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Combination therapy for dyslipidemia: safety and regulatory considerations
Combination Therapy for Dyslipidemia: Safety and Regulatory Considerations Michael H. Davidson,
MD
The use of combination therapy is an effective way to manage dyslipidemia in patients with coronary artery disease (CAD). However, combination therapy is not a frequently used strategy in the treatment of CAD. Aggressive lipid-altering therapy often requires the use of combination therapy involving statins in conjunction with niacin, fibric-acid derivatives, ezetimibe, or bile acid resins. Yet, safety concerns regarding the combina-
tion of statins with other lipid-altering drugs and patient acceptance of combination therapy have influenced its application in the treatment of CAD. This article discusses several safety and regulatory considerations for the use of combination therapy for dyslipidemia. 䊚2002 by Excerpta Medica, Inc. Am J Cardiol 2002;90(suppl):50K– 60K
ombination therapy for the treatment of hypertension or diabetes is a well-recognized strategy for C the management of these major coronary artery dis-
conventional thinking, that the mechanism of blood pressure control may enhance the clinical benefits. Nevertheless, because of the NCEP ATP III guidelines,8 which advocate more aggressive low-density lipoprotein (LDL) goals for high-risk patients, non– high-density lipoprotein (HDL) goals for patients with hypertriglyceridemia, and an increased focus on the management of the metabolic syndrome, there will be increased need to enhance the efficacy and safety of lipid-lowering therapy. For the foreseeable future, statins will remain the therapy of choice for the majority of patients with dyslipidemia. However, combining another drug with a statin to further improve cardiovascular risk reduction or enhance safety will be a trend for the management of dyslipidemia that is likely to parallel the growing use of combination therapy in the therapeutic approach to hypertension and diabetes.
ease (CAD) risk factors.1 However, combination therapy for the management of dyslipidemia remains an infrequently used approach for CAD risk reduction (Figure 1).2 The disparity between the use of combination therapy for the treatment of dyslipidemia compared with hypertension or diabetes is probably the result of several factors. First, statins are highly efficacious as monotherapy.3 Many patients can achieve the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III goals with statin therapy alone,4 as opposed to hypertensive and diabetic patients in which multiple drugs are often necessary to achieve the therapeutic targets. Second, there are safety concerns regarding the combination of statins with other lipid-altering drugs,5 whereas with antihypertensive and glucose-control therapies, there appear to be no significant safety constraints. There are potential safety advantages of combining drugs for the treatment of hypertension. For example, hydrochlorothiazide in combination with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers reduces the incidence of hyperkalemia while enhancing the antihypertensive effects. Third, there are a lack of morbidity/mortality trial data to conclusively demonstrate the benefits of combination therapy for the treatment of dyslipidemia. Recently, the Heart Outcomes Prevention Evaluation study (HOPE)6 and the Losartan Intervention for Endpoint Reduction in Hypertension study (LIFE)7 demonstrated the benefits of ACE inhibitors and angiotensin receptor blockers, respectively, in reducing clinical events with blood pressure levels similar to the randomized treatment control groups. These large endpoint trials support the view that is contrary to the past From the Chicago Center for Clinical Research, Rush Medical College, Chicago, Illinois, USA. Address for reprints: Michael H. Davidson, MD, Chicago Center for Clinical Research, 1725 West Harrison, Suite 1159, Rush Medical College, Chicago, Illinois 60612. E-mail: mdavidson@ protocare.com.
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©2002 by Excerpta Medica, Inc. All rights reserved.
SAFETY OF HIGH-DOSE STATINS COMPARED WITH COMBINATION THERAPY The most serious side effect of statin therapy is myopathy, which is defined as a creatinine phosphokinase elevation of 10 times the upper limit of normal with associated muscle pain or weakness.5 All statins can cause myopathy in a dose-dependent manner. The exact mechanism for the cause of myopathy is unknown but has been suggested to be related to reduction in ubiquinone, an important part of the cell replication pathway synthesized from mevalonic acid.9,10 Despite in vitro evidence that statins decrease ubiquinone levels, a human study of 6 months of simvastatin treatment (20 mg/day) on skeletal muscle concentration of ubiquinone found similar levels at the end of therapy compared with baseline and no difference from control subjects.11 There are also no clinical trial data to support the benefits of oral ubiquinone (coenzyme Q10) in reducing myalgias or preventing myopathy. The best available data for myopathy rates with statins come from the simvastatin clinical trial data base of ⬎25,000 patients (who were carefully monitored and with some interacting drugs excluded): at a simvastatin dose of 20 mg, approximately 0.02% of 0002-9149/02/$ – see front matter PII S0002-9149(02)02970-3
FIGURE 1. Use of combination therapy for hypercholesterolemia as compared with hypertension. NDC ⴝ National Drug Code. *NDC analysis, excludes mail order, includes fixed combination treatments, includes all physician specialties. (Adapted from the National Drug Code Directory.2)
TABLE 1 Increased Risk States for Statin-Associated Myopathy Prevention of statin-associated myopathy can best be accomplished by attention to those factors that might increase the risk for such myopathy: ● Advanced age (especially ⬎80 yrs) in patients (women more than men) ● Small body frame and frailty ● Multisystem disease (eg, chronic renal insufficiency, especially due to diabetes) ● Multiple medications ● Perioperative periods ● Specific concomitant medications or consumption as listed below (check specific statin package insert for warnings): —Fibrates (especially gemfibrozil) —Nicotinic acid (rarely) —Cyclosporine —Azole antifungals —Itraconazole and ketoconazole —Macrolide antibiotics —Erythromycin and clarithromycin —HIV protease inhibitors —Nefazodone (antidepressant) —Verapamil —Amiodarone —Large quantities of grapefruit juice (usually ⬎1 quart [0.95 L]/day) —Alcohol abuse (independently predisposes to myopathy) HIV ⫽ human immunodeficiency virus.
subjects experienced myopathy; at 40 mg, 0.07%; and at 80 mg, 0.3%.12 Rhabdomyolysis, which is myopathy with associated renal damage, is estimated to occur in approximately 1 in 10,000 patients treated with simvastatin.13 In clinical practice, which includes patients at high risk for myopathy, such as the elderly, women, individuals with a smaller body mass index, renal impairment, or on a potentially interacting drug, the incidence of myopathy may be significantly higher.14 The myopathy rate for patients on simvastatin 80 mg in conjunction with amiodarone was documented in 6% of patients, and for patients receiving both verapamil and simvastatin, the myopathy rate was 0.63% compared with 0.061% for patients taking simvastatin without a calcium channel blocker.12 Therefore, potentially interacting drugs increase the rate of myopathy approximately 10-fold. Cerivastatin 0.8 mg
monotherapy has a myopathy rate of 1.3% overall, but for elderly women the rate was 5.7%.15 The American College of Cardiology/American Heart Association/ National Heart, Lung, and Blood Institute (ACC/ AHA/NHLBI) Clinical Advisory on Statins5 has issued guidance regarding risk factors for statin-induced myopathy (Table 1) and the appropriate monitoring parameters (Table 2). In addition to myopathy, liver function abnormalities are also associated with statin therapy and are dose related. Atorvastatin 40 mg is associated with a 0.5% increase in liver enzyme to ⬎3 times the upper limit of normal compared with 2.5% for 80 mg (Figure 2).16 The myopathy and liver function abnormality incidence rates increase approximately 4- to 5-fold when increasing the dose of simvastatin or atorvastatin from 40 to 80 mg. Regarding efficacy, increasing A SYMPOSIUM: COMBINATION THERAPY FOR DYSLIPIDEMIA
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FIGURE 2. Risk-benefit ratio of statin use. Data from prescribing information for atorvastatin, lovastatin, simvastatin. *20 mg includes patients on 40 mg (37%). LDL-C ⴝ low-density lipoprotein cholesterol. (Reprinted with permission from Health Science Center for Continuing Medical Education.) TABLE 2 Monitoring Parameters and Follow-up Schedule for Use of Statins Monitoring Parameters
Follow-up Schedule
Headache, dyspepsia
Evaluate symptoms initially, 6–8 wks after starting therapy
Muscle soreness, tenderness, or pain
Evaluate muscle symptoms and CK before starting therapy. Evaluate muscle symptoms 6–12 wks after starting therapy and at each follow-up visit. Obtain a CK measurement when persons have muscle soreness, tenderness, or pain.
