Consistency of Extended-Release Niacin/Laropiprant Effects on Lp(a), ApoB, non-HDL-C, Apo A1, and ApoB/ApoA1 Ratio Across Patient Subgroups

Bays, Harold; Shah, Arvind; Lin, Jianxin; Sisk, Christine McCrary; Dong, Qian; Maccubbin, Darbie

doi:10.2165/11631530-000000000-00000

Cited by 15 publications

(7 citation statements)

References 25 publications

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“…63,67 In one study of initially healthy women, extremely high levels of Lp(a) ($90th percentile) were associated with increased cardiovascular risk, particularly in women with high levels of low-density lipoprotein cholesterol. 70,71 There are some small studies that suggest that apheresis can help reduce levels also. 68 On the other hand, in African Americans, who have been shown to generally have higher Lp(a) levels, the data is more conflicting.…”

Section: Lipoprotein (A)mentioning

confidence: 99%

New and Emerging Risk Factors for Coronary Heart Disease

Akhabue

Thiboutot

Cheng

et al. 2014

The American Journal of the Medical Sciences

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Section: Lipoprotein (A)mentioning

confidence: 99%

New and Emerging Risk Factors for Coronary Heart Disease

Akhabue

Thiboutot

Cheng

et al. 2014

The American Journal of the Medical Sciences

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“…The combination of niacin/laropiprant plus a statin compared with doubling of the statin dose showed that combination treatment was associated with a significantly greater decrease in TG and LDL-C and a significantly greater increase in HDL-C [9]. An analysis of 4 trials of niacin/laropiprant revealed that this combination led to significantly larger decreases in TG, LDL-C, non-HDL-C, apoB, and Lp(a) and significantly greater increases in HDL-C and apoA-I compared with placebo or active comparator [10]. …”

Section: Niacin and Niacin Receptor Agonistsmentioning

confidence: 99%

Targeting High Density Lipoproteins in the Prevention of Cardiovascular Disease?

2012

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Recent studies involving HDL-raising therapeutics have greatly changed our understanding of this field. Despite effectively raising HDL-C levels, niacin remains of uncertain clinical benefit. Synthetic niacin receptor agonists are unlikely to raise HDL-C or have other beneficial effects on plasma lipids. Despite the failure in phase 3 of two CETP inhibitors, two potent CETP inhibitors that raise HDL-C levels by > 100% (and reduce LDL-C substantially) are in late stage clinical development. Infusions of recombinant HDL containing ‘wild-type’ apoA-I or apoA-I Milano, as well as autologous delipidated HDL, all demonstrated promising early results and remain in clinical development. A small molecule that causes upregulation of endogenous apoA-I production is also in clinical development. Finally, upregulation of macrophage cholesterol efflux pathways through agonism of liver X receptors or antagonism of miR-33 remains of substantial interest. The field of HDL therapeutics is poised to transition from the ‘HDL-cholesterol hypothesis’ to the ‘HDL flux hypothesis’ in which the impact on flux from macrophage to feces is deemed to be of greater therapeutic benefit than the increase in steady-state concentrations of HDL cholesterol.

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“…Unfortunately, robust elevations of apoA‐I have been difficult to achieve by pharmacotherapy. Fibrates and niacin typically achieve <10% elevation, while dalcetrapib and torcetrapib achieved only 10% to 25% elevation . Additionally, the predominant change caused by these agents is an increase in HDL particle size, and larger HDL particles do not efficiently interact with the ABCA1 transporter …”

Section: Introductionmentioning

confidence: 99%

Infusion of Reconstituted High‐Density Lipoprotein, CSL112, in Patients With Atherosclerosis: Safety and Pharmacokinetic Results From a Phase 2a Randomized Clinical Trial

Tricoci

D’Andrea

Gurbel

et al. 2015

JAHA

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BackgroundCSL112 is a new formulation of human apolipoprotein A-I (apoA-I) being developed to reduce cardiovascular events following acute coronary syndrome. This phase 2a, randomized, double-blind, multicenter, dose-ranging trial represents the first clinical investigation to assess the safety and pharmacokinetics/pharmacodynamics of a CSL112 infusion among patients with stable atherosclerotic disease.Methods and ResultsPatients were randomized to single ascending doses of CSL112 (1.7, 3.4, or 6.8 g) or placebo, administered over a 2-hour period. Primary safety assessments consisted of alanine aminotransferase or aspartate aminotransferase elevations >3× upper limits of normal and study drug–related adverse events. Pharmacokinetic/pharmacodynamic assessments included apoA-I plasma concentration and measures of the ability of serum to promote cholesterol efflux from cells ex vivo. Of 45 patients randomized, 7, 12, and 14 received 1.7-, 3.4-, and 6.8-g CSL112, respectively, and 11 received placebo. There were no clinically significant elevations (>3× upper limit of normal) in alanine aminotransferase or aspartate aminotransferase. Adverse events were nonserious and mild and occurred in 5 (71%), 5 (41%), and 6 (43%) patients in the CSL112 1.7-, 3.4-, and 6.8-g groups, respectively, compared with 3 (27%) placebo patients. The imbalance in adverse events was attributable to vessel puncture/infusion-site bruising. CSL112 resulted in rapid (Tmax≈2 hours) and dose-dependent increases in apoA-I (145% increase in the 6.8-g group) and total cholesterol efflux (up to 3.1-fold higher than placebo) (P<0.001).ConclusionsCSL112 infusion was well tolerated in patients with stable atherosclerotic disease. CSL112 immediately raised apoA-I levels and caused a rapid and marked increase in the capacity of serum to efflux cholesterol. This potential novel approach for the treatment of atherosclerosis warrants further investigation.Clinical Trial RegistrationURL: http://www.ClinicalTrials.gov. Unique identifier: NCT01499420.

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Consistency of Extended-Release Niacin/Laropiprant Effects on Lp(a), ApoB, non-HDL-C, Apo A1, and ApoB/ApoA1 Ratio Across Patient Subgroups

Abstract: Registered as Clinicaltrials.gov NCT00269204, NCT00269217, NCT00479388, and NCT00485758.

Cited by 15 publications

References 25 publications

New and Emerging Risk Factors for Coronary Heart Disease

New and Emerging Risk Factors for Coronary Heart Disease

Targeting High Density Lipoproteins in the Prevention of Cardiovascular Disease?

Infusion of Reconstituted High‐Density Lipoprotein, CSL112, in Patients With Atherosclerosis: Safety and Pharmacokinetic Results From a Phase 2a Randomized Clinical Trial

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