William Taggart

Changes in cholesterol absorption and cholesterol synthesis caused by ezetimibe and/or simvastatin in men

This study evaluates changes in cholesterol balance in hypercholesterolemic subjects following treatment with an inhibitor of cholesterol absorption or cholesterol synthesis or coadministration of both agents. This was a randomized, double blind, placebo-controlled, four-period crossover study to evaluate the effects of coadministering 10 mg ezetimibe with 20 mg simvastatin (ezetimibe/simvastatin) on cholesterol absorption and synthesis relative to either drug alone or placebo in 41 subjects. Each treatment period lasted 7 weeks. Ezetimibe and ezetimibe/simvastatin decreased fractional cholesterol absorption by 65% and 59%, respectively (P < 0.001 for both relative to placebo). Simvastatin did not significantly affect cholesterol absorption. Ezetimibe and ezetimibe/simvastatin increased fecal sterol excretion (corrected for dietary cholesterol), which also represents net steady state cholesterol synthesis, by 109% and 79%, respectively (P < 0.001). Ezetimibe, simvastatin, and ezetimibe/simvastatin decreased plasma LDL-cholesterol by 20, 38, and 55%, respectively. The coadministered therapy was well tolerated. The decreases in net cholesterol synthesis and increased fecal sterol excretion yielded nearly additive reductions in LDL-cholesterol for the coadministration of ezetimibe and simvastatin.

VAP II analysis of lipoprotein subclasses in mixed hyperlipidemic patients on treatment with ezetimibe/simvastatin and fenofibrate

This analysis evaluates the effects on lipoprotein subfractions and LDL particle size of ezetimibe/simvastatin with or without coadministration of fenofibrate in patients with mixed hyperlipidemia. This multicenter, double-blind, placebo-controlled, parallel-group study included 611 patients aged 18–79 years randomized in 1:3:3:3 ratios to one of four 12 week treatment groups: placebo; ezetimibe/simvastatin 10/20 mg/day; fenofibrate 160 mg/day; or ezetimibe/simvastatin 10/20 mg/day + fenofibrate 160 mg/day. At baseline and study endpoint, cholesterol associated with VLDL, intermediate density lipoprotein (IDL), LDL, and HDL subfractions was quantified using the Vertical Auto Profile II method. LDL particle size was determined using segmented gradient gel electrophoresis. Whereas fenofibrate reduced cholesterol mass within VLDL and IDL, and shifted cholesterol from dense LDL subfractions into the more buoyant subfractions and HDL, ezetimibe/simvastatin reduced cholesterol mass within all apolipoprotein B-containing particles without significantly shifting the LDL particle distribution profile. When administered in combination, the effects of the drugs were complementary, with more-pronounced reductions in VLDL, IDL, and LDL, preferential loss of more-dense LDL subfractions, and increased HDL, although the effects on most lipoprotein subfractions were not additive. Thus, ezetimibe/simvastatin + fenofibrate produced favorable effects on atherogenic lipoprotein subclasses in patients with mixed hyperlipidemia.

Lipid-altering efficacy of switching to ezetimibe/simvastatin 10/20 mg versus rosuvastatin 10 mg in high-risk patients with and without metabolic syndrome

Metabolic syndrome (MetS) is a clustering of atherosclerotic coronary heart disease risk factors. This post-hoc analysis compared the effects of switching to ezetimibe/simvastatin 10/20 mg or rosuvastatin 10 mg in a cohort of 618 high-risk hypercholesterolaemic patients with (n=368) and without (n=217) MetS who had previously been on statin monotherapy. Patients were randomised 1:1 to double-blind ezetimibe/simvastatin 10/20 mg or rosuvastatin 10 mg for 6 weeks. Least squares mean percent change from baseline and 95% confidence intervals in lipid efficacy parameters were calculated for the population and within subgroups. Treatment with ezetimibe/simvastatin was significantly more effective than rosuvastatin at lowering low-density lipoprotein cholesterol, total cholesterol, non- high-density lipoprotein cholesterol, and apolipoprotein B (all p<0.001). No significant differences in treatment effects were seen between the presence and absence of MetS. In this post-hoc analysis of high-risk hypercholesterolaemic patients the lipid-reducing effects of ezetimibe/simvastatin or rosuvastatin were not altered significantly by the presence of MetS.