ALT/AST
Evaluate ALT/AST initially, approximately 12 wks after starting therapy, then annually or more frequently, if indicated.
ALT ⫽ alanine transferase; AST ⫽ aspartate transferase; CK ⫽ creatinine kinase.
the dose from 40 to 80 mg is associated with a 5% to 6% further decrease in LDL cholesterol.17 Therefore, for patients on simvastatin or atorvastatin, increasing the dose from 40 to 80 mg provides an additional reduction of LDL by 5% to 6% but a 4- to 5-fold increased risk in the development of myopathy or liver function abnormalities. The Heart Protection Study (HPS)18 can be useful as a model to assess the absolute benefits of statin therapy. In this study using simvastatin 40 mg compared with placebo, there was an absolute reduction in major cardiac events of approximately 5% (25.2% event rate for the placebo group vs 19.8% for the simvastatin-treated population). Assuming the benefits of statin therapy are linear, an additional 5% to 6% reduction in LDL should therefore result in an additional 1% reduction in clinical events. An increase in simvastatin or atorvastatin from 40 to 80 mg would also result in at least an additional 1% to 2% absolute incidence in myop52K THE AMERICAN JOURNAL OF CARDIOLOGY姞
athy and/or liver function abnormalities. Therefore, for the additional 1% reduction in cardiac events, there is also a 1% to 2% increase in risk of a serious side effect. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial demonstrates a similar risk– benefit analysis.19 In this trial with 3,086 patients randomized to atorvastatin 80 mg versus placebo, there was an absolute reduction in cardiac events of 2% (15% vs 13%) at 4 months but also a 2% absolute increase in liver function abnormality (0.6% vs 2.5%). Therefore, for every patient who had a cardiac benefit, there was a patient who developed a significant liver function abnormality. A cardiac event is usually a far more serious clinical outcome than liver function abnormalities. However, this analysis demonstrates that the benefits of highdose statins are often offset by an increased risk of safety problems.
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TABLE 3 Ezetimibe (EZE) and Statin Studies: Pooled Safety Results Pooled Statin (n ⫽ 936) Treatment-related adverse events GI Discontinued due to adverse events LFTs (ⱖ3 ⫻ ULN) ALT (consecutive) AST (consecutive) Total bilirubin Alkaline phosphatase CPK ⱖ10 ⫻ ULN
Pooled EZE ⫹ Statin (n ⫽ 925)
17%
20%
⬍2% 4%
⬍2% 6%
0.4% ⬍1% 0 ⬍1%
1.3% ⬍1% 0 ⬍1%
⬍1%
⬍1%
ALT ⫽ alanine transferase; AST ⫽ aspartate transferase; CPK ⫽ creatinine phosphokinase; GI ⫽ gastrointestinal; LFTs ⫽ liver function tests; ULN ⫽ upper limit of normal. Adapted from Merck-Schering Plough, data on file.
The risk– benefit analysis of high-dose statin therapy is therefore determined by the patient population selected. If the absolute risk of a major adverse cardiac event is ⬍1% per year or 10% per 10 years after correction for the improved lipid profile on simvastatin or atorvastatin 40 mg/day, then the safety risk of escalating the dose of the statin to 80 mg is probably greater than the potential benefit. If the patient is at increased risk for high-dose statin–induced myopathy or liver function abnormalities, then the safety risk of escalating the dose also most likely outweighs the cardiovascular benefits. The recent availability of ezetimibe provides an alternative to escalating the statin dose to 80 mg. Based on the data available and the pharmacokinetic profile of combining a statin with ezetimibe, there does not appear to be a safety concern with combining ezetimibe with a statin (Table 3).20 Therefore, for patients not at goal on a statin, especially at higher doses, adding ezetimibe provides an alternative strategy to escalating the statin dose that appears to enhance the safety of aggressive LDL-lowering drug therapy. Colesevelam, a bile acid binding polymer, in combination with a statin can provide a level of safety and efficacy similar to that of ezetimibe with a statin.21 An algorithm of drug therapy based solely on safety concerns can maximize the LDL reduction while maintaining an excellent risk– benefit ratio (Figures 3 and 4).
PHARMACOKINETICS OF COMBINATION THERAPY Pharmacokinetic evaluations of statins as monotherapy and combined with other drugs has consistently explained potential risk factors for drug-induced myopathy. Myopathy is dose dependent22,23 and occurs more frequently with statins (lovastatin, simvastatin, and atorvastatin) in conjunction with drugs that inhibit the cytochrome P450 3A4 pathway and in patients who have impaired drug metabolism, such as the elderly or those with renal insufficiency.14 There-
fore, pharmacokinetic trials of statins in combination with other lipid-altering drugs are very useful in predicting potentially clinically significant drug interactions. Gemfibrozil appears to affect the pharmacokinetics of all the statins,24 –29 with the exception of fluvastatin, whereas fenofibrate, although not as well evaluated, appears not to cause significant interactions with simvastatin, pravastatin, cerivastatin, or rosuvastatin (Table 4).12,24,26 –30,53 Based on published reports and the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS), the risk level for statin-gemfibrozil combination therapy is much higher than for that of a statin and fenofibrate.31 Initially, the pharmacokinetic interaction between statins and gemfibrozil was thought to be the result of an interaction with the cytochrome P450 pathways. Although gemfibrozil may inhibit the CYP 3A4 on the CYP 2C9 (or 2C8) pathway,32 the most recent evidence suggests that gemfibrozil inhibits simvastatin, atorvastatin, and, more prominently, cerivastatin glucuronidation.33,34 Glucuronidation is a pathway for the elimination of the active hydroxy acid metabolites of simvastatin, atorvastatin, and cerivastatin by a family of uridine diphosphate glucuronsyltransferases (UGT) enzymes. Fibrates are also glucuronidated, and gemfibrozil most profoundly inhibits the glucuronidation of cerivastatin. Fenofibrates, however, appear to have a significantly less inhibitory effect on statin glucuronidation, and this may explain the lack of significant drug interaction between fenofibrate and statins. Extended-release niacin also has no significant interaction with lovastatin (Figure 5),35 suggesting that niacin does not interfere with the cytochrome P450 3A4 or glucuronidation pathways. Although niacinlovastatin myopathy has been reported,36 the mechanism appears to be related to niacin-induced hepatotoxicity impairing the liver’s ability to metabolize the statin, leading to higher drug concentration. ThereA SYMPOSIUM: COMBINATION THERAPY FOR DYSLIPIDEMIA
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FIGURE 3. Algorithm to maximize safety of lipid-lowering therapy: low-density lipoprotein (LDL) and triglycerides. *At baseline check liver function test (LFT), creatine phosphokinase (CPK), and thyroid profile; document presence of muscle soreness, tenderness, or † pain. US Food and Drug Association–approved starting-dose statins: lovastatin (20 and 40 mg), simvastatin (10, 20, and 40 mg), atorvastatin (10, 20, and 40 mg), fluvastatin (20, 40, and 80 mg XL [extended-release], and pravastatin (10, 20, and 40 mg). ‡Consider low-dose statin plus ezetimibe for patients at high risk for statin-induced myopathy. §Add ezetimibe if patient is at high risk for myopathy/hepatoxicity (see Table 1). 㥋Alternatively, consider colesevelam.
