Prevention of Cardiovascular Events
The American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guideline recommends statins as first-line therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) in adults. There is extensive evidence demonstrating that statins can substantially reduce ASCVD risk when used for secondary prevention or primary prevention (in high-risk patients). Because the relative reduction in ASCVD risk is correlated with the degree of low-density lipoprotein (LDL)-cholesterol lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits. According to the ACC/AHA guidelines, lovastatin may be used for primary or secondary prevention in adults when moderate-intensity statin therapy is indicated.
(See Prevention of Cardiovascular Events under Dosage and Administration: Dosage.)Nonstatin therapies do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD. For additional details on prevention of ASCVD, and also consult the most recent ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (available at http://www.cardiosource.org or http://my.americanheart.org).
Lovastatin is used as an adjunct to nondrug therapies (i.e., lifestyle modifications) in patients without symptomatic cardiovascular disease who have normal or moderate elevations of total and LDL-cholesterol and below-average high-density lipoprotein (HDL)-cholesterol concentrations to reduce the risk of myocardial infarction (MI) or unstable angina and to reduce the risk of undergoing coronary revascularization procedures.
The ACC/AHA cholesterol management guideline recommends statins as first-line therapy for primary prevention in patients 21 years of age and older without clinical ASCVD who have primary, severe elevations in LDL-cholesterol concentration (190 mg/dL or greater); patients 40-75 years of age with type 1 or 2 diabetes mellitus; and patients 40-75 years of age with LDL-cholesterol concentrations of 70-189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher. Before initiating statin therapy for primary prevention in patients without clinical ASCVD or diabetes mellitus, it is reasonable for clinicians and patients to discuss the potential for ASCVD risk reduction benefits, adverse effects, and drug interactions, as well as patient preferences for treatment.
In a randomized, double-blind, placebo-controlled study (Air Force/Texas Coronary Atherosclerosis Prevention Study [AFCAPS/TexCAPS]) in patients who had total and LDL-cholesterol concentrations averaging 221 and 150 mg/dL, respectively, and HDL-cholesterol concentrations averaging 36 mg/dL (men) or 40 mg/dL (women), lovastatin therapy (20-40 mg daily) reduced the incidence of a first acute major event (i.e., primary end point defined as fatal or nonfatal MI, unstable angina, or sudden cardiac death) by 37% after an average follow-up period of 5.2 years. Lovastatin therapy also produced benefit in terms of secondary end points, including a 33% reduction in coronary revascularization procedures, a 32% reduction in unstable angina, a 40% reduction in the incidence of fatal or nonfatal MI, and a 25% reduction in cardiovascular (e.g., atherosclerotic) events.
Reducing Progression of Coronary Atherosclerosis
Lovastatin is used as an adjunct to nondrug therapies (e.g., dietary management) in patients with coronary heart disease (CHD) to slow the progression of coronary atherosclerosis as part of a treatment strategy to lower total and LDL-cholesterol concentrations to target levels.
Lovastatin has been shown to slow the progression of atherosclerosis in both coronary and carotid arteries by reducing intimal-medial wall thickness. In several double-blind, placebo-controlled studies (e.g., Canadian Coronary Atherosclerosis Intervention Trial [CCAIT], Monitored Atherosclerosis Regression Study [MARS], Familial Atherosclerosis Treatment Study [FATS]) in men and women with or without documented CHD and elevated lipoprotein concentrations, progression of atherosclerosis at 2-3 years (measured as the mean per-patient changes from baseline in mean and minimal coronary artery lumen diameters, percent diameter stenosis, and formation of new lesions) was reduced in patients who received recommended daily dosages of lovastatin.
Treatment with lovastatin has been shown to reduce the rate of progression of atherosclerosis in the carotid arteries. In the MARS and the Asymptomatic Carotid Artery Progression Studies (ACAPS), hypercholesterolemic patients with or without CHD who received recommended daily dosages of lovastatin for a median of 2-4 years showed less progression of atherosclerosis (as determined by B-mode ultrasound quantification of carotid artery intimal-medial thickness [IMT]) compared with those receiving placebo. In addition, treatment with lovastatin also was associated with a reduction in the risk of major cardiovascular events and all-cause mortality.
Intensity of Statin Therapy
The ACC/AHA cholesterol management guideline states that the appropriate intensity of a statin should be used to reduce the risk of ASCVD in patients most likely to benefit. Based on the average LDL-cholesterol response observed with specific statins and dosages used in the randomized controlled studies evaluated by the guideline expert panel, ACC/AHA considers lovastatin 20 mg daily to be a low-intensity statin (producing approximate LDL-cholesterol reductions of less than 30%) and lovastatin 40 mg daily to be a moderate-intensity statin (producing approximate LDL-cholesterol reductions of 30% to less than 50%). Individual patient response may vary in clinical practice.
