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Comparison of the effectiveness of Martin's equation, Friedewald's equation, and a Novel equation in low-density lipoprotein cholesterol estimation.
Song, Y, Lee, HS, Baik, SJ, Jeon, S, Han, D, Choi, SY, Chun, EJ, Han, HW, Park, SH, Sung, J, et al
Scientific reports. 2021;(1):13545
Abstract
Low-density-lipoprotein cholesterol (LDL-C) is the main target in atherosclerotic cardiovascular disease (ASCVD). We aimed to validate and compare a new LDL-C estimation equation with other well-known equations. 177,111 samples were analysed from two contemporary population-based cohorts comprising asymptomatic Korean adults who underwent medical examinations. Performances of the Friedewald (FLDL), Martin (MLDL), and Sampson (SLDL) equations in estimating direct LDL-C by homogenous assay were assessed by measures of concordance (R2, RMSE, and mean absolute difference). Analyses were performed according to various triglyceride (TG) and/or LDL-C strata. Secondary analyses were conducted within dyslipidaemia populations of each database. MLDL was superior or at least similar to other equations regardless of TG/LDL-C, in both the general and dyslipidaemia populations (RMSE = 11.45/9.20 mg/dL; R2 = 0.88/0.91; vs FLDL RMSE = 13.66/10.42 mg/dL; R2 = 0.82/0.89; vs SLDL RMSE = 12.36/9.39 mg/dL; R2 = 0.85/0.91, per Gangnam Severance Hospital Check-up/Korea Initiatives on Coronary Artery Calcification data). MLDL had a slight advantage over SLDL with the lowest MADs across the full spectrum of TG levels, whether divided into severe hyper/non-hyper to moderate hypertriglyceridaemia samples or stratified by 100-mg/dL TG intervals, even up to TG values of 500-600 mg/dL. MLDL may be a readily adoptable and cost-effective alternative to direct LDL-C measurement, irrespective of dyslipidaemia status. In populations with relatively high prevalence of mild-to-moderate hypertriglyceridaemia, Martin's equation may be optimal for LDL-C and ASCVD risk estimation.
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Effect of inclisiran, the small-interfering RNA against proprotein convertase subtilisin/kexin type 9, on platelets, immune cells, and immunological biomarkers: a pre-specified analysis from ORION-1.
Landmesser, U, Haghikia, A, Leiter, LA, Wright, RS, Kallend, D, Wijngaard, P, Stoekenbroek, R, Kastelein, JJ, Ray, KK
Cardiovascular research. 2021;(1):284-291
Abstract
AIMS: Small-interfering RNA (siRNA)-based targeting of proprotein convertase subtilisin/kexin type 9 (PCSK9) represents a novel therapeutic approach that may provide a convenient, infrequent, and safe dosing schedule to robustly lower low-density lipoprotein cholesterol (LDL-C). Given the long duration of action, however, establishing safety in particular with respect to immunogenicity is of paramount importance. In earlier clinical studies of other RNA-targeted treatment approaches (antisense oligonucleotide therapy) immunological and haematological adverse effects, in particular thrombocytopenia and pro-inflammatory effects, have been reported. Here, we present the pre-specified safety analysis from ORION-1 evaluating platelets, immune cells, immunological markers, antidrug antibodies, and clinical immunogenicity adverse events (AEs) under PCSK9 siRNA treatment with inclisiran. METHODS AND RESULTS The pre-specified safety analysis from ORION-1 was performed in six different inclisiran dosing regimens in patients at high risk of cardiovascular disease with elevated LDL-C levels. Patients received either a single dose (SD: 200 mg, n = 60; 300 mg, n = 62 or 500 mg, n = 66) or double-dose starting regimen (DD: 100 mg, n = 62; 200 mg, n = 63; or 300 mg, n = 61 on days 1 and 90) of inclisiran or placebo (SD: n = 65; DD: n = 62). The effects of inclisiran on haematological parameters including platelet counts, lymphocytes, and monocytes as well as on the immune markers interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α) were examined after 180 days. Immunogenicity was further evaluated by analysis of anti-drug-antibodies (ADAs) towards inclisiran in 6068 study samples and by careful analysis of immunogenicity AEs as part of the pharmacovigilance strategy. At day 180, no significant alterations of platelet counts were observed in any of the dosing groups (change from baseline, SD: 200 mg: 0.8%; 300 mg: -0.5%; 500 mg: -1.8%; DD: 100 mg: 1.3%; 200 mg: -0.5%; 300 mg: 1.0%; no significant difference for any group as compared with placebo). No significant effects on other immune cells, including leucocytes, monocytes, or neutrophils were detected. Notably, no significant increase of inflammatory biomarkers (IL-6 or TNF-α) with either the SD or DD regimen became evident. There was no evidence for immunogenicity based on ADA level analysis and careful review of clinical immunogenicity AEs in none of the treatment regimens. CONCLUSION In this pre-specified safety analysis of ORION-1 for the siRNA therapeutic inclisiran, no adverse effects on measures of inflammation or immune activation nor adverse effects on platelets or clinical immunogenicity AEs were observed over at least 6-month treatment. These safety findings in the largest analysis of an RNAi study in humans to date provide strong reassurance about the safety of inclisiran and the potential of cardiovascular RNA-targeted therapies.
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Elevated Serum Small Dense Low-Density Lipoprotein Cholesterol May Increase the Risk and Severity of Coronary Heart Disease and Predict Cardiovascular Events in Patients with Type 2 Diabetes Mellitus.
Huang, J, Gu, JX, Bao, HZ, Li, SS, Yao, XQ, Yang, M, Li, Y, Zhang, AM, Yin, Y, Zhang, N, et al
Disease markers. 2021;:5597028
Abstract
BACKGROUND Coronary heart disease (CHD) is a common and severe complication in type 2 diabetes mellitus (T2DM) patients. Increased amount of circulatory small dense low-density lipoprotein cholesterol (sdLDL-C) particles is known to be a sign of dyslipidemia and can result in atherosclerosis. However, the association between serum sdLDL-C levels and CHD in T2DM patients remains unclear. METHODS A total of 3684 T2DM patients who received selective coronary angiography (CAG) were selected. For analyzing the association between sdLDL-C and CHD severity in T2DM, the patients with CHD were further divided into four subgroups according to the quartiles of sdLDL-C. A multivariate logistic regression was used for analyzing the risks and severity of CHD. A total of 3427 patients with continuous stable CHD were recruited and followed up for 5 years. RESULTS Serum sdLDL-C levels in the CHD group were significantly increased compared with those in the non-CHD group [0.80 (0.49) mmol/L vs. 0.70 (0.30) mmol/L, p < 0.001]. The results from CHD subgroup analysis indicated that the sdLDL-C levels in patients with multiple-vessel disease and high Gensini score (GS) were significantly increased. By adjusting the confounding factors and analyzing with multiple logistic regression, we found that sdLDL-C independently correlated with the presence and severity of CHD (CHD: OR = 2.257; multiple-vessel disease: OR = 3.288; high GS: OR = 2.554). A total of 484 major cardiovascular events (MACEs) were documented. After Kaplan-Meier analysis and chi-squared analysis, the incidence of MACEs in the high sdLDL-C group was higher than that in the low sdLDL-C group (16.04% vs. 12.25%, p = 0.002). CONCLUSION In T2DM patients, elevated serum sdLDL-C may increase the severity of CHD and predict cardiovascular events in the future. Therefore, serum sdLDL-C may be a potential biomarker for the surveillance of CHD in T2DM patients.
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Association of Plasma Branched-Chain Amino Acid With Biomarkers of Inflammation and Lipid Metabolism in Women.
