Atorvastatin calcium, a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (i.e., statin), is an antilipemic agent.1, 18, 65, 79
Reduction in Risk of Cardiovascular Events
Patients without Clinical Evidence of Coronary Heart Disease
Atorvastatin is used as an adjunct to diet and other lifestyle modifications in adults without clinical evidence of coronary heart disease (CHD) who have multiple risk factors (e.g., age, smoking, hypertension, low high-density lipoprotein [HDL]-cholesterol concentrations, family history of early CHD) to reduce the risk of myocardial infarction (MI), stroke, or angina, and to reduce the risk of undergoing revascularization procedures.1, 79, 400 Atorvastatin in fixed combination with amlodipine is used in patients for whom treatment with both atorvastatin and a calcium-channel blocking agent (i.e., amlodipine) is appropriate.65
Safety and efficacy of atorvastatin for primary prevention of cardiovascular disease have been established in several randomized, double-blind, placebo-controlled studies in patients without clinical evidence of CHD.1, 79 In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) in 10,305 hypertensive, hypercholesterolemic (total cholesterol 251 mg/dL or less) patients with no history of MI who had multiple risk factors for CHD, therapy with atorvastatin (10 mg daily) for a median of 3.3 years reduced the risk of coronary events (i.e., fatal CHD or nonfatal MI) by 36% and the risk of undergoing revascularization procedures by 42%.1 Lipoprotein concentrations were lowered to levels similar to those observed with atorvastatin 10 mg daily in previous clinical studies.1 The risk of fatal and nonfatal stroke was reduced by 26%, although this was not statistically significant.1 Treatment with atorvastatin did not reduce the risk of death from cardiovascular or noncardiovascular causes.1
In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study in hypercholesterolemic patients (low-density lipoprotein [LDL]-cholesterol concentrations of 100-190 mg/dL) who had a stroke or transient ischemic attack (TIA) within the past 1-6 months, therapy with high-dose atorvastatin (80 mg daily) for a median of 4.9 years reduced the risk of subsequent nonfatal or fatal stroke and of major cardiovascular events by approximately 16 and 20%, respectively, compared with placebo.73, 74 However, atorvastatin therapy did not reduce overall mortality.73 In addition, nonfatal hemorrhagic stroke and elevated aminotransferase (transaminase) concentrations (to at least 3 times the upper limit of normal [ULN]) were reported in more patients receiving atorvastatin than in those receiving placebo.1, 73 Some clinicians state that the results of this study should be interpreted with caution due to the heterogeneity of enrolled patients (i.e., with respect to stroke etiology and vascular risk).74 Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in patients receiving atorvastatin.1, 79 The manufacturer states the risk of using atorvastatin 80 mg should be weighed against the benefits in patients with recent hemorrhagic stroke.1, 79
Patients with Diabetes Mellitus
Atorvastatin is used as an adjunct to diet and lifestyle modifications in adults without clinical evidence of CHD who have type 2 diabetes mellitus and multiple risk factors for CHD to reduce the risk of MI or stroke.1, 79, 400 Atorvastatin in fixed combination with amlodipine is used in patients for whom treatment with both atorvastatin and a calcium-channel blocking agent is appropriate.65
Safety and efficacy of atorvastatin for prevention of cardiovascular disease in patients with type 2 diabetes mellitus have been established in a randomized, double-blind, placebo-controlled study.1, 79 In the Collaborative Atorvastatin Diabetes Study (CARDS) in 2838 hypercholesterolemic patients (median total cholesterol concentration of 207 mg/dL, LDL-cholesterol concentration of 120 mg/dL, triglyceride concentration of 151 mg/dL) with type 2 diabetes mellitus (mean hemoglobin A1c [HbA1c] of 7.7%) and one or more other risk factors (e.g., smoking, hypertension, retinopathy, microalbuminuria, macroalbuminuria), therapy with atorvastatin (10 mg daily) for a median of 3.9 years reduced the risk of stroke by 48% and the risk of MI by 42% compared with placebo.1 Lipoprotein concentrations were lowered to levels similar to those observed with atorvastatin 10 mg daily in previous clinical studies.1 Treatment with atorvastatin did not reduce the risk of unstable angina, revascularization procedures, or acute CHD death.1
The potential benefits of atorvastatin in patients with chronic kidney disease [CKD], a population at high risk of cardiovascular disease, were evaluated in the Deutsche Diabetes Dialyse Studie (4D), a randomized, double-blind, placebo-controlled study in 1255 patients with type 2 diabetes mellitus on maintenance hemodialysis.387 After a median follow-up of 4 years, therapy with atorvastatin 20 mg daily had no substantial effect on the primary composite end point of cardiovascular death, nonfatal MI, and stroke compared with placebo.387 Although atorvastatin reduced the rate of all cardiac events (a secondary end point in the study) relative to placebo, the difference was only nominally significant.387
Patients with Established Atherosclerotic Cardiovascular Disease (ASCVD)
Atorvastatin is used as an adjunct to diet and lifestyle modifications in patients with clinical evidence of CHD to reduce the risk of nonfatal MI, fatal and nonfatal stroke, angina, or hospitalization for congestive heart failure (CHF), and to reduce the risk of undergoing revascularization procedures.1, 79, 400 Atorvastatin in fixed combination with amlodipine is used in patients for whom treatment with both atorvastatin and a calcium-channel blocking agent is appropriate.65
Safety and efficacy of atorvastatin for secondary prevention of cardiovascular disease were established in several randomized studies in patients with clinically evident CHD.1, 53, 54, 68, 71, 79 In one randomized, double-blind study (Treating to New Targets [TNT]) in 10,001 patients with clinically evident CHD (i.e., history of MI, history of or current angina with objective evidence of atherosclerotic CHD, history of coronary revascularization)69 and LDL-cholesterol concentrations less than 130 mg/dL,1 treatment with intensive antilipemic therapy (atorvastatin 80 mg daily) or moderate antilipemic therapy (atorvastatin 10 mg daily) for a median of 4.9 years reduced LDL-cholesterol concentrations to a mean of 77 or 101 mg/dL, respectively.68 Compared with the moderate regimen, treatment with the intensive regimen resulted in a 22% relative reduction in the risk of the primary composite end point (i.e., death from CHD, nonfatal non-procedure-related MI, resuscitated cardiac arrest, and fatal or nonfatal stroke).1, 68 Of the events that comprised the primary composite end point, treatment with the intensive regimen substantially reduced the rate of nonfatal non-procedure-related MI and fatal and nonfatal stroke, but not death from CHD or resuscitated cardiac arrest.1 Of the predefined secondary end points, treatment with the intensive regimen reduced the rate of coronary revascularization, angina, and hospitalization for CHF, but not peripheral vascular disease.1 The intensive regimen did not reduce overall mortality and was associated with a slightly (but not statistically significant) increased risk of death from noncardiovascular causes.1, 68, 70 In addition, severe adverse effects (e.g., increases in concentrations of aminotransferase or creatine kinase [CK, creatine phosphokinase, CPK] to at least 3 or 10 times greater than the ULN, respectively) and discontinuance of therapy due to adverse effects were more common in patients receiving the intensive regimen compared with the moderate regimen.1, 68 In a post hoc analysis in 5584 patients with CHD and the metabolic syndrome, treatment with the intensive regimen was associated with a lower incidence of major cardiovascular events than treatment with the moderate regimen (9.5 versus 13%); this represented a 29% relative reduction in the risk of major cardiovascular events in favor of the intensive regimen.71 However, consistent with the overall population, the intensive regimen did not reduce overall mortality compared with the moderate regimen.71
In a randomized, comparative study (Incremental Decrease in Endpoints through Aggressive Lipid Lowering [IDEAL]) in 8888 patients with a history of CHD and an average LDL-cholesterol concentration of approximately 122 mg/dL, treatment with atorvastatin (80 mg daily) or simvastatin (20-40 mg daily) for a median of 4.8 years resulted in similar reduction in the risk of the primary composite end point (i.e., fatal CHD, nonfatal MI, and resuscitated cardiac arrest).81 In addition, no difference in overall mortality was observed between atorvastatin- or simvastatin-treated patients, and the rates of death from cardiovascular or noncardiovascular causes were similar in both treatment groups.81
In a multicenter, randomized, open-label study comparing the incidence of ischemic events in CHD patients undergoing angioplasty or receiving aggressive lipid-lowering therapy with atorvastatin 80 mg daily (Atorvastatin Versus Revascularization Treatments [AVERT] trial), atorvastatin was as effective as angioplasty in reducing the incidence of ischemic events (defined as death from cardiac causes, resuscitation after cardiac arrest, nonfatal MI, cerebrovascular accident, coronary artery bypass grafting, angioplasty, or worsening angina with objective evidence resulting in hospitalization) and delaying the onset of the first ischemic event.35, 54 However, atorvastatin-treated patients had smaller increases in quality of life scores and were more likely to report worsening of angina (12 versus 7%) compared with patients in the angioplasty group.54
In a randomized, double-blind, placebo-controlled study (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering [MIRACL]) in patients with unstable angina or non-ST-segment elevation (e.g., non-Q-wave) acute MI, therapy with atorvastatin (80 mg daily), initiated within 24-96 hours after admittance to the hospital, was associated with a lower incidence of recurrent ischemic events (particularly symptomatic ischemia requiring rehospitalization) in the subsequent 16 weeks;61, 62 however, the validity of these results has been questioned due to the large number of atorvastatin-treated patients lost during follow-up.62
In a randomized, double-blind, study (Pravastatin or Atorvastatin Evaluation and Infection Therapy [PROVE-IT]) in over 4000 patients hospitalized for acute coronary syndromes (ACS) within the preceding 10 days, treatment with intensive antilipemic therapy (atorvastatin 80 mg daily) or moderate antilipemic therapy (pravastatin 40 mg daily) for 2 years reduced LDL-cholesterol concentrations to a median of 62 or 95 mg/dL, respectively.66 Compared with the moderate regimen, treatment with the intensive regimen resulted in a 16% reduction in the composite risk of primary endpoints, including a 14% reduction in the need for revascularization procedures and a 29% reduction in the risk of recurrent unstable angina.66 Atorvastatin therapy also was associated with reductions in the rates of death from any cause (28%) and of death or MI (18%) compared with pravastatin therapy, but these differences were not statistically significant.66 Results of this study suggest that, among patients with recent ACS, an intensive antilipemic regimen provides greater protection against death or major cardiovascular events than does a standard regimen.66
Reducing Progression of Coronary Atherosclerosis
Intensive antilipemic therapy with atorvastatin has been shown to slow the progression of coronary atherosclerosis† in patients with CHD. In a randomized, double-blind, active-control study (Reversal of Atherosclerosis with Aggressive Lipid Lowering [REVERSAL]) in 654 patients with CHD, treatment with intensive antilipemic therapy (atorvastatin 80 mg daily) or moderate antilipemic therapy (pravastatin 40 mg daily) for 18 months reduced LDL-cholesterol concentrations to a mean of 79 or 110 mg/dL, respectively; concentrations of C-reactive protein were reduced by 36.4% in atorvastatin-treated patients and by 5.2% in pravastatin-treated patients.67 Treatment with the intensive regimen was associated with a substantially lower progression rate (measured by percent change in atheroma volume) compared with treatment with the moderate regimen.67 Compared with baseline values, patients treated with atorvastatin had no change in atheroma burden, whereas patients treated with pravastatin showed progression of coronary atherosclerosis.67 It has been suggested that the differences in atherosclerosis progression between atorvastatin and pravastatin may be related to the greater reduction in atherogenic lipoproteins and C-reactive protein concentrations in patients treated with atorvastatin.67
