VI. Drug Therapy

Abstract

HomeCirculationVol. 106, No. 25VI. Drug Therapy Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBVI. Drug Therapy Originally published17 Dec 2002https://doi.org/10.1161/circ.106.25.3303Circulation. 2002;106:3303–33251. Thresholds and goals for drug treatmenta. Drug therapy to achieve treatment goals: overviewLDL cholesterol is the primary target of treatment in clinical lipid management. The use of therapeutic lifestyle changes (TLC), including LDL-lowering dietary options (plant stanols/sterols and increased viscous fiber) will achieve the therapeutic goal in many persons. Nonetheless, a portion of the population whose short-term and/or long-term risk for CHD, will require LDL-lowering drugs to reach the prescribed goal for LDL cholesterol. The availability of HMG CoA reductase inhibitors (statins) allows attainment of the LDL goal in most higher risk persons. Other agents—bile acid sequestrants, nicotinic acid, and some fibrates—also can moderately lower LDL levels.If TLC alone fails to achieve the goal for LDL cholesterol, consideration can be given to adding drug therapy. In such cases, the third visit of dietary therapy (Figure V.2-1) will be the visit to initiate drug treatment. When drugs are used, however, TLC also should always be used concomitantly. Dietary therapy provides additional CHD risk reduction beyond drug efficacy. Suggestions for combined use of TLC and drug therapy are given in Table VI.1-1.Table VI.1-1. Suggestions for Combined Use of TLC and Drug TherapyIntensive LDL lowering with TLC, including therapeutic dietary options (plant stanols/sterols and/or increased viscous fiber)May obviate need for drug therapyCan augment LDL-lowering drug therapyMay allow for lower doses of drugsWeight control plus increased physical activityReduces risk beyond LDL-cholesterol loweringConstitutes primary management of the metabolic syndromeRaises HDL-cholesterol levelsEnhances reduction of non-HDL cholesterolInitiating TLC before drug considerationFor most persons, a trial of dietary therapy of about 3 months is advised before initiating drug therapyUnsuccessful trials of dietary therapy without drugs should not be prolonged indefinitely if goals of therapy are not approached in a reasonable period; drug therapy should not be withheld if it is needed to reach targets in persons with a short-term and/or long-term CHD risk that is high.Initiating drug therapy simultaneously with TLCFor severe hypercholesterolemia in which dietary therapy alone cannot achieve LDL targetsFor those with CHD or CHD risk equivalents in whom dietary therapy alone will not achieve LDL targetsThe general scheme for initiation and progression of LDL-lowering drug therapy is outlined in Figure VI.1-1. As with dietary therapy, the first priority of drug therapy is to achieve the goal for LDL cholesterol. For this reason an LDL-lowering drug should be started. The usual drug will be a statin, but alternatives are a bile acid sequestrant or nicotinic acid. The starting dose of statin will depend on the baseline LDL-cholesterol level. In persons with only moderate elevations of LDL cholesterol, the LDL-cholesterol goal will be achieved with low or standard doses, and higher doses will not be necessary. The response to drug therapy should be checked in about 6 weeks. If the treatment goal has been achieved, the current dose can be maintained; if not, LDL-lowering therapy can be intensified, either by increasing the statin dose or by combining a statin with a bile acid sequestrant.Download figureDownload PowerPointFigure VI.1-1. Progression of Drug TherapyAlthough LDL cholesterol is the primary target of therapy, other lipid risk factors besides elevated LDL affect CHD risk. Among these are low HDL cholesterol, elevated triglyceride (especially VLDL remnants), and possibly small LDL particles. This “lipid triad” has been called atherogenic dyslipidemia. It commonly occurs as one component of the metabolic syndrome. Weight reduction and increased physical activity constitute first-line therapy for atherogenic dyslipidemia, and three classes of drugs—statins, nicotinic acid, and fibrates—favorably modify the lipid abnormalities of atherogenic dyslipidemia. Many persons with