fore, in the absence of niacin hepatotoxity, statinniacin combination therapy should not be associated with myopathy rates higher than statin monotherapy. A new dosage form of niacin has been available for several years that substantially overcomes many of the vasodilatory effects associated with use of niacin. Extended-release niacin delivers niacin over an 8-hour period at bedtime, which significantly reduces the flushing side effect. Long-acting niacin was developed to overcome cutaneous flushing symptoms by slowing absorption from minutes to 12 to 24 hours, changing the way niacin is metabolized. Rather than being metabolized through a conjugation pathway, which leads to prostaglandin-mediated vasodilation, longacting niacin was mostly metabolized through a nicotinamide pathway, which produces a variety of pyrimidine breakdown products. This shift was successful in substantially reducing the vasodilatory flushing side effects. Unfortunately, long-acting 54K THE AMERICAN JOURNAL OF CARDIOLOGY姞
niacin has now been found to cause serious, potentially life-threatening liver toxicity in up to 50% of patients who administer ⱖ2 g of the drug daily. For this reason, most authorities discourage the use of long-acting niacin altogether or recommend that daily doses be limited to ⬍2 g/day. However, extendedrelease niacin delays the absorption by only 8 hours, minimizing the prostaglandin-mediated vasodilation, but is associated with a very low hepatotoxicity rate (⬍1%). Ezetimibe, although undergoing glucuronidation, does not affect simvastatin drug concentration (Figure 6).20 Ezetimibe used a different family of UGT that does not compete with the statin glucuronidation enzymes (UGTIA1 and UGTIA3). In ⬎3,000 patients evaluated with ezetimibe in combination with a statin, there have been no reports of myopathy.38 To detect an adverse event that occurs in 1 of 1,000 patients with a 95% confidence level, 3,000 patients need to
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FIGURE 4. Algorithm to maximize safety of lipid-lowering therapy: low-density lipoprotein (LDL). *At baseline, check liver function test (LFT), creatine phosphokinase (CPK), and thyroid profile; document presence of muscle soreness, tenderness, or pain. †US Food and Drug Association–approved starting-dose statins: lovastatin (20 and 40 mg), simvastatin (10, 20, and 40 mg), atorvastatin (10, 20, and 40 mg), fluvastatin (20, 40, and 80 mg XL [extended-release], and pravastatin (10, 20, and 40 mg). ‡Combination niacin-ER/ lovastatin tablet may be substituted; alternative options for patients at high risk for statin myopathy (see Table 1) include ezetimibe plus niacin or fenofibrate.
receive the drug,13 which is approximately the number of patients who have been exposed to ezetimibe in combination with a statin in the premarketing clinical development program.
SAFETY OF STATIN-NIACIN COMBINATION THERAPY The combination of a statin with niacin for the management of dyslipidemia is a well-recognized A SYMPOSIUM: COMBINATION THERAPY FOR DYSLIPIDEMIA
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TABLE 4 Pharmacokinetic Interactions Between Statins and Fibrates
Atorvastatin Pravastatin Fluvastatin Simvastatin Cerivastatin Rosuvastatin
Gemfibrozil
Fenofibrate
Not available Significant increase in Cmax26 No effect29 Increased Cmax by 112%24 Increased Cmax by 2 to 3-fold51–52 Not available
Not available No effect30 Not available No effect12 No effect51–52 No effect28
FIGURE 5. Bioequivalence of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition of lovastatin alone, lovastatin and extended-release niacin, and lovastatin-extended-release niacin formulation combination therapy (Advicor; Kos Pharmaceuticals, Miami, FL). MEV ⴝ MeVacor; NSP ⴝ Niaspan. (Reprinted with permission from Heart Dis.35)
FIGURE 6. Plasma simvastatin pharmacokinetics with ezetimibe combination therapy. (Adapted from Atherosclerosis.20)
therapy for patients with an elevated LDL in conjunction with a low HDL and/or high triglycerides. A combination tablet containing lovastatin and extended-release niacin (Advicor; Kos Pharmaceuticals, Miami, FL) is commercially available in the United States, the first FDA-approved combination therapy for the management of hyperlipidemia. The most serious side effect associated with niacin therapy is hepatotoxicity. Niacin hepatotoxicity appears to be correlated with the length of daily exposure. Sustained-release niacin, given multiple times during the day, is associated with a very significant rate of liver 56K THE AMERICAN JOURNAL OF CARDIOLOGY姞
function abnormalities that is dose related (Figure 7).37,39 Immediate-release niacin, given at doses of up to 2,000 mg/day is associated with a liver function abnormality rate of ⬍3%, and this rate appears not to be adversely affected by combination therapy with a statin.40 The lowest rates of liver toxicity with a niacin product is with extended-release niacin (Niaspan; Kos Pharmaceuticals) given as a tablet once a day in the evening.41 This extended-release niacin product delays the release of niacin by up to 8 hours and results in a relatively short systemic exposure time (Figure 8). In large clinical trials, the incidence of liver toxicity
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FIGURE 7. Safety of once-daily niacin extended-release (ER) compared with generic niacin. ALT ⴝ alanine aminotransferase; AST ⴝ aspartate aminotransferase. (Adapted from JAMA37 and Am J Cardiol.39)
FIGURE 8. Niacin metabolism. 6HN ⴝ 6-hydroxynicotinamide; MNA ⴝ methylnicotinamide; NAD ⴝ nicotinamide adenine dinucleotide; NAM ⴝ nicotinamide; NNO ⴝ nicotinamide-N-oxide; NUA ⴝ nicotinuric acid; 2PY ⴝ N-methyl-2-pyridone-5-carboxamide; 4PY ⴝ N-methyl-4-pyridone-5-carboxamide. (Reprinted with permission from Kos Pharmaceuticals.)
(defined as aspartate aminotransferase or alanine aminotransferase ⬎3 times the upper limit of normal on 2 successive occasions) is approximately 1%, and in combination with lovastatin as a single tablet at doses of up to 2,000 mg/day plus lovastatin 40 mg, the hepatotoxicity rate remains approximately 1%.42 Therefore, by significantly shortening the systemic exposure time, extended-release niacin alone or in combination with a statin has a surprisingly low rate of hepatotoxicity. Over 5,000 patients have been exposed in clinical trials to extendedrelease niacin/lovastatin without confirmed cases of drug-induced myopathy or rhabdomyolysis. Niacin and statins appear not to have a pharmacokinetic interaction that results in higher blood levels for each drug, and therefore the cause of myopathy with niacin and statin combination therapy is poorly understood.20 Although myopathy has been reported with the combination of a statin and niacin, the inci-
dence rates appear to be significantly lower than with a statin and gemfibrozil.43 Using the AERS of the FDA on statin-induced rhabdomyolysis of the 871 cases reported, only 4 cases (all outside the United States) were associated with niacin compared with 80 cases with fibrates. There have been no cases of myopathy reported with extended-release niacin in the AERS of the FDA or in the clinical trials with 1,700 patients studied.44 This evidence supports the hypothesis that myopathy associated with statin-niacin combination therapy is the result of niacin-induced hepatotoxicity impairing the liver’s ability to metabolize the statins, resulting in much higher systemic levels. Therefore, if the hepatotoxicity rate is low, the myopathy incidence should be exceedingly low; this relationship is supported by the clinical trial data and the postmarketing surveillance information regarding extended-release niacin. This excellent safety record of A SYMPOSIUM: COMBINATION THERAPY FOR DYSLIPIDEMIA
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extended-release niacin can be maintained by avoiding doses above the approved FDA limit of 2,000 mg/day or giving the drug more than once per day.
