Cardiology

Practical Approach to Managing Dyslipidemia: Role of Statins

General (including evidence of efficacy)

The central tenet of the lipid hypothesis emphasizes a causal relationship between dyslipidemia and atherogenesis. Individuals with life-long low LDL-C (low-density lipoprotein) levels have a low risk of developing coronary artery disease. Dietary and pharmacologic interventions that lower serum cholesterol have been shown to reduce incidence and recurrence of major coronary events, revascularization, and stroke irrespective of pretreatment cholesterol, age, gender, preexisting cardiovascular disease, and to reduce cardiovascular and overall mortality in subsets of patients with dyslipidemia.

Statins reduce total cholesterol, LDL cholesterol, Apo B, non HDL cholesterol, and triglycerides, and also increase high-density lipoprotein (HDL) cholesterol levels in most patients with hypercholesterolemia and combined hyperlipidemia. Statins are not indicated in individuals with Frederickson Class I and V hyperlipidemias.

Extensive literature supports use of statins in coronary heart disease (CHD) patients for treatment of dyslipidemia and secondary prevention.  It has also been recognized that in secondary prevention and ACS populations lower LDL may be better. Trials have compared moderate with more robust LDL-C reduction, using maximum doses of atorvastatin or simvastatin. These trials include: Aggrastat-to-Zocor (A-to-Z), Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT), Treating to New Targets (TNT), Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL), and Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) . Results from these trials and other secondary prevention trials that have investigated statins for secondary prevention are summarized in Table 1.

Table 1.

Selected secondary prevention trials that enrolled > 1000 patients for > 1 year

As outlined in the recent AHA Scientific Statement on the recommendations for management of clinically significant drug-drug interactions (DDIs) with statins and select agents used in patients with cardiovascular disease, combination therapy is not only likely but it is critical to consider potentially significant DDIs in patients treated with statin given the important role of statins in patients with CHD or those at high risk of CHD.

Serial angiographic and intravascular ultrasound (IVUS) studies have shown that aggressive cholesterol lowering can retard the progression, and in some cases, induce regression of coronary atherosclerosis.

Differences between drugs within the class

Available statins differ in their ability to reduce atherogenic lipoproteins and raise the level of high-density lipoprotein (HDL) cholesterol.  Depending on dose used and specific statin, LDL cholesterol reduction of 18% to 55% can be expected. Atorvastatin and rosuvastatin are the most potent statins for lowering LDL-C cholesterol levels, yielding average reductions that approach 50% for atorvastatin and exceed 50% for rosuvastatin at the highest dose.

Reduction in triglycerides with statins ranges from 7% to 30%, and is higher in hypertriglyceridemic populations and at higher statin doses.  HDL levels usually rise by 5% to 10%.  No consistent dose response relationship between statin dose and degree of HDL increase is seen.

Equipotent doses of various statins available in U.S. market are shown in Table 2.  For properties of various statins, refer to Table 3 (data abstracted from package inserts).

Table 2.

Equivalent doses of statins in the U.S. market

Table 3.

Properties of individual statins compared and contrasted: information based on package inserts (as of November 2012)

Administration

Statins are typically administered once daily.  Package inserts of specific statins like pravastatin and simvastatin recommend that they be taken at night due to lower plasma half-life and that most cholesterol is synthesized when dietary intake is at its lowest, which is usually during sleep. 

Clinical trials with simvastatin have shown better total cholesterol and LDL reduction when simvastatin was taken in the evening than in the morning (differences have ranged from 13.1 to 14.7 mg/dL for total cholesterol and 9.7 to 15.1 mg/dL for LDL cholesterol, nonsignificant results for HDL cholesterol).  Package inserts for pravastatin, fluvastatin, and lovastatin also suggest that dosing in the evening may have marginally higher efficacy. Atorvastatin, rosuvastatin, and pitavastatin  have longer half-lives, and can be taken at any time in the day.

Statin dosage may need modification in the setting of chronic kidney disease when glomerular filtration rate (GFR) <30 ml/min/1.73 m2 and in dialysis patients. For details on individual statins refer to Table 3.

In patients who experience significant myalgias, alternate day dosing or once weekly dosing of longer acting statins, such as rosuvastatin, atorvastatin, and fluvastatin may be tried to improve tolerability.  Small clinical trials have demonstrated improvement in myalgia symptoms in some patients.  Readers are cautioned that there are no outcomes studies using these alternate dosing regimens.