Combination Antilipemic Therapy
The ACC/AHA cholesterol management guideline states that nonstatin drugs may be useful adjuncts to statin therapy in certain high-risk patients (e.g., patients with ASCVD, LDL-cholesterol concentrations of at least 190 mg/dL, or diabetes mellitus) who have a less-than-anticipated response to statins, are unable to tolerate a less-than-recommended intensity of a statin, or are completely intolerant to statin therapy, particularly if there is evidence from randomized controlled studies suggesting that the addition of the nonstatin drug further reduces ASCVD events. 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.
Primary Hypercholesterolemia or Mixed Dyslipidemia
Lovastatin is used as an adjunct to nondrug therapies (e.g., dietary management) in adults to decrease elevated serum total and LDL-cholesterol, apolipoprotein B (apo B), and triglyceride concentrations, and to increase HDL-cholesterol concentrations in the treatment of primary hypercholesterolemia, including heterozygous familial hypercholesterolemia and other primary causes of hypercholesterolemia (e.g., polygenic hypercholesterolemia). Lovastatin as conventional (immediate-release) tablets also is used as an adjunct to dietary therapy to reduce elevated serum total cholesterol, LDL-cholesterol, and apo B concentrations in the treatment of heterozygous familial hypercholesterolemia in boys and girls (who are at least 1 year postmenarchal) 10-17 years of age who, despite an adequate trial of dietary management, have a serum LDL-cholesterol concentration of 190 mg/dL or greater or a serum LDL-cholesterol concentration exceeding 160 mg/dL and either a family history of premature cardiovascular disease or 2 or more other cardiovascular risk factors. Statins such as lovastatin also are used in combination with fenofibrate to decrease triglyceride concentrations and increase HDL-cholesterol concentrations in patients with mixed dyslipidemia and CHD or CHD risk equivalents who are receiving optimal statin therapy; however, no additional benefit on cardiovascular morbidity and mortality has been demonstrated with such combination therapy beyond that already established with statin monotherapy.
Although lovastatin also has been used to reduce elevated LDL-cholesterol concentrations in patients with combined hypercholesterolemia and hypertriglyceridemia caused by genotypic familial combined hyperlipidemia, the drug has not been studied in conditions where the major abnormality is elevation of chylomicrons, very-low-density lipoproteins (VLDLs), or intermediate-density lipoproteins (IDLs).
Nondrug therapies and measures specific for the type of dyslipidemia (therapeutic lifestyle changes) are the initial treatments of choice, including dietary management (e.g., restriction of total and saturated fat and cholesterol intake, addition of plant stanols/sterols and viscous fiber to diet), weight control, an appropriate program of physical activity, and management of potentially contributory disease (e.g., hypothyroidism). Drug therapy is not a substitute for but an adjunct to these nondrug therapies and measures, which should be continued when drug therapy is initiated.
Reductions in total and LDL-cholesterol produced by usual dosages of lovastatin substantially exceed those of placebo and appear to be similar to or greater than those produced by monotherapy with usual dosages of certain other antilipemic agents. Mean reductions in total cholesterol concentrations of 13-34%, LDL-cholesterol concentrations of 17-48%, and triglyceride concentrations of 6-27% have been observed in controlled and uncontrolled studies in patients with heterozygous familial hypercholesterolemia or other forms of primary hypercholesterolemia who received 10-80 mg of lovastatin daily. Modest and variable increases in HDL-cholesterol concentrations (1-10%) also were observed in these patients. In 2 multicenter, placebo-controlled studies, 89% of patients with heterozygous familial hypercholesterolemia or 97% of patients with other forms of primary hypercholesterolemia who received lovastatin 40 mg twice daily and dietary management had reductions in LDL-cholesterol of at least 20%, while 61 or 51% of such patients had LDL-cholesterol reductions of at least 40%; reductions in LDL-cholesterol averaged 39% in both groups of patients.
Reductions in total and LDL-cholesterol concentrations produced by usual dosages of lovastatin generally appear to be similar to or greater than those produced by monotherapy with usual dosages of some statins (e.g., fluvastatin, pravastatin, simvastatin) but less than those produced by usual dosages of atorvastatin and rosuvastatin. In a randomized, multicenter, parallel-group study comparing the efficacy of various statins, patients with hypercholesterolemia who received lovastatin 20-80 mg daily experienced similar or greater reductions in total and LDL-cholesterol concentrations (21-36 and 29-48%, respectively) than those receiving fluvastatin 20-40 mg daily (13-19 and 17-23%, respectively), pravastatin 10-40 mg daily (13-24 and 19-34%, respectively), or simvastatin 10-40 mg daily (21-30 and 28-41%, respectively). However, atorvastatin dosages of 10-80 mg daily produced greater reductions in total and LDL-cholesterol concentrations (28-42 and 38-54%, respectively) than lovastatin. Maximum reductions in LDL-cholesterol concentrations with lovastatin reportedly average about 35-40% at maximum recommended dosages (80 mg daily in 1 or 2 divided doses).
