HMG-CoA reductase inhibitors. ATC Code:
Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low-density lipoproteins (VLDL) and released into the plasma for delivery to peripheral tissues. Low-density lipoprotein LDL is formed from VLDL and is catabolised primarily through the receptor with high affinity to LDL (LDL receptor).
Atorvastatin lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver and increases the number of hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL.
Atorvastatin reduces LDL production and the number of LDL particles. Atorvastatin produces a profound and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles. Atorvastatin is effective in reducing LDL-C in patients with homozygous familial hypercholesterolaemia, a population that has not usually responded to lipid-lowering medication.
Atorvastatin has been shown to reduce concentrations of total-C (30%-46%), LDL-C (41% -61%), apolipoprotein B (34% -50%), and triglycerides (14% -33%) while producing variable increases in HDL-C and apolipoprotein A1 in a dose response study. These results are consistent in patients with heterozygous familial hypercholesterolaemia, nonfamilial forms of hypercholesterolaemia, and mixed hyperlipidaemia, including patients with noninsulin-dependent diabetes mellitus.
Reductions in total-C, LDL-C, and apolipoprotein B have been proven to reduce risk for cardiovascular events and cardiovascular mortality. Mortality and morbidity studies with atorvastatin have not yet completed.
In the Reversing Atherosclerosis with Aggressive Lipid-Lowering Study (REVERSAL), the effect of intensive lipid lowering with atorvastatin 80 mg and standard degree of lipid lowering with pravastatin 40 mg on coronary atherosclerosis was assessed by intravascular ultrasound (IVUS), during angiography, in patients with coronary heart disease. In this randomized, double-blind, multicenter, controlled clinical trial, IVUS was performed at baseline and at 18 months in 502 patients. In the atorvastatin group (n = 253), there was no progression of atherosclerosis.
The median percent change, from baseline, in total atheroma volume (the primary study criteria) was -0.4% (p = 0.98) in the atorvastatin group and + 2.7% (p = 0.001) in the pravastatin group (n = 249). When compared to pravastatin the effects of atorvastatin were statistically significant (p = 0.02). The effect of intensive lipid lowering on cardiovascular endpoints (e.g. need for revascularisation, non fatal myocardial infarction, coronary death) was not investigated in this study.
In the atorvastatin group, LDL-C was reduced to a mean of 2.04 mmol/L ± 0.8 (78.9 mg/dl ± 30) from baseline 3.89 mmol/L ± 0.7 (150 mg/dl ± 28) and in the pravastatin group, LDL-C was reduced to a mean of 2.85 mmol/L ± 0.7 (110 mg/dl ± 26) from baseline 3.89 mmol/L ± 0.7 (150 mg/dl ± 26) (p <0.0001). Atorvastatin also significantly reduced mean TC by 34.1% (pravastatin : -18.4%, p <0.0001), mean TG levels by 20% (pravastatin : -6.8%, p <0.0009), and mean apolipoprotein B by 39.1% (pravastatin : -22.%, p <0.0001). Atorvastatin increased mean HDL-C by 2.9% (pravastatin : +5.6%, p = NS). There was a 36.4% mean reduction in CRP in the atorvastatin group compared to a 5.2% reduction in the pravastatin group (p <0.0001).
Study results were obtained with the 80 mg dose strength. Therefore, they cannot be extrapolated to the lower dose strengths.
The safety and tolerability profiles of the two treatment groups were comparable.
Acute Coronary Syndrome:
In the MIRACL study, atorvastatin 80 mg has been evaluated in 3,086 patients (atorvastatin n = 1,538; placebo n = 1,548) with an acute coronary syndrome (non Q-wave MI or unstable angina). Treatment was initiated during the acute phase after hospital admission and lasted for a period of 16 weeks. Treatment with atorvastatin 80 mg/day increased the time to occurrence of the combined primary endpoint, defined as death from any cause, nonfatal MI, resuscitated cardiac arrest, or angina pectoris with evidence of myocardial ischaemia requiring hospitalization, indicating a risk reduction by 16% (p = 0.048). this was mainly due to a 26% reduction in re-hospitalization for angina pectoris with evidence of myocardial ischaemia (p=0.018). The other secondary endpoints did not reach statistical significance on their own (overall: Placebo: 22.2%, Atorvastatin: 22.4%).