SAFETY OF STATIN-FIBRATE COMBINATION THERAPY There have been a number of relatively small controlled clinical trials that have evaluated the lipoprotein effects of statin and fibrate combination therapy.45,46 Fibrate treatment alone appears to be associated with some (probably similar) risk of myopathy. Of the nearly 600 subjects who have participated in controlled clinical trials of a statin and fibrate combination, 1% have experienced a creatinine phosphokinase level ⬎3 times the upper limit of normal without muscle symptoms, and 1% have been withdrawn from therapy because of muscle discomfort.5,47–51 None of these findings were considered serious by the trial investigators. No cases of rhabdomyolysis or myoglobinuria have been encountered in these clinical trials. The experience in these trials is predominantly with lovastatin and gemfibrozil, but it is reasonable to believe that the experiences with other statin-fibrate combinations would be similar. Most references regarding the safety of statins in combination with fibrates discuss fibrates as a class of drugs that should be avoided or used cautiously with a statin. In the FDA labeling of all statins, caution is advised for combination therapy with a fibrate. However, controlled clinical trials may markedly underestimate the risk of myopathy, because patients with confounding illness, such as hypertension, diabetes with altered renal function, or the elderly, are excluded. However, there are compelling data that fibrates differ in their effects on statin pharmacokinetics and safety. Gemfibrozil, which affects statin pharmacokinetics, has been associated with a high rate of myopathy when combined with a statin, especially cerivastatin.27 However, the incidence rate with fenofibrate is much less frequently reported. Based on the AERS of the FDA, pharmacokinetic studies, and clinical trial data, although not yet conclusive, fenofibrate used in combination with a statin does appear to have less risk of myopathy than does gemfibrozil.
REGULATORY CONSIDERATIONS The noted myotoxicity and subsequent withdrawal of cerivastatin from the worldwide markets has heightened the awareness of regulatory agencies for the safety of statins and combination therapy. Several important lessons were learned from the cerivastatin experience. The safety of statins is not a class effect. Statins of comparable efficacy may have different safety profiles, whereby the degree of LDL lowering and toxicity are not necessarily linked. In the future, statins that have a level of risk that exceeds that of the existing approved statin without significant enhanced efficacy will not receive regulatory clearance. Simvastatin 80 mg, with a myopathy rate of 0.3% to 0.5%, and atorvastatin 80 mg, with a liver function abnormality incidence of 2.5% to 3%, probably represent the thresholds by which lipid-lowering therapies will 58K THE AMERICAN JOURNAL OF CARDIOLOGY姞
be judged for approval. These thresholds, however, may be exceeded if a lipid-altering or antiatherosclerotic compound has a documented enhanced clinical benefit. A pharmacokinetic evaluation of cerivastatin has identified a number of factors that may explain the greater myotoxicity rate. Cerivastatin is by far the most potent statin per milligram of drug. The drug is also the most lipophilic and bioavailable with significant renal clearance. Therefore, several factors could lead to higher systemic levels, such as renal impairment or coadministration of a drug such as gemfibrozil, and the higher potency and/or lipophilicity of cerivastatin resulted in greater muscle toxicity (Table 1).25 Therefore, statins that are less lipophilic with fewer drug interactions and lower rates of renal excretion may be less prone to myotoxicity. In the preapproval data base, cerivastatin 0.8 mg had an overall myopathy rate of 1.3% and a 5.6% rate in elderly women. The FDA has acknowledged that this was a signal that cerivastatin was more myotoxic than other statins and that the elderly population, who are often not included in significant numbers in a preapproval regulatory submission, represent a group at higher risk for safety problems. Rosuvastatin is the first statin submitted for regulatory approval for which a large number of elderly patients were included in the New Drug Application. In the future, regulatory agencies are likely to require the inclusion of more elderly patients and pharmacokinetic studies of frequently coadministered drugs to assess safety. Although the coadministration of cerivastatin with gemfibrozil was contraindicated in the package labeling information starting in December 1999, clinicians continued to prescribe the 2 drugs together, which resulted in a number of serious and fatal cases of rhabdomyolysis. This experience underscores the inability of package labeling alone to completely prevent serious iatrogenic drug interactions. Many of the cases of cerivastatin-gemfibrozil–induced myopathy are the result of managed care plans advocating the switching of the prescribed statin to cerivastatin based on cost considerations. Therefore, regulatory agencies have learned that labeling alone is insufficient to prevent drug interactions, and it is incumbent upon them to not approve drugs if frequent serious drug interactions may occur. A combination tablet of lovastatin and extendedrelease niacin (Advicor) was approved by the FDA in 2001, and a combination of simvastatin and ezetimibe is in clinical development. This trend in combination tablet approval is likely to continue, but there will be increasing demands by regulatory agencies for sponsors to ascertain the safety of these therapies. A potential option for a combination therapy is fenofibrate and a statin in a single tablet. Although the risk of myopathy with fenofibrate and a statin is perhaps lower than gemfibrozil, the difficulty of defining the incidence of risk may be significant. The FDA has acknowledged that assessing the safety of these combinations is very difficult.13 Because the myopathy rate of statin monotherapy is approximately 1 in
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1,000, the average patient exposure for a lipid-lowering drug during development (3,000 to 4,000 patients) will have about a 95% likelihood of seeing 1 case. Therefore, agencies may require a significant number of patients (⬎10,000) to be evaluated in clinical development to assess whether there is an increased risk of myopathy with combination therapy over monotherapy.
CONCLUSIONS In our appropriate zeal to reduce the risk of CAD with lipid-lowering therapy, the trend to aggressively treat all lipoprotein abnormalities will continue. This more aggressive approach will require the use of higher doses of statins and combination therapy. A balance of efficacy and safety will be necessary to maximize the overall benefits of treatment. The withdrawal of cerivastatin has heightened the concern of both patients and physicians regarding the safety of lipid-lowering therapy. However, with recent information regarding the benefits of lipid-lowering therapy, such as the HPS, a new appreciation of at-risk subpopulations of patients, and a better understanding of potential drug interactions, physicians have the enhanced knowledge they need to maximize the risk: benefit ratio of drug therapy for dyslipidemia.
1. Joint National Committee on Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413–2445. 2. National Drug Code Directory. US Food and Drug Administration. Center for Drug Evaluation and Research. Available at: http://www.fda.gov/cder/ndc/. Accessed: September 4, 2002. 3. Stein EA. New statins and new doses of older statins. Curr Atheroscler Rep 2000;3:14 –28. 4. Brown AS, Bakker-Arkema RG, Yellen L, Henley RW Jr, Guthrie R, Campbell CF, Koren M, Woo W, McLain R, Black DM. 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;32:665–672. 5. Pasternak RC, Smith SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol 2002;40:567–572. 6. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145–153. 7. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, et al, for the LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;23:995–1003. 8. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486 – 2497. 9. Gebhard RL, Ewing SL, Schlasner LA, Hunninghake DB, Prigge WF. Effect of 3-hydroxy-3-methyl coenzyme. A reductase inhibition on human gut mucosa. Lipids 1991;26:492–494. 10. Di Mauro S, Bonilla E, Davidson M, Hirano M, Schon EA. Mitochondria in neuromuscular disorders. Biochem Biophys Acta 1998;1366:199 –210. 11. Laaksonen R, Jokelainen K, Sahi T, Tikkanen MJ, Himberg JJ. Decreases in serum ubiquinone concentrations do not result in reduced levels in muscle tissue during short-term simvastatin treatments in humans. Clin Pharmacol Ther 1995; 57:62–66. 12. Simvastatin. Physician’s Desk Reference. MontVale, NJ: Medical Economics Company, 2002. 13. Isaacsohn J, Black D, Troendle A, Orloff D. The impact of the National Cholesterol Education Program Adult Treatment Panel III guidelines on drug development. Am J Cardiol 2002;89(suppl):45C–49C.
