Fluvastatin and niacin in hypercholesterolemia: a preliminary report on gender differences in efficacy.

A total of 74 hypercholesterolemic patients were randomized to receive double-blind treatment for 6 weeks with either 20 mg of fluvastatin daily or placebo. Open-label niacin, to a maximum of 3 g daily, was added to each treatment for a further 9 weeks. Changes in lipid parameters were derived from averaged data, with monotherapy at weeks 3 and 6 and with combination therapy at weeks 12 and 15. The reduction in low-density lipoprotein cholesterol (LDL-C) was significantly greater with fluvastatin (20.8%) compared with placebo (p < 0.001) after 3-6 weeks of treatment. At the end of 12-15 weeks, the addition of niacin potentiated the response to 43.7% with the fluvastatin+niacin combination and to 26.5% with the placebo+niacin combination (p < 0.001, vs baseline and between treatment groups). Significant gender differences were noted in the LDL-C response to the fluvastatin+niacin combination. Women achieved LDL-C reductions of 54.6% whereas men achieved reductions of 38.2% (p < 0.0005, between gender groups). Women also tended to have greater LDL-C reductions with the placebo+niacin combination, compared with men (p < 0.05). At the end of 12-15 weeks, there were HDL-C increases of 33.1% (p < 0.001) whereas triglyceride levels declined by 32.3% (p < 0.001). In conclusion, fluvastatin, both as monotherapy and in combination with niacin, proved to be an effective and well-tolerated alternative for the treatment of hypercholesterolemia. The differential response in LDL-C between men and women should be further explored in other trials of lipid-lowering therapy.

Efficacy and safety of fluvastatin in patients with non-insulin-dependent diabetes mellitus and hyperlipidemia.

The purpose of this study was to investigate the triglyceride-lowering effect of fluvastatin, a new 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, in the combined hyperlipidemia of non-insulin-dependent diabetes mellitus (NIDDM). In this double-blind trial, 66 patients with NIDDM (24 men and 42 women, age 37-71), with low-density lipoprotein cholesterol (LDL-C) levels of 130-300 mg/dL (3.4-7.8 mmol/L) and triglyceride (TG) levels of 200-1,000 mg/dL (2.3-11.3 mmol/L) despite an 8-week period of diet modification, were randomized to receive either fluvastatin at 20 mg once daily (at night) or placebo for 6 weeks, followed by an increase of fluvastatin to 20 mg twice daily for an additional 6 weeks of treatment. After 12 weeks, fluvastatin decreased plasma levels of total cholesterol by 19.9% (p < 0.001), LDL-C by 24.3% (p < 0.001), TG by 15.3% (p < 0.01), very low-density lipoprotein cholesterol (VLDL-C) by 19.7% (p < 0.001), apolipoprotein (apo) B by 21.3% (p < 0.001), and apo E by 18.1% (p < 0.05), whereas high-density lipoprotein cholesterol (HDL-C) levels were increased by 4.6% (p < 0.05). Within the intermediate-density lipoprotein cholesterol (IDL-C) fraction, a constituent analysis revealed a total cholesterol reduction of 35% (p < 0.01). Greater decreases in TG were seen in patients who had higher levels of TG at baseline. Slight increases in glycemic indices and body weight were seen in both treatment groups. The occurrence of clinical and laboratory abnormalities was similar with both active treatment and placebo, and no myositis was observed. Slight increases in aspartate (ASAT; mean 5.6 U/L at the higher dose) and alanine (ALAT; mean 5.1 U/L at the higher dose) aminotransferases were not clinically significant. In this first, parallel-group placebo-controlled trial of a reductase inhibitor in a free-living NIDDM population, fluvastatin safely improved the combined TG, VLDL-C, IDL-C, LDL-C, and HDL-C abnormalities associated with NIDDM.

Updated clinical safety experience with fluvastatin.

Clinical experience with fluvastatin in > 1,800 North American patients treated for an average of 61 weeks has shown it to be safe and well tolerated. Frequencies of transaminase and creatine kinase elevations compare favorably with those observed during long-term administration of other 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. Further, whereas frank rhabdomyolysis has been encountered with treatment with all other HMG-CoA reductase inhibitors, this syndrome has not been observed to date with fluvastatin in studies here or abroad; a single case of myopathy, which was probably related to physical exertion, was reported in a patient receiving fluvastatin. Although dyspepsia was observed more commonly in fluvastatin patients the incidence, along with that of other adverse events (e.g., headache), and the number of treatment discontinuations proved statistically indistinguishable from those of placebo controls. Whether the favorable safety profile of fluvastatin is related to this synthetic agent's unique biopharmaceutical profile is a matter of ongoing long-term inquiry.

Fluvastatin with and without niacin for hypercholesterolemia.