atherogenic dyslipidemia have high triglycerides (≥200 mg/dL). Such persons usually have an increase in atherogenic VLDL remnants, which can be estimated clinically by measuring VLDL cholesterol. In persons with high triglycerides, the combination of LDL cholesterol + VLDL cholesterol (non-HDL cholesterol) represents atherogenic cholesterol. Non-HDL cholesterol thus represents a secondary target of therapy (after LDL cholesterol) when triglycerides are elevated. Statins alone will be sufficient to attain the non-HDL-cholesterol goal in some persons, but a combination of statins and nicotinic acid (or fibrates) can be helpful in others.The general strategy for initiation and progression of drug therapy is outlined in Figure VI.1-1. Consideration of drug therapy often occurs simultaneously with the decision to initiate TLC therapy for the metabolic syndrome (Figure V.2-1). Thus weight reduction and increased physical activity may begin at the same time as drug treatment.After another 6 weeks, the response to therapy should be assessed. If the LDL-cholesterol goal is still not achieved, further intensification of therapy should be considered, with re-evaluation in another 6 weeks. Once the LDL-cholesterol goal has been attained, attention turns to other lipid risk factors when present. If triglycerides are high (≥200 mg/dL), the secondary target of treatment becomes non-HDL cholesterol. If the LDL-cholesterol goal has been attained but not the non-HDL-cholesterol goal, there are two alternative approaches: (a) the dose of the LDL-lowering drug can be increased to reduce both LDL and VLDL, or (b) consideration can be given to adding a triglyceride-lowering drug (fibrate or nicotinic acid) to LDL-lowering therapy, which will mainly lower VLDL (see Section VII). The latter approach has the advantage of raising HDL cholesterol in addition to lowering non-HDL cholesterol. Thereafter, persons can be monitored for response to therapy every 4 or 6 months, or more often if considered necessary.Some cholesterol-lowering agents are currently available over-the-counter (OTC) (e.g., nicotinic acid), and manufacturers of several classes of LDL-lowering drugs (e.g., statins, bile acid sequestrants) have applied to the Food and Drug Administration (FDA) to allow these agents to become OTC medications. At the time of publication of ATP III, the FDA has not granted permission for OTC status for statins or bile acid sequestrants. If an OTC cholesterol-lowering drug is or becomes available, patients should continue to consult with their physicians about whether to initiate drug treatment, about setting goals of therapy, and about monitoring for therapeutic responses and side effects.b. Cholesterol management in persons with CHD or CHD risk equivalentsThe general approach to drug therapy in persons with CHD or CHD risk equivalents is shown in Figure IV.2-1. The LDL-cholesterol goal is <100 mg/dL. Most persons with CHD or CHD risk equivalents should be treated to achieve this goal. Special considerations for LDL-lowering therapy with drugs are given for the following subcategories of persons with CHD or CHD risk equivalents.1) Baseline LDL cholesterol ≥130 mg/dLSecondary prevention trials consistently show benefit from LDL-lowering drugs when baseline LDL cholesterol is ≥130 mg/dL. Thus, most persons with baseline LDL cholesterol ≥130 mg/dL should be started on LDL-lowering drugs simultaneously with TLC since many such persons cannot achieve the LDL-cholesterol goal of <100 mg/dL on dietary therapy alone. Nonetheless, the use of dietary therapy is essential because it provides benefits not available through drugs. In some persons, to achieve the LDL goal, relatively high doses of LDL-lowering drugs will be required. Statins typically are the drug of first choice. In persons whose baseline LDL cholesterol is very high, drugs in combination (e.g., statins + bile acid sequestrants) will be necessary to reduce the LDL cholesterol to <100 mg/dL.2) On-treatment LDL cholesterol 100-129 mg/dLIf the LDL-cholesterol level is reduced to <100 mg/dL, current drug therapy can be continued. However, even in controlled clinical trials, less than half of persons with CHD achieved an LDL-cholesterol goal of <100 mg/dL on