What Atorvastatin Does
Atorvastatin is a potent HMG-CoA reductase inhibitor that lowers LDL cholesterol by 30-60% (depending on dose), reduces triglycerides by 15-30%, modestly increases HDL cholesterol by 5-10%, and significantly reduces cardiovascular events including myocardial infarction, stroke, and the need for coronary revascularization. 1, 2, 3
Primary Mechanism of Action
Atorvastatin selectively inhibits HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol, thereby blocking cholesterol synthesis in the liver. 1
The drug upregulates hepatic LDL receptors on liver cell surfaces, which enhances uptake and catabolism of circulating LDL particles while simultaneously reducing hepatic production of new LDL particles. 1
Active metabolites contribute approximately 70% of the total HMG-CoA reductase inhibitory activity, extending the drug's effective half-life to 20-30 hours despite a plasma elimination half-life of only 14 hours for the parent compound. 1
Lipid-Lowering Effects by Dose
| Dose | LDL-C Reduction | Triglyceride Reduction | HDL-C Increase |
|---|---|---|---|
| 10 mg daily | ~38% | ~15-20% | ~5-9% |
| 40 mg daily | ~45-50% | ~20-25% | ~5-10% |
| 80 mg daily | ~50-60% | ~25-30% | ~5-10% |
Atorvastatin 80 mg achieves LDL-C levels of approximately 62 mg/dL in high-risk patients, making it the most potent currently available statin for intensive lipid lowering. 4, 5
Atorvastatin produces greater LDL-C reductions than lovastatin, pravastatin, simvastatin, and fluvastatin at equivalent or lower doses across all patient populations studied. 4, 2, 3
Cardiovascular Event Reduction
Each 39 mg/dL (1 mmol/L) reduction in LDL-C with statin therapy reduces major coronary events by 24%, non-fatal MI by 27%, stroke by 16% (ischemic stroke by 21%), and coronary revascularization by 34%. 6
In the PROVE IT-TIMI 22 trial, atorvastatin 80 mg reduced the composite cardiovascular endpoint by 16% compared to pravastatin 40 mg over 2 years in patients hospitalized for acute coronary syndrome (P<0.005). 4, 5
In the ASCOT-LLA trial, atorvastatin 10 mg reduced nonfatal MI and fatal CHD by 36% (hazard ratio 0.64, P=0.0005), total cardiovascular events by 21%, and stroke by 27% in hypertensive patients with multiple risk factors over 3.3 years. 4
In patients with type 2 diabetes and coronary disease, atorvastatin reduces cardiovascular and cerebrovascular events by 15-31%, with similar relative risk reductions regardless of baseline LDL-C levels. 4
Effects on LDL Particle Composition
Atorvastatin significantly increases LDL particle diameter and decreases small, dense LDL subclasses, which are particularly atherogenic in patients with hypertriglyceridemia and diabetes. 6, 7
The drug reduces cholesterol content across all LDL subfractions, with preferential reduction of large-buoyant and intermediate-dense LDL particles in hypercholesterolemic patients (45% and 35% reduction respectively) compared to small-dense LDL (32% reduction). 7
In diabetic patients with dyslipoproteinemia, atorvastatin produces uniform cholesterol reduction across all LDL subtypes (27-32% reduction), suggesting the effect on LDL subtype distribution depends on the underlying lipid disorder. 7
Additional Pleiotropic Effects
Atorvastatin improves endothelial function by reducing lysophosphatidylcholine content in oxidized LDL by 11%, which partially restores endothelium-dependent relaxation of blood vessels. 8
The drug has antiproliferative effects on vascular smooth muscle, reduces platelet aggregation, and exerts anti-inflammatory effects independent of cholesterol lowering. 9
Atorvastatin may modestly reduce plasma glucose levels, though statins as a class are associated with a small increased risk of incident type 2 diabetes (1 extra case per 255 patients treated for 4 years, while preventing 5.4 vascular events). 4
Pharmacokinetics and Dosing
Peak plasma concentrations occur within 1-2 hours of oral administration, with an absolute bioavailability of approximately 14% due to extensive first-pass hepatic metabolism. 1
Food decreases absorption by 25% (Cmax) and 9% (AUC), but LDL-C reduction is identical whether taken with or without food, so atorvastatin can be administered at any time of day. 1
The drug is ≥98% bound to plasma proteins with a mean volume of distribution of 381 liters and poor penetration into red blood cells. 1
Atorvastatin is extensively metabolized by cytochrome P450 3A4 to active ortho- and para-hydroxylated metabolites, making drug interactions with CYP3A4 inhibitors (e.g., erythromycin, clarithromycin, itraconazole, ritonavir) clinically significant. 1
Safety Profile and Monitoring
The most common adverse events are gastrointestinal effects (dyspepsia, constipation, nausea), which are generally mild and transient. 2, 3
Hepatic transaminase elevations >3-fold ULN occur in 3.3% of patients on atorvastatin 80 mg versus 1.1% on pravastatin 40 mg, requiring baseline and periodic monitoring of liver enzymes. 4, 5, 6
Myopathy and rhabdomyolysis are rare (<0.1% at guideline-recommended doses), with no cases of severe myopathy observed in the PROVE IT trial with atorvastatin 80 mg. 4, 6
Advanced age (≥65 years), renal impairment, and concomitant use of CYP3A4 inhibitors increase the risk of myopathy, requiring closer monitoring in these populations. 1
Critical Clinical Considerations
Atorvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis, as plasma concentrations are markedly increased 4-fold in Child-Pugh A and 11-16-fold in Child-Pugh B disease. 1
Renal impairment does not affect plasma concentrations of atorvastatin, so no dosage adjustment is needed in patients with kidney disease, though these patients remain at higher risk for myopathy. 1
The cardiovascular benefits of atorvastatin far outweigh the modest risk of incident diabetes, with a clear net clinical benefit favoring statin therapy even in patients with pre-existing type 2 diabetes. 4
Atorvastatin is FDA-approved for adolescents aged 10-18 years (boys and post-menarchal girls) with heterozygous familial hypercholesterolemia and LDL-C ≥190 mg/dL or ≥160 mg/dL with family history of premature CVD. 4