Pharmacologic action

Statins competitively inhibit the enzyme HMG-CoA reductase, which plays an important role in the first committed step of the HMG CoA reductase pathway.  By inhibiting this enzyme, statins block the pathway for synthesizing cholesterol in the liver.

To maintain cellular homeostasis, expression of LDL receptors increases, and the rate of cholesteryl ester formation declines.  This leads to increased LDL clearance from plasma, and decreased hepatic production of very-low-density lipoprotein (VLDL) and LDL.  Upregulation of LDL receptors also leads to increased clearance of intermediate density lipoproteins (IDL) and VLDL, and consequently a reduction in triglyceride levels.

Statins  influence HDL cholesterol levels by preventing geranylgeranylation of Rho A and phosphorylation of peroxisome proliferator-activated receptor alpha (PPARα).  Statins also have a number of so-called “pleiotropic” effects that affect inflammation (e.g., decrease in C-reactive protein levels), induce apoptosis in smooth-muscle cells, augment collagen content of atherosclerotic plaques and improve endothelial function among others.  To what degree these pleiotropic effects influence cardiovascular outcomes remains controversial.  A recent meta-regression analysis suggests that the reduction in cardiovascular events with statins in stable coronary heart disease may be explained by the reduction in LDL-C levels.

Indications and contraindications

Statin therapy is a Class I indication for patients with acute and chronic CHD with a goal LDL-C of <100 mg/dL.  Based on an update to the ATP III guidelines published in 2004, targeting LDL <70 mg/dL is an optional goal for patients with established CHD. 

The ACC/AHA guidelines for secondary prevention published in 2011 recommend that in patients with established CHD, the dose of statin used should reduce LDL-C to <100 mg/dL and achieve at least a 30% lowering of LDL-C (Class I recommendation; level of evidence C).

Moreover, patients who have triglycerides >200 mg/dL should be treated with statins to lower non–HDL-C to <130 mg/dL  (Class I recommendation; level of evidence B).  In very high-risk patients, an LDL-C goal of <70 mg/dL is reasonable (Class IIa recommendation; level of evidence C).  This includes patients with established CAD plus multiple major risk factors, especially diabetes or poorly controlled risk factors or multiple components of metabolic syndrome and ACS.

ATP III guidelines  recommend that persons hospitalized for a coronary event or procedure should be discharged on drug therapy if the LDL cholesterol is ≥130 mg/dL.  If the LDL is 100 to 129 mg/dL, clinical judgment should be used in deciding whether to initiate drug treatment at discharge.  For patients at very high CHD risk (established CHD or 10-year CHD risk >20%) with LDL <100 mg/dL at baseline, if statins are employed for risk reduction, the dose should be adequate to effect at least 30% to 40% reduction in cholesterol levels.

Besides patients with established CHD, ATP III guidelines recommend statin therapy for individuals with “CHD equivalents” including:

1. Diabetes mellitus

2. Peripheral arterial disease

3. Symptomatic carotid artery disease

4. Abdominal aortic aneurysm

5. Multiple risk factors that confer a 10-year risk of CHD >20 % using the ATP III modification of the Framingham risk tables.

Note that an increasing literature suggests that not everyone with diabetes has a "CHD risk equivalent" (i.e., is at high near-term risk of CHD events).  Lifetime risk, however, is increased and statin therapy is reasonable across the spectrum of CHD risk among individuals with diabetes.

Although data in adults aged >85 years are limited, older chronologic age should not exclude patients from receiving statin therapy, especially if an otherwise healthy older patient’s remaining years of life may benefit from prevention of the morbidity and disability associated with a coronary event.  Available evidence from clinical trials (including PROSPER, HPS, and SAGE) and the Cholesterol Treatment Trialists (CTT) meta-analysis suggests that older adults aged 65 to 80 years with established CAD derive benefit from statins in terms of reduction of major coronary events.

Undesirable effects

Large trials and extensive postmarketing surveillance studies have shown that statins are well tolerated.  Despite widely publicized side effects, the acceptability and safety of the statins contrasts favorably with the poor palatability and high discontinuation rates of niacin and the bile acid sequestrant formulations.  Key adverse effects of statins are profiled below.

Liver

Elevated hepatic transaminases occur in 0.5% to 2.0% of patients treated with statins, and tend to be dose-dependent.  Reversal of transaminase elevation is generally noted with reduction in the dose of statin.