Hamaya, R, Mora, S, Lawler, PR, Cook, NR, Ridker, PM, Buring, JE, Lee, IM, Manson, JE, Tobias, DK
Circulation. Genomic and precision medicine. 2021;(4):e003330
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Abstract
BACKGROUND Branched-chain amino acids (BCAAs; isoleucine, leucine, and valine) correlate with insulin resistance and poor glucose control, which may in part explain associations between type 2 diabetes and cardiovascular disease. However, the relationships of BCAAs with other cardiometabolic pathways, including inflammation and dyslipidemia, are unclear. We hypothesized that plasma BCAAs would correlate with multiple pathways of cardiometabolic dysfunction. METHODS We conducted a cross-sectional analysis among 19 472 participants (mean age=54.9 years, SD=7.2 years) in the Women's Health Study without a history of type 2 diabetes, cardiovascular disease, or cancer. We quantified the concentrations of individual biomarkers of inflammation and lipids, across quartiles of BCAAs, adjusting for age, smoking, body mass index, physical activity, and other established cardiovascular disease risk factors at blood draw. RESULTS Women in the highest versus lowest quartiles of plasma BCAAs had higher inflammatory markers including high-sensitivity C-reactive protein (multivariable-adjusted means: 1.96 versus 1.43 mg/L), fibrinogen (367 versus 362 mg/dL), soluble intercellular cell adhesion molecule-1 (361 versus 353 ng/mL), and glycoprotein acetylation (407 versus 371 µmol/L; P trend=0.0002 for fibrinogen; P<0.0001 for others). Similarly for lipids, women with higher BCAAs had lower HDL-C (high-density lipoprotein cholesterol; 49.0 versus 55.0 mg/dL), and higher triglycerides (143 versus 114 mg/dL), LDL-C (low-density lipoprotein cholesterol; 133 versus 124 mg/dL), and lipoprotein insulin resistance score (52.6 versus 37.3; all: P<0.0001). Similar associations with these biomarkers were observed in isoleucine, leucine, and valine, respectively. CONCLUSIONS Higher circulating BCAA concentrations are associated with adverse profiles of biomarkers of inflammation and dyslipidemia independent of established cardiovascular disease risk factors, and thus, may reflect poorer cardiometabolic health through multiple pathways. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00000479.
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Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy.
Ballantyne, CM, Laufs, U, Ray, KK, Leiter, LA, Bays, HE, Goldberg, AC, Stroes, ES, MacDougall, D, Zhao, X, Catapano, AL
European journal of preventive cardiology. 2020;(6):593-603
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AIMS: The aim of this study was to evaluate the low-density lipoprotein cholesterol lowering efficacy and safety of a bempedoic acid 180 mg and ezetimibe 10 mg fixed-dose combination in patients with hypercholesterolemia and a high risk of cardiovascular disease receiving maximally tolerated statin therapy. METHODS This phase 3, double-blind clinical trial enrolled adult patients at high risk of cardiovascular disease due to atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or multiple cardiovascular disease risk factors. Patients were randomly assigned (2:2:2:1) to treatment with the fixed-dose combination, bempedoic acid 180 mg, ezetimibe 10 mg or placebo added to stable background statin therapy for 12 weeks. The primary efficacy endpoint was the percentage change from baseline to week 12 in low-density lipoprotein cholesterol. RESULTS Among the 301 patients included in the primary analysis, the mean baseline low-density lipoprotein cholesterol level was 3.87 mmol/L (149.8 mg/dL). At week 12, the fixed-dose combination lowered low-density lipoprotein cholesterol (-36.2%) significantly more than placebo (1.8% (placebo-corrected difference -38.0%); P < 0.001), ezetimibe alone (-23.2%; P < 0.001) or bempedoic acid alone (-17.2%; P < 0.001). The fixed-dose combination lowered low-density lipoprotein cholesterol levels similarly across subgroups, including patients receiving high-intensity, other-intensity or no statin therapy. Improvements with the fixed-dose combination were also observed in secondary efficacy endpoints, including high-sensitivity C-reactive protein. In this trial, fixed-dose combination treatment had a generally similar safety profile compared with bempedoic acid, ezetimibe or placebo. CONCLUSION The bempedoic acid and ezetimibe fixed-dose combination significantly lowered low-density lipoprotein cholesterol versus placebo or other oral monotherapies and had a favourable safety profile when added to maximally tolerated statin therapy in patients with hypercholesterolemia and high cardiovascular disease risk. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT03337308.
