Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia

Goldberg, Anne C.; Alagona, Peter; Capuzzi, David M.; Guyton, John R.; Morgan, John; Rodgers, Joseph T.; Sachson, Richard; Samuel, Paul

doi:10.1016/s0002-9149(00)00703-7

Cited by 202 publications

(101 citation statements)

References 15 publications

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“…18 The two combination regimens produced the greatest changes in lipid parameters among patients > 65 years; age-related differences in response were less evident with the two single-drug regimens.…”

Section: Efficacymentioning

confidence: 89%

A dose‐ranging study of a new, once‐daily, dual‐component drug product containing niacin extended‐release and lovastatin

Hunninghake

McGovern²,

Koren

et al. 2003

Clinical Cardiology

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SummaryBackground: Combination therapy for dyslipidemia holds promise as effective treatment for patients with multiple lipid disorders, especially those at high risk.Hypothesis: This study evaluated dose-response relationships and safety of a new dual-component drug product containing niacin extended-release (niacin ER) and lovastatin.Methods: The 28-week double-blind multicenter trial randomized 237 patients with type IIA or IIB hyperlipidemia to one of four escalating-dose treatment groups: niacin ER/lovastatin 1,000/20 mg, niacin ER/lovastatin 2,000/40 mg, niacin ER 2,000 mg, or lovastatin 40 mg.Results: Niacin ER/lovastatin was more effective than each of its components for improving levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG), and exhibited a clear doseresponse effect and additivity across the dosage range. The 2,000/40 dose achieved greater mean reductions in LDL-C (Ϫ42%) than 1,000/20 (Ϫ28%, p < 0.001), lovastatin 40 mg (Ϫ32%, p < 0.05), or niacin ER 2,000 mg (Ϫ14%, p < 0.05). The 2,000/40 dose was significantly more effective in increasing HDL-C levels (+ 30%) than the 1,000/20 dose (+ 21%, p = 0.016). The decrease in TG was greater with 2,000/40

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Section: Efficacymentioning

confidence: 89%

A dose‐ranging study of a new, once‐daily, dual‐component drug product containing niacin extended‐release and lovastatin

Hunninghake

McGovern²,

Koren

et al. 2003

Clinical Cardiology

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“…Subsequent preclinical studies on overexpression of apolipoprotein A-I (apoA-I), the major protein constituent of HDL, have reported significant reduction in CHD risk (3,4). Although raising HDL levels is a longstanding strategy for mitigating CHD risk, the current lipidtargeted therapies, including the usage of statins, fibrates, and niacin, have shown reduced therapeutic potential (5)(6)(7). Hence, there is a continuous requirement for new strategies that can elevate HDL levels to halt the progression of CHD.…”

mentioning

confidence: 99%

Structural Plasticity of Cholesteryl Ester Transfer Protein Assists the Lipid Transfer Activity

Chirasani

Revanasiddappa

Senapati

2016

Journal of Biological Chemistry

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Coronary heart disease (CHD)2 is one of the prime causes of an increase in the mortality rate worldwide. Over the past few years, various epidemiological studies have provided ample evidence that increased levels of HDL, by transporting cholesterol from atherosclerotic plaques to liver for excretion, can arrest the progression of CHD (1, 2). Subsequent preclinical studies on overexpression of apolipoprotein A-I (apoA-I), the major protein constituent of HDL, have reported significant reduction in CHD risk (3, 4). Although raising HDL levels is a longstanding strategy for mitigating CHD risk, the current lipidtargeted therapies, including the usage of statins, fibrates, and niacin, have shown reduced therapeutic potential (5-7). Hence, there is a continuous requirement for new strategies that can elevate HDL levels to halt the progression of CHD.Cholesteryl ester transfer protein (CETP), a plasma glycoprotein with 476 residues, has been found to mediate the transfer of cholesteryl esters (CEs) from HDL to LDL and VLDL as well as the reciprocal transfer of triglycerides (TGs) from LDL and VLDL to HDL (8, 9). The identification of deficient CETP gene levels and correlated high HDL levels in a Japanese population (10 -13) brought CETP into focus as a therapeutic target for controlling HDL levels. Preclinical animal model studies have further substantiated these findings by showing an elevated level of HDL in mice with non-expressing CETP (14 -16). Since then, the inhibition of CETP activity by small molecule inhibitors has been pursued as an active approach to prevent atherosclerosis with varying levels of success at clinical trial phases (17)(18)(19)(20). Given the complexity of lipid metabolism and the pivotal role of CETP in the process, understanding CETP structure, CETP inhibition, and the mechanism by which CETP transfers neutral lipids is of prime importance. The last decade, therefore, has seen the employment of sophisticated techniques, like cryo-EM (21, 22), x-ray (23, 24), and MD simulations (25-28) on this front. Nevertheless, the story of CETP remains far from complete.The crystal structure of CETP (Protein Data Bank entry 2OBD) has been solved with four bound lipid molecules (23). The structure shows two ␤-barrel domains at the N and C termini, each with a twisted ␤-sheet and a long ␣-helix; a central ␤-sheet between the two ␤-barrels; a C-terminal ␣-helix; and a 60-Å-long hydrophobic tunnel occupied by two CE molecules. Additionally, there were two plug-in dioleoylphosphatidylcholine molecules with polar headgroups exposed to plasma and acyl chains buried in the hydrophobic tunnel of CETP. Interestingly, one of the CEs in the hydrophobic tunnel was in the bent conformation, whereas the second CE molecule was in the linear conformation. Recent cryopositive staining EM and optimized negative-staining electron microscopy (OpNS-EM) protocols combined with CETP C terminus-specific polyclonal antibody studies have suggested that CETP penetrates its C-terminal ␤-barrel domain into LDL or VLDL and its N-termi...

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“…Using dose titration to help manage adverse effects such as flushing, the dose is gradually increased by 500 mg/day or less over four weeks to reach a daily 1500 mg or 2000 mg dose for maintenance therapy (16). Despite the efficacy of ERN in achieving comprehensive lipid management and its increased tolerability over other niacin formulations (13,(18)(19)(20), therapy with ERN is frequently associated with flushing, which often undermines treatment adherence and results in a high rate of discontinuation (13,19,21).…”

mentioning

confidence: 99%

Utilization patterns of extended-release niacin in Canada: Analysis of an administrative claims database

Dorais

Chirovsky

Ambegaonkar

et al. 2010

Canadian Journal of Cardiology

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Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia

Cited by 202 publications

References 15 publications

A dose‐ranging study of a new, once‐daily, dual‐component drug product containing niacin extended‐release and lovastatin

A dose‐ranging study of a new, once‐daily, dual‐component drug product containing niacin extended‐release and lovastatin

Structural Plasticity of Cholesteryl Ester Transfer Protein Assists the Lipid Transfer Activity

Utilization patterns of extended-release niacin in Canada: Analysis of an administrative claims database

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