention. Lipid variability can be calculated in the EHR environment but more research is needed to determine its clinical utility.

Effects of Combined Lipid-Lowering Therapy on Low-Density Lipoprotein Cholesterol Variability and Cardiovascular Adverse Events in Patients with Acute Coronary Syndrome.

To investigate the effect of combined lipid-lowering therapy on low-density lipoprotein cholesterol (LDL-C) variability and cardiovascular adverse events in patients with acute coronary syndrome (ACS). A total of 200 patients with acute coronary syndrome, admitted to the first Hospital of Hebei Medical University from January 2018 to June 2019, were randomly divided into the observation group (100 cases were treated with combined lipid-lowering drugs, including 10mg/day atorvastatin and 10mg/day ezetimibe) and the control group (100 cases were given an intensive statin regimen, including 40mg/day atorvastatin). The levels of blood lipids, creatine kinase (CK), alanine transaminase (ALT), matrix metalloproteinase-9 (MMP-9) and high-sensitivity C-reactive protein (hsCRP) were observed and compared between the two groups. Focus was laid on the concentration of the above-mentioned parameters and follow-up results including the drug safety and incidence of cardiovascular adverse events. Before treatment, there was no significant difference in total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), CK, ALT, MMP-9, hsCRP and LDL-C between the two groups (P > 0.05). After 6months, 12months and 24months of treatment, TC, HDL-C, CK, ALT, MMP-9, hsCRP and LDL-C were improved in both groups, and TC, HDL-C, CK, ALT, MMP-9, hsCRP and LDL-C in the observation group elicited greater results than those in the control group with significant difference (P < 0.05). In the course of treatment, the drug safety of the two groups was compared (P > 0.05), and the incidence of cardiovascular adverse events in the observation group was significantly lower than that in the control group (6.59% vs. 11.96%) (P < 0.05). Combination therapy with atorvastatin and ezetimibe potentially provides remarkable effects in terms of treating acute coronary syndrome, controlling the variation of LDL-C, alleviating the inflammatory state and reducing the incidence of cardiovascular adverse events with a safe profile. Combined lipid-lowering drugs are considered valid and alternative approaches for wide clinical practice.

Prediction of atrial fibrillation and sudden cardiac death in type 2 diabetic patients on insulin: a territory-wide observational cohort study

Abstract Funding Acknowledgements Type of funding sources: None. Introduction With the global shift towards a more personalized approach in the management of diabetes, there is an increasing interest in exploring the application of new parameters, such as HbA1c and lipid variability, to better monitor disease progression and evaluate the prognosis. Given that metabolic abnormalities may exacerbate the risk of adverse outcomes in patients with type 2 diabetes mellitus, patients who are partially or fully dependent on insulin are more likely to have severe disease and may be at higher risks of arrhythmias. Purpose The aim of the present study aims was to assess the predictive value of HbA1c and lipid variability towards ventricular tachycardia (VT), ventricular fibrillation (VF), or SCD, as well as incident AF in type 2 diabetic patients receiving insulin therapy. Methods The territory-wide retrospective observational study consists of type 2 diabetic patients prescribed with insulin, who attended publicly funded clinics and hospitals in Hong Kong between January 1st, 2009 to December 31st, 2009. Variability in total cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglyceride, and HbA1c were assessed through their standard deviation (SD) and coefficient of variation (CV) for patients with at least three measurements of the respective indices. Univariate and multivariate Cox regression analysis was used to predict for the primary outcomes- incident SCD and AF. Results A total of 23329 patients (mean ± SD age: 64 ± 14 years old; 51% male; mean HbA1c 8.6 ± 1.3%) were included. In total, 2512 and 1846 patients experienced incident SCD and AF respectively over the course of follow-up. On multivariate analysis, higher HbA1c variability (SD: hazard ratio [HR]: 1.45, 95% confidence interval [CI] 1.21-1.75; p &amp;lt; 0.0001) and triglyceride variability (SD: HR: 1.36, 95%CI: 1.24-1.49; p &amp;lt; 0.0001) were associated with increased of SCD risk. By contrast, only the increase in LDL-C variability was predictive of AF (SD: HR 2.95, 95%CI 1.37-6.39; p= 0.006). Conclusions Higher HbA1c variability and lipid variability were associated with increased of SCD risk while only higher LDL-C variability was predictive of incident AF. Therefore, poor glucose control and variability in lipid parameters in diabetic patients are associated with SCD and incident AF. These observations suggest the need to re-evaluate the extent of glycemic control required for outcome optimization.