standard doses of statins (i.e., simvastatin 20-40 mg/day in the 4S trial435 or pravastatin 40 mg/day in CARE436 and LIPID206). In the majority of participants, on-treatment LDL cholesterol was in the range of 100-129 mg/dL. For such persons, several therapeutic options are available (Table VI.1-2).Table VI.1-2. Therapeutic Options for Clinical Management of Persons with On-Treatment LDL-Cholesterol Levels of 100-129 mg/dL #1Increase intensity of TLC for LDL lowering to achieve LDL-cholesterol goal<100 mg/dLReinforce reduction of saturated fats and cholesterolAdd other dietary therapies[UNK] Plant stanols/sterols[UNK] Increase viscous fiberPromote weight loss in overweight/obese persons #2Intensify LDL-lowering drug therapy to achieve LDL-cholesterol goal <100 mg/dLIncrease dose of statinAdd a second LDL-lowering drug (bile acid sequestrant or nicotinic acid) #3Introduce lifestyle therapies for treatment of the metabolic syndrome, if presentPromote weight loss in overweight/obese personsRecommend increased physical activity #4Employ drug therapy for treatment of atherogenic dyslipidemia, if presentNicotinic acidFibric acids #5Intensify treatment of nonlipid risk factorsHypertensionHyperglycemiaProthrombotic state (antiplatelet drugs/anticoagulants)First, dietary options for LDL lowering can be intensified. These include reinforcement of lifestyle therapies (reduced intakes of saturated fat and cholesterol and weight reduction); referral to a dietitian for medical nutrition therapy is advisable. These changes in eating habits, combined with other dietary therapies (plant stanols/sterols and increased viscous fiber), often will reduce LDL-cholesterol levels to near 100 mg/dL. Second, LDL-lowering drug therapy can be intensified. The dose of statins can be increased, or a second LDL-lowering drug (bile acid sequestrant or nicotinic acid) can be combined with statin therapy. Third, if the patient has the metabolic syndrome, attention can turn to managing this condition through weight loss and increased physical activity; besides improvement of lipid and nonlipid risk factors of this syndrome, further LDL lowering often is obtained. Fourth, if the patient has atherogenic dyslipidemia, other drugs (nicotinic acid or fibric acids) can be added to the regimen, or LDL-lowering therapy can be intensified. Nicotinic acid not only will improve atherogenic dyslipidemia, but it also can lower LDL-cholesterol levels. If elevated triglycerides are present, addition of one of these drugs will assist in reaching the non-HDL-cholesterol goal. And fifth, treatment of nonlipid risk factors can be intensified. Finally, a combination of these options is advisable for some persons.3) Baseline LDL cholesterol 100-129 mg/dLNHANES III data showed that more than 30 percent of people with CHD have baseline LDL-cholesterol levels in the 100-129 mg/dL range. In clinical practice, however, misclassification of LDL-cholesterol levels from single measurements in individuals will be high. Many persons will have true baseline LDL-cholesterol levels ≥130 mg/dL. Baseline levels of LDL cholesterol are labile from one measurement to another. Regardless of apparent baseline level, the LDL-cholesterol goal for all CHD patients and CHD risk equivalents is<100 mg/dL. The various options outlined in Table VI.1-2 can be applied to this category. Many persons with baseline LDL-cholesterol levels between 100 and 129 mg/dL will be able to attain LDL cholesterol <100 mg/dL through TLC especially if it includes plant stanols/sterols and increased viscous fiber. Others will require cholesterol-lowering drugs to reach this target. Clinical judgment is required as to when to initiate a cholesterol-lowering drug. If the LDL cholesterol falls near 100 mg/dL on dietary therapy alone, the physician has the option to forego a cholesterol-lowering drug for the present. This is particularly so if other lipid or nonlipid risk factors seem to need greater attention.Once adequate LDL-lowering therapy has been attained, other lipid risk factors deserve attention. For example, if the patient has an elevated triglyceride or low-HDL cholesterol, a different lipid-lowering drug can be considered (e.g., nicotinic acid or fibric acid). The positive