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Baseline, delta, and achieved low-density lipoprotein cholesterol levels and cardiovascular risk in patients on statin therapy: A post-hoc resampling mediation analysis of treating new targets [TNT] trial.
Hyun, MH, Jang, JW, Lee, E, An, H, Seog Seo, H
Clinical and experimental pharmacology & physiology. 2020;(10):1649-1658
Abstract
Clinical guidelines for monitoring low-density lipoprotein cholesterol (LDL-C) after statin therapy do not clearly define the clinical roles of baseline LDL-C, ΔLDL-C, and achieved LDL-C according to statin intensity. We performed post-hoc analysis of the Treating to New Target (TNT) study to evaluate individual LDL-C parameters after statin therapy. Primary outcome was the risk for total major adverse cardiovascular events (MACE). We use resampling multilevel mediation analysis to analyze complex relationships among LDL-C parameters based on similar statin intensities. Tertiles for resample A (matched baseline LDL-C; distinct achieved LDL), resample B (matched ΔLDL-C; distinct baseline LDL-C), and resample C (matched achieved LDL-C; distinct ΔLDL-C) were analyzed using Cox proportional hazard ratios. In original data analysis, the incidence of MACE was reduced in those with lower achieved LDL-C in total, low, and high intensity statin users (hazard ratios [HRs] = 0.990, 0.992, 0.992; respectively; all P-values < .001). In mediation analysis, resample A showed consistently high incidence for MACE in the middle tertile (HR = 1.237; 95% confidential interval [CI] = 1.008-1.517; P-value = .041) and highest tertile (HR = 1.275; 95% CI = 1.021-1.592; P-value = .032) compared to the lowest tertile. However, resamples B and C did not show consistent differences. Similarly, no consistent statistical difference in MACE according to statin intensity. Lower achieved LDL-C decreased MACE in participants with a similar baseline LDL-C after statin therapy. However, the change in absolute values of ΔLDL-C and achieved LDL-C should be interpreted in an individualized manner due to their complex collinearity, and statin intensity should also be taken into consideration.
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A U-shaped association between the LDL-cholesterol to HDL-cholesterol ratio and all-cause mortality in elderly hypertensive patients: a prospective cohort study.
Yu, Y, Li, M, Huang, X, Zhou, W, Wang, T, Zhu, L, Ding, C, Tao, Y, Bao, H, Cheng, X
Lipids in health and disease. 2020;(1):238
Abstract
BACKGROUND The low-density lipoprotein cholesterol/high-density lipoprotein- cholesterol (LDL-C/HDL-C) ratio is an excellent predictor of cardiovascular disease (CVD). However, previous studies linking the LDL-C/HDL-C ratio to mortality have yielded inconsistent results and been limited by short follow-up periods. Therefore, the aim of the present study was to determine whether the LDL-C/HDL-C ratio could be an effective predictor of all-cause mortality in elderly hypertensive patients. METHODS A total of 6941 hypertensive patients aged 65 years or older who were not treated with lipid-lowering drugs were selected from the Chinese Hypertension Registry for analysis. The endpoint of the study was all-cause mortality. The relationship between the LDL-C/HDL-C ratio and all-cause mortality was determined using multivariate Cox proportional hazards regression, smoothing curve fitting (penalized spline method), subgroup analysis and Kaplan-Meier survival curve analysis. RESULTS During a median follow-up of 1.72 years, 157 all-cause deaths occurred. A U-shaped association was found between the LDL-C/HDL-C ratio and all-cause mortality. Patients were divided according to the quintiles of the LDL-C/HDL-C ratio. Compared to the reference group (Q3: 1.67-2.10), patients with both lower (Q1 and Q2) and higher (Q4 and Q5) LDL-C/HDL-C ratios had higher all-cause mortality (< 1.67: HR 1.81, 95% CI: 1.08-3.03; ≥2.10: HR 2.00, 95% CI: 1.18-3.39). Compared with the lower and higher LDL-C/HDL-C ratio groups, patients with LDL-C/HDL-C ratios of 1.67-2.10 had a significantly higher survival probability (log-rank P = 0.038). CONCLUSIONS The results suggest that there is a U-shaped association between the LDL-C/HDL-C ratio and all-cause mortality. Both lower and higher LDL-C/HDL-C ratios were associated with increased all-cause mortality in elderly hypertensive patients.
