Loss of early gains in low-density lipoprotein cholesterol goal attainment among high-risk patients

Foody, JoAnne M.; Sajjan, Shiva; Hu, Xiaohan; Ramey, Dena R.; Neff, David; Tershakovec, Andrew M.; Tomassini, Joanne E.; Wentworth, Chuck; Tunceli, Kaan

doi:10.1016/j.jacl.2010.01.007

Cited by 21 publications

(18 citation statements)

References 16 publications

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“…4,5 Overall trends observed in both the treated and untreated population from 2004 to 2012 in this study are similar to those described in previous studies. 6,7 Our findings highlight that the mean LDL-C level has decreased among both treated and untreated patients; however, as expected, the rate of decrease was more significant in the treated population compared with the untreated population. Numerous publications have shown that there has been significant progress in the reduction of cholesterol levels, especially LDL-C over time.…”

Section: Discussionsupporting

confidence: 71%

Frequency of High-Risk Patients Not Receiving High-Potency Statin (from a Large Managed Care Database)

Rodríguez¹,

Olufade²,

Heithoff³

et al. 2015

The American Journal of Cardiology

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Section: Discussionsupporting

confidence: 71%

Frequency of High-Risk Patients Not Receiving High-Potency Statin (from a Large Managed Care Database)

Rodríguez¹,

Olufade²,

Heithoff³

et al. 2015

The American Journal of Cardiology

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“…4 Among high-risk individuals, it is estimated that only 50% achieve the target LDL cholesterol of less than 2·59 mmol/L at 6 months after statin treatment, despite close monitoring and optimisation of the drug regimen. 5–9 With the LDL cholesterol target of less than 1·81 mmol/L in high-risk individuals, the number who reach their LDL cholesterol goals is even lower at 30%. 9,10 Thus, a clear unmet medical need exists for hypercholesterolaemia treatments, especially in high-risk patient populations.…”

Section: Introductionmentioning

confidence: 99%

“…5–9 With the LDL cholesterol target of less than 1·81 mmol/L in high-risk individuals, the number who reach their LDL cholesterol goals is even lower at 30%. 9,10 Thus, a clear unmet medical need exists for hypercholesterolaemia treatments, especially in high-risk patient populations.…”

Section: Introductionmentioning

confidence: 99%

Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial

et al. 2014

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Summary Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to LDL receptors, leading to their degradation. Genetics studies have shown that loss-of-function mutations in PCSK9 result in reduced plasma LDL cholesterol and decreased risk of coronary heart disease. We aimed to investigate the safety and efficacy of ALN-PCS, a small interfering RNA that inhibits PCSK9 synthesis, in healthy volunteers with raised cholesterol who were not on lipid-lowering treatment. Methods We did a randomised, single-blind, placebo-controlled, phase 1 dose-escalation study in healthy adult volunteers with serum LDL cholesterol of 3·00 mmol/L or higher. Participants were randomly assigned in a 3:1 ratio by computer algorithm to receive one dose of intravenous ALN-PCS (with doses ranging from 0·015 to 0·400 mg/kg) or placebo. The primary endpoint was safety and tolerability of ALN-PCS. Secondary endpoints were the pharmacokinetic characteristics of ALN-PCS and its pharmacodynamic effects on PCSK9 and LDL cholesterol. Study participants were masked to treatment assignment. Analysis was per protocol and we used ANCOVA to analyse pharmacodynamic endpoint data. This trial is registered with ClinicalTrials.gov, number NCT01437059. Findings Of 32 participants, 24 were randomly allocated to receive a single dose of ALN-PCS (0·015 mg/kg [n=3], 0·045 mg/kg [n=3], 0·090 mg/kg [n=3], 0·150 mg/kg [n=3], 0·250 mg/kg [n=6], or 0·400 mg/kg [n=6]) and eight to placebo. The proportions of patients affected by treatment-emergent adverse events were similar in the ALN-PCS and placebo groups (19 [79%] vs seven [88%]). ALN-PCS was rapidly distributed, with peak concentration and area under the curve (0 to last measurement) increasing in a roughly dose-proportional way across the dose range tested. In the group given 0·400 mg/kg of ALN-PCS, treatment resulted in a mean 70% reduction in circulating PCSK9 plasma protein (p<0·0001) and a mean 40% reduction in LDL cholesterol from baseline relative to placebo (p<0·0001). Interpretation Our results suggest that inhibition of PCSK9 synthesis by RNA interference (RNAi) provides a potentially safe mechanism to reduce LDL cholesterol concentration in healthy individuals with raised cholesterol. These results support the further assessment of ALN-PCS in patients with hypercholesterolaemia, including those being treated with statins. This study is the first to show an RNAi drug being used to affect a clinically validated endpoint (ie, LDL cholesterol) in human beings. Funding Alnylam Pharmaceuticals.

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“…Statin therapy is the recommended first‐line therapeutic approach for lipid management of high‐risk patients; however, many patients with diabetic dyslipidemia do not achieve adequate low‐density lipoprotein (LDL) cholesterol (LDL‐C) lowering on statin monotherapy 7, 8, 9, 10, 11. This residual risk may be attributed in part to atherogenic dyslipidemia, characterized by high levels of triglycerides, low levels of high‐density lipoprotein (HDL) cholesterol (HDL‐C), and high LDL‐particle (LDL‐P) numbers in these patients 1.…”

Section: Introductionmentioning

confidence: 99%

Effect of Switching From Statin Monotherapy to Ezetimibe/Simvastatin Combination Therapy Compared With Other Intensified Lipid‐Lowering Strategies on Lipoprotein Subclasses in Diabetic Patients With Symptomatic Cardiovascular Disease

Tomassini

Tershakovec

et al. 2015

JAHA

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BackgroundPatients 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 ResultsTreatment 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.ConclusionsIn 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 RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00862251.

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Loss of early gains in low-density lipoprotein cholesterol goal attainment among high-risk patients

Cited by 21 publications

References 16 publications

Frequency of High-Risk Patients Not Receiving High-Potency Statin (from a Large Managed Care Database)

Frequency of High-Risk Patients Not Receiving High-Potency Statin (from a Large Managed Care Database)

Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial

Effect of Switching From Statin Monotherapy to Ezetimibe/Simvastatin Combination Therapy Compared With Other Intensified Lipid‐Lowering Strategies on Lipoprotein Subclasses in Diabetic Patients With Symptomatic Cardiovascular Disease

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