Seventy-four patients with plasma low-density lipoprotein cholesterol levels > or = 160 mg/dl after an American Heart Association phase 1 diet were randomized to double-blind treatment with fluvastatin, 20 mg/day, or placebo for 6 weeks. Immediate-release niacin was then added to both treatment regimens and titrated to a maximum of 3 g/day for a further 9 weeks. After 6 weeks of fluvastatin monotherapy, low-density lipoprotein cholesterol levels decreased by 21% (p < 0.001 vs placebo), and after the addition of niacin, response was potentiated to 40% compared with 25% for the niacin control group at study end point (p < 0.001). Fluvastatin, alone and in combination with niacin, also significantly improved high-density lipoprotein cholesterol (increases of about 30%) and triglyceride profiles (decreases of approximately 28%) from baseline. Lipoprotein(a) decreased by 37% in those receiving fluvastatin-niacin but was unaltered in those receiving fluvastatin alone. No serious adverse events were ascribed to fluvastatin, and no cases of myositis were observed. Small, transient, asymptomatic increases in aspartate aminotransferase were noted with fluvastatin-niacin treatment but were not considered clinically relevant. Although the fluvastatin-niacin combination in this study was without evidence of significant transaminitis, myopathy, or rhabdomyolysis, it would seem prudent to continue to monitor its safety with longer term use. In conclusion, fluvastatin, both as monotherapy and in combination with niacin, proved to be an effective, safe, and well-tolerated therapeutic alternative for hypercholesterolemia.

Pharmacokinetics of fluvastatin and specific drug interactions.

Fluvastatin sodium (Lescol) is the first synthetic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-reductase inhibitor to be studied extensively in humans. Absorption of fluvastatin is complete and unaffected by the presence of food. Systemic exposure is limited because of extensive sequestration by the liver and/or first-pass metabolism, a plasma half-life of approximately 30 min, no circulating active metabolites, and no accumulation of drug during chronic dosing. Approximately 95% of a single dose of fluvastatin is excreted via the biliary route with less than 2% as the parent compound. Studies investigating the effect of food on fluvastatin pharmacokinetics have demonstrated marked reductions in the rate of bioavailability (Cmax) of 40% to 60%. A comparison of drug administration with the evening meal or at bedtime revealed no significant differences in either the extent of bioavailability (area under the curve; AUC) or pharmacodynamic effect [reduction in low-density lipoprotein cholesterol (LDL-C)]. Relative to the general population, plasma fluvastatin concentrations do not vary as a function of either age or gender. Administration of a single 40-mg dose to a patient population with hepatic insufficiency resulted in a 2.5-fold increase in both AUC and Cmax. Drug interaction studies with fluvastatin and cholestyramine (CME) demonstrated a lower rate and extent of fluvastatin bioavailability; no impact on efficacy was demonstrated when CME was given 4 h before fluvastatin dosing in clinical trials. Interaction studies with niacin and propranolol demonstrated no effects on fluvastatin plasma levels, and fluvastatin administered to a patient population chronically receiving digoxin had no effect on the AUC of digoxin compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Development and pharmacology of fluvastatin.

Fluvastatin is the first synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitor to be approved for clinical use, and has been studied extensively in humans since 1986. It is structurally distinct from the other currently available HMGCoA reductase inhibitors (lovastatin, simvastatin, and pravastatin), leading to unique biopharmaceutical properties relative to the other agents of this class. Absorption of fluvastatin is virtually complete across all species, including man, and is not affected by the presence of food. Systemic exposure is limited, as fluvastatin is subject to first-pass metabolism, and the plasma half-life of the drug is approximately 30 minutes. Some 95% of a single dosage of fluvastatin is excreted via the biliary route, with less than 2% of this being the parent compound. Additionally, there is no evidence of circulating active metabolites or accumulation during chronic dosing. Studies of the effect of food on the pharmacokinetics of fluvastatin have demonstrated marked reductions in the rate of bioavailability--from 40% to 60%; however, a comparison of fluvastatin administration with the evening meal or at bedtime has revealed no significant differences in the extent of bioavailability (area under the curve) of these two regimens. Furthermore, no significant difference in pharmacodynamic effect (reduction in low-density lipoprotein cholesterol levels) could be ascertained between mealtime dosing and bedtime dosing. The pharmacokinetics of fluvastatin have also been assessed in various demographic groups. Relative to the general population, plasma concentrations of fluvastatin do not vary as a function of either age or gender. In addition, administration to a patient population with hepatic insufficiency resulted in a 2.5-fold increase in both the rate and extent of bioavailability relative to controls. Also, although minimal alterations of fluvastatin clearance in patients with renal insufficiency are anticipated due to limited renal excretion (5%), a study in this patient group is currently underway to examine this further. Interaction studies have been performed with fluvastatin and several drugs with which it might be coadministered. Cholestyramine, an anionic-binding resin, has a considerable effect in lowering the rate and extent of fluvastatin bioavailability. Although this effect was noted even when cholestyramine was given 4 hours prior to fluvastatin, this regimen did not result in diminished efficacy. Further, no effects on either warfarin levels or prothrombin times were observed in a study involving concomitant administration of warfarin and fluvastatin. Moreover, additional interaction studies with niacin and propranolol have not demonstrated any effect on fluvastatin plasma levels, and administration to a patient population chronically receiving digoxin resulted in no difference in the extent of bioavailability of digoxin relative to control data. The results generated to date in clinical pharmacokinetic studies with fluvastatin thus support its use in a broad population of hypercholesterolaemic patients.