14. Davidson MH. Does differing metabolism by cytochrome P450 have clinical importance. Curr Atheroscler Rep 2000;2:14 –19. 15. Insull W Jr, Isaacsohn J, Kwiterovich P, Ma P, Brazg R, Dujovne C. Efficacy and safety of cerivastatin 0.8 mg in patients with hypercholesterolemia: the pivotal placebo-controlled clinical trial. J Int Med Res 2000;28:47–68. 16. Atorvastatin. Physician’s Desk Reference. MontVale, NJ: Medical Economics Company, 2002. 17. Jones P, Kafonek S, Hunninghake D. Comparative dose efficacy of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998;81:582–587. 18. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360:7–22. 19. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR. Effects of atorvastatin on early recurrent ischaemic events in acute coronary syndromes. The MIRACL study: a randomized controlled trial. JAMA 2001;285:1711–1718. 20. Kosoglou T, Meyer I, Musiol B, Mellars L, Statkevich P, Miller MF, Soni PP, Affrime MB. Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin [abstract]. Atherosclerosis 2000;151:135. 21. Davidson MH, Dicklin MR, Maki KC, Kleinpell RM. Colesevelam hydrochloride: a non-absorbed, polymeric cholesterol-lowering agent. Opin Invest Drugs 2000;9:2663–2671. 22. Bradford RH, Shear CL, Chermos AN, Dujovne CA, Franklin FA, Grillo RB, Higgins J, Langendorfer A, Nash DT, Pool JL. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolaemia. Arch Intern Med 1991;151:43–49. 23. Davidson MH, Stein EA, Dujovne CA, Hunninghake DB, Weiss SR, Knopp RH, Illingworth DR, Mitchel YB, Melino MR, Zupkis RV, Dobrinska MR, Amin RD, Tobert JA. The efficacy and six-week tolerability of simvastatin 80 and 160 mg/day. Am J Cardiol 1997;257:38 –42. 24. Backman JT, Kyrklund C, Kivisto KT, Wang JS, Neuvonen PJ. Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther 2000;68:122–129. 25. Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther 1999;84:413–428. 26. Pravastatin. Physician’s Desk Reference. MontVale, NJ: Medical Economics Company, 2002. 27. Davidson MH. Controversy surrounding the safety of cerivastatin. Expert Opinions in Drug Safety 2002;1:207–212. 28. Davidson MH. Rosuvastastin: a highly efficacious statin for the treatment of dyslipidaemia. Expert Opin Investig Drugs 2002;11:125–141. 29. Spence JD, Munoz CE, Hendricks L, Latchinian L, Khouri HE. Pharmacokinetics of the combination of fluvastatin and gemfibrozil. Am J Cardiol 1995; 76:80A–83A. 30. Pan WJ, Gustavson LE, Achari R, Rieser MJ, Ye X, Gutterman C, Wallin BA. Lack of a clinically significant pharmacokinetic interaction between fenofibrate and pravastatin in healthy volunteers. J Clin Pharmacol 2000;40:316 –323. 31. Herman RJ. Drug interactions and the statins. CMAJ 1999;161:1281–1286. 32. Wen X, Wang JS, Backman JT, Kivisto KT, Neuvonen PJ. Gemfibrozil is a potent inhibitor of human cytochrome P450 2C9. Drug Metab Dispos 2001;29: 1359 –1361. 33. Prueksaritanont T, Zhao JJ, Ma B, Roadcap BA, Tang C, Ziu Y, Liu L, Lin JH, Pearson PG, Baillie TA. Mechanistic studies on metabolic interactions between gemfibrozil and statins. J Pharmacol Exp Ther 2002;301:1042–1051. 34. Evans M, Rees A. The myotoxicity of statins. Curr Opin Lipidol 2002;13: 415–420. 35. Gupta EK, Ito MK. Lovastatin and extended-release niacin combination product: the first drug combination for the management of hyperlipidemia. Heart Dis 2002;4:124 –137. 36. Reaven P, Witztum JL. Lovastatin, nicotinic acid, and rhabdomyolysis. Ann Intern Med 1988;109:597–598. 37. McKenney JM, Proctor JD, Harris S, Chinchili VM. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA 1994;271:672–677. 38. Data on file. Merck-Schering Plough, Whitehouse Station, NJ, 2002. 39. Goldberg A, Alagona P Jr, Capuzzi DM, Guyton J, Morgan JM, Rodgers J, Sachson R, Samuel P. Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia. Am J Cardiol 2000;85: 1100 –1105. 40. Guyton JR, Goldberg AC, Kreisberg RA, Sprecher DL, Superko HR, O’Connor CM. Effectiveness of once-nightly dosing of extended-release niacin alone and in combination for hypercholesterolemia. Am J Cardiol 1998;82:737– 743. 41. Wolfe ML, Vartanian SF, Ross JL, Bansavich LL, Mohler ER III, Meagher E, Friedrich C, Rader DJ. Safety and effectiveness of extended-release niacin when added sequentially to a statin for treatment of dyslipidemia. Am J Cardiol 2001;87:476 –479. 42. Kashyap ML, Evans R, Simmons PD, Kohler RM, McGovern ME. New combination niacin/statin formulation shows pronounced effects on major lipoproteins and is well tolerated [abstract]. J Am Coll Cardiol 2000;35(suppl A):326A.
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43. Omar MA, Wilson JP, Cox TS. Rhabdomyolysis and HMG-CoA reductase inhibitors. Ann Pharmacother 2001;35:1096 –1107. 44. Data on file. Kos Pharmaceutical Company, Miami, FL, 2002. 45. Wiklund O, Angelin B, Bergman M, Berglund L, Bondjers G, Carlsson A, Linden T, Miettinen T, Odman B, Olofsson SO. Pravastatin and gemfibrozil alone and in combination for the treatment of hypercholesterolemia. Am J Med 1993; 94:13–20. 46. Ellen RL, McPherson R. Long-term efficacy and safety of fenofibrate and a statin in the treatment of combined hyperlipidemia. Am J Cardiol 1998;81:60B–65B. 47. Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA 1990;264:71–75.
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48. Hanston D, Horn JR. Drug interactions with HMG CoA reductase inhibitors. Drug Interactions Newsletter 1998;103:103–106. 49. Rosenson RS, Frauenheim WA. Safety of combined pravastatin-gemfibrozil therapy. Am J Cardiol 1994;74:499 –500. 50. Murdock DK, Murdock AK, Murdock RW, Olson KJ, Frane AM, Kersten
ME, Joyce DM, Gantner SE. Long-term safety and efficacy of combination gemfibrozil and HMB-CoA reductase inhibitors for the treatment of mixed lipid disorders. Am Heart J 1999;138:151–155. 51. Iliadis EA, Rosenson RS. Long-term safety of pravastatin-gemfibrozil therapy in mixed hyperlipidemia. Clin Cardiol 1999;22:25–28. 52. Data on file. Bayer Pharmaceutical Company, West Haven, CT.