results of the VA-HIT trial showing the efficacy of gemfibrozil therapy alone in CHD patients have led some authorities to favor fibrates over statins in low-LDL patients with CHD.48 Overall, however, for monotherapy, clinical trials with statins have been more robust in their favorable outcomes than have fibrates. In addition, combined drug therapy (low-dose statin + fibrate [or nicotinic acid]) remains an option in such persons, provided that precautions are taken to prevent and monitor for side effects of lipid-lowering drugs used in combination.4) Baseline LDL cholesterol <100 mg/dLSome patients with CHD or CHD risk equivalent will have a baseline LDL cholesterol <100 mg/dL. These patients are already at their LDL-cholesterol goal. For them, further LDL lowering is not required. Attention shifts to other lipid or nonlipid risk factors. If triglycerides are elevated (≥200 mg/dL), the non-HDL cholesterol remains a secondary target of therapy. Alternative therapies to reduce VLDL-cholesterol levels to attain the non-HDL-cholesterol goal are statins or triglyceride-lowering drugs (nicotinic acid or fibrate). Furthermore, nonlipid risk factors may be largely responsible for the patient's CHD and thus may deserve intensive modification.5) Initiating cholesterol-lowering drugs in hospitalized patientsHospitalization for a coronary event or procedure provides a unique opportunity to initiate LDL-lowering therapy. Physicians should take advantage of this opportunity. In the past, this opportunity has often been lost due to confusion about the meaning of LDL-cholesterol levels obtained during hospitalization. Although it is true that LDL levels can change during an acute illness, this should not stand in the way of starting needed therapy. A few simple recommendations can guide initiation of LDL-lowering therapy during hospitalization. The guiding principle is that LDL cholesterol should be measured in all patients, preferably on admission, but in any case at some time during hospitalization, and can be used as a guide to start treatment.793 Thus, the first 24 hours of hospital admission should be considered a “window of opportunity” during which a fasting lipoprotein profile should be obtained. Whereas as much as a 10 percent fall in LDL cholesterol may occur during this first day (due to heparinization, stress, diet, and other factors), a value quite close to the actual baseline for that individual will be obtained and will be crucial in the decision to initiate early cholesterol-lowering therapy.If this first 24-hour “window” is missed, a fasting lipoprotein profile should still be obtained during hospitalization since an elevated LDL cholesterol in that setting will identify persons with even higher baseline LDL cholesterol. The following summarizes the ATP III position on initiation of LDL-lowering drugs during hospitalization of CHD-related events or procedures.First, persons hospitalized with a coronary event or procedure should be discharged on both dietary therapy and drug therapy if the LDL cholesterol is ≥130 mg/dL.Second, if the LDL is 100-129 mg/dL during hospitalization, clinical judgment should be used in deciding whether to initiate drug treatment at discharge. The initial LDL-cholesterol level obtained in the hospital may be the lowest value seen for this patient. LDL-cholesterol levels are decreased beginning in the first 24-48 hours after an event and may remain low for many weeks. Later, if necessary, therapy can be adjusted according to the LDL response.Initiation of both TLC and LDL-lowering drugs at the time of hospital discharge has several advantages. First, at this time persons are particularly motivated to undertake and adhere to risk-lowering interventions. Second, failure to initiate indicated therapy early is one of the causes of a large“ treatment gap” as outpatient follow up is often less consistent and more fragmented. Finally, new and ongoing studies suggest a very early benefit of LDL-cholesterol-lowering therapy.471,794-797 Recent support for this approach comes from the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Trial of over 3,000 persons hospitalized with non-Q myocardial infarction or unstable angina, with a mean hospital LDL-cholesterol