The 2018 American Heart Association (AHA)/American College of Cardiology (ACC) cholesterol management guideline emphasizes lifestyle modification as the foundation of atherosclerotic cardiovascular disease (ASCVD) risk reduction.400 If pharmacologic therapy is needed, hydroxymethyl-glutaryl-CoA (HMG-CoA) reductase inhibitor (statin) therapy is recommended.400 Statins are considered the first-line drugs of choice for reducing LDL-cholesterol, the lipoprotein fraction found to be a major cause of clinical ASCVD.400, 401, 402 There is extensive evidence demonstrating that statins can substantially reduce LDL-cholesterol concentrations and associated risk of ASCVD when used for secondary or primary prevention in high-risk patients.336, 337, 338, 400, 401, 402 Because the relative risk reduction is correlated with the degree of LDL lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits.400, 401, 402
When considering whether to initiate statin therapy for primary prevention, the 2018 AHA/ACC cholesterol management guideline recommends a shared decision-making approach between the patient and clinician.400 The guideline recommends consideration of statin therapy in certain high-risk groups such as adults 20-75 years of age with LDL-cholesterol levels ≥190 mg/dL, adults 40-75 years of age with diabetes mellitus, adults 40-75 years of age without diabetes mellitus but with LDL-cholesterol levels ≥70 mg/dL and an estimated 10-year ASCVD risk ≥7.5%, and adults 40-75 years of age with CKD (not treated with dialysis or transplantation) and LDL-cholesterol concentrations of 70-189 mg/dL who have a 10-year ASCVD risk ≥7.5%.400, 401
The guideline states that patients with clinical ASCVD (defined as those with ACS, history of MI, stable or unstable angina or coronary or other arterial revascularization, stroke, TIA, or peripheral artery disease [PAD], including those with aortic aneurysm) should be treated with a statin in conjunction with lifestyle modification to reduce LDL-cholesterol concentrations.400 Because patients >75 years of age may have a higher risk of adverse effects and lower adherence to therapy, the expected benefits versus adverse effects should be considered before initiating statin therapy in this population.400 The maximum tolerated intensity of a statin should be used to achieve optimum ASCVD benefits.400 AHA/ACC recommends the use of high-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by at least 50%).400 If high-intensity statin therapy is not possible (e.g., because of a contraindication or intolerable adverse effect), moderate-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by 30-49%) may be used.400
The appropriate intensity of a statin should be used to reduce the risk of ASCVD.400 Based on the average LDL-cholesterol response observed with specific statins and dosages used in the randomized controlled studies evaluated by the AHA/ACC guideline panel, atorvastatin 40-80 mg daily is considered to be a high-intensity statin (producing average LDL-cholesterol reductions of at least 50%) and atorvastatin 10-20 mg daily is considered to be a moderate-intensity statin (producing approximate LDL-cholesterol reductions of 30-49%).400
Combination Antilipemic Therapy
The addition of a nonstatin drug (e.g., ezetimibe, PCSK9 inhibitor) to statin therapy may be useful in certain high-risk patients who experience an inadequate reduction in LDL-cholesterol concentrations despite maximally tolerated statin therapy (e.g., <50% reduction in LDL-cholesterol or LDL-cholesterol concentration ≥55 mg/dL or non-HDL-cholesterol ≥85 mg/dL).400, 403 If combination therapy is necessary, selection of the nonstatin drug should be based on the risk and benefit profile (i.e., reduction in ASCVD risk outweighs the drug's potential for adverse effects and drug interactions) and patient preferences.400, 403
A 2022 consensus decision pathway published by the ACC addresses the use of nonstatin therapies for primary or secondary prevention of ASCVD.403 In patients with primary hypercholesterolemia without ASCVD who require additional LDL-lowering therapy despite maximal statin therapy, ezetimibe and/or a PCSK9 inhibitor are considered preferred initial nonstatin therapies due to demonstrated benefits in cardiovascular outcomes.403 If therapeutic goals are not achieved, other nonstatin therapies (e.g., inclisiran, bempedoic acid, evinacumab, lomitapide) may be considered.403
In patients receiving statin therapy as secondary prevention who are at very high risk of ASCVD and require additional LDL-lowering therapy despite maximal statin therapy, ezetimibe and/or a PCSK9 inhibitor are considered preferred initial nonstatin therapies.403 In patients receiving statin therapy as secondary prevention who are not at very high risk of ASCVD, ezetimibe is considered the preferred initial nonstatin therapy, followed by addition or replacement with a PCSK9 inhibitor if additional LDL-lowering therapy is needed.403 If therapeutic goals are not achieved in the secondary prevention setting, inclisiran (in place of a PCSK9 inhibitor) or bempedoic acid may be considered.403
A 2022 scientific statement published by the National Lipid Association (NLA) addresses the use of nonstatin therapies for ASCVD risk reduction in patients with statin intolerance.406 Nonstatin LDL-lowering therapy may be considered in patients with complete or partial statin intolerance, including during the course of attempting to identify a tolerable alternate statin regimen in patients with high or very high ASCVD risk.406 When nonstatin therapies are used, agents that have demonstrated cardiovascular outcome benefit in randomized trials are preferred.406
Atorvastatin is used as an adjunct to nondrug therapies (e.g., dietary management) for the management of primary hyperlipidemia, heterozygous familial hypercholesterolemia (HeFH), hypertriglyceridemia, primary dysbetalipoproteinemia, and/or homozygous familial hypercholesterolemia.1, 79 Atorvastatin has not been studied in conditions where the principal lipoprotein abnormality is elevated chylomicrons (Fredrickson types I and V).1, 79 Atorvastatin in fixed combination with amlodipine is used in patients for whom treatment with both atorvastatin and a calcium-channel blocking agent is appropriate.65
Atorvastatin, alone or in combination with ezetimibe, is used as an adjunct to diet in adults with primary hyperlipidemia, including HeFH, to reduce LDL-cholesterol.1, 64, 79
Reductions in total and LDL-cholesterol concentrations produced by usual dosages of atorvastatin substantially exceed those of placebo.1, 9, 12, 13, 15, 17, 18, 19, 20, 23, 25, 44, 52, 79 Mean reductions of 29-45% in total cholesterol, 39-60% in LDL-cholesterol, 32-50% in apolipoprotein (apo) B, and 19-37% in triglyceride concentrations, and increases of 5-9% in HDL-cholesterol concentrations have been reported in 2 controlled studies in 107 patients with primary hypercholesterolemia who received atorvastatin 10-80 mg daily for 6 weeks.1 Increases in HDL-cholesterol concentrations also have been observed in other studies in patients with primary hypercholesterolemia or mixed dyslipidemia; pooled data from 24 controlled studies indicate median increases of 5-9% in HDL-cholesterol concentrations in patients receiving atorvastatin 10-80 mg daily.65 Analysis of pooled data demonstrated consistent and substantial decreases in total cholesterol, LDL-cholesterol, triglyceride, total-cholesterol/HDL-cholesterol ratio, and LDL-cholesterol/HDL-cholesterol ratio in patients receiving atorvastatin.65 In patients with dyslipidemia and hypertension who received atorvastatin (10-80 mg daily) in combination with amlodipine (5-10 mg daily), LDL-cholesterol concentrations were reduced by 36-48% following 8 weeks of therapy.65
Data from comparative studies indicate that therapy with atorvastatin may produce greater reductions in total and LDL-cholesterol concentrations than certain other statins.1, 7, 27, 30, 51 In three multicenter, double-blind, comparative studies, patients with hypercholesterolemia who received atorvastatin 10 mg daily for 16 weeks experienced greater reductions in total and LDL-cholesterol concentrations (25-29 and 35-37%, respectively) than those receiving lovastatin 20 mg daily (19 and 27%, respectively), pravastatin 20 mg daily (17 and 23%, respectively), or simvastatin 10 mg daily (24 and 30%, respectively).1 In other multicenter, randomized, open-label, comparative studies, patients with hypercholesterolemia who received atorvastatin 10-40 mg daily experienced greater reductions in total and LDL-cholesterol concentrations (25-40 and 35-51%, respectively) than those receiving fluvastatin 20-40 mg daily (13-19 and 17-23%, respectively), lovastatin 20-40 mg daily (21-23 and 29-31%, respectively),30 pravastatin 10-40 mg daily (13-24 and 19-34%, respectively),56 or simvastatin 10-40 mg daily (21-31 and 28-41%, respectively).27, 36, 51
Compared with certain other statins, the effects of atorvastatin on HDL-cholesterol concentrations may be less pronounced, particularly with higher doses of atorvastatin.5 In several studies designed to evaluate the effects of atorvastatin (20-80 mg daily) and simvastatin (40-80 mg) on HDL-cholesterol and apo A-I concentrations, increases in HDL-cholesterol and apo A-I concentrations were greater with simvastatin therapy (7-9 and 3-6%, respectively) than with atorvastatin (0-7 and 0-5%, respectively).5, 24 The mechanisms of these effects have not been fully elucidated but may be related to differences in the 2 drugs' plasma elimination half-lives and/or differential effects of the drugs on lipolytic enzymes (e.g., lipoprotein lipase, hepatic lipase).5, 26
Limited data from comparative studies suggest that reductions in total and LDL-cholesterol concentrations produced by atorvastatin may exceed those produced by fibric acid derivatives.16 In an open-label study in patients with mixed dyslipidemia, treatment with atorvastatin (10 mg daily) was associated with greater reductions in serum total and LDL-cholesterol concentrations compared with fenofibrate therapy (200 mg daily); however, fenofibrate-treated patients had greater reductions in triglyceride concentrations and larger increases of HDL-cholesterol and apo A-I concentrations than those who received atorvastatin.16
The combination of atorvastatin and other antilipemic agents (e.g., bile acid sequestrants, ezetimibe) generally results in additive antilipemic effects; however, the risk of myopathy and rhabdomyolysis may be increased.20, 64 The addition of a bile acid sequestrant (e.g., colestipol 20 g daily) to atorvastatin therapy (10 mg daily) further reduced LDL-cholesterol by 10%, resulting in an overall LDL-cholesterol reduction of 45% in patients receiving the combination; however, frequent adverse effects (e.g., GI effects such as constipation) reported with this combination regimen may discourage adherence to therapy.20 The addition of ezetimibe (10 mg daily) to atorvastatin therapy (10-80 mg daily) further reduced LDL-cholesterol by 7-16%, resulting in an overall LDL-cholesterol reduction of 53-61%.64
Atorvastatin is used as an adjunct to diet to decrease elevated LDL-cholesterol in the management of HeFH in males and postmenarchal females 10-17 years of age.1, 79
In a double-blind, placebo-controlled study (followed by an open-label phase), 187 males and postmenarchal females 10-17 years of age with HeFH or severe hypercholesterolemia (mean baseline LDL-cholesterol concentration of 219-230 mg/dL) were randomized to receive either atorvastatin (10 mg daily for the first 4 weeks, increased to 20 mg daily if LDL-cholesterol concentration exceeded 130 mg/dL) or placebo for 26 weeks; after 26 weeks of the double-blind phase, all patients entered an open-label phase and received atorvastatin for an additional 26 weeks.1, 79 During the 26-week, double-blind phase, treatment with atorvastatin 10-20 mg daily resulted in mean reductions of 31% in total cholesterol, 40% in LDL-cholesterol, 34% in apo B, and 12% in triglyceride concentrations, while concentrations of these lipoprotein fractions in placebo recipients changed minimally.1 HDL-cholesterol concentrations increased by 2.8% in atorvastatin-treated patients and decreased by 1.9% in placebo recipients.1 The mean LDL-cholesterol concentration achieved with atorvastatin therapy was 130.7 mg/dL compared with 228.5 mg/dL achieved with placebo during the 26-week, double-blind phase.1
In a 3 year, open-label, uncontrolled trial, 82 males and 81 females 10-15 years of age with a clinical diagnosis of HeFH confirmed by genetic analysis (if not already confirmed by family history) were treated with atorvastatin 10 mg once daily; dosage was adjusted to achieve a target LDL-cholesterol <130 mg/dL.1, 79 The reductions in LDL-cholesterol from baseline were generally consistent across age groups within the trial as well as with previous clinical trials in both adult and pediatric placebo-controlled trials.1, 79
Atorvastatin is used as an adjunct to diet in the treatment of adults with hypertriglyceridemia.1, 79