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MD
The use of combination therapy is an effective way to manage dyslipidemia in patients with coronary artery disease (CAD). However, combination therapy is not a frequently used strategy in the treatment of CAD. Aggressive lipid-altering therapy often requires the use of combination therapy involving statins in conjunction with niacin, fibric-acid derivatives, ezetimibe, or bile acid resins. Yet, safety concerns regarding the combina-
tion of statins with other lipid-altering drugs and patient acceptance of combination therapy have influenced its application in the treatment of CAD. This article discusses several safety and regulatory considerations for the use of combination therapy for dyslipidemia. 䊚2002 by Excerpta Medica, Inc. Am J Cardiol 2002;90(suppl):50K– 60K
ombination therapy for the treatment of hypertension or diabetes is a well-recognized strategy for C the management of these major coronary artery dis-
conventional thinking, that the mechanism of blood pressure control may enhance the clinical benefits. Nevertheless, because of the NCEP ATP III guidelines,8 which advocate more aggressive low-density lipoprotein (LDL) goals for high-risk patients, non– high-density lipoprotein (HDL) goals for patients with hypertriglyceridemia, and an increased focus on the management of the metabolic syndrome, there will be increased need to enhance the efficacy and safety of lipid-lowering therapy. For the foreseeable future, statins will remain the therapy of choice for the majority of patients with dyslipidemia. However, combining another drug with a statin to further improve cardiovascular risk reduction or enhance safety will be a trend for the management of dyslipidemia that is likely to parallel the growing use of combination therapy in the therapeutic approach to hypertension and diabetes.
ease (CAD) risk factors.1 However, combination therapy for the management of dyslipidemia remains an infrequently used approach for CAD risk reduction (Figure 1).2 The disparity between the use of combination therapy for the treatment of dyslipidemia compared with hypertension or diabetes is probably the result of several factors. First, statins are highly efficacious as monotherapy.3 Many patients can achieve the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III goals with statin therapy alone,4 as opposed to hypertensive and diabetic patients in which multiple drugs are often necessary to achieve the therapeutic targets. Second, there are safety concerns regarding the combination of statins with other lipid-altering drugs,5 whereas with antihypertensive and glucose-control therapies, there appear to be no significant safety constraints. There are potential safety advantages of combining drugs for the treatment of hypertension. For example, hydrochlorothiazide in combination with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers reduces the incidence of hyperkalemia while enhancing the antihypertensive effects. Third, there are a lack of morbidity/mortality trial data to conclusively demonstrate the benefits of combination therapy for the treatment of dyslipidemia. Recently, the Heart Outcomes Prevention Evaluation study (HOPE)6 and the Losartan Intervention for Endpoint Reduction in Hypertension study (LIFE)7 demonstrated the benefits of ACE inhibitors and angiotensin receptor blockers, respectively, in reducing clinical events with blood pressure levels similar to the randomized treatment control groups. These large endpoint trials support the view that is contrary to the past From the Chicago Center for Clinical Research, Rush Medical College, Chicago, Illinois, USA. Address for reprints: Michael H. Davidson, MD, Chicago Center for Clinical Research, 1725 West Harrison, Suite 1159, Rush Medical College, Chicago, Illinois 60612. E-mail: mdavidson@ protocare.com.
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©2002 by Excerpta Medica, Inc. All rights reserved.
SAFETY OF HIGH-DOSE STATINS COMPARED WITH COMBINATION THERAPY The most serious side effect of statin therapy is myopathy, which is defined as a creatinine phosphokinase elevation of 10 times the upper limit of normal with associated muscle pain or weakness.5 All statins can cause myopathy in a dose-dependent manner. The exact mechanism for the cause of myopathy is unknown but has been suggested to be related to reduction in ubiquinone, an important part of the cell replication pathway synthesized from mevalonic acid.9,10 Despite in vitro evidence that statins decrease ubiquinone levels, a human study of 6 months of simvastatin treatment (20 mg/day) on skeletal muscle concentration of ubiquinone found similar levels at the end of therapy compared with baseline and no difference from control subjects.11 There are also no clinical trial data to support the benefits of oral ubiquinone (coenzyme Q10) in reducing myalgias or preventing myopathy. The best available data for myopathy rates with statins come from the simvastatin clinical trial data base of ⬎25,000 patients (who were carefully monitored and with some interacting drugs excluded): at a simvastatin dose of 20 mg, approximately 0.02% of 0002-9149/02/$ – see front matter PII S0002-9149(02)02970-3
FIGURE 1. Use of combination therapy for hypercholesterolemia as compared with hypertension. NDC ⴝ National Drug Code. *NDC analysis, excludes mail order, includes fixed combination treatments, includes all physician specialties. (Adapted from the National Drug Code Directory.2)
TABLE 1 Increased Risk States for Statin-Associated Myopathy Prevention of statin-associated myopathy can best be accomplished by attention to those factors that might increase the risk for such myopathy: ● Advanced age (especially ⬎80 yrs) in patients (women more than men) ● Small body frame and frailty ● Multisystem disease (eg, chronic renal insufficiency, especially due to diabetes) ● Multiple medications ● Perioperative periods ● Specific concomitant medications or consumption as listed below (check specific statin package insert for warnings): —Fibrates (especially gemfibrozil) —Nicotinic acid (rarely) —Cyclosporine —Azole antifungals —Itraconazole and ketoconazole —Macrolide antibiotics —Erythromycin and clarithromycin —HIV protease inhibitors —Nefazodone (antidepressant) —Verapamil —Amiodarone —Large quantities of grapefruit juice (usually ⬎1 quart [0.95 L]/day) —Alcohol abuse (independently predisposes to myopathy) HIV ⫽ human immunodeficiency virus.
subjects experienced myopathy; at 40 mg, 0.07%; and at 80 mg, 0.3%.12 Rhabdomyolysis, which is myopathy with associated renal damage, is estimated to occur in approximately 1 in 10,000 patients treated with simvastatin.13 In clinical practice, which includes patients at high risk for myopathy, such as the elderly, women, individuals with a smaller body mass index, renal impairment, or on a potentially interacting drug, the incidence of myopathy may be significantly higher.14 The myopathy rate for patients on simvastatin 80 mg in conjunction with amiodarone was documented in 6% of patients, and for patients receiving both verapamil and simvastatin, the myopathy rate was 0.63% compared with 0.061% for patients taking simvastatin without a calcium channel blocker.12 Therefore, potentially interacting drugs increase the rate of myopathy approximately 10-fold. Cerivastatin 0.8 mg
monotherapy has a myopathy rate of 1.3% overall, but for elderly women the rate was 5.7%.15 The American College of Cardiology/American Heart Association/ National Heart, Lung, and Blood Institute (ACC/ AHA/NHLBI) Clinical Advisory on Statins5 has issued guidance regarding risk factors for statin-induced myopathy (Table 1) and the appropriate monitoring parameters (Table 2). In addition to myopathy, liver function abnormalities are also associated with statin therapy and are dose related. Atorvastatin 40 mg is associated with a 0.5% increase in liver enzyme to ⬎3 times the upper limit of normal compared with 2.5% for 80 mg (Figure 2).16 The myopathy and liver function abnormality incidence rates increase approximately 4- to 5-fold when increasing the dose of simvastatin or atorvastatin from 40 to 80 mg. Regarding efficacy, increasing A SYMPOSIUM: COMBINATION THERAPY FOR DYSLIPIDEMIA
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FIGURE 2. Risk-benefit ratio of statin use. Data from prescribing information for atorvastatin, lovastatin, simvastatin. *20 mg includes patients on 40 mg (37%). LDL-C ⴝ low-density lipoprotein cholesterol. (Reprinted with permission from Health Science Center for Continuing Medical Education.) TABLE 2 Monitoring Parameters and Follow-up Schedule for Use of Statins Monitoring Parameters
Follow-up Schedule
Headache, dyspepsia
Evaluate symptoms initially, 6–8 wks after starting therapy
Muscle soreness, tenderness, or pain
Evaluate muscle symptoms and CK before starting therapy. Evaluate muscle symptoms 6–12 wks after starting therapy and at each follow-up visit. Obtain a CK measurement when persons have muscle soreness, tenderness, or pain.