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Effects of Renal Impairment on the Pharmacokinetics, Efficacy, and Safety of Inclisiran: An Analysis of the ORION-7 and ORION-1 Studies.
Wright, RS, Collins, MG, Stoekenbroek, RM, Robson, R, Wijngaard, PLJ, Landmesser, U, Leiter, LA, Kastelein, JJP, Ray, KK, Kallend, D
Mayo Clinic proceedings. 2020;(1):77-89
Abstract
OBJECTIVE To investigate the pharmacodynamic properties of inclisiran, a small interfering RNA targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), in individuals with normal renal function and renal impairment (RI). PATIENTS AND METHODS The analysis included participants with normal renal function and mild, moderate, and severe RI from the phase 1 ORION-7 renal study (n=31) and the phase 2 ORION-1 study (n=247) who received 300 mg of inclisiran sodium or placebo. RESULTS In ORION-7, PCSK9 values were reduced at day 60 in the normal renal function group (68.1%±12.4%), mild RI group (74.2%±12.3%), moderate RI group (79.8%±4.9%), and severe RI group (67.9%±16.4%) (P<.001 vs placebo in all groups). Low-density lipoprotein cholesterol levels were significantly reduced versus placebo: normal renal function, 57.6%±10.7%; mild RI, 35.1%±13.5%; moderate RI, 53.1%±21.3%; severe RI, 49.2%±26.6% (P<.001 for all). In ORION-1, PCSK9 level reductions at day 180 were 48.3% to 58.6% in the 300-mg single-dose groups and 67.3% to 73.0% in the 300-mg 2-dose groups (P<.001 vs placebo in all groups). The corresponding low-density lipoprotein cholesterol level reductions were 35.7% to 40.2% in the 300-mg single-dose groups and 50.9% to 58.0% in the 300 mg 2-dose groups (P<.001 vs placebo in all groups). In ORION-7, exposure to inclisiran was proportionally greater in individuals with increasing RI; inclisiran was undetectable in plasma 48 hours after administration in any group. CONCLUSION The pharmacodynamic effects and safety profile of inclisiran were similar in study participants with normal and impaired renal function. Dose adjustments of inclisiran are not required in these patients. TRIAL REGISTRATION clinicaltrials.gov Identifiers: NCT02597127 and NCT03159416.
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Low-Density Lipoprotein Cholesterol Target Attainment in Patients Surviving an Acute Coronary Syndrome in Thailand: Results From the Dyslipidaemia International Study (DYSIS) II.