Fluvastatin in combination with other lipid-lowering agents.

Fluvastatin, a new synthetic inhibitor of HMGCoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, has been studied in several models to examine its effects when used in combination with other lipid-modifying agents such as derivatives of fibric acid (bezafibrate), resins (cholestyramine), and niacin. The combination of fluvastatin with bezafibrate has been studied in a double-blind trial involving patients with well-documented familial hypercholesterolaemia. Fluvastatin 40 mg/day, combined with either bezafibrate 400 mg/day or cholestyramine 8 g/day, resulted in reductions in levels of low-density lipoprotein cholesterol (LDL-C), these being indistinguishable between the groups; however, significantly greater increases in levels of high-density lipoprotein cholesterol (21.3%) and reductions in levels of triglycerides (25.1%) were seen with the fluvastatin-bezafibrate combination. No notable increases were seen in levels of serum creatine kinase, aspartate aminotransferase, or alanine aminotransferase, and no cases of myopathy were observed. In a study model that examined low-dose combinations of fluvastatin with cholestyramine, reductions in levels of LDL-C of 15.8% and 19.3% were seen with fluvastatin 10 mg and 20 mg, respectively. After an 8-week interval in which a daily dosage of cholestyramine 8 g was added, from baseline, reductions of 26.3% in the 10 mg fluvastatin-cholestyramine group and 31.2% in the 20 mg fluvastatin-cholestyramine group were observed, whereas the placebo-cholestyramine group displayed a reduction of 14.9%. Doubling the resin dosage to 16 g/day for the final 8 weeks of the study provided little additional benefit. Myotoxicity has been observed when lovastatin is coadministered with niacin, and so the combination of niacin with fluvastatin has also been studied to examine the possibility of this effect occurring. Patients were randomised to either fluvastatin 20 mg or placebo for 6 weeks, after which time open-label niacin was administered to all patients and titrated to a final dosage of 3 g/day. After 6 weeks, fluvastatin produced a 20.8% reduction in LDL-C levels from baseline. When combined with niacin, a 43.7% reduction was noted at the week 15 endpoint, against the 26.5% reduction seen with niacin monotherapy. The combination was well tolerated, with no reports of myopathy or of significant elevations in creatine kinase or liver transaminase levels. Combinations of fluvastatin with a variety of other agents have been shown to have significant effects on lipid profiles, with no evidence to date of clinically remarkable safety findings. Thus, the use of combination therapies may result in optimal management of patients with moderately severe hypercholesterolaemia and mixed dyslipidaemic profiles.

Development and pharmacology of fluvastatin.

Fluvastatin is the first synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitor to be approved for clinical use, and has been studied extensively in humans since 1986. It is structurally distinct from the other currently available HMGCoA reductase inhibitors (lovastatin, simvastatin, and pravastatin), leading to unique biopharmaceutical properties relative to the other agents of this class. Absorption of fluvastatin is virtually complete across all species, including man, and is not affected by the presence of food. Systemic exposure is limited, as fluvastatin is subject to first-pass metabolism, and the plasma half-life of the drug is approximately 30 minutes. Some 95% of a single dosage of fluvastatin is excreted via the biliary route, with less than 2% of this being the parent compound. Additionally, there is no evidence of circulating active metabolites or accumulation during chronic dosing. Studies of the effect of food on the pharmacokinetics of fluvastatin have demonstrated marked reductions in the rate of bioavailability--from 40% to 60%; however, a comparison of fluvastatin administration with the evening meal or at bedtime has revealed no significant differences in the extent of bioavailability (area under the curve) of these two regimens. Furthermore, no significant difference in pharmacodynamic effect (reduction in low-density lipoprotein cholesterol levels) could be ascertained between mealtime dosing and bedtime dosing. The pharmacokinetics of fluvastatin have also been assessed in various demographic groups. Relative to the general population, plasma concentrations of fluvastatin do not vary as a function of either age or gender. In addition, administration to a patient population with hepatic insufficiency resulted in a 2.5-fold increase in both the rate and extent of bioavailability relative to controls. Also, although minimal alterations of fluvastatin clearance in patients with renal insufficiency are anticipated due to limited renal excretion (5%), a study in this patient group is currently underway to examine this further. Interaction studies have been performed with fluvastatin and several drugs with which it might be coadministered. Cholestyramine, an anionic-binding resin, has a considerable effect in lowering the rate and extent of fluvastatin bioavailability. Although this effect was noted even when cholestyramine was given 4 hours prior to fluvastatin, this regimen did not result in diminished efficacy. Further, no effects on either warfarin levels or prothrombin times were observed in a study involving concomitant administration of warfarin and fluvastatin. Moreover, additional interaction studies with niacin and propranolol have not demonstrated any effect on fluvastatin plasma levels, and administration to a patient population chronically receiving digoxin resulted in no difference in the extent of bioavailability of digoxin relative to control data. The results generated to date in clinical pharmacokinetic studies with fluvastatin thus support its use in a broad population of hypercholesterolaemic patients.

