Efficacy and safety of an extended-release formulation of fluvastatin for once-daily treatment of primary hypercholesterolemia

doi:10.1016/S0002-9149(00)01076-6

The American Journal of Cardiology

Volume 86, Issue 7, 1 October 2000, Pages 759-763

https://doi.org/10.1016/S0002-9149(00)01076-6 Get rights and content

Abstract

An extended-release (ER) formulation of fluvastatin 80 mg has been developed for once-daily treatment of primary hypercholesterolemia in patients who require fluvastatin dosages of >40 mg/day. The study aimed to determine the efficacy and safety of the new formulation and to assess the dose response over the range of 40 to 160 mg/day. After a 4-week placebo/dietary run-in period, 123 patients with primary hypercholesterolemia (Fredrickson type IIa/IIb) were randomized to receive fluvastatin 40, 80, or 160 mg/day for 6 weeks. The 40 mg/day dosage was administered as the marketed immediate-release (IR) capsule and the 80 mg/day dosage as 1 80-mg ER tablet. Patients receiving 160 mg/day were administered 80 mg/day (1 ER tablet) for the first 2 weeks, followed by 160 mg/day (2 ER tablets) for the remainder of the study. All doses were administered once daily at bedtime. The results showed a linear dose-response relation. Doubling the fluvastatin dosage resulted in a 6% greater mean percent reduction in low-density lipoprotein cholesterol (40 mg IR –29%; 80 mg ER –35%; 160 mg ER –41%). In the 160-mg ER group, 62% of patients achieved ≥40% reductions in low-density lipoprotein cholesterol compared with 32% and 10% of patients in the 80-mg ER and 40-mg IR groups, respectively. Dose ordering of the response was also observed for the other lipid parameters. Fluvastatin ER was well tolerated. Thus, the new ER formulation of fluvastatin was effective and well tolerated in the once-daily treatment of primary hypercholesterolemia.

Section snippets

Study design

This was a prospective, randomized, double-blind, parallel-group study in men and women aged ≥18 years with primary hypercholesterolemia (type IIa or IIb; LDL cholesterol ≥160 mg/dl [4.1 mmol/L], triglycerides ≤400 mg/dl [4.5 mmol/L]) conducted at 13 centers in the United States. The total study duration was 10 weeks, comprising a 4-week placebo/dietary run-in phase followed by 6 weeks’ active treatment (Figure 1).

The study protocol was approved by the Ethics Committee/Institutional Review

Results

A total of 283 patients entered the dietary/placebo run-in period at week –4, 123 of whom (43%) were subsequently randomized. The main reason for exclusion from randomization (>80%) was failure to meet the LDL cholesterol and triglyceride inclusion criteria; other reasons included withdrawal of consent, abnormal laboratory values, and adverse events.

Baseline demographic and clinical characteristics of the randomized patient population are summarized in Table 1. Patients were between 20 and 81

Discussion

This study demonstrates that improved efficacy of fluvastatin was accomplished by altering the pharmacokinetics as a result of changing the mode of drug delivery, not by changing the molecular structure of the drug itself or its ability to inhibit the enzyme HMG-CoA reductase. The ER formulation of fluvastatin 80 mg was developed to provide a starting dosage that ensures optimal reductions in LDL cholesterol, with once-daily administration to improve compliance. The results of a previous pilot

Acknowledgements

In addition to the authors, the following investigators participated in this study: Mark Goodman, MD, Cardiovascular Medical Associates, Garden City, NY; Brian Meyerhoff, MD, Palomar Medical Group, Escondido, CA; Stephen T. Miller, MD, Methodist Teaching Practice, Memphis, TN; William B. Smith, MD, New Orleans Center for Clinical Research, New Orleans, LA; Donald Brandon, MD, California Research Foundation, San Diego, CA; Paul E. Ziajka, MD, PhD, Lipid Clinic of Orlando, Orlando, FL; Arthur