Long-term (48-week) safety of ezetimibe 10 mg/day coadministered with simvastatin compared to simvastatin alone in patients with primary hypercholesterolemia

ABSTRACT Objective: This study evaluated the long-term safety and tolerability of ezetimibe/simvastatin coadministration therapy compared to simvastatin monotherapy in patients with primary hypercholesterolemia. Research design and methods: After completing a 12-week randomized, double-blind, placebo-controlled, factorial, 10-armed study comparing ezetimibe 10 mg/simvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; ezetimibe 10 mg; or placebo, 768 patients entered a 48-week extension, with randomized, blinded, reassignment of the simvastatin 10 mg, ezetimibe, and placebo groups to one of the ezetimibe/simvastatin groups. Patients previously receiving ezetimibe/simvastatin combination therapy, or simvastatin 20, 40, and 80 mg monotherapy continued the same therapies in this 7-arm extension study. During the extension study, investigators assessed adverse events (AEs). Main outcome measures and results: Ezetimibe/simvastatin (n = 539) and simvastatin monotherapy (n = 229) groups generally had a similar incidence of all clinical AEs (73 vs. 69%), treatment-related AEs (14 vs. 11%), clinical serious AEs (SAE) (5.2 vs. 2.6%), treatment-related SAEs (0.2 vs. 0%), discontinuations due to all clinical AEs (4.5 vs. 2.6%) and discontinuations due to treatment-related AEs (2.8 vs. 2.2%), respectively. The incidence of total laboratory-related AEs for the ezetimibe/simvastatin and simvastatin monotherapy groups was also similar (12.2 vs. 11.9%), as was treatment-related laboratory AEs (6.2 vs. 5.3%), laboratory SAEs (0 vs. 0%), treatment-related laboratory SAEs (0 vs. 0%), discontinuations due to laboratory AEs (3.0 vs. 0.9%) and discontinuations due to treatment-related laboratory AEs (3.0 vs. 0.4%), respectively. There were no cases of myopathy, rhabdomyolysis, or serious hepatotoxicity observed in any group during this extension study. Conclusions: During this 48-week extension study, the coadministration of ezetimibe/simvastatin was generally as well tolerated as simvastatin monotherapy. The direct application of study observations to clinical practice is limited by patient selection criteria and dosage regime, which randomly applied relatively high doses rather than titration which often occurs in clinical practice.

Effects of Coadministered Ezetimibe Plus Fenofibrate in Mixed Dyslipidemic Patients with Metabolic Syndrome

OBJECTIVE Patients with metabolic syndrome are at increased risk of atherosclerotic coronary heart disease, often have mixed dyslipidemia, and may thus require more aggressive treatment of multiple lipid parameters. The objective of this investigation was to compare the treatment response of ezetimibe co-administered with fenofibrate in mixed dyslipidemic patients with and without metabolic syndrome. METHODS This post hoc analysis evaluated 625 patients 18-75 years of age with mixed dyslipidemia, defined as elevated low-density lipoprotein cholesterol (LDL-C) levels (130-220 mg/dL) and elevated triglycerides (TG) levels (200-500 mg/dL). Patients were randomized in a 1:3:3:3 ratio to 1 of 4 treatments for 12 weeks: Placebo; ezetimibe 10 mg; fenofibrate 160 mg; or ezetimibe 10 mg plus fenofibrate 160 mg. Metabolic syndrome was defined by the National Cholesterol Education Program Adult Treatment Panel III criteria and was identified at baseline in 450 patients. RESULTS Ezetimibe alone, fenofibrate alone, or their combination produced expected, and generally similar, lipid effects among those with or without metabolic syndrome with respect to LDL-C, apolipoprotein B (ApoB), and non-high-density lipoprotein cholesterol (HDL-C) levels. Ezetimibe alone may have resulted in greater LDL-C and ApoB lowering in the metabolic syndrome group than the non-metabolic syndrome group (P ≤ 0.05 for both). TG and high-sensitivity C-reactive protein had greater reductions in the fenofibrate and fenofibrate plus ezetimibe groups than the ezetimibe alone group (P ≤ 0.05 for both) CONCLUSIONS In this analysis of patients with mixed dyslipidemia, the lipid effects of ezetimibe plus fenofibrate were generally similar in metabolic syndrome patients versus those without metabolic syndrome.

Pharmacokinetics of digoxin in healthy subjects receiving taranabant, a novel cannabinoid-1 receptor inverse agonist