level of 124 mg/dL. Statin treatment, initiated in the hospital, was safe and resulted in a 16 percent relative risk reduction in subsequent coronary events at 16 weeks.469 Finally, a large observational study from Sweden showed an adjusted 25 percent reduction in total mortality at one year for myocardial infarction patients started on statins in-hospital.471These latter trials,469,471 while suggesting benefit from starting LDL-lowering therapy at time of acute coronary syndrome, do not preclude the need for further research on efficacy of drug therapy started at this time.6) Special considerations for drug therapy in CHD patientsIn most persons with CHD, goals for LDL-lowering therapy can be achieved with lifestyle therapies and drug monotherapy. The benefits of intensive LDL reduction with the use of drugs apparently extend to those with advanced age and poor cardiac prognosis; nonetheless, some persons with severe co-existing medical conditions that severely impair quality of life or life expectancy will not benefit.A low HDL cholesterol (<40 mg/dL) is common in patients with CHD. A low HDL level can be secondary to other modifiable risk factors such as cigarette smoking, obesity, or physical inactivity. Beta-blockers can also lower HDL-cholesterol levels in CHD patients, but have been shown to be efficacious for reducing subsequent CHD events after myocardial infarction. Therefore, their benefit in CHD patients outweighs the drawback of HDL lowering. Secondary prevention trials show that statin therapy significantly reduces risk for major coronary events even in patients with low HDL cholesterol; therefore in these patients, LDL remains the primary target of therapy. The VA-HIT study48 suggests that fibrate therapy also may be beneficial for patients with low HDL levels in whom LDL-cholesterol levels are near optimal.c. General principles of primary prevention with drug therapyPrimary prevention pertains to individuals without clinically evident CHD. For those with CHD risk equivalents, primary and secondary prevention merge. The guidelines for consideration of drug therapy and target goals for primary prevention are shown in Table VI.1-3.Table VI.1-3. Drug Therapy Consideration and Goals of Therapy for Primary PreventionLDL cholesterolRisk Category10-Year Risk for CHDLevel at Which to Consider Drug TherapyPrimary Goal of TherapyMultiple (2+) risk factors> 20% (includes all CHD Risk Equivalents*)> 100 mg/dL†<100 mg/dL 10-20%≥ 130 mg/dL‡<130 mg/dL<10%≥ 160 mg/dL<130 mg/dL 0-1 risk factor<10%≥ 190 mg/dL¥<160 mg/dL*Most patients with CHD risk equivalents have multiple risk factors and a 10-year risk >20 percent. They include patients with non-coronary forms of clinical atherosclerosis, diabetes, and multiple (2+) risk factors with a 10-year risk >20 percent by Framingham scoring.†When LDL cholesterol is ≥130 mg/dL, a cholesterol-lowering drug can be started concomitantly with TLC. If baseline LDL cholesterol is 100-129 mg/dL, TLC should be started immediately. Concomitant use of drugs is optional; several options for drug therapy are available (e.g., statins, bile acid sequestrants, fibrates, nicotinic acid).‡When LDL cholesterol is in the range of 130-159 mg/dL, drug therapy can be used if necessary to reach the LDL-cholesterol goal of <130 mg/dL, after an adequate trial of TLC.¥When LDL cholesterol is in the range of 160-189 mg/dL, use of cholesterol-lowering drugs is optional, depending on response to TLC diet.d. Drug considerations for persons with multiple (2+) risk factors1) 10-year risk >20 percentPersons with multiple (2+) risk factors whose 10-year risk for hard CHD is> 20 percent are included in the category of CHD risk equivalent. As discussed in section VI.1.b, they are managed similarly to other CHD risk equivalents that include non-coronary forms of clinical atherosclerotic disease and diabetes. The LDL cholesterol goal in these patients is <100 mg/dL, and when LDL cholesterol is ≥130 mg/dL, an LDL-lowering drug can be started together with theraputic lifestyle changes. When baseline LDL cholesterol is 100-129 mg/dL, TLC is indicated and concomitant use of drugs is optional. Drug options include statins, bile acid sequestrants, fibrates, and nicotinic acid.2) 10-year