Fluvastatin in combination with other lipid-lowering agents.

Fluvastatin, a new synthetic inhibitor of HMGCoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, has been studied in several models to examine its effects when used in combination with other lipid-modifying agents such as derivatives of fibric acid (bezafibrate), resins (cholestyramine), and niacin. The combination of fluvastatin with bezafibrate has been studied in a double-blind trial involving patients with well-documented familial hypercholesterolaemia. Fluvastatin 40 mg/day, combined with either bezafibrate 400 mg/day or cholestyramine 8 g/day, resulted in reductions in levels of low-density lipoprotein cholesterol (LDL-C), these being indistinguishable between the groups; however, significantly greater increases in levels of high-density lipoprotein cholesterol (21.3%) and reductions in levels of triglycerides (25.1%) were seen with the fluvastatin-bezafibrate combination. No notable increases were seen in levels of serum creatine kinase, aspartate aminotransferase, or alanine aminotransferase, and no cases of myopathy were observed. In a study model that examined low-dose combinations of fluvastatin with cholestyramine, reductions in levels of LDL-C of 15.8% and 19.3% were seen with fluvastatin 10 mg and 20 mg, respectively. After an 8-week interval in which a daily dosage of cholestyramine 8 g was added, from baseline, reductions of 26.3% in the 10 mg fluvastatin-cholestyramine group and 31.2% in the 20 mg fluvastatin-cholestyramine group were observed, whereas the placebo-cholestyramine group displayed a reduction of 14.9%. Doubling the resin dosage to 16 g/day for the final 8 weeks of the study provided little additional benefit. Myotoxicity has been observed when lovastatin is coadministered with niacin, and so the combination of niacin with fluvastatin has also been studied to examine the possibility of this effect occurring. Patients were randomised to either fluvastatin 20 mg or placebo for 6 weeks, after which time open-label niacin was administered to all patients and titrated to a final dosage of 3 g/day. After 6 weeks, fluvastatin produced a 20.8% reduction in LDL-C levels from baseline. When combined with niacin, a 43.7% reduction was noted at the week 15 endpoint, against the 26.5% reduction seen with niacin monotherapy. The combination was well tolerated, with no reports of myopathy or of significant elevations in creatine kinase or liver transaminase levels. Combinations of fluvastatin with a variety of other agents have been shown to have significant effects on lipid profiles, with no evidence to date of clinically remarkable safety findings. Thus, the use of combination therapies may result in optimal management of patients with moderately severe hypercholesterolaemia and mixed dyslipidaemic profiles.

Efficacy and safety of fluvastatin in hyperlipidaemic patients with non-insulin-dependent diabetes mellitus.

In this preliminary report of a 20-week trial, 66 patients with non-insulin-dependent diabetes mellitus (NIDDM) and hyperlipidaemia who remained eligible after an 8-week dietary stabilization phase were randomly allocated to receive 20 mg of fluvastatin or placebo once daily for 6 weeks. Fluvastatin was subsequently increased to 20 mg twice daily and administered according to the same schedule, versus placebo, for a further 6 weeks. Both dosages of fluvastatin substantially improved serum lipid profiles compared with baseline and placebo. Both dosages of fluvastatin significantly reduced low-density- and very-low-density-lipoprotein (LDL, VLDL), cholesterol and triglyceride (TG) compared with placebo, and both dosages significantly elevated high-density-lipoprotein (HDL) cholesterol. The ratio of LDL to HDL was also significantly decreased. Amongst the 58 patients who completed the study, there was no evidence either of myopathy or of hepatotoxicity; mean creatine kinase values remained stable in the fluvastatin arm. Fasting glucose, glycosylated haemoglobin, and fructosamine levels were not markedly affected by active treatment. No serious adverse events attributable to the drug were reported. In conclusion, both dosages of fluvastatin appear to be effective and safe in the management of hyperlipidaemia in this outpatient, maturity-onset, diabetic population.