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Cited by (27)

A Prudent Algorithm for Hyperlipoproteinemia in Renal Transplant Recipients
2009, Transplantation Proceedings
Citation Excerpt :
In a double-blind prospective randomized study, 80 mg ER fluvastatin provided an additional 6% decrease in LDL-C level when compared with the 40 mg IR formulation. However, this decrease was not matched by a clinically relevant reduction in adverse cardiovascular events.12 The Assessment of Lescol in Renal Transplantation (ALERT) Study, which was the first, large-scale outcome study in kidney transplant recipients, has been interpreted with different outcomes.
Hyperlipidemia and particularly low-density lipoprotein cholesterol (LDL-C) have been proposed as independent risk factors predisposing to chronic allograft nephropathy.
The primary objective of this prospective randomized study was to evaluate the efficacy of the modified National Cholesterol Education Program (NCEP) Step I Diet to prevent posttransplantation hyperlipidemia. The secondary objective was to assess the impact of fluvastatin on the lipid profile of patients unresponsive to dietary measures.
The study population consisted of 143 consecutive patients who underwent transplantation between October 1998 and January 2005. Patients who failed to demonstrate total and LDL-C levels below the optimal values of 200 mg/dL and 130 mg/dL respectively, were recruited for fluvastatin treatment. The remaining patients who achieved and maintained the target lipid levels continued on the same dietary regimen.
Baseline demographic characteristics were not different among the fluvastatin and modified Step I Diet groups. Mean total cholesterol (231.2 vs 187.3 mg/dL; P < .000), LDL-C (134.5 vs 99.2 mg/dL; P < .000), high-density lipoprotein cholesterol (HDL-C; 62.9 vs 55.7 mg/dL; P = .012), and triglyceride (170.3 vs 138.7 mg/dL; P = .011) levels following the dietary run-in period were significantly different between the patients assigned to fluvastatin treatment and those left on the diet, respectively. Fluvastatin achieved reductions ranging from 12% to 14% in the concentrations of total cholesterol (231.2 ± 4.29 mg/dL to 202.7 ± 3.89 mg/dL; P < .000) and LDL-C (134.5 ± 3.53 mg/dL to 115.6 ± 3.18 mg/dL; P < .000) among 91% of patients after 1 year of treatment. A substantial decrease in all lipoprotein concentrations occurred in 53 patients in the modified Step I Diet group with significant reductions in total cholesterol (187.3 ± 4.98 mg/dL to 172.7 ± 3.8 mg/dL; P < .000) and LDL-C (99.2 ± 4.0 mg/dL to 96.2 ± 3.44 mg/dL; P < .000).
Initiation and education of the Step I Diet should be provided during hospitalization. The 3-month dietary run-in period was deemed sufficient to determine the effect of diet on lipid abnormalities. Reduction of lipoprotein levels by a 40-mg daily fluvastatin dose was sufficient, safe, and tolerable.
The effect of an HMG-CoA reductase inhibitor on arteriosclerotic nanoplaque formation and size in a biosensor model
2003, Biosensors and Bioelectronics
Proteoheparan sulfate can be adsorbed to a methylated silica surface in a monomolecular layer via its transmembrane hydrophobic protein core domain. Due to electrostatic repulsion, its anionic glycosaminoglycan side chains are stretched out into the blood substitute solution, thereby representing a receptor site for specific lipoprotein binding through basic amino acid-rich residues within their apolipoproteins. The binding process was studied by ellipsometric techniques. Low-density lipoprotein (LDL) was found to deposit strongly at the proteoheparan sulfate-coated surface, particularly in the presence of Ca²⁺, apparently through complex formation ‘proteoglycan–LDL–calcium’. This ternary complex build-up may be interpreted as arteriosclerotic nanoplaque formation on the molecular level responsible for the arteriosclerotic primary lesion. HDL bound to heparan sulfate proteoglycan protected against LDL deposition and completely suppressed calcification of the proteoglycan–lipoprotein complex. In addition, HDL was able to decelerate the ternary complex deposition and to disrupt newly formed nanoplaques. Therefore, HDL attached to its proteoglycan receptor sites is thought to raise a multidomain barrier, selection and control motif for transmembrane and paracellular lipoprotein uptake into the arterial wall. The molecular arteriosclerosis model was tested on its reliability in a biosensor application in order to unveil possible acute pleiotropic effects of the lipid lowering drug fluvastatin. The very low-density lipoprotein (VLDL)/intermediate-density lipoprotein (IDL)/LDL and VLDL/IDL/LDL/HDL plasma fractions from a high-risk patient with dyslipoproteinemia and type 2 diabetes mellitus showed beginning arteriosclerotic nanoplaque formation already at a normal blood Ca²⁺ concentration, with a strong increase at higher Ca²⁺ concentrations. Nanoplaque formation and size of the HDL-containing lipid fraction remained well below that of the LDL-containing lipid fraction. Fluvastatin, whether applied acutely to the patient (one single 80 mg slow release matrix tablet) or in a 2-months medication regimen, markedly slowed down this process of ternary aggregational nanoplaque build-up and substantially inhibited nanoplaque size development at all Ca²⁺ concentrations used. The acute action resulted without any significant change in lipid concentrations of the patient. Furthermore, after nanoplaque generation, fluvastatin, similar to HDL, was able to reduce nanoplaque formation and size. These immediate effects of fluvastatin have to be taken into consideration while interpreting the clinical outcome of long-term studies.