risk 10-20 percentHere the LDL-cholesterol goal is <130 mg/dL. TLC should be introduced first. If this goal is not achieved after 3 months of TLC, drug therapy should be considered. A low dose of drug may suffice if TLC drops the LDL cholesterol to near 130 mg/dL. If not, a higher dose can be used. At the same time, if the metabolic syndrome is present, weight reduction and physical activity should be emphasized. Later, consideration can be given to modifying other lipid risk factors with nicotinic acid or fibrates if they have not been adequately controlled by TLC.3) 10-year risk <10 percentThe LDL-cholesterol goal for multiple risk factors and 10-year risk <10 percent also is <130 mg/dL. However, LDL-lowering drugs are not to be considered unless LDL cholesterol remains ≥160 mg/dL on TLC. When 10-year risk is <10 percent, cost-effectiveness of drug therapy begins to erode, especially when the LDL-cholesterol level remains in the range of 130 to 159 mg/dL and other risk factors are appropriately controlled. On the other hand, when LDL-cholesterol concentrations ≥160 mg/dL occur with multiple (2+) risk factors, long-term (>10-year) risk for CHD is relatively high. Thus, drug therapy deserves consideration. Of course, costs and side effects of drugs must also be taken into account when contemplating lifetime drug therapy.e. Drug considerations for persons with 0-1 risk factor, 10-year risk<10 percentThe LDL-cholesterol goal in this risk category is <160 mg/dL. For adults with severe elevations of LDL cholesterol (e.g., ≥220 mg/dL), drug therapy can be started simultaneously with TLC. When baseline LDL cholesterol is in the range of 190-219 mg/dL, a 3-month trial of TLC is indicated. If the LDL-cholesterol level remains ≥190 mg/dL after TLC, drug therapy should be considered for most persons. However, if LDL cholesterol falls to the range of 160-189 mg/dL on TLC, drug therapy is optional, depending on clinical judgment. Similarly, if baseline LDL cholesterol is 160-189 mg/dL, a 3-month trial of TLC is indicated; again, if the LDL level persists ≥160 mg/dL on TLC, drug therapy is optional. In either case, factors that favor drug therapy are severe, single risk factors, such as heavy smoking, a family history of premature CHD, very low HDL-cholesterol levels, and the presence of other emerging risk factors (see Section II). Likewise, if triglycerides are high (≥200 mg/dL), non-HDL cholesterol will be a secondary target of therapy.2. Available drug therapiesa. Overview and general approachThe major classes of drugs for consideration are:HMG CoA reductase inhibitors (statins)—lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatinBile acid sequestrants—cholestyramine, colestipol, colesevelamNicotinic acid—crystalline, timed-release preparations, Niaspan®Fibric acid derivatives (fibrates)—gemfibrozil, fenofibrate, clofibrateHormones are also discussed below:Estrogen replacementSelective estrogen receptor modulatorsb. Major drugs1) HMG CoA reductase inhibitors (statins*—lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatinThese drugs are summarized in Table VI.2-1. The HMG CoA reductase inhibitors are the most effective and practical class of drugs for reducing LDL-cholesterol concentrations. Results from five clinical trials with a mean duration of 5.4 years have documented a decrease in CHD and total mortality, reductions in myocardial infarctions, revascularization procedures, stroke, and peripheral vascular disease.206,207,416,435,436,489 These trials documented benefits in men and women, in middle-aged and older persons, and in primary and secondary prevention. Approximately 30,000 individuals were randomized to either placebo or statin therapy in these five clinical outcome trials. Statin therapy proved remarkably safe, with no major or unexpected adverse effects observed. Several other types of clinical trials with statin therapy also showed favorable results.434,456 Beneficial outcomes in CHD parameters have been reported with almost all of the statins. Thus, statins are highly effective in lowering LDL-cholesterol levels (the primary target of therapy). Statin therapy reduces the risk of essentially every clinical manifestation of the atherosclerotic process; they are easy to administer with good patient acceptance. They have few drug-drug interactions, and they have a good record for safety.