ALT/AST
Evaluate ALT/AST initially, approximately 12 wks after starting therapy, then annually or more frequently, if indicated.
ALT ⫽ alanine transferase; AST ⫽ aspartate transferase; CK ⫽ creatinine kinase.
the dose from 40 to 80 mg is associated with a 5% to 6% further decrease in LDL cholesterol.17 Therefore, for patients on simvastatin or atorvastatin, increasing the dose from 40 to 80 mg provides an additional reduction of LDL by 5% to 6% but a 4- to 5-fold increased risk in the development of myopathy or liver function abnormalities. The Heart Protection Study (HPS)18 can be useful as a model to assess the absolute benefits of statin therapy. In this study using simvastatin 40 mg compared with placebo, there was an absolute reduction in major cardiac events of approximately 5% (25.2% event rate for the placebo group vs 19.8% for the simvastatin-treated population). Assuming the benefits of statin therapy are linear, an additional 5% to 6% reduction in LDL should therefore result in an additional 1% reduction in clinical events. An increase in simvastatin or atorvastatin from 40 to 80 mg would also result in at least an additional 1% to 2% absolute incidence in myop52K THE AMERICAN JOURNAL OF CARDIOLOGY姞
athy and/or liver function abnormalities. Therefore, for the additional 1% reduction in cardiac events, there is also a 1% to 2% increase in risk of a serious side effect. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial demonstrates a similar risk– benefit analysis.19 In this trial with 3,086 patients randomized to atorvastatin 80 mg versus placebo, there was an absolute reduction in cardiac events of 2% (15% vs 13%) at 4 months but also a 2% absolute increase in liver function abnormality (0.6% vs 2.5%). Therefore, for every patient who had a cardiac benefit, there was a patient who developed a significant liver function abnormality. A cardiac event is usually a far more serious clinical outcome than liver function abnormalities. However, this analysis demonstrates that the benefits of highdose statins are often offset by an increased risk of safety problems.
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TABLE 3 Ezetimibe (EZE) and Statin Studies: Pooled Safety Results Pooled Statin (n ⫽ 936) Treatment-related adverse events GI Discontinued due to adverse events LFTs (ⱖ3 ⫻ ULN) ALT (consecutive) AST (consecutive) Total bilirubin Alkaline phosphatase CPK ⱖ10 ⫻ ULN
Pooled EZE ⫹ Statin (n ⫽ 925)
17%
20%
⬍2% 4%
⬍2% 6%
0.4% ⬍1% 0 ⬍1%
1.3% ⬍1% 0 ⬍1%
⬍1%
⬍1%
ALT ⫽ alanine transferase; AST ⫽ aspartate transferase; CPK ⫽ creatinine phosphokinase; GI ⫽ gastrointestinal; LFTs ⫽ liver function tests; ULN ⫽ upper limit of normal. Adapted from Merck-Schering Plough, data on file.
The risk– benefit analysis of high-dose statin therapy is therefore determined by the patient population selected. If the absolute risk of a major adverse cardiac event is ⬍1% per year or 10% per 10 years after correction for the improved lipid profile on simvastatin or atorvastatin 40 mg/day, then the safety risk of escalating the dose of the statin to 80 mg is probably greater than the potential benefit. If the patient is at increased risk for high-dose statin–induced myopathy or liver function abnormalities, then the safety risk of escalating the dose also most likely outweighs the cardiovascular benefits. The recent availability of ezetimibe provides an alternative to escalating the statin dose to 80 mg. Based on the data available and the pharmacokinetic profile of combining a statin with ezetimibe, there does not appear to be a safety concern with combining ezetimibe with a statin (Table 3).20 Therefore, for patients not at goal on a statin, especially at higher doses, adding ezetimibe provides an alternative strategy to escalating the statin dose that appears to enhance the safety of aggressive LDL-lowering drug therapy. Colesevelam, a bile acid binding polymer, in combination with a statin can provide a level of safety and efficacy similar to that of ezetimibe with a statin.21 An algorithm of drug therapy based solely on safety concerns can maximize the LDL reduction while maintaining an excellent risk– benefit ratio (Figures 3 and 4).
PHARMACOKINETICS OF COMBINATION THERAPY Pharmacokinetic evaluations of statins as monotherapy and combined with other drugs has consistently explained potential risk factors for drug-induced myopathy. Myopathy is dose dependent22,23 and occurs more frequently with statins (lovastatin, simvastatin, and atorvastatin) in conjunction with drugs that inhibit the cytochrome P450 3A4 pathway and in patients who have impaired drug metabolism, such as the elderly or those with renal insufficiency.14 There-
fore, pharmacokinetic trials of statins in combination with other lipid-altering drugs are very useful in predicting potentially clinically significant drug interactions. Gemfibrozil appears to affect the pharmacokinetics of all the statins,24 –29 with the exception of fluvastatin, whereas fenofibrate, although not as well evaluated, appears not to cause significant interactions with simvastatin, pravastatin, cerivastatin, or rosuvastatin (Table 4).12,24,26 –30,53 Based on published reports and the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS), the risk level for statin-gemfibrozil combination therapy is much higher than for that of a statin and fenofibrate.31 Initially, the pharmacokinetic interaction between statins and gemfibrozil was thought to be the result of an interaction with the cytochrome P450 pathways. Although gemfibrozil may inhibit the CYP 3A4 on the CYP 2C9 (or 2C8) pathway,32 the most recent evidence suggests that gemfibrozil inhibits simvastatin, atorvastatin, and, more prominently, cerivastatin glucuronidation.33,34 Glucuronidation is a pathway for the elimination of the active hydroxy acid metabolites of simvastatin, atorvastatin, and cerivastatin by a family of uridine diphosphate glucuronsyltransferases (UGT) enzymes. Fibrates are also glucuronidated, and gemfibrozil most profoundly inhibits the glucuronidation of cerivastatin. Fenofibrates, however, appear to have a significantly less inhibitory effect on statin glucuronidation, and this may explain the lack of significant drug interaction between fenofibrate and statins. Extended-release niacin also has no significant interaction with lovastatin (Figure 5),35 suggesting that niacin does not interfere with the cytochrome P450 3A4 or glucuronidation pathways. Although niacinlovastatin myopathy has been reported,36 the mechanism appears to be related to niacin-induced hepatotoxicity impairing the liver’s ability to metabolize the statin, leading to higher drug concentration. ThereA SYMPOSIUM: COMBINATION THERAPY FOR DYSLIPIDEMIA
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FIGURE 3. Algorithm to maximize safety of lipid-lowering therapy: low-density lipoprotein (LDL) and triglycerides. *At baseline check liver function test (LFT), creatine phosphokinase (CPK), and thyroid profile; document presence of muscle soreness, tenderness, or † pain. US Food and Drug Association–approved starting-dose statins: lovastatin (20 and 40 mg), simvastatin (10, 20, and 40 mg), atorvastatin (10, 20, and 40 mg), fluvastatin (20, 40, and 80 mg XL [extended-release], and pravastatin (10, 20, and 40 mg). ‡Consider low-dose statin plus ezetimibe for patients at high risk for statin-induced myopathy. §Add ezetimibe if patient is at high risk for myopathy/hepatoxicity (see Table 1). 㥋Alternatively, consider colesevelam.
