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Elizabeth Marrett,1 Changgeng Zhao,1 Ning Jackie Zhang,2 Qiaoyi Zhang,1 Dena R Ramey,1 Joanne E Tomassini,1 Andrew M Tershakovec,1 David R Neff11Merck & Co, Inc., Whitehouse Station, NJ, USA; 2College of Health and Public Affairs, University of Central Florida, Orlando, FL, USABackground: Guidelines endorse statin therapy for lowering low-density lipoprotein cholesterol (LDL-C) to recommended levels, in patients with cardiovascular disease (CVD) risk, if needed, after lifestyle changes. Atorvastatin is a common statin with greater LDL-C lowering efficacy than most other statins; its availability in generic form will likely increase its use. This study assessed attainment of guideline-recommended LDL-C levels in high-risk CVD patients treated with atorvastatin monotherapy.Methods: Analyses of two retrospective US cohorts of patients who received a prescription for atorvastatin monotherapy between January 1, 2008 and December 31, 2010 (index date defined as first prescription date) in the GE Centricity Electronic Medical Record (EMR) (N=10,693) and Humana Medicare (N=16,798) databases. Eligible patients were ≥18 years, diagnosed with coronary heart disease or atherosclerotic vascular disease, with ≥1 LDL-C measurement between 3 months and 1 year postindex date, and continuously enrolled for 1 year prior to and following the index date.Results: Of the eligible patients, 21.8%, 29.6%, 29.9%, and 18.7% (GE Centricity EMR) and 25.4%, 32.9%, 27.8%, and 14.0% (Humana Medicare) received 10, 20, 40, and 80 mg doses of atorvastatin, respectively. The mean ± standard deviation (SD) follow-up LDL-C levels were 2.1±0.8 mmol/L (83±30 mg/dL) and 2.3±0.8 mmol/L (88±31 mg/dL) for the GE Centricity EMR and Humana Medicare cohorts, respectively. Regardless of dose, only 28.3%-34.8% of patients had LDL-C levels 1.8 mmol/L (>70 mg/dL), and of these, 30%-40% had LDL-C levels ≥0.5 mmol/L (≥20 mg/dL) above this, regardless of dose. This suggests that more effective lipid-lowering strategies, such as statin uptitration, switching to a higher efficacy statin, and/or combination therapy, may be required to achieve optimal LDL-C lowering in high-risk patients.Keywords: statin therapy, managed-care, lipid-lowering therapy

Despite the established role of low-density lipoprotein cholesterol (LDL-C) as a major risk factor for cardiovascular disease (CVD), and the persistence of CVD as the leading cause of morbidity and mortality in the United States, national quality assurance metrics no longer include LDL-C measurement as a required performance metric. This clinical perspective reviews the history of LDL-C as a quality and performance metric and the events that led to its replacement. It also presents patient, healthcare provider, and health system rationales for re-establishing LDL-C measurement as a performance measure to improve cholesterol control in high-risk groups and to stem the rising tide of CVD morbidity and mortality, cardiovascular care disparities, and related healthcare costs., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Salim S. Virani reports a relationship with Department of Veterans Affairs, National Institutes of Health, World Heart Federation, Tahir and Jooma Family that includes: funding grants. Salim S. Virani reports a relationship with American College of Cardiology in his role as associate editor for innovations, acc.org that includes honorarium. Karen Aspry reports a relationship with Amgen, Esperion, Novartis, Ionis that includes: funding grants. Karen Aspry reports a relationship with National Lipid Association that includes: speaking and lecture fees. Dave L. Dixon reports a relationship with Boehringer Ingelheim Corp USA that includes: funding grants. Keith C. Ferdinand reports a relationship with Amgen, Novartis that includes: consulting or advisory. Elizabeth J. Jackson reports a relationship with Regeneron, Novartis that includes: consulting or advisory. Elizabeth J. Jackson reports a relationship with Esperion Therapeutics Inc that includes: consulting or advisory and speaking and lecture fees. Terry A. Jacobson reports a relationship with Astra Zeneca, Esperion, Novartis, Amgen, Regeneron that includes: consulting or advisory. Janice L. McAlister reports a relationship with Amgen Inc that includes: consulting or advisory and speaking and lecture fees. Janice L. McAlister reports a relationship with Esperion Therapeutics Inc that includes: speaking and lecture fees. Martha Gulati reports a relationship with Siemans that includes: speaking and lecture fees. Martha Gulati reports a relationship with Novartis, Bayer that includes: consulting or advisory. Christie M. Ballantyne reports a relationship with Abbott Diagnostic, Amgen, Arrowhead, Esperion, Merck, Novartis, Novo Nordisk, Regeneron, Roche Diagnostic that includes: consulting or advisory and funding grants. Christie M. Ballantyne reports a relationship with Akcea, Ionis that includes: funding grants. Christie M. Ballantyne reports a relationship with 89Bio, Alnylam Pharmaceuticals, Althera, Amarin, Astra Zeneca, Denka Seiken, Genentech, Gilead, Illumina, Matinas BioPharma Inc, New Amsterdam, Pfizer that includes: consulting or advisory., (© 2023 The Authors. Published by Elsevier B.V.)