The acute effect of fluvastatin on lipoprotein deposition in a model substrate for ellipsometry studies at an endothelial membrane equivalent
2002, Desalination
Proteoheparan sulfate can be adsorbed to a methylated silica surface in a monomolecular layer via its transmembrane hydrophobic protein core domain. Due to electrostatic repulsion, its anionic glycosaminoglycan side chains are stretched out into the blood substitute solution representing one receptor site for specific lipoprotein binding through basic amino acid-rich residues within their apolipoproteins. The binding process was studied by ellipsometric techniques. LDL was found to deposit strongly at the proteoheparan sulfate, particularly in the presence of Ca²⁺ thus creating the complex formation proteoglycan — low-density lipoprotein — calcium. This ternary complex build-up may be interpreted as arteriosclerotic nanoplaque formation on the molecular level responsible for the arteriosclerotic primary lesion. Although much remains unclear regarding the mechanism of lipoprotein depositions at proteoglycan-coated surfaces, it seems clear that the use of such systems offers possibilities for investigating lipoprotein deposition at a nanoscopic level under close to physiological conditions. Therefore, we tested the system on its reliability in a biosensor application in order to unveil possible acute pleiotropic effects of the lipid lowering drug fluvastatin. Already with a normal blood Ca²⁺ concentration, the VLDL/IDL/LDL plasma fraction from a high-risk patient with dyslipoproteinemia and type 2 diabetes mellitus showed beginning arteriosclerotic nanoplaque formation that massively increased at higher Ca²⁺ concentrations. Fluvastatin, whether applied to the patient (one single 80 mg slow release matrix tablet) or acutely in the experiment (2.2 μmol/l), markedly slowed down this process of ternary aggregational nanoplaque complexation at all Ca²⁺ concentrations used. This action resulted without any change in lipid concentrations of the patient. Furthermore, after ternary complex build-up, fluvastatin was able to reduce nanoplaque adsorption and size. These immediate effects of fluvastatin have to be taken into consideration while interpreting the results of long-term studies. Altogether, the proteoglycan coated hydrophobic silica surface used in these experiments, mimics the endothelial cell membrane in quite a perfect manner with respect to lipoprotein interactions at the blood-endothelium-matrix interface.
Comparison of the efficacy and tolerability of fluvastatin extended-release and immediate-release formulations in the treatment of primary hypercholesterolemia: A randomized trial
2001, Clinical Therapeutics
Background: A new extended-release (ER) formulation of fluvastatin 80 mg has been developed for once-daily treatment of primary hypercholesterolemia.
Objective: The purpose of this study was to compare the lipid-lowering efficacy and tolerability of fluvastatin ER (80 mg once daily) versus fluvastatin immediate-release (IR) (40 mg once or twice daily).
Methods: Following a 4-week placebo/dietary run-in period, patients with primary hypercholesterolemia type IIa or IIb (low-density lipoprotein cholesterol [LDL-C] ≥160 mg/dL and triglycerides [TG] ≤400 mg/dL) were randomized (2:1:1) to receive fluvastatin ER 80 mg once daily at bedtime (QPM), fluvastatin IR 40 mg QPM, or fluvastatin IR 40 mg BID for 24 weeks. Patients who had homozygous familial hypercholesterolemia; type I, III, IV, V, or secondary hyperlipoproteinemia; diabetes; or evidence of liver or renal impairment were excluded. At weeks 0, 2, 4, 8, 12, 16, 20, and 24 of the active-treatment period, levels of LDL-C, high-density lipoprotein cholesterol (HDL-C), TG, and total cholesterol (TC) were measured.
Results: Of the 1183 patients enrolled, 695 were randomly assigned to treatment—346 to fluvastatin ER 80 mg QPM, 174 to fluvastatin IR 40 mg QPM, and 175 to fluvastatin IR 40 mg BID. Patients were well matched between groups, with a mean age of ∼56 years and body mass index of 27 kg/m²; 56.0% of patients (389/695) were female and 97.7% (679/695) were white. Fluvastatin ER 80 mg QPM lowered LDL-C levels significantly more than did flu-
The ldl-receptor and its molecular properties: From theory to novel biochemical and pharmacological approaches in reducing ldl-cholesterol
2020, Current Medicinal Chemistry
Fluvastatin for lowering lipids
2018, Cochrane Database of Systematic Reviews