(See Intensity of Statin Therapy under Uses: Prevention of Cardiovascular Events.)
Limited data from comparative studies suggest that reductions in total and LDL-cholesterol concentrations produced by lovastatin are similar to or greater than those produced by certain other antilipemic agents (i.e., bile acid sequestrants, niacin, fibric acid derivatives). Lovastatin 40-80 mg daily reportedly has produced greater reductions in total cholesterol than cholestyramine 12-24 g daily. HDL-cholesterol increases produced by lovastatin are similar to or greater than those reported with usual cholestyramine dosages. Lovastatin appears to produce greater reductions in total and LDL-cholesterol than niacin or fibric acid derivatives (i.e., fenofibrate, gemfibrozil) in reducing total and LDL-cholesterol concentrations but is less effective than these agents in reducing triglycerides or increasing HDL-cholesterol concentrations. In several comparative studies in patients with primary hypercholesterolemia or familial combined hyperlipidemia, therapy with lovastatin (20-40 mg daily) reduced total and LDL-cholesterol concentrations by 17-23 and 21-28%, respectively, while total and LDL-cholesterol reductions averaged 6 and 5%, respectively, with niacin; 9 and 2%, respectively, with gemfibrozil; and 13 and 12%, respectively, with fenofibrate. Reductions in triglycerides and increases in HDL-cholesterol concentrations generally were less pronounced among patients treated with lovastatin (8-25% reduction and 6-13% increase) than in those receiving niacin (22% reduction and 18% increase), gemfibrozil (48% reduction and 18% decrease), or fenofibrate (42% reduction and 22% increase).
When lovastatin monotherapy combined with dietary management does not reduce LDL-cholesterol concentrations to optimal levels in patients with dyslipidemia, combination drug therapy may be required. Although combined therapy with lovastatin and another antilipemic agent generally results in cholesterol reductions exceeding those achieved with either therapy alone, the risk of myopathy and rhabdomyolysis may be increased with such concomitant use. Therapy with lovastatin (20-40 mg daily) in fixed combination with extended-release niacin (1-2 g daily) (no longer commercially available in the US) reduced LDL-cholesterol or triglyceride concentrations by 30-42 or 32-44%, respectively, and increased HDL-cholesterol concentrations by 20-30%. Limited data indicate that concomitant therapy with gemfibrozil and lovastatin may be superior to that with gemfibrozil and a bile acid sequestrant in patients with familial combined hyperlipidemia, in part because the bile acid sequestrant appears to lessen the favorable effects of gemfibrozil on HDL- and VLDL-cholesterol and total triglycerides. Lovastatin has been used concomitantly with the bile acid sequestrants colestipol or cholestyramine in a limited number of patients with heterozygous familial hypercholesterolemia or other forms of primary hypercholesterolemia. The addition of a bile acid sequestrant to lovastatin therapy further reduced LDL-cholesterol by 19-26%, resulting in overall LDL-cholesterol reductions of 46-60% in patients receiving lovastatin 40-80 mg daily and either colestipol hydrochloride 10-20 g daily or cholestyramine 4-24 g daily. Triple-drug therapy with lovastatin, niacin, and a bile acid sequestrant in patients with severe heterozygous familial hypercholesterolemia or other forms of severe primary hypercholesterolemia has produced further sustained reductions in LDL-cholesterol compared with those produced by combinations of any two of these drugs, and some clinicians have suggested that niacin may be more effective than a fibric acid derivative (e.g., gemfibrozil) in a three-drug regimen in patients whose cholesterol concentrations are controlled inadequately by the combination of a statin and a bile acid sequestrant. However, because of the increased risk of adverse muscular effects with combination therapy, some antilipemic drug combinations should be avoided or used with caution.
Lovastatin has reduced total and LDL-cholesterol concentrations in a few patients with familial dysbetalipoproteinemia or with hypercholesterolemia associated with or exacerbated by diabetes mellitus (diabetic dyslipidemia), cardiac or renal transplantation, nephrotic syndrome (nephrotic hyperlipidemia), or distal ileal bypass surgery. The drug also has been used to lower total cholesterol, LDL-cholesterol, and/or apolipoprotein B in a limited number of patients with hypoalphalipoproteinemia or in those with mild endogenous (primary) hypertriglyceridemia and borderline elevated total cholesterol, decreased HDL-cholesterol, and elevated apolipoprotein B (type IV hyperlipoproteinemia with elevated total apo B). Additional studies are necessary to determine the role, if any, of lovastatin therapy in patients with these disorders.
For additional information on these and other uses of lovastatin or other statins, see General Principles of Antilipemic Therapy and see Uses in the HMG-CoA Reductase Inhibitors General Statement 24:06.08.