Background: Patients with diabetes mellitus and cardiovascular disease may not achieve adequate low-density lipoprotein cholesterol (LDL-C) lowering on statin monotherapy, attributed partly to atherogenic dyslipidemia. More intensive LDL-C-lowering therapy can be considered for these patients. A previous randomized, controlled study demonstrated greater LDL-C lowering in diabetic patients with symptomatic cardiovascular disease who switched from simvastatin 20 mg (S20) or atorvastatin 10 mg (A10) to combination ezetimibe/simvastatin 10/20 mg (ES10/20) therapy, compared with statin dose-doubling (to S40 or A20) or switching to rosuvastatin 10 mg (R10). The effect of these regimens on novel biomarkers of atherogenic dyslipidemia (low- and high-density lipoprotein particle number and lipoprotein-associated phospholipase A2 [Lp-PLA2]) was assessed., Methods and Results: Treatment effects on low- and high-density lipoprotein particle number (by NMR) and Lp-PLA2 (by ELISA) were evaluated using plasma samples available from 358 subjects in the study. Switching to ES10/20 reduced low-density lipoprotein-particle number numerically more than did statin dose-doubling and was comparable with R10 (-133.3, -94.4, and -56.3 nmol/L, respectively; P>0.05). Increases in high-density lipoprotein particle number were significantly greater with switches to ES10/20 versus statin dose-doubling (1.5 and -0.5 μmol/L; P<0.05) and comparable with R10 (0.7 μmol/L; P>0.05). Percentages of patients attaining low-density lipoprotein particle number levels <990 nmol/L were 62.4% for ES10/20, 54.1% for statin dose-doubling, and 57.0% for R10. Switching to ES10/20 reduced Lp-PLA2 activity significantly more than did statin dose-doubling (-28.0 versus -3.8 nmol/min per mL, P<0.05) and was comparable with R10 (-28.0 versus -18.6 nmol/min per mL; P>0.05); effects on Lp-PLA2 concentration were modest., Conclusions: In diabetic patients with dyslipidemia, switching from statins to combination ES10/20 therapy generally improved lipoprotein subclass profile and Lp-PLA2 activity more than did statin dose-doubling and was comparable with R10, consistent with its lipid effects., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00862251., (© 2015 The Authors. [Ngoc‐Anh Le and Peter W. F. Wilson] and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. All rights reserved. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Combination therapy with ezetimibe/simvastatin (E/S) and extended-release niacin (N) has been reported to be safe and efficacious in concomitantly reducing low-density lipoprotein cholesterol and increasing high-density lipoprotein cholesterol in hyperlipidemic patients at high risk for atherosclerotic cardiovascular events. This analysis evaluated the effect of E/S coadministered with N on low-density lipoprotein particle number (LDL-P) and high-density lipoprotein particle number (HDL-P) as assessed by nuclear magnetic resonance (NMR) spectroscopy in patients with type IIa or IIb hyperlipidemia., Methods and Results: This was an analysis of a previously reported 24-week randomized, double-blind study in type IIa/IIb hyperlipidemic patients randomized to treatment with E/S (10/20 mg/day)+N (titrated to 2 g/day) or N (titrated to 2 g/day) or E/S (10/20 mg/day). Samples from a subset of patients (577 of 1220) were available for post hoc analysis of LDL-P and HDL-P by NMR spectroscopy. Increases in HDL-P (+16.2%) and decreases in LDL-P (-47.7%) were significantly greater with E/S+N compared with N (+9.8% for HDL-P and -21.5% for LDL-P) and E/S (+12.8% for HDL-P and -36.8% for LDL-P). In tertile analyses, those with the lowest baseline HDL-P had the greatest percent increase in HDL-P (N, 18.4/7.9/2.1; E/S, 19.3/12.2/5.3; and E/S+N, 26.9/13.8/6.9; all P<0.001). Individuals in the highest tertile of LDL-P had the greatest percent reduction in LDL-P (N, 18.3/23.1/24.6; E/S, 29.7/38.3/41.8; and E/S+N, 44.3/49.0/50.5; all P<0.001)., Conclusions: These results suggest that E/S+N improves lipoprotein particle number, consistent with its lipid-modifying benefits in type IIa or IIb hyperlipidemia patients and may exert the greatest effect in those with high LDL-P and low HDL-P at baseline.

Cardiovascular disease is increased in patients with chronic kidney disease (CKD) and is the principle cause of morbidity and mortality in these patients. In patients with stage 5 CKD, structural changes in the myocardium have been implicated as the principle cardiovascular processes leading to this increase in morbidity and mortality, while atherosclerotic events including acute myocardial infarction and strokes are responsible for approximately 10-15% of cardiovascular deaths. Dyslipidemia is common in CKD patients and is usually not characterized by elevated cholesterol levels, except in patients with marked proteinuria. Increased triglyceride levels in conjunction with decreased high-density lipoprotein levels are the commonest qualitative abnormality. Characteristically, abnormalities in the metabolism of apolipoprotein (apo) B-containing lipoproteins have been described, including both gut derived (apoB-48) as well as those produced by hepatic synthesis (apoB-100). A decrease in enzymatic delipidation as well as reduced receptor removal of these lipoproteins both contribute to the increased levels of these apo-B-containing particles and their remnants (which are believed to be highly atherogenic). Abnormalities in the metabolism of apoA-containing lipoproteins are also present and these changes contribute to the lower levels of HDL seen. Qualitative abnormalities of these HDL particles may be associated with cellular oxidative injury and contribute to a pro-inflammatory, pro-thrombotic milieu that is frequently present in CKD patients.