Buddhari, W, Uerojanaungkul, P, Sriratanasathavorn, C, Sukonthasarn, A, Ambegaonkar, B, Brudi, P, Horack, M, Lautsch, D, Vyas, A, Gitt, AK
Heart, lung & circulation. 2020;(3):405-413
Abstract
BACKGROUND Patients suffering an acute coronary syndrome (ACS) are at increased risk for future cardiovascular events. Effective management of hyperlipidaemia in such patients is essential. We aimed to document the use of lipid-lowering therapy (LLT) and low-density lipoprotein cholesterol (LDL-C) target achievement in patients hospitalised with an ACS in Thailand. METHODS The Dyslipidemia International Study (DYSIS) II was a multinational, observational study that enrolled patients over 18 years of age who were hospitalised with an ACS in 2013-2014 and survived until discharge. Patients were analysed according to whether or not they were treated with LLT prior to hospital admission. A lipid profile was carried forward from blood taken within the first 24 hours after admission, and attainment of the LDL-C target of <70 mg/dL (1.8 mmol/L) for very high-risk subjects was reported. Details of LLTs were collected. Lipid levels, LLT use and cardiovascular events since discharge were collected at a follow-up interview 4 months later. RESULTS A total of 320 ACS patients were enrolled from seven sites across Thailand, 188 (58.8%) of whom were being treated with LLT prior to the acute event. The mean LDL-C levels of the LLT and no LLT patients were 106.2 ± 39.4 mg/dL (2.75 ± 1.02 mmol/L) and 139.8 ± 46.6 mg/dL (3.62 ± 1.21), respectively, with 15.4% and 4.5% having an LDL-C level below 70 mg/dL (1.8 mmol/L). Lipid-lowering therapy consisted mainly of statins, with an atorvastatin-equivalent daily dosage of 17 ± 13 mg/day. At the 4-month follow-up, LDL-C target attainment remained low at 26.7% for the initial LLT group and 24.1% for the no LLT group. Although most patients were being treated with LLT at this point, the dosage was still low (28 ± 16 mg/day) and there was little use of combination therapy. CONCLUSION In this cohort of Thai ACS patients, LDL-C levels were highly elevated, placing them at extreme risk of recurrent adverse cardiovascular events. Lipid-lowering therapy was widely used after the ACS; however, treatment was rarely optimised. Huge improvements are required in the management of hyperlipidaemia in Thailand.
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Evinacumab for Homozygous Familial Hypercholesterolemia.
Raal, FJ, Rosenson, RS, Reeskamp, LF, Hovingh, GK, Kastelein, JJP, Rubba, P, Ali, S, Banerjee, P, Chan, KC, Gipe, DA, et al
The New England journal of medicine. 2020;(8):711-720
Abstract
BACKGROUND Homozygous familial hypercholesterolemia is characterized by premature cardiovascular disease caused by markedly elevated levels of low-density lipoprotein (LDL) cholesterol. This disorder is associated with genetic variants that result in virtually absent (null-null) or impaired (non-null) LDL-receptor activity. Loss-of-function variants in the gene encoding angiopoietin-like 3 (ANGPTL3) are associated with hypolipidemia and protection against atherosclerotic cardiovascular disease. Evinacumab, a monoclonal antibody against ANGPTL3, has shown potential benefit in patients with homozygous familial hypercholesterolemia. METHODS In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned in a 2:1 ratio 65 patients with homozygous familial hypercholesterolemia who were receiving stable lipid-lowering therapy to receive an intravenous infusion of evinacumab (at a dose of 15 mg per kilogram of body weight) every 4 weeks or placebo. The primary outcome was the percent change from baseline in the LDL cholesterol level at week 24. RESULTS The mean baseline LDL cholesterol level in the two groups was 255.1 mg per deciliter, despite the receipt of maximum doses of background lipid-lowering therapy. At week 24, patients in the evinacumab group had a relative reduction from baseline in the LDL cholesterol level of 47.1%, as compared with an increase of 1.9% in the placebo group, for a between-group least-squares mean difference of -49.0 percentage points (95% confidence interval [CI], -65.0 to -33.1; P<0.001); the between-group least-squares mean absolute difference in the LDL cholesterol level was -132.1 mg per deciliter (95% CI, -175.3 to -88.9; P<0.001). The LDL cholesterol level was lower in the evinacumab group than in the placebo group in patients with null-null variants (-43.4% vs. +16.2%) and in those with non-null variants (-49.1% vs. -3.8%). Adverse events were similar in the two groups. CONCLUSIONS In patients with homozygous familial hypercholesterolemia receiving maximum doses of lipid-lowering therapy, the reduction from baseline in the LDL cholesterol level in the evinacumab group, as compared with the small increase in the placebo group, resulted in a between-group difference of 49.0 percentage points at 24 weeks. (Funded by Regeneron Pharmaceuticals; ELIPSE HoFH ClinicalTrials.gov number, NCT03399786.).