IntroductionInteraction studies with digoxin (Lanoxin®; GlaxoSmithKline, Research Triangle Park, NC, USA), a commonly prescribed cardiac glycoside with a narrow therapeutic index and a long half-life, are typically required during the development of a new drug, particularly when it is likely that digoxin may be given to patients also treated with the new agent, taranabant—a cannabinoid-1 receptor inverse agonist—for weight loss. This study was designed to establish if this combination of therapy has the potential of a significant pharmacokinetic interaction.MethodsThis open-label, fixed-sequence, two-period study investigated whether taranabant, administered to steady state, affects the well-described single-dose pharmacokinetics of digoxin. During the first period, 12 healthy men and women ranging in age from 21 to 35 years received a single oral dose of digoxin 0.5 mg. Following a 10-day wash out, they started a 19-day taranabant dosing regimen (6 mg once daily from day −14 to day 5) designed to establish and maintain steady-state levels of taranabant. On study day 1, subjects received a single oral dose of digoxin 0.5 mg. The plasma levels of digoxin were followed for an additional 4 days while the dosing of taranabant continued.ResultsThe geometric mean ratio and 90% confidence intervals for digoxin AUC0-∞ were 0.91 (0.83, 0.99), falling within the prespecified comparability intervals (CI) of (0.8, 1.25), which is within the usually allowed interval for bioequivalence. The geometric mean ratio and 90% CI for digoxin maximum plasma concentration (Cmax) were 1.23 (1.09, 1.40). The median time to Cmax was the same for both treatments.ConclusionMultiple doses of 6 mg taranabant do not have a clinically meaningful effect on the pharmacokinetics of a single oral dose of digoxin.

Influence of simvastatin, fenofibrate and/or ezetimibe on correlation of low-density lipoprotein and nonhigh-density lipoprotein cholesterol with apolipoprotein B in mixed dyslipidemic patients

OBJECTIVES Correlations between low-density lipoprotein cholesterol (LDL-C), or nonhigh-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (Apo B) change after statin therapy has been initiated in hypercholesterolemic patients. This post-hoc analysis studied the correlation between these parameters in patients with mixed dyslipidemia before and after receiving lipid-lowering treatment. RESULTS Data from two randomized, double-blind studies of 1112 patients with mixed dyslipidemia receiving treatment (ezetimibe 10 mg, ezetimibe/simvastatin 10/20 mg, fenofibrate 160 mg, ezetimibe + fenofibrate 10/160 mg, or ezetimibe/simvastatin + fenofibrate 10/20/160 mg) were pooled. Correlation analyses and simple linear regression analyses were performed at baseline in untreated patients and after 12 weeks of treatment in the whole pooled population, the treatment groups, and after stratification by baseline triglyceride levels (150-250, ≥ 250 mg/dL) within the treatment groups. Both LDL-C and non-HDL-C were closely correlated with levels of Apo B at baseline, and these correlations improved after treatment. When using the fitted simple linear regression equations, we found that the on-treatment LDL-C and non-HDL-C levels corresponding to an Apo B of 90, 80, and 70 mg/dL were lower than proposed LDL-C and non-HDL-C treatment targets. For TG ≥ 250 mg/dL, the corresponding LDL-C was generally lower than that for triglycerides 150-250 mg/dL, except in the cases with fenofibrate in the treatment. CONCLUSION The results of these analyses suggest that achieving goal-specified levels of Apo B in statin-treated patients with mixed dyslipidemia would require more aggressive LDL-C lowering to achieve the greatest reduction in LDL particle number.

Inhibition of prostacyclin and thromboxane biosynthesis in healthy volunteers by single and multiple doses of acetaminophen and indomethacin

This double‐blind, randomized crossover study assessed the effect of acetaminophen (1000 mg every 8 hours) versus indomethacin (50 mg every 8 hours) versus placebo on cyclooxygenase enzymes (COX‐1 and COX‐2). Urinary excretion of 2,3‐dinor‐6‐keto‐PGF1α, (prostacyclin metabolite, PGI‐M; COX‐2 inhibition) and 11‐dehydro thromboxane B2 (thromboxane metabolite, Tx‐M; COX‐1 inhibition) were measured after 1 dose and 5 days of dosing. Peak inhibition of urinary metabolite excretion across 8 hours following dosing was the primary end point. Mean PGI‐M excretion was 33.7%, 55.9%, and 64.6% on day 1 and 49.4%, 65.1%, and 80.3% on day 5 (placebo, acetaminophen, and indomethacin, respectively). Acetaminophen and indomethacin inhibited PGI‐M excretion following single and multiple doses (P = .004 vs placebo). PGI‐M excretion inhibition after 1 dose was similar for indomethacin and acetaminophen, but significantly greater with indomethacin after multiple doses (P = .006). Mean Tx‐M excretion was 16.2%, 45.2%, and 86.6% on day 1 and 46.2%, 58.4%, and 92.6% on day 5 (placebo, acetaminophen, and indomethacin, respectively). Tx‐M excretion inhibition following 1 dose was reduced by acetaminophen (P ≤ .003). Indomethacin reduced Tx‐M excretion significantly more than acetaminophen and placebo after single and multiple doses (P ≤ .001). Acetaminophen and indomethacin inhibited COX‐1 and COX‐2 following a single dose, but acetaminophen was a less potent COX‐1 inhibitor than indomethacin.