*Cerivastatin was voluntarily withdrawn from the market by the manufacturer following reports of fatal rhabdomyolysis to the FDA. A substantial proportion of the deaths occurred in patients taking both cerivastatin and gemfibrozil. Rhabdomyolysis associated with cerivastatin use has been reported significantly more frequently than for other statin drugs. Myopathy associated with other statin drugs occurs infrequently, and in most cases, stopping the drug reverses the problem. The significant benefits of statins—lowering cholesterol and reducing the risk for MI and death from CHD—outweigh the risk of developing myopathy or rhabdomyolysis. For additional information on statin side effects, see the ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins, J Am Coll Cardiol 2002;40:567-72; Circulation 2002;106:1024-8; www.nhlbi.nih.gov/guidelines/cholesterol/statins.htm.Table VI.2-1. Summary of HMG CoA Reductase InhibitorsAvailable Drugs* Lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatinLipid/lipoprotein effectsLDL cholesterol- ↓ 18-55%HDL cholesterol- ↑ 5-15%Triglycerides- ↓ 7-30%Major useTo lower LDL cholesterolContraindications▪ AbsoluteActive or chronic liver disease▪ RelativeConcomitant use of cyclosporine, macrolide antibiotics, various anti-fungal agents and cytochrome P-450 inhibitors (fibrates and nicotinic acid should be used with appropriate caution)EfficacyReduce risk for CHD and strokeSafetySide effects minimal in clinical trialsMajor side/adverse effectsMyopathy, increased liver transaminasesUsual starting doseLovastatin- 20 mgPravastatin- 20 mgSimvastatin- 20 mgFluvastatin- 20 mgAtorvastatin- 10 mgMaximum FDA-approved doseLovastatin- 80 mgPravastatin- 80 mgSimvastatin- 80 mgFluvastatin- 80 mgAtorvastatin- 80 mgAvailable preparationsLovastatin- 10, 20, 40 mg tabletsPravastatin- 10, 20, 40 mg tabletsSimvastatin- 5, 10, 20, 40, 80 mg tabletsFluvastatin- 20, 40 mg capsules, 80 mg XL tablets Atorvastatin - 10, 20, 40, 80 mg tablets*Cerivastatin was withdrawn from the market by the manufacturer in August, 2001.Statins inhibit HMG CoA reductase, the rate-limiting step in cholesterol biosynthesis.798 This change produces a lowering of LDL-cholesterol levels.799-802 Inhibition of cholesterol synthesis reduces hepatic cholesterol content, resulting in increased expression of LDL receptors, which lowers serum LDL-cholesterol levels.803 Intermediate density lipoprotein (IDL) and VLDL remnants also are removed via the LDL receptor. The latter effect contributes to lowering of triglyceride-rich lipoproteins (TGRLP) by statins.86,804,805 Statins also appear to reduce hepatic release of lipoproteins into the circulation;806,807 this effect may be due in part to enhanced removal of lipoproteins by LDL receptors within hepatocytes or in the space of Disse.808 In some persons with homozygous familial hypercholesterolemia, high doses of statins lower LDL-cholesterol levels.809-811 This latter action is mediated either by increased expression of residual LDL-receptor activity or by inhibition of lipoprotein assembly.The statins are generally administered with the evening meal or at bedtime. Somewhat greater LDL-cholesterol reductions occur when they are administered at night than in the morning. Most statins have a high first-pass clearance by the liver and a short half-life. Atorvastatin and its metabolites, in contrast, have very long half-lives and thus morning administration is equally effective. Depending upon the specific statin and the dose administered, reductions in LDL cholesterol of 18-55 percent are observed.812,813 The reductions in LDL cholesterol are dose-dependent and log-linear, so that with each doubling of the dose of statin, LDL-cholesterol levels fall by about 6 percent. HDL cholesterol generally rises by 5-10 percent, but greater increases usually occur in persons with low HDL and elevated triglycerides.206,207,435,436,489,813-815The reductions in triglycerides with the statins generally range from 7-30 percent.206,207,416,435,436,489,813,815 In individuals with triglyceride levels of <150 mg/dL, triglyceride responses are inconsisten