In several clinical studies in 64 patients with isolated hypertriglyceridemia, treatment with atorvastatin (10-80 mg daily) resulted in median reductions of 39-52% in triglycerides, 28-44% in total cholesterol, 27-41% in LDL-cholesterol, 45-62% in very low-density lipoprotein (VLDL)-cholesterol, and 33-52% in non-HDL-cholesterol concentrations, and a median increase of 8-14% in HDL-cholesterol concentrations; however, no patient achieved normal triglyceride concentrations as a result of treatment.1, 13
Atorvastatin 10 mg daily reportedly has produced greater reductions in LDL-cholesterol than niacin 3 g daily or fenofibrate 300 mg daily in patients with combined hyperlipidemia or isolated hypertriglyceridemia.9, 10 However, reductions in triglyceride concentrations and increases in HDL-cholesterol concentrations were less than those reported with usual dosages of niacin or fenofibrate.9
Primary Dysbetalipoproteinemia
Atorvastatin is used as an adjunct to diet for the treatment of adults with primary dysbetalipoproteinemia.1, 79
In an open-label, crossover study in 16 patients with primary dysbetalipoproteinemia (genotypes 14 apo E2/E2 and 2 apo E3/E2), treatment with atorvastatin (10 or 80 mg daily) resulted in substantial reductions in total cholesterol (37 or 58%, respectively), triglycerides (39 or 53%, respectively), combined intermediate-density lipoprotein (IDL)- and VLDL-cholesterol (32 or 63%, respectively), and non-HDL-cholesterol concentrations (43 or 64%, respectively).1, 79
In an uncontrolled, open-label study of 36 patients with familial dysbetalipoproteinemia (molecularly diagnosed), treatment with atorvastatin 40 mg daily for 40 weeks resulted in significant reductions in total cholesterol (46%), triglycerides (40%), and apo B (43%) concentrations.82
Homozygous Familial Hypercholesterolemia (HoFH)
Atorvastatin is used alone or in combination with ezetimibe to decrease elevated serum total and LDL-cholesterol concentrations in adult and pediatric patients ≥10 years of age with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering therapies (e.g., plasma LDL-apheresis) or when such therapies are not available.1, 64, 79 In an uncontrolled study in 29 patients 6-37 years of age with HoFH, LDL-cholesterol concentrations were reduced by 7-53% (mean reduction of 20%) in 25 of 29 patients (86%) and increased by 7-24% in 4 of 29 patients (14%) who received atorvastatin dosages of 20-80 mg daily; 5 of the 29 patients had absent LDL-receptor function (of these, 2 patients also had a portacaval shunt and no substantial reduction in LDL-cholesterol concentrations, and the remaining 3 receptor-negative patients had a mean LDL-cholesterol reduction of 22%).1 Similar reductions (17-28%) were observed in another open-label study in which patients received atorvastatin dosages of 40-80 mg daily for at least 4 weeks.40 In a limited number of patients undergoing plasma LDL-apheresis to lower cholesterol concentrations, addition of atorvastatin (80 mg daily) for 8 weeks reduced plasma total and LDL-cholesterol concentrations by an additional 29 and 31%, respectively.45 Limited evidence indicates that treatment with atorvastatin also may slow the progression of atherosclerosis in these patients.28
In a randomized, double-blind study of 12 weeks' duration in a limited number of patients with a clinical and/or genotypic diagnosis of HoFH who were already receiving simvastatin (40 mg daily) or atorvastatin (40 mg daily), with or without concomitant LDL apheresis, the addition of ezetimibe (10 mg daily) to atorvastatin or simvastatin therapy (40 or 80 mg daily) was more effective in reducing LDL-cholesterol concentrations (21% additional reduction based on pooled data from 40-mg and 80-mg statin groups) than increasing the dosage of atorvastatin or simvastatin monotherapy from 40 to 80 mg daily (7% additional reduction based on pooled data from 40-mg and 80-mg statin groups).64 In patients receiving ezetimibe (10 mg daily) in combination with higher dosages (80 mg daily) of atorvastatin or simvastatin, LDL-cholesterol concentrations were reduced by an additional 27% compared with LDL-cholesterol reductions achieved with the 40-mg daily statin dosage.64
Elevated serum cholesterol, especially the LDL-cholesterol fraction, is a major cause of clinical ASCVD; other major risk factors include cigarette smoking, hypertension, diabetes, age, HeFH, CKD (estimated glomerular filtration rate [eGFR] 15-59 mL/minute per 1.73 m2), history of heart failure, and other lipoprotein abnormalities.400, 403 Therefore, the goal of antilipemic therapy in patients with hyperlipidemia is to reduce the risk of ASCVD.400 Clinical studies have demonstrated that atorvastatin 40-80 mg daily is considered to be a high-intensity statin (producing average LDL-cholesterol reductions of at least 50%) and atorvastatin 10-20 mg daily is considered to be a moderate-intensity statin (producing approximate LDL-cholesterol reductions of 30-49%).400
The 2018 AHA/ACC cholesterol management guideline emphasizes lifestyle modification as the foundation of ASCVD risk reduction.400 If pharmacologic therapy is needed, statin therapy is recommended.400 Statins are considered the first-line drugs of choice for reducing LDL-cholesterol, the lipoprotein fraction found to be a major cause of clinical ASCVD.400, 401, 402
When considering whether to initiate statin therapy for dyslipidemia in the setting of primary prevention, the 2018 AHA/ACC cholesterol management guideline recommends a shared decision-making approach between the patient and clinician.400 The guideline recommends consideration of statin therapy in certain high-risk groups such as adults 20-75 years of age with LDL-cholesterol levels ≥190 mg/dL, adults 40-75 years of age with diabetes mellitus, adults 40-75 years of age without diabetes mellitus but with LDL-cholesterol levels ≥70 mg/dL and an estimated 10-year ASCVD risk ≥7.5%, and adults 40-75 years of age with CKD (not treated with dialysis or transplantation) and LDL-cholesterol concentrations of 70-189 mg/dL who have a 10-year ASCVD risk of 7.5% or higher.400, 401
There is extensive evidence demonstrating that statins can substantially reduce LDL-cholesterol concentrations and associated risk of ASCVD when used for such patients.336, 337, 338, 400, 401, 402, 403 Because the relative risk reduction is correlated with the degree of LDL lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits.400, 401, 402
Combination Antilipemic Therapy
An ACC expert committee update on nonstatin drug therapies recommends that adults without clinical ASCVD with baseline LDL-cholesterol concentrations greater than 190 mg/dL not due to secondary causes may be considered for ezetimibe and/or a PCSK9 inhibitor if they have not met certain thresholds of LDL-cholesterol reduction on maximally tolerated statin therapy for primary prevention (e.g., at least 50% reduction in LDL-cholesterol with an LDL-cholesterol <100 mg/dL or a non-HDL-cholesterol concentration <130 mg/dL).403 Individuals with LDL-cholesterol concentrations greater than 190 mg/dL are more likely to have genetic disorders associated with hypercholesterolemia, such as HeFH or HoFH.403 Current treatments for patients with familial hypercholesterolemia include lifestyle modifications (e.g., low-fat diet, maintenance of a healthy body weight, smoking cessation), first-line treatment with statins, and, if necessary, combination therapy with other lipid-lowering medications (e.g., bile acid sequestrants, ezetimibe, PCSK9 inhibitors, bempedoic acid, inclisiran) among other options.403
Patients with moderate or severe hypertriglyceridemia, fasting or non-fasting triglyceride levels 175-499 mg/dL or fasting levels ≥500 mg/dL, respectively, generally are at increased risk of ASCVD and pancreatitis (especially in patients with fasting levels ≥500 mg/dL).400, 403 The AHA/ACC cholesterol management guideline recommends assessment and modification of lifestyle (obesity and metabolic syndrome), secondary disorders (e.g., diabetes mellitus, chronic liver or kidney disease and/or nephrotic syndrome, hypothyroidism), and medications that increase triglycerides.400 Initiation or intensification of statin therapy may be considered in adults 40-75 years of age with moderate or severe hypertriglyceridemia and ASCVD risk of ≥7.5%.400 Experts state statins alone cannot prevent increasing levels of triglycerides in the face of secondary causes from triggering acute hypertriglyceridemic pancreatitis.400
Homozygous Familial Hypercholesterolemia
Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extreme elevations of serum LDL-cholesterol concentrations (often in excess of 400-500 mg/dL).407, 408 Such extreme elevations, when left untreated, can lead to premature ASCVD as early as childhood; management of the condition requires referral to a lipid specialist and is focused on the aggressive reduction of LDL-cholesterol concentrations to slow ASCVD development.407, 408 The treatment of HoFH often requires the use of multiple therapies, including pharmacologic and non-pharmacologic approaches, to reduce LDL-cholesterol concentrations.408 Current treatments for patients with HoFH include dietary lifestyle modifications with maximally tolerated dosages of high-intensity statins, ezetimibe, and PCSK9 inhibitors.403, 408, 409 In patients with HoFH who do not achieve target reductions in LDL-cholesterol levels, other options such as evinacumab and lomitapide can be added to therapy with or without lipoprotein apheresis.408, 409
In addition to early identification of children with familial hypercholesterolemia (FH), dietary (e.g., caloric restriction, Mediterranean-style diet) and lifestyle modification (e.g., physical activity) are prioritized for the management of hypercholesterolemia in children and adolescents.400, 404 Evidence from randomized controlled trials coupled with the increased risk of cardiovascular disease in untreated severe hypercholesterolemia, support the use of statins in children and adolescents at ages ≥10 years who have FH.400
In children and adolescents ≥10 years of age with an LDL-cholesterol level persistently ≥190 mg/dL or ≥160 mg/dL with a clinical presentation consistent with FH and who do not respondadequately with 3-6 months of lifestyle therapy, experts state it is reasonable to initiate statintherapy.400 Experts state that statins may be considered as early as 8 years of age in the presence of concerning family history, extremely elevated LDL-cholesterol level, or elevated lipoprotein (a) and in the context of informed shared decision-making and counseling with the patient and family.400, 404 Treatment intensity should be based on the severity of the hypercholesterolemia and should incorporate patient/family preference; some experts recommend initiation at the lowest recommended dose and up-titration according to the LDL-cholesterol lowering response and tolerability.400, 404 Some experts recommend a target LDL-cholesterol level <130 mg/dL or ≥50% reduction from pre-treatment levels, particularly in those with high-risk conditions or other major risk factors; combination therapy with other lipid-lowering medications (e.g., bile acid sequestrants, ezetimibe) may be required.404
Atorvastatin is administered orally once daily at the same time each day, at any time of day.1, 65, 79
Atorvastatin oral suspension: Administer the oral suspension orally once daily at any time of day, only on an empty stomach (1 hour before or 2 hours after a meal).79 Shake the bottle well before measuring the dose.79 Measure the oral suspension using a calibrated oral syringe or other oral dosing device scored using metric units of measurements (i.e., mL).79 Store the oral suspension at 20-25°C with excursions permitted to 15-30°C.79 Store and dispense the commercially available oral suspension in its original bottle.79 Use within 60 days of first opening the bottle, then discard any remaining suspension.79
Atorvastatin oral tablets: Administer the tablets orally once daily at any time of day, with or without food.1 Store the tablets at 20-25°C.1
Atorvastatin and amlodipine fixed-combination tablets: Administer the tablets orally once daily at any time of day, at about the same time each day, with or without food.65 Do not break the tablet before administration.65 Store the fixed-combination tablets at 25°C with excursions permitted to 15-30°C.65
If a dose of atorvastatin, including the fixed-combination preparation containing amlodipine, is missed, administer the missed dose as soon as possible.1, 65, 79 If the dose was missed by more than 12 hours, do not administer the missed dose; resume the medication with the next scheduled dose.1, 65, 79
Dosage of atorvastatin calcium is expressed in terms of atorvastatin.1, 65, 79
Dosage adjustment based on LDL-cholesterol levels may occur as early as 4 weeks after atorvastatin initiation and/or titration.1, 65, 79
Reduction in Risk of Cardiovascular Events
The manufacturer states 10-20 mg once daily is the usual initial dosage of atorvastatin for the reduction of risk of cardiovascular events, primary or secondary prevention, in adults; the dosage range is 10-80 mg once daily.1, 79