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^☆: This study was supported by a research grant from Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.

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The American Journal of Cardiology

Abstract

Section snippets

Study design

Results

Discussion

Acknowledgements

References (8)

Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in transplant patientsare statins mechanistically similar?

Pharmacol Ther

Pharmacokinetics of fluvastatin and specific drug interactions

Am J Hypertens

Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers

J Clin Pharmacol

Expanded Clinical Evaluation of Lovastatin (EXCEL) Study resultsI

Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. Arch Intern Med

Cited by (27)

A Prudent Algorithm for Hyperlipoproteinemia in Renal Transplant Recipients

The effect of an HMG-CoA reductase inhibitor on arteriosclerotic nanoplaque formation and size in a biosensor model

The acute effect of fluvastatin on lipoprotein deposition in a model substrate for ellipsometry studies at an endothelial membrane equivalent

Comparison of the efficacy and tolerability of fluvastatin extended-release and immediate-release formulations in the treatment of primary hypercholesterolemia: A randomized trial

The ldl-receptor and its molecular properties: From theory to novel biochemical and pharmacological approaches in reducing ldl-cholesterol

Fluvastatin for lowering lipids

Preventive cardiologyEfficacy and safety of an extended-release formulation of fluvastatin for once-daily treatment of primary hypercholesterolemia☆

Abstract

Section snippets

Study design

Results

Discussion

Acknowledgements

Pharmacol Ther

Pharmacokinetics of fluvastatin and specific drug interactions

Am J Hypertens

Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers

J Clin Pharmacol

Expanded Clinical Evaluation of Lovastatin (EXCEL) Study resultsI

Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. Arch Intern Med

Preventive cardiology
Efficacy and safety of an extended-release formulation of fluvastatin for once-daily treatment of primary hypercholesterolemia☆