Elevations do not usually recur with either rechallenge or selection of another statin.  Nevertheless for many years, regular monitoring of liver enzymes was the standard of practice.  In an advisory dated February 2012, the FDA recommended that liver enzyme tests should be performed before starting statin therapy, and then only as clinically indicated thereafter.  This is based on the conclusion that serious liver injury with statins is rare and unpredictable in individual patients.  Routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing this rare side effect.

However, cholestasis and active liver disease are listed as contraindications for initiating statins per package inserts for various statins approved by the FDA.  Review of existing literature does not show exacerbation of existing liver disease with judicious statin use.

Myopathy

In most RCTs, myalgias have been observed with similar frequency in treatment and placebo groups (1% to 5%).  Incidence of muscular symptoms in large RCTs is less than what one may encounter in regular clinical practice.

The main reasons to explain this include exclusion of patients from most RCT’s who have significant renal disease or other major organ dysfunction, prior muscle complaints, and those taking medications that may interact with statins.  The clinical impact of muscular symptoms while on statin therapy should not be underestimated as many patients who experience these side effects elect to stop their lipid lowering therapy.

Observational studies in nonselected outpatients have shown a higher incidence of statin-induced myalgias.  The best known study is the PRIMO study, which showed that 10.5% of individuals treated with high-dose statins developed myalgias, with a median time of onset of 1 month following initiation of statin therapy.

PRIMO included 7,924 French outpatients with hypercholesterolemia, aged 18 to 75 years, on high-dose statins.  Daily statin regimens included atorvastatin 40 to 80 mg, fluvastatin (Lescol) 80 mg, pravastatin (Pravachol) 40 mg, and simvastatin (Zocor) 40 to 80 mg.  In multivariate analysis, predictors of muscular symptoms included personal history of muscular symptoms on another lipid lowering therapy, family history of muscular symptoms (on or without lipid lowering therapy), unexplained cramps, and history of CK elevation (with or without lipid lowering therapy). 

Recently, Parker et al investigated the effects of high dose statin therapy on development of myalgias and exercise performance in a randomized double-blind controlled trial.  They randomized 420 healthy subjects to either atorvastatin, 80 mg daily or a placebo and observed that patients on statin had a higher incidence of myalgias than a placebo (n = 19 vs. 10; P = 0.05).

Although no difference in muscle strength or exercise performance was noted between patients treated with statins and placebo, average CK increased about 21 U/L (P <0.0001) with atorvastatin.  Patients who developed myalgias on statin and placebo, experienced decreased performance in 4-5 out of 14 variables that examined muscle strength.

Given the variation in existing literature about the definition of muscular side effects with statins, readers are referred to the ACC/AHA/NHLBI clinical advisory on the use and safety of statins for definitions of myalgia, myositis, and rhabdomyolysis.  Myalgia comprises muscle pain or weakness in the absence of CK elevation.  Muscle symptoms with increased CK levels define myositis.  Mild elevations in CK levels may be seen with or without symptoms in patients treated with statins.  Myositis is more likely to occur at higher statin doses than at lower doses.

The advisory does not recommend routine monitoring of CK in patients who are not having symptoms to suggest myositis.  However, the ATP III report recommended that baseline CK measurement be performed as asymptomatic CK elevations are common, and knowledge of this condition before treatment is initiated can aid in later clinical decision making, especially as patients can have mild-to-moderate elevations of creatine kinase without muscle complaints.

Large databases have suggested that the incidence of severe myositis (CK elevation greater than 10 X ULN) is approximately 0.08% to 0.09% with all statins (except with cerivastatin, which was withdrawn because of higher incidence of adverse effects).  Severe myositis, if not treated can lead to rhabdomyolysis, myoglobinuria, and acute renal failure.

Risk factors for statin-induced rhabdomyolysis include advanced age (especially more than 80 years), multiple active medical conditions (especially chronic kidney disease with diabetes), small body frame (and frailty), and use of multiple medications that may interact with metabolism of statins through cytochrome P-450 drug-metabolizing system.  Although rhabdomyolysis can occur with statin monotherapy, it occurs more frequently when statins are used in combination with a variety of medications (e.g., cyclosporine, fibrates, macrolide antibiotics, certain antifungal drugs (azole antifungals, such as ketoconazole and itraconazole), verapamil, and amiodarone.  Because of these interactions, clinicians need to be familiar with contra-indications for concomitant therapy and recommendations for statin dosage limitations as reflected in FDA labels.  Readers are referred to package inserts of specific statins for warnings, cautions, and potential for drug-drug interactions.