The AHA/ACC cholesterol management guideline states that the appropriate intensity of statin therapy should be used to reduce ASCVD risk.400 The guideline recommends use of high-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by at least 50%); if high-intensity statin therapy is not possible (e.g., because of a contraindication or intolerable adverse effect), moderate-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by 30-49%) should be used.400 The AHA/ACC guideline panel considers atorvastatin 40-80 mg daily to be a high-intensity statin and atorvastatin 10-20 mg daily to be a moderate-intensity statin.400
Primary Hypercholesterolemia (Heterozygous Familial and Nonfamilial) or Mixed Dyslipidemia
The recommended initial oral dosage of atorvastatin in adults for the management of primary hypercholesterolemia (heterozygous familial or nonfamilial) or mixed dyslipidemia is 10-20 mg once daily.1, 65, 79 The manufacturer states that patients requiring reductions in LDL-cholesterol of more than 45% may be started on an atorvastatin dosage of 40 mg daily.1, 79 The usual maintenance dosage of atorvastatin in adults is 10-80 mg once daily.1, 79
The recommended initial dosage of atorvastatin for the management of heterozygous familial hypercholesterolemia (HeFH) in pediatric patients ≥10 years of age is 10 mg once daily.1, 65, 79 The dosage range is 10-20 mg once daily.1, 65, 79
Homozygous Familial Hypercholesterolemia
Atorvastatin should be used as an adjunct to other lipid-lowering therapies (e.g., plasma LDL-apheresis) or when such therapies are not available.1, 79
The usual oral dosage of atorvastatin for the management of homozygous familial hypercholesterolemia (HoFH) in adults is 10-80 mg once daily.1, 65, 79
The recommended initial dosage of atorvastatin for the management of HoFH in pediatric patients ≥10 years of age is 10-20 mg once daily.1, 79 The dosage range is 10-80 mg once daily.1, 79
Atorvastatin/Amlodipine Combination Therapy
The fixed-combination preparation containing atorvastatin and amlodipine (Caduet® and generic equivalents) may be used as a substitute for individually titrated drugs.65 In patients currently receiving atorvastatin and amlodipine, the initial dosage of the fixed-combination preparation should be the equivalent of titrated dosages of atorvastatin and amlodipine.65 Increased amounts of atorvastatin, amlodipine, or both components may be added for additional antilipemic, antianginal, or antihypertensive effects.65
The fixed-combination preparation may be used to provide additional therapy for patients currently receiving one component of the preparation.65 The fixed-combination preparation also may be used to initiate treatment in patients with dyslipidemias and either hypertension or angina.65 Doses of amlodipine and atorvastatin should be selected independently.65 The maximum dosage of atorvastatin or amlodipine in the fixed-combination preparation is 80 or 10 mg daily, respectively.65
Dosage Modification for Concomitant Therapy
Antiviral drugs: In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, atorvastatin dosage should not exceed 20 mg once daily.1, 79 In patients taking nelfinavir, atorvastatin dosage should not exceed 40 mg once daily.1, 65, 79
Clarithromycin: In patients taking clarithromycin, atorvastatin dosage should not exceed 20 mg once daily.1, 65, 79
Itraconazole: In patients taking itraconazole, atorvastatin dosage should not exceed 20 mg once daily.1, 65, 79
Atorvastatin should be used with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease.1, 79 Atorvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis.1, 79 The manufacturer makes no specific recommendations for dosage adjustment in patients with hepatic impairment.1, 65, 79
Because renal impairment does not affect plasma concentrations or antilipemic effects of atorvastatin, the manufacturer states that dosage modification in patients with renal impairment is not necessary.1, 31, 32, 65, 79 Renal impairment is a risk factor for myopathy and rhabdomyolysis; monitor all patients with renal impairment for the development of myopathy.1, 65, 79
There are no specific dosage recommendations for geriatric patients.1, 79 Dose selection in geriatric patients (≥65 years of age) should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy.1, 79 Monitor geriatric patients for the increased risk of myopathy.1, 79
Pharmacogenomic Considerations
Patients with solute carrier organic anion transporter (SLCO) 1B1 decreased, possible decreased, or poor function phenotypes will have increased atorvastatin exposure, which may translate to an increased risk of statin-associated musculoskeletal symptoms.500
Patients with SLCO1B1 decreased or possible decreased function phenotypes will have increased atorvastatin exposure compared to those with normal function, which may translate to an increased risk of statin-associated musculoskeletal symptoms if dosage is ≥40 mg per day.500 In such patients, based on pharmacokinetic data, initiate atorvastatin at ≤40 mg per day and adjust dosage based on disease-specific guidelines.500 If a higher dose (>40 mg) is needed for desired efficacy, consider combination therapy (i.e., atorvastatin plus a nonstatin guideline directed medical therapy).500
Patients with SLCO1B1 poor function phenotypes will have increased atorvastatin exposure compared to those with decreased or possible decreased function, which may translate to an increased risk of statin-associated musculoskeletal symptoms.500 In such patients, based on pharmacokinetic data, initiate atorvastatin at ≤20 mg per day and adjust dosage based on disease-specific guidelines.500 If a higher dose (>20 mg) is needed for desired efficacy, consider rosuvastatin or combination therapy (i.e., atorvastatin plus a nonstatin guideline directed medical therapy).500
Myopathy (defined as muscle pain, tenderness, or weakness in conjunction with increases in creatine kinase [CK, creatine phosphokinase, CPK] and rhabdomyolysis) has been reported in patients receiving statins, including atorvastatin.1, 79 Rhabdomyolysis with acute kidney injury secondary to myoglobinuria also has been reported in patients receiving statins, including atorvastatin; rare fatalities have occurred.1, 79
The risk of myopathy or rhabdomyolysis is increased in geriatric patients (65 years of age or older), in patients with uncontrolled hypothyroidism or renal impairment, and those receiving a higher atorvastatin dosage.1, 79 Atorvastatin exposure may be increased by drug interactions due to inhibition of cytochrome P-450 (CYP) 3A4 and/or transporters (e.g., breast cancer resistant protein [BCRP], organic anion-transporting polypeptide [OATP1B1/OATP1B3] and P-glycoprotein [P-gp]), resulting in an increased risk of myopathy and rhabdomyolysis.1, 79 Concomitant use of cyclosporine, gemfibrozil, tipranavir plus ritonavir, or glecaprevir plus pibrentasvir with atorvastatin is not recommended.1, 79 Atorvastatin dosage modifications are recommended for patients taking certain anti-viral, azole antifungals, or macrolide antibiotic medications.1, 79 Concomitant intake of large quantities, more than 1.2 liters daily, of grapefruit juice is not recommended in patients taking atorvastatin.1, 79 Cases of myopathy and/or rhabdomyolysis have been reported when atorvastatin is used concomitantly with fibric acid derivatives, antilipemic dosages (1 g daily or higher) of niacin, colchicine, and ledipasvir plus sofosbuvir.1, 79 The benefits of combined use of such drugs should be carefully weighed against the potential risks.1, 79
AHA/ACC cholesterol management guideline recommends measurement of CK levels in patients with severe statin-associated muscle symptoms; however, routine monitoring is not useful.400
Atorvastatin should be discontinued if CK concentrations become markedly elevated or if myopathy is diagnosed or suspected.1, 79 Muscle symptoms and CK elevations may resolve if atorvastatin is discontinued.1, 79 Atorvastatin therapy should be temporarily withheld or discontinued in any patient experiencing an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; uncontrolled seizures).1, 79
Immune-Mediated Necrotizing Myopathy
Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has been reported rarely in patients receiving statins, including reports of recurrence when the same or a different statin was administered.1, 79 The condition is characterized by proximal muscle weakness and elevated CK concentrations that persist despite discontinuance of statin therapy, positive anti-HMG CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement following therapy with immunosuppressive agents.1, 79 Additional neuromuscular and serologic testing may be necessary and treatment with immunosuppressive agents may be required in patients who develop IMNM.1, 79
Discontinue atorvastatin if IMNM is suspected.1, 79
Increases in serum aminotransferase (i.e., AST, ALT) concentrations have been reported in patients receiving statins, including atorvastatin.1, 79 In most cases, the elevations appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy.1, 79 Persistent increases (exceeding 3 times the upper limit of normal [ULN] and occurring on 2 or more occasions) in serum aminotransferase concentrations occurred in 0.7% of patients receiving atorvastatin in clinical trials (including in 0.2% of those receiving atorvastatin 10 or 20 mg daily, 0.6% of those receiving 40 mg daily, and 2.3% of those receiving 80 mg daily).1
Cases of fatal and nonfatal hepatic failure have been reported rarely in patients receiving statins, including atorvastatin, during postmarketing surveillance.1, 79
Consider liver enzyme tests prior to initiation of atorvastatin therapy and repeat as clinically indicated.1, 79 Serious statin-related liver injury is rare and unpredictable in individual patients, and routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury.200 The AHA/ACC cholesterol management guideline states that, during statin therapy, it is reasonable to obtain liver function tests in adults experiencing symptoms of hepatotoxicity (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark colored urine, yellowing of the skin or sclera); however, routine monitoring is not recommended.200, 350, 400
If serious liver injury with clinical manifestations and/or hyperbilirubinemia or jaundice occurs, atorvastatin therapy should be promptly interrupted.1, 79
Atorvastatin should be used with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease.1, 79 The drug is contraindicated in patients with acute liver failure or decompensated cirrhosis.1, 79
Increases in glycosylated hemoglobin (hemoglobin A1c [HbA1c]) and fasting serum glucose concentrations have been reported in patients receiving statins, including atorvastatin.1, 79, 200 Data from clinical trials and meta-analyses indicate that statin therapy may increase the risk of developing diabetes mellitus.200
AHA/ACC cholesterol management guideline states that patients receiving statin therapy should be evaluated for new-onset diabetes mellitus; because the benefits of statin therapy outweigh the risks of new-onset diabetes, the possibility of this adverse effect should not be a contraindication to statin therapy or a reason for discontinuance of therapy.400
Use in Patients with Recent Stroke or Transient Ischemic Attack
In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study in hypercholesterolemic patients without clinically evident coronary heart disease (CHD) who had a stroke or transient ischemic attack (TIA) within the past 1-6 months, therapy with high-dose atorvastatin (80 mg daily) for a median of 4.9 years was associated with a higher incidence of hemorrhagic stroke (2.3%) compared with placebo (1.4%).1, 73, 79 The incidence of fatal hemorrhagic stroke was similar between atorvastatin and placebo, while the incidence of nonfatal hemorrhagic stroke was substantially higher with atorvastatin (1.6%) compared with placebo (0.7%).1, 79 Among patients receiving atorvastatin, those with a history of hemorrhagic or lacunar stroke at study entry were at increased risk of developing hemorrhagic stroke.1, 79 The benefits of atorvastatin 80 mg in patients with recent hemorrhagic stroke should be carefully weighed against the potential risks.1, 79
When atorvastatin is used in fixed combination with amlodipine, the usual cautions, precautions, and contraindications associated with amlodipine must be considered in addition to those associated with atorvastatin.65
All statins were previously contraindicated in pregnant females because the fetal risk with these drugs was thought to outweigh any possible benefit.405 This determination was based on several factors including safety signals from animal data.405 Increased post-implantation loss occurred in rats and rabbits at maternally toxic doses of 300- and 50- or 100 mg/kg per day, respectively; decreased fetal body weight was observed at 300- and 100 mg/kg per day, respectively.1, 79 Decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups, decreased pup body weight through postnatal day 21 and 91, and pup developmental delays were observed when pregnant and lactating rats received 100- or 225 mg/kg per day (a maternally toxic dose), doses corresponding to 6- and 22-times the human exposure at the maximum recommended human dose, based on AUC.1, 79 In addition, congenital anomalies including severe CNS defects and unilateral limb deficiencies were reported in a case series of pregnant females who were exposed to a lipophilic statin during the first trimester.402