The safety profile of atorvastatin in the MIRACL study was consistent with what is described in Adverse Reactions.
Prevention of Cardiovascular Disease:
The effect of atorvastatin on fatal and non-fatal coronary heart disease was assessed in a randomized, double-blind, placebo-controlled study, the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA). Patients were hypertensive, 40-79 years of age, with no previous myocardial infarction or treatment for angina, and with TC levels ≤6.5 mmol/l (251 mg/dl). All patients had at least 3 of the pre-defined cardiovascular risk factors : male gender, age ≥55 years, smoking, diabetes, history of CHD in a first-degree relative, TC : HDL-C >6, peripheral vascular disease, left ventricular hypertrophy, prior cerebrovascular event, specific ECG abnormality, proteinuria/ albuminuria. Not all included patients were estimated to have a high risk for a first cardiovascular event.
Patients were treated with anti-hypertensive therapy (either amlodipine or atenolol-based regimen) and either atorvastatin 10 mg daily (n = 5,168) or placebo (n = 5,137).
The absolute and relative risk reduction effect of atorvastatin was as follows: See Table 1.
Click on icon to see table/diagram/image
Total mortality and cardiovascular mortality were not significantly reduced (185 vs. 212 events, p = 0.17 and 74 vs. 82 events, p = 0.51). In the subgroup analyses by gender (81% males, 19% females), a beneficial effect of atorvastatin was seen in males but could not be established in females possibly due to the low event rate in the female patients (38 vs. 30 and 17 vs. 12), but this was not statistically significant. There was significant treatment interaction by antihypertensive baseline therapy. The primary endpoint (fatal CHD plus non-fatal MI) was significantly reduced by atorvastatin in patients treated with Amlodipine (HR 0.47 (0.32-0.69), p = 0.00008), but not in those treated with Atenolol (HR 0.83 (0.59-1.17), p = 0.287).
The effect of atorvastatin on fatal and non-fatal cardiovascular disease was also assessed in a randomized, double-blind, multicenter, placebo-controlled trial, the Collaborative Atorvastatin Diabetes Study (CARDS) in patients with type 2 diabetes, 40-75 years of age, without prior history of cardiovascular disease, and with LDL-C ≤4.14 mmol/l (160 mg/dl) and TG ≤6.78 mmol/l (600 mg/dl). All patients had at least 1 of the following risk factors : hypertension, current smoking, retinopathy, microalbuminuria or macroalbuminuria.
Patients were treated with either atorvastatin 10 mg daily (n = 1,428) or placebo (n = 1,410) for a median follow-up of 3.9 years. The absolute and relative risk reduction effect of atorvastatin was as follows: See Table 2.
Click on icon to see table/diagram/image
There was no evidence of a difference in the treatment effect by patient's gender, age, or baseline LDL-C level. A favourable trend was observed regarding the mortality rate (82 deaths in the placebo group vs. 61 deaths in the atorvastatin group, p = 0.0592). Pharmacotherapeutic category: HMG-CoA reductase inhibitors, ATC code: C10AA 05. Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase. This rate-limiting enzyme catalyses the conversion of 3-hydroxy-3-methyl-glutaryl coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In the liver, triglycerides and cholesterol are incorporated into very low-density lipoproteins (VLDL) and released into the plasma for delivery to peripheral tissues. Low-density lipoproteins (LDL) are formed from VLDL and catabolised predominantly by the receptor with high affinity for LDL (LDL receptor).
Atorvastatin lowers concentrations of plasma cholesterol and lipoproteins in serum by inhibiting HMG-CoA reductase and hence cholesterol biosynthesis in the liver, and increases the number of hepatic LDL receptors on the cell surface resulting in accelerated uptake and catabolism of LDL. Atorvastatin reduces LDL production and the number of LDL particles. It produces a profound and sustained increase in LDL receptor activity coupled with an improvement in the quality of circulating LDL particles. Atorvastatin reduces LDL cholesterol in patients with homozygous familial hypercholesterolaemia, a patient population that does not usually respond to lipid-lowering medicinal products.