Clinical approach to patients with myalgias and on statins

Prior to starting statins, patients should be asked about current and prior muscular symptoms and a baseline CK level should be obtained.  If patients develop muscular symptoms while on therapy, a careful history is critical to ascertain the type and severity of symptoms, setting in which the muscular symptoms occurred, evidence of rhabdomyolysis (e.g., discoloration of urine, change in urine output) and potential concomitant conditions, which could cause or contribute to muscular symptoms while on statin therapy (e.g., strenuous exercise, hypothyroidism, heavy alcohol use, concomitant medications, dietary factors such as grapefruit consumption etc). In symptomatic patients, CK levels should be checked and compared to baseline.

If a CK level greater than 10 ULN is encountered in a patient with symptoms suggestive of myositis on statin, the statin should be stopped.  If the patient is on combination therapy, the fibrate and/or niacin should be stopped as well.  If a patient experiences significant myalgias in the absence of CK elevation or has modest CK elevation (3 to 10 times ULN), symptoms and CK levels should be carefully monitored until they resolve or get worse (in the latter case, statin should be discontinued).  If symptoms and CK levels are not noted to resolve, consideration should be given to temporarily stopping statin or reducing statin dose.

Situations may arise where asymptomatic elevations in CK are noted when physicians decide to follow CK levels in patients treated with statins.  In asymptomatic patients with CK levels greater than 10 ULN, the statin (or combination therapy) should be stopped. The same statin at a lower dose or different statin may be reintroduced at a later time.  For asymptomatic patients with elevations between 3 and 10 times, ULN statin can usually be continued in most cases with attention to development of symptoms and CK monitoring.

In patients presenting with CK elevation, consideration should be given to evaluation for other causes of myopathy if clinical exam and/or electromyography (EMG) suggest so.  Rarely macroenzymes (Macro CK 1 and 2) may cause stable elevations in measured CK levels.  These are usually apparent on electrophoresis due to different electrophoretic mobility than usual CK fractions: MM, BB, and MB.

In 2011 the U.S. Food and Drug Administration (FDA)  recommended that use of the highest approved dose of simvastatin (80 mg) be limited because of increased risk of muscle damage.  Simvastatin 80 mg should be used only in patients who have been taking this dose for 12 months or more without evidence of muscle injury (myopathy).

This FDA advisory was primarily based on data from Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), where risks for myopathy (unexplained muscle weakness or pain with a serum CK >10 X ULN) and rhabdomyolysis (unexplained muscle weakness or pain with a serum CK >40 X ULN) with simvastatin 80 mg were highest in the first 12 months of treatment (5 per 1,000 person-years and 2 per 1,000 person-years, respectively), and decreased (1 per 1,000 person-years and 0.4 per 1,000 person-years, respectively) after that.   Simvastatin 80 mg daily should not be started in new patients, including patients already taking lower doses of the drug.  Common variants in the SLCB01 gene have been linked to development of myositis among users of simvastatin.

Diabetes

The JUPITER investigators  first reported small increases in both HbA1c (5.9 vs. 5.8, P= 0.001) and physician reported diabetes (270 vs. 216 cases, P= 0.01) in rosuvastatin treated patients compared to placebo.  Data from JUPITER suggest that most patients who developed diabetes during the study had metabolic syndrome and insulin resistance at baseline.

In subsequent meta-analyses, the increase in diabetes incidence was shown to be a class effect.  In a recent analysis of pooled trial data from TNT and IDEAL, Waters et al showed that atorvastatin 80 mg daily did not increase risk of development of diabetes in patients with 0-1 risk factors for development of diabetes when compared to 10 mg atorvastatin and 20 to 40 mg simvastatin.

These risk factors were: fasting blood glucose >100 mg/dL, history of hypertension, body mass index  ≥30 kg/m2, and fasting triglycerides >150 mg/dL.  However, in patients with 2-4 risk factors for diabetes, atorvastatin 80 mg increased risk of development of diabetes by 24% (HR: 1.24; 95% CI: 1.08 to 1.42; P = 0.0027).

In a meta-analysis, Sattar et al estimated that one additional patient would develop diabetes for every 255 patients treated (95% CI: 150 to 852) for 4 years with a statin.  However, they estimated that 5.4 deaths or myocardial infarctions would be avoided over these 4 years, and nearly the same number of strokes or coronary revascularization procedures would also be avoided.  This suggests that in secondary prevention patients, benefits of statin therapy outweigh the risk of developing diabetes.