Because statins decrease synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, there is also a concern that these drugs can potentially cause fetal harm.405 More recent data from case series and observational cohort studies have not shown evidence of an increased risk of major birth defects with statin use during pregnancy, and this was observed after controlling for potential confounders such as maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use.405 The overall evidence from animal studies suggests limited potential for statins to cause malformations or other adverse fetal effects.405 While an increased risk of miscarriage has been reported in pregnant females exposed to statins, it is not clear whether this effect is related to the drugs or to other confounding factors.400, 405
FDA conducted a comprehensive review of all available clinical and nonclinical data of statin use in pregnant women and concluded that the totality of evidence suggests limited potential for statins to cause malformations and other adverse embryofetal effects.405 Because statins may prevent serious or potentially fatal cardiovascular events in certain high-risk patients who are pregnant, FDA has requested that the contraindication in pregnant women be removed from the prescribing information for all statins.405 While FDA still advises that most pregnant patients discontinue statins because of the possibility of fetal harm, there may be some patients (e.g., those with homozygous familial hypercholesterolemia or established cardiovascular disease) in whom continued therapy may be beneficial; therefore, decisions should be individualized based on the patient's risks versus benefits.400, 402, 405 Patients who become pregnant or suspect that they are pregnant while receiving a statin should notify their clinician who can advise them on the appropriate course of action.405
Atorvastatin is distributed into milk in rats.1, 79 It is not known whether atorvastatin is distributed into human milk; however, the drug is probably distributed into human milk because a small amount of another statin is distributed into human milk.1, 79 Because of the potential for serious adverse reactions from atorvastatin in nursing infants, the drug is not recommended in nursing females.1, 79 Females who require atorvastatin therapy should not breast-feed their infants.1, 79 Many patients can stop statin therapy temporarily until breast-feeding is complete; patients who require ongoing statin treatment should not breast-feed and should use alternatives such as infant formula.400, 402, 405
Females and Males of Reproductive Potential
Atorvastatin at doses up to 225 mg/kg (56 times the human exposure) did not cause adverse effects on fertility In female rats.1, 79 Low testis and epididymal weights, aplasia and aspermia in the epididymis, decreased sperm motility, spermatid head concentration, and increased abnormal sperm were observed in rats receiving atorvastatin up to 100 mg/kg per day (16 times the human AUC at the 80 mg dose).1, 79 Studies in male rats performed at doses up to 175 mg/kg produced no changes in fertility.1, 79 Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10-, 40-, or 120 mg/kg for 2 years.1, 79
AHA/ACC cholesterol management guideline recommends females (including adolescents) of childbearing age who are sexually active should be counseled to use a reliable form of contracep.400
Safety and efficacy of atorvastatin have not been evaluated in children younger than 10 years of age with heterozygous- [HeFH] or homozygous familial hypercholesterolemia (HoFH), or in pediatric patients with other types of hyperlipidemia.1, 79 Safety and effectiveness of atorvastatin as an adjuct to diet to reduce LDL-cholesterol in pediatric patients ≥10 years of age with HeFH have been established in a limited (N=187), randomized, double-blind, placebo-controlled study.1, 79 There were no substantial adverse effects on growth or sexual maturation in adolescent males or on duration of menstrual cycle in females.1, 79
In an open-label, 8-week study that included pediatric HeFH patients (10-17 years of age), the apparent oral clearance of atorvastatin appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in the atorvastatin population pharmacokinetic model.1, 65, 79
Safety and effectiveness of atorvastatin as an adjunct to other LDL-cholesterol-lowering therapies to reduce LDL-cholesterol in pediatric patients ≥10 years of age with HoFH have been established based on an uncontrolled study in 8 pediatric patients (10 years of age or older).1, 79
Safety and efficacy of atorvastatin in fixed combination with amlodipine (Caduet®and generic equivalents) have not been established in pediatric patients.65 The effect of the amlodipine component, of the atorvastatin/amlodipine (Caduet® and generic equivalents) fixed preparation, on blood pressure in patients less than 6 years of age is not known.65
Of the total number of patients receiving atorvastatin in clinical studies, 40% were 65 years of age or older, and 7% were 75 years of age or older.1, 79 No overall differences in efficacy or safety were observed between geriatric and younger patients.1, 79 Data from a pharmacokinetic study indicate that peak plasma concentration and AUC of atorvastatin were 40 or 30% higher, respectively, in geriatric individuals (65 years of age or older) compared with younger adults.1, 79
Because advanced age (65 years and older) is a predisposing factor for myopathy, including rhabdomyolysis, atorvastatin should be used with caution in geriatric patients.1, 79 The manufacturer recommends cautious dosage selection of atorvastatin in geriatric patients, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy.1, 79 Monitor geriatric patients receiving atorvastatin for the increased risk of myopathy.1, 79
Because patients older than 75 years of age may have a higher risk of adverse effects and lower adherence to therapy, the expected benefits versus adverse effects of statin therapy should be considered before initiating statin therapy in this population.400
Safety and efficacy of atorvastatin in fixed combination with amlodipine (Caduet®) have not been established in geriatric patients.65
Plasma concentrations of atorvastatin are markedly increased in patients with chronic alcoholic liver disease.1, 79 Peak plasma concentration and AUC of atorvastatin are increased by fourfold in patients with Child-Pugh class A disease and by approximately 16- and 11-fold, respectively, in patients with Child-Pugh class B disease.1, 79
Atorvastatin should be used with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease.1, 79 Atorvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis.1, 79
Renal impairment does not affect plasma concentrations or antilipemic effects of atorvastatin; therefore, dosage modification in patients with renal impairment is not necessary.1, 79 However, because history of renal impairment may be a risk factor for development of myopathy and rhabdomyolysis, patients with renal impairment should be monitored for myopathy.1, 79
Studies have not been conducted in patients with end-stage renal disease (ESRD).1, 79 However, hemodialysis is not expected to substantially enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins.1, 79
Pharmacogenomic Considerations
Genetic variation in the solute carrier organic anion transporter (SLCO) family member (SLCO1B1), ABCG2 (also known as BCRP), and CYP2C9 genes alter systemic exposure to statins (i.e., lovastatin, simvastatin, rosuvastatin, pravastatin, pitavastatin, atorvastatin, fluvastatin), which can increase the risk for statin-associated musculoskeletal symptoms.500 SLCO1B1 encodes a transporter (SLCO1B1; alternative names include OATP 1B1 or OATP-C) that facilitates the hepatic uptake of all statins.500 ABCG2 encodes an efflux transporter (BCRP) that modulates the absorption and disposition of rosuvastatin and atorvastatin; CYP2C9 encodes a phase I drug metabolizing enzyme responsible for the oxidation of some statins (e.g., fluvastatin).500
In patients with phenotypes that result in increased statin exposure, the potential for other patient-specific issues that may increase statin exposure (e.g., renal and hepatic function, drug-drug interactions) must also be considered.500 Experts state that given the balance of statin-associated musculoskeletal symptoms risk versus known cardiovascular disease benefit, for patients who are candidates for new statin therapy, pharmacogenetic test results may provide additional useful information.500
Pharmacogenetic test results may be used as the basis for changing to another statin type or dose for patients currently prescribed statin therapy, depending on how long the patient has been tolerating the statin.500 Experts state statin therapy should neither be discontinued nor avoided based on SLCO1B1, ABCG2, or CYP2C9 genotype results for patients with an indication for statin therapy, especially if the statin therapy is based on the shared decision making between patient and provider.500
Patients with solute carrier organic anion transporter SLCO1B1 decreased, possible decreased, or poor function phenotypes will have increased atorvastatin exposure, which may translate to an increased risk of statin-associated musculoskeletal symptoms.500 Patients with such phenotypes may require lower doses or an alternative statin to achieve therapeutic goals without increasing the risk of myopathy.500, 500
There are no data available regarding SLCO1B1 genotype effects on statin response or myopathy in pediatric patients.
Adverse effects reported in ≥5% of patients receiving atorvastatin include nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection.1, 79
Atorvastatin is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.1, 79
Atorvastatin is a substrate of P-glycoprotein (P-gp), breast cancer resistant protein (BCRP), and organic anion transporter protein (OATP) 1B1/1B3.1, 65, 79, 339, 501, 502
When atorvastatin is used in fixed combination with amlodipine, interactions associated with amlodipine should be considered.65 No formal drug interaction studies have been performed to date with the fixed-combination preparation containing atorvastatin and amlodipine.65
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Concomitant use of atorvastatin with potent inhibitors of CYP3A4 (e.g., clarithromycin, itraconazole, HIV protease inhibitors, grapefruit juice) may result in increased plasma atorvastatin concentrations and increase the risk of myopathy or rhabdomyolysis.1, 79
Concomitant use of atorvastatin with inducers of CYP3A4 (e.g., efavirenz, rifampin) may result in variable reductions in plasma concentrations of atorvastatin.1, 79
Drugs Affecting or Affected by Transport Systems
Atorvastatin and its metabolites are substrates of OATP1B1.1, 79 Atorvastatin is a also substrate of P-gp, BCRP, and OATP1B3.1, 79 Drugs that inhibit OATP1B1 (e.g., cyclosporine, gemfibrozil), OAT1B3, P-gp, and BCRP may increase atorvastatin exposure and increase the risk of myopathy and rhabdomyolysis.1, 79
Drugs Affecting Gastric Acidity
Following concomitant use of atorvastatin (10 mg once daily for 15 days) and a liquid antacid (Maalox TC® 30 mL four times a day for 17 days), atorvastatin peak plasma concentrations and AUC decreased by 33 and 34%, respectively.1, 79 Following concomitant use of atorvastatin (10 mg once daily for 2 weeks) and cimetidine (300 mg four times a day for 2 weeks), atorvastatin peak plasma concentrations decreased 11%; there was no change in the AUC.1, 79
Concomitant use of atorvastatin and azole antifungals (e.g., itraconazole) increases the risk of myopathy or rhabdomyolysis.1, 79 Following concomitant use of atorvastatin (40 mg as a single dose) and itraconazole (200 mg once daily for 4 days), atorvastatin peak plasma concentration and AUC were increased by 20% and 3.3-fold, respectively.1, 79
Clinicians considering concomitant use of atorvastatin and itraconazole or other azole antifungals should weigh the benefits and risks of such concomitant therapy.1, 79 During concomitant therapy with itraconazole, the dosage of atorvastatin should not exceed 20 mg daily.1, 79 Patients receiving concomitant therapy with atorvastatin and azole antifungals should be monitored for signs and symptoms of myopathy, particularly during the initial months of therapy and following an increase in dosage of either drug.1, 79
The cholesterol-lowering effects of atorvastatin and bile acid sequestrants (e.g., cholestyramine) are additive.20 Following concomitant use of atorvastatin (40 mg once daily for 8 weeks) and colestipol (10 g twice daily for 24 weeks), atorvastatin peak plasma concentration was decreased by 26%.20 Since bile acid sequestrants may decrease absorption of various drugs, some clinicians state that statins (e.g., atorvastatin) generally should be administered one hour before or 4 hours after the bile acid sequestrant.20
Calcium-channel Blocking Agents
