Prolonged inhibition of cholesterol synthesis explains the efficacy of atorvastatin (original) (raw)
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Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia
Atherosclerosis, 2000
Patients with homozygous familial hypercholesterolaemia (HoFH) have markedly elevated low density lipoprotein (LDL) cholesterol levels that are refractory to standard doses of lipid-lowering drug therapy. In the present study we evaluated the effect of atorvastatin on steady state concentrations of plasma lipids and mevalonic acid (MVA), as well as on 24-h urinary excretion of MVA in patients with well characterized HoFH. Thirty-five HoFH patients (18 males; 17 females) received 40 mg and then 80 mg atorvastatin/day. The dose of atorvastatin was increased further to 120 mg/day in 20 subjects and to 160 mg/day in 13 subjects who had not achieved LDL cholesterol goal, or in whom the dose of atorvastatin had not exceeded 2.5 mg/kg body wt per day. LDL cholesterol levels were reduced by 17% at the 40 mg/day and by 28% at the 80 mg/day dosage (P B 0.01). Reduction in LDL cholesterol in the five receptor negative patients was similar to that achieved in the 30 patients with residual LDL receptor activity. Plasma MVA and 24-h urinary excretion of MVA, as markers of in vivo cholesterol synthesis, were elevated at baseline and decreased markedly with treatment. Urinary MVA excretion decreased by 57% at the 40 mg/day dose and by 63% at the 80 mg/day dosage (PB0.01). There was a correlation between reduction in LDL cholesterol and reduction in urinary MVA excretion; those patients with the highest basal levels of MVA excretion and thus the highest rates of cholesterol synthesis having the greatest reduction in LDL cholesterol (r= 0.38; P=0.02). Increasing the dose of atorvastatin to 120 and 160 mg/day did not result in any further reduction in LDL cholesterol or urinary MVA excretion suggesting a plateau effect with no further inhibition of cholesterol synthesis at doses of atorvastatin greater than 80 mg/day.
Effective Analysis of Atorvastatin Versus in Simvastatin Patients with Hyperlipidemia
2009
evaluate the safety and dose efficacy of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG- CoA) reductase inhibitor atorvastatin (X-tor) and simvastatin (Zocor) in hypercholesterolemic patients. Fifty hyperlipidemia patients between the ages of 20 and 75 years with baseline of low-density-lipoprotein (LDL) cholesterol (>160 mg/dl) and triglycerides (>400 mg/dl) received once-daily dosing with atorvastatin 10, 20 mg or simvastatin 10, 20 mg. The efficacy end points were mean percent change in plasma LDL cholesterol, total cholesterol, triglycerides, and high-density lipoprotein cholesterol (HDL-C) concentrations from baseline to the end of treatment (week 8). Atorvastatin 10, 20 mg caused significantly greater reductions in total cholesterol, LDL cholesterol and apolipoprotein B, respectively, than the milligram equivalent doses of simvastatin. On the other hand Atorvastatin 10 mg caused triglycerides and HDL cholesterol were not different between atorvastatin and the other reduc...
Lipid modifying action of atorvastatin in escalating doses in patients of coronary artery disease
International Journal of Basic & Clinical Pharmacology, 2014
India is passing through an epidemic of coronary artery disease (CAD) and it is expected to be the most important cause of mortality in India by the year 2015. 1 The usual lipid profile prevalent in Indians is relatively low high-density lipoprotein cholesterol (HDL-C) and high triglycerides (TG) with normal or slightly elevated low-density lipoprotein cholesterol (LDL-C). 2 Statin-mediated lowering of LDL-C is regarded as the foundation of lipid-modifying therapy. However, this has failed to reduce cardiovascular event rates more than 20-40% relative to placebo 3 indicating the need for comprehensive lipid modification as well as control of nonlipid risk factors to combat the residual risk. Since low levels of HDL-C are established as a strong independent risk factor for cardiovascular disease (CVD), lifestyle modification and pharmacological measures must be taken together to achieve the target. 4 Atorvastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase lowers LDL-C significantly, but has very little impact on HDL-C. It is frequently used in doses 10 mg, 20 mg, 40 mg and 80 mg for different levels of LDL-C elevation at baseline and the magnitude of associated major adverse cardiac event risk in future. 5 Various studies indicate that statins (which include atorvastatin), tend to decrease LDL-C for an additional 6% on doubling the dose at each level from 10 to 80 mg. This is popularly known as the "Rule of six," 6 but from literature search no such data for eastern Indian population could be established. Indians are expected to differ in their lipid distribution pattern as compared to their Caucasian counterpart owing partly to different genetic constitution and different lifestyle. Hence, the present study was undertaken to ascertain whether the same rule holds good for our population or not and also to assess the efficacy and ABSTRACT Background: A prospective, randomized controlled study with parallel treatment groups carried out to assess efficacy and tolerability of atorvastatin in escalating doses (10 mg, 20 mg, 40 mg and 80 mg) in modulating the lipid profile in patients of coronary artery disease in eastern Indian population and whether "Rule of six" commonly referred to in context of low-density lipoprotein (LDL) reduction by statins stands true in our population. Methods: Patients randomly allocated into four groups (n=632) as per selection criteria. Groups A, B, C, D received atorvastatin 10 mg, 20 mg, 40 mg and 80 mg, respectively once daily at bedtime, for 24 weeks after which evaluation of efficacy and tolerability was done. Comparison between groups performed with one-way ANOVA; p<0.05 considered to be statistically significant. Results: There was a significant reduction in cholesterol, LDL and triglycerides in all the groups, but between group comparisons did not reveal any significant reduction in lipid parameters between Groups C and D. "Rule of six" was not observed at higher doses of atorvastatin (40, 80 mg). Further, there was significant reduction of high-density lipoprotein (HDL) in Groups C and D, which is not accepted especially in Indian context where it is already low at baseline. Conclusion: In Indian perspective, where HDL is low, and the LDL values are not very high, escalating dose of atorvastatin does not give additional clinical benefit. On the contrary, reduction of HDL itself predicts an adverse cardiovascular outcome. Increased adverse events and burden of cost must be taken into account, while prescribing atorvastatin.