In a dose-response study, atorvastatin was shown to reduce concentrations of total cholesterol (by 30-46%), LDL cholesterol (by 41-61%), apolipoprotein B (by 34-50%) and triglycerides (by 14-33%) and, at the same time, produce variable increases in the concentrations of HDL cholesterol and apolipoprotein A1. These results apply equally to patients with heterozygous familial hypercholesterolaemia, non-familial forms of hypercholesterolaemia and mixed hyperlipidaemia, including patients with non-insulin dependent diabetes mellitus.
The reduction in total cholesterol, LDL cholesterol and apolipoprotein B provided demonstrable evidence of a reduction in the risk of cardiovascular events and cardiovascular deaths.
Prevention of Cardiovascular Disease:
In the ASCOT-LLA study (Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm), a randomised, double-blind, placebo-controlled study, the effect of atorvastatin on fatal and non-fatal coronary heart disease was assessed.
The patients received antihypertensive therapy (based on either amlodipine or atenolol) and either 10 mg of atorvastatin daily (n=5168) or placebo (n=5137).
The primary endpoint (fatal coronary heart disease and non-fatal myocardial infarction) was significantly reduced by atorvastatin in patients treated with amlodipine (HR 0.47 (0.32 to 0.69), p=0.00008) but not in those treated with atenolol (HR 0.83 (0.59 to 1.17), p=0.287).
Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations (Cmax
) occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. After oral administration, atorvastatin film-coated tablets are 95% to 99% bioavailable compared to the oral solution. The absolute bioavailibity of atorvastatin is approximately 12% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism.
Mean volume of distribution of atorvastatin is approximately 381 L. Atorvastatin is ≥98% bound to plasma proteins.
Atorvastatin is metabolized by cytochrome P450 3A4 to ortho-and parahydroxylated derivates and various beta-oxidation products. Apart from other pathways these products are further metabolized via glucuronidation. In vitro
, inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.
Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism. However, the medicinal product does not appear to undergo significant enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours. The half-life of inhibitory activity for HMG-CoA reductase is approximately 20 to 30 hours due to the contribution of active metabolites.
Geriatric: plasma concentrations of atorvastatin and its active metabolites are higher in healthy elderly subjects than in young adults while the lipid effects were comparable to those seen in younger patients' populations.
Paediatric: pharmacokinetic data in the paediatric population are not available.
Gender: concentrations of atorvastatin and its active metabolites in women differ from those in men (women: approx. 20% higher for Cmax
and approx. 10% lower for AUC).
These differences were of no clinical significance, resulting in no clinically significant differences in lipid effects among men and women.
Renal Insufficiency: renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin and its active metabolites.
Hepatic insufficiency: plasma concentrations of atorvastatin and its active metabolites are markedly increased (approx. 16-fold in Cmax
and approx. 11-fold in AUC) in patients with chronic alcoholic liver disease (Childs-Pugh B).
Toxicology: Preclinical Safety Data:
Atorvastatin was not carcinogenic in rats. The maximum dose used was 63-fold higher than the highest human dose (80 mg/day) on a mg/kg body-weight basis and 8-to 16fold higher based on AUC(0-24)
values as determined by total inhibitory activity. In a 2-year study in mice, incidences of hepatocellular adenoma in males and hepatocellular carcinomas in females were increased at the maximum dose used and the maximum dose used was 250-fold higher than the highest human dose on a mg/kg body-weight basis. Systemic exposure was 6-to11-fold higher based on AUC(0-24)
. Atorvastatin did not demonstrate mutagenic or clastogenic potential in 4 in vitro
tests with and without metabolic activation and in 1 in vitro
assay. In animal studies atorvastatin had no effect on male or female fertility at doses up to 175 and 225 mg/kg/day, respectively, and was not teratogenic.