Following concomitant use of atorvastatin (40 mg as a single dose) and diltiazem (240 mg once daily for 28 days), atorvastatin AUC was increased by 51%; peak plasma concentration did not change.1, 79 Experts state concomitant use of atorvastatin and diltiazem is reasonable.339 Following concomitant administration of atorvastatin (80 mg as a single dose) and amlodipine (10 mg as a single dose), atorvastatin AUC was increased by 18%, a change that is considered to be not clinically meaningful.1, 79
Myopathy, including rhabdomyolysis, has been reported in patients receiving atorvastatin concomitantly with colchicine.1, 79 If concomitant use is necessary, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration.1, 79
Concomitant use of atorvastatin and cyclosporine increases plasma atorvastatin concentrations, which may increase the risk of myopathy or rhabdomyolysis.1, 79, 339 Following concomitant use of atorvastatin (10 mg daily for 28 days) and cyclosporine (5.2 mg/kg daily), atorvastatin peak plasma concentration and AUC were increased by 10.7- and 8.7-fold, respectively.1, 79 Concomitant use of atorvastatin and cyclosporine is not recommended, however some experts state dosages up to 10 mg once daily may be considered with close monitoring for signs or symptoms of muscle-related toxicity.1, 79, 339, 502
Concomitant use of atorvastatin (80 mg once daily for 10 days) and digoxin (0.25 mg once daily for 20 days) resulted in 20 and 15% increases in digoxin peak plasma concentration and AUC, respectively.1, 79, 339 Therefore, patients receiving such concomitant therapy should be monitored appropriately.1, 339
Following concomitant use of atorvastatin and cobicistat-boosted elvitegravir, atorvastatin peak plasma concentration and AUC were increased by 2.3- and 2.6-fold, respectively.503 During such concomitant therapy, experts recommend careful atorvastatin titration to the lowest effective dosage not to exceed 20 mg; patients should be monitored for adverse events.503
Concomitant use of atorvastatin with efavirenz, a CYP3A4 inducer, may result in decreased atorvastatin exposure.1 Following concomitant use of atorvastatin (10 mg daily for 3 days) and efavirenz (600 mg once daily for 14 days), atorvastatin AUC was decreased by 41%.1, 79, 339 Experts recommend atorvastatin dose adjustment based on clinical response, but not to exceed the maximum recommended dosage.503
Concomitant use of atorvastatin with etravirine, a CYP3A4 inducer, may result in a 32-43% reduction in atorvastatin AUC.503 Experts recommend atorvastatin dose adjustment based on clinical response, but not to exceed the maximum recommended dosage.503
Concomitant use of atorvastatin and fibric acid derivatives (e.g., gemfibrozil, fenofibrate) increases the risk of myopathy.1, 79 Following concomitant use of atorvastatin (40 mg as a single dose) and gemfibrozil (600 mg twice daily for 7 days), atorvastatin AUC was increased by 35%.1, 79 Following concomitant use of atorvastatin (40 mg as a single dose) and fenofibrate (160 mg once daily for 7 days), atorvastatin peak plasma concentration and AUC were increased by 2 and 3%, respectively.1, 79
Concomitant use of atorvastatin and gemfibrozil is not recommended.1, 79 The benefits of concomitant use of atorvastatin and other fibric acid derivatives (e.g., fenofibrate) should be weighed against the possible risk of myopathy and rhabdomyolysis.1, 79 The manufacturer states that if concomitant use is necessary, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.1, 79 The AHA/ACC cholesterol management guideline states it is safer to use fenofibrate than gemfibrozil because of a lower risk of severe myopathy.400
Because grapefruit juice contains one or more components that inhibit CYP3A4, ingestion of grapefruit juice may result in increased atorvastatin concentrations and may increase the risk of myopathy and rhabdomyolysis.1, 79 Following concomitant use of atorvastatin (40 mg as a single dose) with grapefruit juice (240 mL once daily), atorvastatin peak plasma concentration and AUC were increased by 16 and 37%, respectively.1, 79 Ingestion of large quantities (more than 1.2 liter daily) of grapefruit juice is not recommended.1, 79
Following concomitant use of atorvastatin (10 mg daily for 7 days) and glecaprevir 400 mg once daily with pibrentasvir 120 mg once daily for 7 days, atorvastatin peak plasma concentration and AUC were increased by 22- and 8.3-fold, respectively.1, 79 Concomitant use of these drugs is not recommended.1, 79
Following concomitant use of atorvastatin (10 mg as a single dose) and elbasvir 50 mg once daily with grazoprevir 200 mg once daily for 13 days, atorvastatin peak plasma concentration and AUC were increased by 4.3- and 1.95-fold, respectively.1, 79 When these drugs are used concomitantly, dosage of atorvastatin should not exceed 20 mg daily.1, 79
Cases of myopathy and/or rhabdomyolysis have been reported when atorvastatin is co-administered with ledipasvir in combination with sofosbuvir.1, 79 The benefits of concomitant use of atorvastatin and ledipasvir/sofosbuvir should be weighed against the possible risk of myopathy or rhabdomyolysis.1, 79 Patients should be carefully monitored for signs and symptoms of myopathy, particularly during the initial months of therapy and following an increase in dosage of either drug.1, 79
Concomitant use of atorvastatin and atazanavir, with or without ritonavir, may increase atorvastatin exposure.503 During such concomitant therapy, experts recommend the lowest effective dosage of atorvastatin should be used while monitoring for adverse events.503
Following concomitant use of atorvastatin and cobicistat-boosted atazanavir, atorvastatin peak plasma concentration and AUC were increased by 18.9- and 9.2-fold, respectively.503 Do not coadminister atorvastatin and cobicistat-boosted atazanavir.503
Concomitant use of atorvastatin and ritonavir-boosted darunavir increases the risk of myopathy or rhabdomyolysis.1, 79 Following concomitant use of atorvastatin (10 mg daily for 4 days) and ritonavir-boosted darunavir (darunavir 300 mg twice daily with ritonavir 100 mg twice daily for 9 days), atorvastatin peak plasma concentration and AUC were increased by 2.25- and 3.5-fold, respectively.1, 79
During such concomitant therapy, the lowest necessary dosage of atorvastatin should be used, and dosage of atorvastatin should not exceed 20 mg daily.1, 79, 503 Patients should be carefully monitored for signs and symptoms of myopathy, particularly during the initial months of therapy and following an increase in dosage of either drug.1, 79
Following concomitant use of atorvastatin and cobicistat-boosted darunavir, atorvastatin peak plasma concentration and AUC were increased by 4.2- and 3.9-fold, respectively.503 During such concomitant therapy, experts recommend the lowest effective dosage should be used, the dosage of atorvastatin should not exceed 20 mg daily, and patients should be monitored for adverse events.503
Concomitant use of atorvastatin and fosamprenavir (with or without low-dose ritonavir) increases the risk of myopathy or rhabdomyolysis.1, 79 Following concomitant use of atorvastatin (10 mg daily for 4 days) and fosamprenavir (1.4 g twice daily for 14 days), atorvastatin peak plasma concentration and AUC were increased by 4- and 2.3-fold, respectively, while fosamprenavir peak plasma concentration and AUC were decreased by 18 and 27%, respectively.1, 79 Following concomitant use of atorvastatin (10 mg daily for 4 days) and ritonavir-boosted fosamprenavir (fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily for 14 days), atorvastatin peak plasma concentration and AUC were increased by 2.84- and 2.53-fold, respectively.1, 79
During concomitant use of atorvastatin and fosamprenavir (with or without low-dose ritonavir), the dosage of atorvastatin should not exceed 20 mg daily.1, 79 Patients should be carefully monitored for signs and symptoms of myopathy, particularly during the initial months of therapy and following an increase in dosage of either drug.1, 79
Concomitant use of atorvastatin with the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) increases the risk of myopathy or rhabdomyolysis.1, 79
The benefits of concomitant use of atorvastatin and lopinavir/ritonavir should be weighed against the possible risk of myopathy or rhabdomyolysis.1, 79 Caution is advised if such concomitant therapy is employed.1, 502 During such concomitant therapy, experts recommend the lowest necessary dosage (maximum 20 mg daily) of atorvastatin should be used.1, 502, 503 Patients should be carefully monitored for signs and symptoms of myopathy, particularly during the initial months of therapy and following an increase in dosage of either drug.1, 79, 503
Following concomitant use of atorvastatin (10 mg daily for 28 days) and nelfinavir (1.25 g twice daily for 14 days), atorvastatin peak plasma concentration and AUC were increased by 2.2-fold and 74%, respectively.1, 79
Patients receiving atorvastatin concomitantly with nelfinavir should be carefully monitored for signs and symptoms of myopathy, particularly during the initial months of therapy and following an increase in dosage of either drug.1, 79 During such concomitant therapy, the dosage of atorvastatin should not exceed 40 mg daily.1, 79
Concomitant use of atorvastatin and ritonavir-boosted tipranavir increases the risk of myopathy or rhabdomyolysis.1, 79 Following concomitant use of atorvastatin (10 mg as a single dose) and ritonavir-boosted tipranavir (tipranavir 500 mg twice daily with ritonavir 200 mg twice daily for 7 days), atorvastatin peak plasma concentration and AUC were increased by 8.6- and 9.4-fold, respectively, while tipranavir peak plasma concentration and AUC were unchanged.1, 79
Concomitant use of atorvastatin and ritonavir-boosted tipranavir is not recommended.1, 79, 502
Concomitant use of atorvastatin and lenacapavir may increase atorvastatin exposure.503 Experts state no dosage adjustment is necessary.503
Following concomitant use of atorvastatin (20 mg as a single dose) and letermovir 480 mg once daily for 10 days, atorvastatin peak plasma concentration and AUC were increased by 2.2- and 3.3-fold, respectively.1, 79 When used concomitantly with letermovir, atorvastatin dosage should not exceed 20 mg daily.1, 79
Following concomitant use of atorvastatin (single 20-mg dose) with lomitapide (10 mg once daily for 7 days), peak plasma concentration and AUC of atorvastatin acid were increased by 19 and 11%, respectively.374 Following concomitant use of lomitapide (60 mg once daily for 7 days) with atorvastatin (single 20-mg dose), peak plasma concentration and AUC of atorvastatin acid were increased by 63 and 52%, respectively.374 Following concomitant use of lomitapide (single 20-mg dose) with atorvastatin (80 mg once daily), peak plasma concentration and AUC of lomitapide were increased by 2.1- and 2-fold, respectively.374 When lomitapide is used concomitantly with atorvastatin, adjustment of atorvastatin dosage is not required; however, lomitapide dosage should not exceed 30 mg daily.374
Concomitant use of atorvastatin and macrolide antibiotics (e.g., clarithromycin, erythromycin) increases the risk of myopathy or rhabdomyolysis.1, 79 Following concomitant use of atorvastatin (80 mg daily for 8 days) and clarithromycin (500 mg twice daily for 9 days), atorvastatin peak plasma concentration and AUC were increased by 5.4- and 4.5-fold, respectively.1, 79 Following concomitant use of atorvastatin (10 mg as a single dose) and erythromycin (500 mg 4 times daily for 7 days), atorvastatin peak plasma concentration and AUC were increased by 38 and 33%, respectively.1, 79
The benefits of concomitant use of atorvastatin and macrolide antibiotics (e.g., clarithromycin, erythromycin) should be weighed against the possible risk of myopathy or rhabdomyolysis.1, 79 During concomitant therapy with clarithromycin, the dosage of atorvastatin should not exceed 20 mg daily.1, 79 Patients receiving atorvastatin concomitantly with macrolide antibiotics should be carefully monitored for signs and symptoms of myopathy, particularly during the initial months of therapy and following an increase in dosage of either drug.1, 79
Concomitant use of atorvastatin with nevirapine, a CYP3A4 inducer, may result in decreased atorvastatin exposure.503 Experts recommend atorvastatin dosage adjustment based on clinical response, but not to exceed the maximum recommended dose.503
Cases of myopathy and rhabdomyolysis have been reported with ocncomitant use of atorvastatin and antilipemic dosages (1 g daily or higher) of niacin.1, 79
The benefits of concomitant use of atorvastatin and antilipemic dosages of niacin should be weighed against the possible risk of myopathy.1, 79 If concomitant therapy is employed, caution is advised, and lower initial and maintenance dosages of atorvastatin should be considered; in addition, patients should be carefully monitored for signs and symptoms of myopathy, particularly during the initial months of therapy and following an increase in dosage of either drug.1, 79