Memory loss

Data from observational studies investigating effects of statin therapy on cognitive decline have been conflicting, reporting both protective and detrimental effects.  However, data from two large statin trials (HPS and PROSPER) where cognitive function was systematically evaluated, do not show any difference between patients randomized to statin therapy and placebo with respect to cognitive decline.  Case reports and case series of neurologic symptoms and altered cognition with statins have reported short-term and long-term memory loss, behavioral changes, and impaired concentration and attention.

In 2012, based on postmarketing surveillance data, the FDA changed statin labels to reflect that certain patients may experience reversible ill-defined memory loss and confusion with statins.  Reported cases had been taking statins for as little as a day or as long as years.  These cases have not been linked to progressive dementia.  The FDA advisory also states that “data from the observational studies and clinical trials did not suggest that cognitive changes associated with statin use are common or lead to clinically significant cognitive decline.”

Meta-analyses have shown no association between statin use and increased risk of depression and suicide.

Cancer

Results of cohort studies suggested that low cholesterol was associated with long-term development of cancer.  However, none of these studies adjusted for use of cholesterol-lowering treatment and are limited by selection bias.  Moreover, numerous meta-analyses done using data from primary and secondary prevention studies have not confirmed any association of statin use with cancer. The most recent meta-analysis from the Cholesterol Treatment Trialists (CTT) collaboration compiled individual data from 134,537 participants in 22 randomized trials of statin versus control (median duration 4.8 years) and 39,612 participants in 5 trials of more intensive versus less intensive statin therapy (median duration 5.1 years). Statin use was not associated with newly diagnosed cancer or deaths from any cancer (combined and 23 individual categories). No susceptible subgroups were identified. Moreover, among individuals with low baseline LDL-C (<77 mg/dL), LDL-C reduction (from about 66 to 39 mg/dL) was not linked to increased cancer risk (381 [1.6% per year] versus 408 [1.7% per year]; RR 0.92 [99% CI 0.76–1.10]).

Use in Pregnancy

In the United States, statins are classified as category X for use during pregnancy. Their discontinuation prior to pregnancy is recommended.  Although limited human data suggest that statins are not major human teratogens, an analysis of an FDA surveillance database suggests possible association of congenital central nervous system and limb abnormalities with exposure to lipophilic statins.  In absence of adequate data to support use among breastfeeding women, use during lactation is also discouraged.

Alternative approaches

There are very limited data to support clinical benefit of lipid lowering agents other than statins in patients with cardiovascular disease. In the Coronary Drug Project (CDP), niacin was shown to lower all-cause mortality by almost 11% over a mean follow-up period of 15 years, when compared to a placebo.

The CDP enrolled 8,341 men aged 30 to 64 years with electrocardiogram-documented previous myocardial infarction to 2.5 mg/day of conjugated estrogens, 5.0 mg/day of conjugated estrogens, 1.8 g/day of clofibrate, 6.0 mg/day of dextrothyroxine sodium, 3.0 g/day of niacin, or 3.8 g/day of lactose placebo.  Mortality in rhe niacin arm was 11% lower than mortality in the control group (52.0 versus 58.2%; P= 0.0004). However, recent trials like AIM-HIGH (extended release niacin) and HPS2 THRIVE (extended release niacin and laropiprant) have failed to show any protective effect of niacin on cardiovascular outcomes in patients with existing cardiovascular disease.

The VA-HIT study investigated effect of gemfibrozil 1,200 mg/day on cardiovascular outcomes (primary outcome:nonfatal MI and death from coronary heart disease) in 2,531 men with coronary heart disease in a randomized double-blind design.  All men had HDL-cholesterol levels <40 mg dL (mean 32 mg/dL) and LDL-cholesterol levels <140 mg/dL.  Main outcome occurred in 275 of the 1,267 patients assigned to placebo (21.7 percent), and in 219 of the 1,264 patients assigned to gemfibrozil (17.3%).  Risk reduction was 4.4%, and the reduction in relative risk was 22% (95% CI, 7% to 35%; P= 0.006).  In a systematic review by Jun et al (published in Lancet in 2010) fibrate therapy was associated with 10% RR reduction (95% CI, 0% to 18%) for major cardiovascular events (P = 0·048) and a 13% RR reduction (7–19) for coronary events (P <0·0001).  No significant effect on all-cause or cardiovascular mortality was seen.

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