Efficacy and safety of atorvastatin compared to pravastatin in patients with hypercholesterolemia
Atherosclerosis, 1997
Plasma cholesterol and other lipoproteins play a significant role in the development of atherosclerosis and subsequent coronary heart disease (CHD). This 1 year study was designed to confirm the efficacy and safety of atorvastatin (Lipitor) compared to pravastatin, a marketed agent for low density lipoprotein cholesterol (LDL-C) reduction in hypercholesterolemic patients. Patients were recruited at 26 centers in six European countries. After a 6 week placebo baseline phase, patients were randomized to receive atorvastatin 10 mg or pravastatin 20 mg daily. The dose could be doubled at week 16, if LDL-C levels remained ] 3.4 mmol/l (135 mg/dl). Atorvastatin significantly lowered LDL-C from baseline by 35% compared with 23% for pravastatin (P B0.05). A total of 72% of atorvastatin patients attained the LDL-C target level of B 3.4 mmol/l, compared to 26% of pravastatin patients. Atorvastatin also significantly reduced TC, TG and apo B (PB 0.05). Safety was assessed by recording adverse events and measuring clinical laboratory parameters. The adverse event profile was similar for both treatment groups and neither treatment caused clinically relevant laboratory abnormalities. Atorvastatin 10 and 20 mg once daily is superior to pravastatin 20 and 40 mg once daily in treating patients with hypercholesterolemia.
South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde, 1991
The aim of this study was to evaluate the long-term efficacy and tolerability of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor simvastatin, over a 24-week period. Patients (108) with primary hypercholesterolaemia were clinically, haematologically and biochemically evaluated and established on a cholesterol-lowering diet. After a wash-out period free from other lipid-lowering drugs and a baseline period on placebo of 1 month each, 10 mg simvastatin was introduced at night. The dose was increased to 20 mg and 40 mg at 6 and 12 weeks' follow-up respectively if the total cholesterol (TC) level was still above 5.17 mmol/l. Follow-up took place every 6 weeks and included lipid, haematological, biochemical and clinical evaluation. A full ophthalmological evaluation was conducted at baseline and at 24 weeks' follow-up. Overall the TC level was reduced below the baseline level by 34.3% at week 18 of follow-up and 32.5% at week 24. Patients with higher initia...
The American Journal of Cardiology, 2008
Maximal doses of atorvastatin and rosuvastatin are highly effective in lowering low-density lipoprotein (LDL) cholesterol and triglyceride levels; however, rosuvastatin has been shown to be significantly more effective than atorvastatin in lowering LDL cholesterol and in increasing high-density lipoprotein (HDL) and its subclasses. Our purpose in this post hoc subanalysis of an open-label study was to compare the effects of daily oral doses of rosuvastatin 40 mg with atorvastatin 80 mg over a 6-week period on direct LDL cholesterol and small dense LDL (sdLDL) cholesterol in 271 hyperlipidemic men and women versus baseline values. Rosuvastatin was significantly (p <0.01) more effective than atorvastatin in decreasing sdLDL cholesterol (؊53% vs ؊46%), direct LDL cholesterol (؊52% vs ؊50%), total cholesterol/HDL cholesterol ratio (؊46% vs ؊39%), and non-HDL cholesterol (؊51% vs ؊48%), The magnitude of these differences was modest, and the 2 statins caused similar decreases in triglyceride levels (؊24% and ؊26%). In conclusion, our data indicate that the 2 statins, given at their maximal doses, significantly and beneficially alter the entire spectrum of lipoprotein particles, but that rosuvastatin is significantly more effective than atorvastatin in lowering direct LDL cholesterol and sdLDL cholesterol. © 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;101:315-318)
International Journal of Cardiology, 2005
Background: The presence of increased levels of small dense (sd) LDL (phenotype B) is associated with a substantial increase of cardiovascular disease risk. Since lowering of plasma low-density lipoprotein-cholesterol (LDL-C) by statins involves an up-regulation of the LDL receptor, we questioned whether LDL lowering by atorvastatin affects different LDL subfractions equally. Methods: Fifty-four hypercholesterolemic patients, requiring treatment for prevention of coronary heart disease received atorvastatin (10, 20 or 40 mg/day), either as initial therapy (n=33), or as replacement therapy (n=21) for pravastatin or simvastatin (both at 40 mg/day). In addition to plasma lipid measurements, cholesterol LDL subfractions were separated and analysed before and after 3 months of treatment.