Concomitant use of atorvastatin (80 mg daily) with omega-3-acid ethyl esters (4 g daily) for 14 days did not affect the rate or extent of exposure to atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin at steady state.505
Concomitant use of atorvastatin (40 mg once daily for 22 days) and an oral contraceptive (ethinyl estradiol 35 mcg with norethindrone 1 mg once daily for 2 months) resulted in 30 and 19% increases in ethinyl estradiol peak plasma concentration and AUC, respectively, and 23 and 28% increases in norethindrone peak plasma concentration and AUC, respectively.1, 79 This interaction should be considered when selecting oral contraceptives for patients receiving atorvastatin.1, 79
Administration of rifampin (600 mg once daily for 5 days) followed by delayed administration of atorvastatin (40 mg as a single dose) resulted in 40 and 80% decreases in atorvastatin peak plasma concentration and AUC, respectively, while simultaneous administration of the drugs (rifampin 600 mg once daily for 7 days with atorvastatin 40 mg as a single dose) resulted in 2.9-fold and 12% increases in atorvastatin peak plasma concentration and AUC, respectively.1, 79 Therefore, if atorvastatin and rifampin are used concomitantly, these drugs should be administered simultaneously.1, 79
Atorvastatin had no clinically important effect on prothrombin time (PT) when administered to patients receiving long-term warfarin therapy.1, 79 Some experts recommend closer monitoring of the international normalized ratio (INR) after initiation of a statin or a change in statin dosage.339
Atorvastatin calcium is a synthetic antilipemic agent.1, 501 The drug is a selective, competitive inhibitor of 3-hydroxymethylglutaryl-CoA (HMG-CoA) reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate (an early and rate-limiting step in cholesterol biosynthesis).1, 79 Inhibition of HMG-CoA reductase results in reduction of hepatic cholesterol biosynthesis, which leads to a compensatory increase in the expression of low-density lipoprotein (LDL) receptors on hepatic cell surfaces and, subsequently, increased hepatic uptake and clearance of LDL-cholesterol from blood.1 Atorvastatin reduces serum total cholesterol, LDL-cholesterol, apolipoprotein B (apo B), triglyceride, very low-density lipoprotein (VLDL)-cholesterol, intermediate-density lipoprotein (IDL)-cholesterol, and non-high-density lipoprotein (HDL) cholesterol concentrations, and increases serum HDL-cholesterol and apolipoprotein A-1 (apo A-1) concentrations5, 24 in patients with primary hypercholesterolemia, mixed dyslipidemia, hypertriglyceridemia, or primary dysbetalipoproteinemia.1 Other favorable effects of statins (pleiotropic effects) include an antiproliferative influence on smooth muscle cells, reconstruction of endothelial activity, antioxidant, antithrombotic, anticancer, and anti-inflammatory effects.501
Atorvastatin is lipophilic, undergoes first-pass metabolism in the liver, and peak plasma concentration is attained in 1-2 hours.1, 79, 501 The absolute bioavailability of atorvastatin is 14%, however the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%.1, 79 The extent of atorvastatin absorption increases in proportion to the dose.1, 79 Following the administration of atorvastatin tablets with food, the rate and extent of absorption is decreased approximately 25 and 9%, respectively, as assessed by atorvastatin peak plasma concentration and AUC.1 LDL-cholesterol reduction is similar whether the tablets are administered with or without food.1 Following the administration of atorvastatin oral suspension with a high fat meal, atorvastatin AUC and peak plasma concentration decreased approximately 30 and 63%, respectively, compared with what was observed in the fasted state.79 This decreased exposure can be clinically significant, and therefore atorvastatin oral suspension should be administered on an empty stomach (1 hour before or 2 hours after a meal).79 Atorvastatin peak plasma concentrations and AUC are approximately 30% lower following evening drug administration compared with morning; LDL-cholesterol reduction is the same regardless of the time of day of drug administration.1, 79 Atorvastatin is ≥98% bound to plasma proteins.1, 79
Atorvastatin is distributed mainly to the liver, the primary site of action and principal site of cholesterol synthesis and LDL-cholesterol clearance.1 Drug dosage, rather than systemic drug concentration, correlates better with LDL-cholesterol reduction; therefore, individualization of drug dosage should be based on therapeutic response.1 Therapeutic response is observed within 2 weeks, and maximum response is usually achieved within 4 weeks and maintained during long-term therapy.1
Atorvastatin is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 to active metabolites (i.e., o - and p -hydroxylated derivatives, various β-oxidation products). In vitro inhibition of HMG-CoA reductase by the active o - and p -hydroxylated metabolites is similar to that by atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In animals, the o -hydroxy metabolite undergoes further glucuronidation.1 Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extrahepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation.1 The mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20-30 hours due to the contribution of active metabolites.1 Less than 2% of an orally administered dose of atorvastatin is recovered in urine.1 Atorvastatin peak plasma concentrations and AUC are approximately 20% higher and 10% lower, respectively, in females compared to males; however, there is no clinically significant difference in LDL-cholesterol reduction.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Suspension | 4 mg (of atorvastatin) per mL* | Atorvastatin Calcium Suspension | |
Atorvaliq® | CMP Pharma | |||
Tablets, film-coated | 10 mg (of atorvastatin)* | Atorvastatin Calcium Tablets | ||
20 mg (of atorvastatin)* | Atorvastatin Calcium Tablets | |||
Lipitor® | Pfizer | |||
40 mg (of atorvastatin)* | Atorvastatin Calcium Tablets | |||
Lipitor® | Pfizer | |||
80 mg (of atorvastatin)* | Atorvastatin Calcium Tablets | |||
Lipitor® | Pfizer |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 10 mg (of atorvastatin) with Amlodipine Besylate 2.5 mg (of amlodipine)* | Atorvastatin Calcium and Amlodipine Besylate Tablets | |
Pfizer | ||||
10 mg (of atorvastatin) with Amlodipine Besylate 5 mg (of amlodipine)* | Atorvastatin Calcium and Amlodipine Besylate Tablets | |||
Caduet® | Pfizer | |||
10 mg (of atorvastatin) with Amlodipine Besylate 10 mg (of amlodipine)* | Atorvastatin Calcium and Amlodipine Besylate Tablets | |||
Caduet® | Pfizer | |||
20 mg (of atorvastatin) with Amlodipine Besylate 2.5 mg (of amlodipine)* | Atorvastatin Calcium and Amlodipine Besylate Tablets | |||
Caduet® | Pfizer | |||
20 mg (of atorvastatin) with Amlodipine Besylate 5 mg (of amlodipine)* | Atorvastatin Calcium and Amlodipine Besylate Tablets | |||
Caduet® | Pfizer | |||
20 mg (of atorvastatin) with Amlodipine Besylate 10 mg (of amlodipine)* | Atorvastatin Calcium and Amlodipine Besylate Tablets | |||
Caduet® | Pfizer | |||
40 mg (of atorvastatin) with Amlodipine Besylate 2.5 mg (of amlodipine)* | Atorvastatin Calcium and Amlodipine Besylate Tablets | |||
Caduet® | Pfizer | |||
40 mg (of atorvastatin) with Amlodipine Besylate 5 mg (of amlodipine)* | Atorvastatin Calcium and Amlodipine Besylate Tablets | |||
Caduet® | Pfizer | |||
40 mg (of atorvastatin) with Amlodipine Besylate 10 mg (of amlodipine)* | Atorvastatin Calcium and Amlodipine Besylate Tablets | |||
Caduet® | Pfizer | |||
80 mg (of atorvastatin) with Amlodipine Besylate 5 mg (of amlodipine)* | Atorvastatin Calcium and Amlodipine Besylate Tablets | |||
Caduet® | Pfizer | |||
80 mg (of atorvastatin) with Amlodipine Besylate 10 mg (of amlodipine)* | Atorvastatin Calcium and Amlodipine Besylate Tablets | |||
Caduet® | Pfizer |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
1. Pfizer. Lipitor® (atorvastatin calcium) tablets prescribing information. New York, NY; 2022 Dec.
5. Kastelein JJP, Isaacsohn JL, Ose L et al. Comparison of effects of simvastatin versus atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I levels. Am J Cardiol . 2000; 86:221-3. [PubMed 10913488]
7. Lea AP, McTavish D. Atorvastatin: A review of its pharmacology and therapeutic potential in the management of hyperlipidaemias. Drugs . 1997;53(5):828-847. [PubMed 9129869]
9. McKenney JM, McCormick LS, Weiss S et al. A randomized trial of the effects of atorvastatin and niacin in patients with combined hyperlipidemia or isolated hypertriglyceridemia. Am J Med . 1998;104:137-43. [PubMed 9528731]
10. Ooi TC, Heinonen T, Alaupovic P, et al. Efficacy and safety of a new hydroxymethylglutaryl-coenzyme A reductase inhibitor, atorvastatin, in patients with combined hyperlipidemia: comparison with fenofibrate. Arterioscler Thromb Vasc Biol . 1997;17:1793-9. [PubMed 9327779]
12. Heinonen T, Stein E, Issacsohn J, et al. Atorvastatin in the treatment of severe hypercholesterolemia. In: 66th Congress of the European Atherosclerosis Society Abstract Book: 1996 July 13-17, Florence Italy, 214. Abstract.
13. Bakker-Arkema RG, Davidson MH, Goldstein RJ, et al. Efficacy and safety of a new HMG Co-A reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. JAMA . 1996;275:128-33.
15. Heinonen T, Black D. Atorvastatin monotherapy and combination therapy in the treatment of severe hypercholesterolemia. Atherosclerosis . 1995;115 (Suppl):S20. Abstract.
16. Bairaktari ET, Tzallas CS, Tsimihodimos VK, et al. Comparison of the efficacy of atorvastatin and micronized fenofibrate in the treatment of mixed hyperlipidemia. J Cardiovasc Risk . 1999;6:113-6. [PubMed 10353071]
17. Hunninghake D, Bakker-Arkema RG, Wigand JP, et al. Treating to meet NCEP-recommended LDL-cholesterol concentrations with atorvastatin, fluvastatin, lovastatin, or simvastatin in patients with risk factors for coronary heart disease. J Fam Pract . 1998;47(5):349-56. [PubMed 9834769]
18. Nawrocki JW, Weiss SR, Davidson MH, et al. Reduction of LDL-C cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor. Arterioscler Thromb Vasc Biol . 1995;15:678-82. [PubMed 7749881]
19. Heinonen TM, Stein F, Weiss SR, et al. The lipid lowering effects of atorvastatin, a new HMG-CoA reductase inhibitor: results of a randomized, double-masked study. Clin Ther . 1996;18(5):853-63. [PubMed 8930429]
20. Heinonen TM, Schrott H, McKenney JM, et al. Atorvastatin, a new HMG-CoA reductase inhibitor as monotherapy and combined with colestipol. J Cardiovasc Pharmacol Therapeut . 1996;1(2):117-22.
21. Murillas J, Martin T, Ramos A et al. Atorvastatin for protease inhibitor-related hyperlipidaemia. AIDS . 1999; 13:1424-5. [PubMed 10449305]
22. Witzum JL. Drugs used in the treatment of hyperlipoproteinemias. In: Hardman JG, Limbird LE, Molinoff PB et al eds. Goodman and Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1996:875-97.
23. McVey D, Patel H, Eminton Z et al. An assessment of the efficacy of atorvastatin in treating patients with dyslipidaemia to target LDL-cholesterol goals: the atorvastatin matrix study. Int J Clin Pract . 1999; 53:509-13. [PubMed 10692735]
24. Wierzbicki AS, Lumb PJ, Crook MA et al. Comparison of therapy with simvastatin 80 mg and atorvastatin 80 mg in patients with familial hypercholesterolaemia. Int J Clin Pract . 1999; 53:609-11. [PubMed 10692755]
25. Cilla DD, Gibson DM, Whitfield LR, et al. Pharmacodynamic effects and pharmacokinetics of atorvastatin after administration to normocholesterolemic subjects in the morning and evening. J Clin Pharmacol . 1996;36:604-9. [PubMed 8844442]
26. Crouse JR, Frohlich J, Ose L, et al. Effects of high doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I. Am J Cardiol . 1999;83:1476-80. [PubMed 10335764]
27. Dart A, Jerums G, Nicholson G, et al. A multicenter, double-blind, one year study comparing safety and efficacy of atorvastatin versus simvastatin in patients with hypercholesterolemia. Am J Cardiol . 1997;80:39-44. [PubMed 9205017]
28. Raal FJ, Pilcher GJ, Veller MG et al. Efficacy of vitamin E compared with either simvastatin or atorvastatin in preventing the progression of atherosclerosis in homozygous familial hypercholesterolemia. Am J Cardiol . 1999; 84:1344-6. [PubMed 10614803]
30. Davidson MM, McKenney JM, Stein EA, et al. Comparison of one-year efficacy and safety of atorvastatin versus lovastatin in primary hypercholesterolemia. Am J Cardiol . 1997;79:1475-1481. [PubMed 9185636]
31. Stern R, Yang B, Horton M, et al. Renal dysfunction does not alter the pharmacokinetics or low density lipoprotein concentration reduction of atorvastatin. J Clin Pharmacol . 1997;37(9):816-9. [PubMed 9549635]
32. Gibson DM, Yang BB, Abel RB, et al. Effects of hepatic and renal impairment on pharmacokinetics (pk) and pharmacodynamics (pd) of atorvastatin (abstract). Pharm Res . 1996;13(suppl):428S.
35. Waters DD. Medical therapy versus revascularization: the atorvastatin versus revascularization treatment AVERT trial. Can J Cardiol . 2000; 16(suppl A):11-3A.
36. Farnier M, Portal JJ, Maigret P. Efficacy of atorvastatin compared with simvastatin in patients with hypercholesterolemia. J Cardiovasc Pharmacol Therapeut . 2000; 5:27-31.