Greater variability in lipid measurements associated with kidney diseases in patients with type 2 diabetes mellitus in a 10-year diabetes cohort study

This study aimed to evaluate the associations between variability of lipid parameters and the risk of kidney disease in patients with type 2 diabetes mellitus. Low-density lipoprotein-cholesterol, total cholesterol to high-density lipoprotein-cholesterol ratio and triglyceride were specifically addressed in this study. This retrospective cohort study included 105,552 patients aged 45–84 with type 2 diabetes mellitus and normal kidney function who were managed under Hong Kong public primary care clinics during 2008–2012. Those with kidney disease (estimated glomerular filtration rate < 60 mL/min/1.73 m2 or urine albumin to creatinine ratio ≥ 3 mg/mmol) were excluded. Variabilities of low-density lipoprotein-cholesterol, total cholesterol to high-density lipoprotein-cholesterol ratio and triglyceride were determined using the standard deviation of the respective parameter obtained from a mixed effects model to minimize regression dilution bias. The associations between lipid variability and renal outcomes including incident kidney disease, renal function decline defined as ≥ 30% reduction in estimated glomerular filtration rate since baseline, and end-stage renal disease (estimated glomerular filtration rate < 15 mL/min/1.73 m2) were evaluated by multivariable Cox regression. After a median follow-up of 66.5 months (0.5 million person-years in total), 49,653 kidney disease, 29,358 renal function decline, and 1765 end-stage renal disease cases were recorded. Positive linear associations between low-density lipoprotein-cholesterol and total cholesterol to high-density lipoprotein-cholesterol ratio variabilities and the risk of all renal outcomes were demonstrated. However, no association between triglyceride variability and any outcome was found. Each mmol/L increase in low-density lipoprotein-cholesterol variability was associated with 20% (Hazard ratio 1.20 [95% CI 1.15–1.25]), 38% (Hazard ratio 1.37 [95% CI 1.30–1.45]), and 108% (Hazard ratio 2.08 [95% CI 1.74–2.50]) higher risk in incident kidney disease, renal function decline and end-stage renal disease respectively. Similarly, each unit increase in total cholesterol to high-density lipoprotein-cholesterol ratio variability was associated with 35% (Hazard ratio 1.15 [95% CI 1.10–1.20]), 33% (Hazard ratio 1.33 [95% CI 1.26–1.40]), and 75% (Hazard ratio 1.75 [95% CI 1.46–2.09]) heightened risk in incident kidney disease, renal function decline and end-stage renal disease respectively. Cholesterol variability may potentially be a useful predictor of kidney diseases in patients with type 2 diabetes mellitus. Attention should be drawn to cholesterol variability when managing diabetic patients and further research is warranted to investigate the modifiable risk factors for lipid variability.

The association of blood lipid parameters variability with ischemic stroke in hypertensive patients

Background and aimsThe relationship between lipid variability and stroke among patients with hypertension were inconclusive. We aimed to investigate the association of lipid variability with ischemic stroke in hypertensive patients. Methods and resultsThis retrospective cohort study included 4995 individuals with hypertension between 2013 and 2015, and recorded their status of ischemic stroke until the end of 2018. The variability in total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured using the standard deviation (SD), coefficient of variation (CV), variability independent of the mean (VIM) and average absolute difference between successive values (ASV). Multivariate Cox proportional hazards models with hazard ratios (HRs) and 95% confidence interval (CI) were performed. There were 110 cases of ischemic stroke during a median follow up of 4.2 years. The multivariable adjusted HRs and 95% CIs comparing the highest versus the lowest quartiles of SD of TC, LDL-C, HDL-C and TG were 4.429 (95% CI: 2.292, 8.560), 2.140 (95% CI: 1.264, 3.621), 1.368 (95% CI: 0.793, 2.359) and 1.421 (95% CI: 0.800, 2.525), respectively. High variability in TC and LDL-C were associated with a higher risk for ischemic stroke. Similarly, the results were consistent when calculating variability of TC and LDL-C using CV, ASV and VIM, and in various subgroup analyses. ConclusionHigher variability of TC and LDL-C associated with the risk of ischemic stroke among hypertensive patients. These findings suggest reducing variability of lipid parameters may decrease adverse outcomes.