40. Raal FJ, Pappu AS, Illingworth DR et al. Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia. Atherosclerosis . 2000; 150:421-8. [PubMed 10856535]
44. Japan Cholesterol Lowering Atorvastatin Study (J-CLAS) Group. Efficacy of atorvastatin in primary hypercholesterolemia. Am J Cardiol . 1997;79:1248-51. [PubMed 9164896]
45. Marais AD, Naoumova RP, Firth JC, et al. Decreased production of low density lipoprotein by atorvastatin after apheresis in homozygous familial hypercholesterolemia. J Lipid Res . 1997;38:2071-78. [PubMed 9374129]
51. Jones P, Kafonek S, Laurora I, et al. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (The CURVES Study). Am J Cardiol . 1998;81:582-587. [PubMed 9514454]
52. Brown AS, Bakker-Arkema RG, Yellen L, et al. Treating patients with documented atherosclerosis to National Cholesterol Education Program-recommended low-density-lipoprotein cholesterol goals with atorvastatin, fluvastatin, lovastatin, and simvastatin. J Am Coll Cardiol . 1998;32(3):665-72. [PubMed 9741509]
53. McCormick L, Black DM, Waters D, et al. Rationale, design, and baseline characteristics of a trial comparing aggressive lipid lowering with atorvastatin versus revascularization treatments (AVERT). Am J Cardiol . 1997;80:1130-33. [PubMed 9359537]
54. Pitt B, Waters D, Brown WV, et al. Aggresive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med . 1999;341(2):70-76. [PubMed 10395630]
56. Bertolini S, Bon GB, Campbell LM, et al. Efficacy and safety of atorvastatin compared to pravastatin in patients with hypercholesterolemia. Atherosclerosis . 1997;130:191-7. [PubMed 9126664]
57. Brown MS, Goldstein JL. Lipoprotein receptors in the liver: control signals for plasma cholesterol traffic. J Clin Invest . 1983;72:743-7. [PubMed 6309907]
58. Goldstein JL, Brown MS. The low-density lipoprotein pathway and its relation to atherosclerosis. Ann Rev Biochem . 1977; 46:897-930. [PubMed 197883]
61. Schwartz GG, Olsson AG, Ezekowitz MD et al for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study investigators. JAMA . 2001;285:1711-8.
62. Anon. Choice of lipid-regulating drugs. Med Lett Drugs Ther . 2001; 43:43-8. [PubMed 11378632]
64. Organon. Zetia® (ezetimibe) tablets prescribing information.Jersey City, NJ; 2024 Feb.
65. Pfizer Labs. Caduet® (amlodipine besylate/atorvastatin calcium) tablets prescribing information. New York, NY; 2023 Oct.
66. Cannon CP, Braunwald E, McCabe CH et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med . 2004; 350: 1495-504. [PubMed 15007110]
67. Nissen SE, Tuzcu EM, Schoenhagen P et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA . 2004; 291: 1071-80. [PubMed 14996776]
68. LaRosa JC, Grundy SM, Waters DD et al for the Treating to New Targets (TNT) investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med . 2005; 352:1425-35. [PubMed 15755765]
69. Waters DD, Guyton JR, Herrington DM et al for the TNT steering committee members and investigators. Treating to New Targets (TNT) study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit? Am J Cardiol . 2004; 93:154-8.
70. Pitt B. Low-density lipoprotein cholesterol in patients with stable coronary heart disease—is it time to shift our goals? N Engl J Med . 2005; 352:1483-4.
71. Deedwania P, Barter P, Carmena R et al for the Treating to New Targets Investigators. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study. Lancet . 2006; 368:919-28. [PubMed 16962881]
73. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transiet ischemic attack. N Engl J Med . 2006; 355:549-59. [PubMed 16899775]
74. Kent DM. Stroke—An equal opportunity for the initiation of statin therapy. N Engl J Med . 2006; 355:613-5. [PubMed 16899782]
79. CMP Pharma. Atorvaliq®(atorvastatin calcium) oral suspension prescribing information. Farmville, NC; 2023 Feb.
81. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J; Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005 Nov 16;294(19):2437-45. doi: 10.1001/jama.294.19.2437. Erratum in: JAMA. 2005 Dec 28;294(24):3092. PMID: 16287954.
82. van Dam M, Zwart M, de Beer F, Smelt AH, Prins MH, Trip MD, Havekes LM, Lansberg PJ, Kastelein JJ. Long term efficacy and safety of atorvastatin in the treatment of severe type III and combined dyslipidaemia. Heart. 2002 Sep;88(3):234-8. doi: 10.1136/heart.88.3.234. PMID: 12181212; PMCID: PMC1767327.
200. Food and Drug Administration. FDA drug safety communication: Important safety label changes to cholesterol-lowering statin drugs. Rockville, MD; 2012 Feb 28. From FDA website. [Web]
201. Food and Drug Administration. FDA expands advice on statin risks. Rockville, MD; 2012 Feb 27. From FDA website. [Web]
202. McKenney JM, Davidson MH, Jacobson TA et al. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol . 2006; 97(suppl):89-94C.
309. Cannon CP, Blazing MA, Giugliano RP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med . 2015; 372:2387-97. [PubMed 26039521]
336. Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet . 2012; 380:581-90. [PubMed 22607822]
337. Baigent C, Keech A, Kearney PM et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet . 2005; 366:1267-78. [PubMed 16214597]
338. Cholesterol Treatment Trialists' (CTT) Collaboration, Baigent C, Blackwell L et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet . 2010; 376:1670-81. [PubMed 21067804]
339. Wiggins BS, Saseen JJ, Page RL et al. Recommendations for Management of Clinically Significant Drug-Drug Interactions With Statins and Select Agents Used in Patients With Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation . 2016; 134:e468-e495.
350. Stone NJ, Robinson J, Lichtenstein AH et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol . 2013; :. [Web]
351. Stone NJ, Robinson JG, Lichtenstein AH et al. Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk in Adults: Synopsis of the 2013 ACC/AHA Cholesterol Guideline. Ann Intern Med . 2014; :. [PubMed 24474185]
352. Eckel RH, Jakicic JM, Ard JD et al. 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol . 2014; 63:2960-84. [PubMed 24239922]
353. ACCORD Study Group, Ginsberg HN, Elam MB et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med . 2010; 362:1563-74. [PubMed 20228404]
354. AIM-HIGH Investigators, Boden WE, Probstfield JL et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med . 2011; 365:2255-67. [PubMed 22085343]
356. Miller M, Stone NJ, Ballantyne C et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation . 2011; 123:2292-333. [PubMed 21502576]
357. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents, National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics . 2011; 128 Suppl 5:S213-56. [PubMed 22084329]
369. HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med . 2014; 371:203-12. [PubMed 25014686]
371. Anderson TJ, Boden WE, Desvigne-Nickens P et al. Safety profile of extended-release niacin in the AIM-HIGH trial. N Engl J Med . 2014; 371:288-90. [PubMed 25014706]
373. GlaxoSmithKline. Lovaza® (omega-3-acid ethyl esters) capsules prescribing information. Research Triangle Park, NC; 2014 May.
374. Amryt Pharmaceuticals. Juxtapid® (lomitapide mesylate) capsules prescribing information. Dublin, Ireland; 2020 Sep.
387. Wanner C, Krane V, März W et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med . 2005; 353:238-48. [PubMed 16034009]
400. Grundy SM, Stone NJ, Bailey AL et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation . 2019; 139:e1082-e1143. [PubMed 30586774]
401. American Diabetes Association Professional Practice Committee. 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes-2024. Diabetes Care. 2024 Jan 1;47(Suppl 1):S179-S218. doi: 10.2337/dc24-S010. PMID: 38078592; PMCID: PMC10725811.
402. Virani SS, Newby LK, Arnold SV, Bittner V, Brewer LC, Demeter SH, Dixon DL, Fearon WF, Hess B, Johnson HM, Kazi DS, Kolte D, Kumbhani DJ, LoFaso J, Mahtta D, Mark DB, Minissian M, Navar AM, Patel AR, Piano MR, Rodriguez F, Talbot AW, Taqueti VR, Thomas RJ, van Diepen S, Wiggins B, Williams MS. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2023 Aug 29;148(9):e9-e119. Doi: 10.1161/CIR.0000000000001168. Epub 2023 Jul 20. Erratum in: Circulation. 2023 Sep 26;148(13):e148. Erratum in: Circulation. 2023 Dec 5;148(23):e186. PMID: 37471501.
403. Writing Committee; Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Covington AM, DePalma SM, Minissian MB, Orringer CE, Smith SC Jr, Waring AA, Wilkins JT. 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2022 Oct 4;80(14):1366-1418. doi: 10.1016/j.jacc.2022.07.006. Epub 2022 Aug 25. Erratum in: J Am Coll Cardiol. 2023 Jan 3;81(1):104. PMID: 36031461.
404. Wiegman A, Gidding SS, Watts GF, Chapman MJ, Ginsberg HN, Cuchel M, Ose L, Averna M, Boileau C, Borén J, Bruckert E, Catapano AL, Defesche JC, Descamps OS, Hegele RA, Hovingh GK, Humphries SE, Kovanen PT, Kuivenhoven JA, Masana L, Nordestgaard BG, Pajukanta P, Parhofer KG, Raal FJ, Ray KK, Santos RD, Stalenhoef AF, Steinhagen-Thiessen E, Stroes ES, Taskinen MR, Tybjærg-Hansen A, Wiklund O; European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J. 2015 Sep 21;36(36):2425-37. doi: 10.1093/eurheartj/ehv157. Epub 2015 May 25. PMID: 26009596; PMCID: PMC4576143.
405. US Food and Drug Administration. FDA Drug Safety Communication: FDA requests removal of strongest warning against using cholesterol-lowering statins during pregnancy; still advises most pregnant patients should stop taking statins. Silver Spring, MD; 2021 July 20. From FDA website. Accessed 2021 Sept 9. [Web]
406. Cheeley MK, Saseen JJ, Agarwala A et al. NLA scientific statement on statin intolerance: a new definition and key considerations for ASCVD risk reduction in the statin intolerant patient. J Clin Lipidol. 2022; 16:361-375.
407. Bouhairie VE, Goldberg AC. Familial hypercholesterolemia. Cardiol Clin. 2015;33(2):169-179.
408. Bajaj A, Cuchel M. Advancements in the treatment of homozygous familial hypercholesterolemia. J Atheroscler Thromb. 2022;29(8):1125-1135.
409. Watts GF, Gidding SS, Hegele RA, etc. International Atherosclerosis Society guidance for implementing best practice in the care of familial hypercholesterolemia. Nat Rev Cardiol. 2023; Jun 15. [online ahead of print].
500. Cooper-DeHoff RM, Niemi M, Ramsey LB, et al. The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin-Associated Musculoskeletal Symptoms. Clin Pharmacol Ther. 2022 May;111(5):1007-1021. doi: 10.1002/cpt.2557. Epub 2022 Mar 11. PMID: 35152405; PMCID: PMC9035072.
501. Sadowska A, Osiński P, Roztocka A, Kaczmarz-Chojnacka K, Zapora E, Sawicka D, Car H. Statins-From Fungi to Pharmacy. Int J Mol Sci. 2023 Dec 29;25(1):466. doi: 10.3390/ijms25010466. PMID: 38203637; PMCID: PMC10779115.
502. Balasubramanian R, Maideen NMP. HMG-CoA Reductase Inhibitors (Statins) and their Drug Interactions Involving CYP Enzymes, P-glycoprotein and OATP Transporters-An Overview. Curr Drug Metab. 2021;22(5):328-341. doi: 10.2174/r2029200222666210114122729. PMID: 33459228.
503. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. (February 27, 2024). Accessed 2024 Apr 18. Available at http://clinicalinfo.hiv.gov/en/guidelines [Web]
504. Gagné C, Gaudet D, Bruckert E; Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation. 2002 May 28;105(21):2469-75. doi: 10.1161/01.cir.0000018744.58460.62. PMID: 12034651.
505. Ho CK, Walker SW. Statins and their interactions with other lipid-modifying medications: safety issues in the elderly. Ther Adv Drug Saf. 2012 Feb;3(1):35-46. doi: 10.1177/2042098611428486. PMID: 25083224; PMCID: PMC4110829.