fore, in the absence of niacin hepatotoxity, statinniacin combination therapy should not be associated with myopathy rates higher than statin monotherapy. A new dosage form of niacin has been available for several years that substantially overcomes many of the vasodilatory effects associated with use of niacin. Extended-release niacin delivers niacin over an 8-hour period at bedtime, which significantly reduces the flushing side effect. Long-acting niacin was developed to overcome cutaneous flushing symptoms by slowing absorption from minutes to 12 to 24 hours, changing the way niacin is metabolized. Rather than being metabolized through a conjugation pathway, which leads to prostaglandin-mediated vasodilation, longacting niacin was mostly metabolized through a nicotinamide pathway, which produces a variety of pyrimidine breakdown products. This shift was successful in substantially reducing the vasodilatory flushing side effects. Unfortunately, long-acting 54K THE AMERICAN JOURNAL OF CARDIOLOGY姞
niacin has now been found to cause serious, potentially life-threatening liver toxicity in up to 50% of patients who administer ⱖ2 g of the drug daily. For this reason, most authorities discourage the use of long-acting niacin altogether or recommend that daily doses be limited to ⬍2 g/day. However, extendedrelease niacin delays the absorption by only 8 hours, minimizing the prostaglandin-mediated vasodilation, but is associated with a very low hepatotoxicity rate (⬍1%). Ezetimibe, although undergoing glucuronidation, does not affect simvastatin drug concentration (Figure 6).20 Ezetimibe used a different family of UGT that does not compete with the statin glucuronidation enzymes (UGTIA1 and UGTIA3). In ⬎3,000 patients evaluated with ezetimibe in combination with a statin, there have been no reports of myopathy.38 To detect an adverse event that occurs in 1 of 1,000 patients with a 95% confidence level, 3,000 patients need to
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FIGURE 4. Algorithm to maximize safety of lipid-lowering therapy: low-density lipoprotein (LDL). *At baseline, check liver function test (LFT), creatine phosphokinase (CPK), and thyroid profile; document presence of muscle soreness, tenderness, or pain. †US Food and Drug Association–approved starting-dose statins: lovastatin (20 and 40 mg), simvastatin (10, 20, and 40 mg), atorvastatin (10, 20, and 40 mg), fluvastatin (20, 40, and 80 mg XL [extended-release], and pravastatin (10, 20, and 40 mg). ‡Combination niacin-ER/ lovastatin tablet may be substituted; alternative options for patients at high risk for statin myopathy (see Table 1) include ezetimibe plus niacin or fenofibrate.
receive the drug,13 which is approximately the number of patients who have been exposed to ezetimibe in combination with a statin in the premarketing clinical development program.
SAFETY OF STATIN-NIACIN COMBINATION THERAPY The combination of a statin with niacin for the management of dyslipidemia is a well-recognized A SYMPOSIUM: COMBINATION THERAPY FOR DYSLIPIDEMIA
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TABLE 4 Pharmacokinetic Interactions Between Statins and Fibrates
Atorvastatin Pravastatin Fluvastatin Simvastatin Cerivastatin Rosuvastatin
Gemfibrozil
Fenofibrate
Not available Significant increase in Cmax26 No effect29 Increased Cmax by 112%24 Increased Cmax by 2 to 3-fold51–52 Not available
Not available No effect30 Not available No effect12 No effect51–52 No effect28
FIGURE 5. Bioequivalence of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition of lovastatin alone, lovastatin and extended-release niacin, and lovastatin-extended-release niacin formulation combination therapy (Advicor; Kos Pharmaceuticals, Miami, FL). MEV ⴝ MeVacor; NSP ⴝ Niaspan. (Reprinted with permission from Heart Dis.35)
FIGURE 6. Plasma simvastatin pharmacokinetics with ezetimibe combination therapy. (Adapted from Atherosclerosis.20)
therapy for patients with an elevated LDL in conjunction with a low HDL and/or high triglycerides. A combination tablet containing lovastatin and extended-release niacin (Advicor; Kos Pharmaceuticals, Miami, FL) is commercially available in the United States, the first FDA-approved combination therapy for the management of hyperlipidemia. The most serious side effect associated with niacin therapy is hepatotoxicity. Niacin hepatotoxicity appears to be correlated with the length of daily exposure. Sustained-release niacin, given multiple times during the day, is associated with a very significant rate of liver 56K THE AMERICAN JOURNAL OF CARDIOLOGY姞
function abnormalities that is dose related (Figure 7).37,39 Immediate-release niacin, given at doses of up to 2,000 mg/day is associated with a liver function abnormality rate of ⬍3%, and this rate appears not to be adversely affected by combination therapy with a statin.40 The lowest rates of liver toxicity with a niacin product is with extended-release niacin (Niaspan; Kos Pharmaceuticals) given as a tablet once a day in the evening.41 This extended-release niacin product delays the release of niacin by up to 8 hours and results in a relatively short systemic exposure time (Figure 8). In large clinical trials, the incidence of liver toxicity
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FIGURE 7. Safety of once-daily niacin extended-release (ER) compared with generic niacin. ALT ⴝ alanine aminotransferase; AST ⴝ aspartate aminotransferase. (Adapted from JAMA37 and Am J Cardiol.39)
FIGURE 8. Niacin metabolism. 6HN ⴝ 6-hydroxynicotinamide; MNA ⴝ methylnicotinamide; NAD ⴝ nicotinamide adenine dinucleotide; NAM ⴝ nicotinamide; NNO ⴝ nicotinamide-N-oxide; NUA ⴝ nicotinuric acid; 2PY ⴝ N-methyl-2-pyridone-5-carboxamide; 4PY ⴝ N-methyl-4-pyridone-5-carboxamide. (Reprinted with permission from Kos Pharmaceuticals.)
(defined as aspartate aminotransferase or alanine aminotransferase ⬎3 times the upper limit of normal on 2 successive occasions) is approximately 1%, and in combination with lovastatin as a single tablet at doses of up to 2,000 mg/day plus lovastatin 40 mg, the hepatotoxicity rate remains approximately 1%.42 Therefore, by significantly shortening the systemic exposure time, extended-release niacin alone or in combination with a statin has a surprisingly low rate of hepatotoxicity. Over 5,000 patients have been exposed in clinical trials to extendedrelease niacin/lovastatin without confirmed cases of drug-induced myopathy or rhabdomyolysis. Niacin and statins appear not to have a pharmacokinetic interaction that results in higher blood levels for each drug, and therefore the cause of myopathy with niacin and statin combination therapy is poorly understood.20 Although myopathy has been reported with the combination of a statin and niacin, the inci-
dence rates appear to be significantly lower than with a statin and gemfibrozil.43 Using the AERS of the FDA on statin-induced rhabdomyolysis of the 871 cases reported, only 4 cases (all outside the United States) were associated with niacin compared with 80 cases with fibrates. There have been no cases of myopathy reported with extended-release niacin in the AERS of the FDA or in the clinical trials with 1,700 patients studied.44 This evidence supports the hypothesis that myopathy associated with statin-niacin combination therapy is the result of niacin-induced hepatotoxicity impairing the liver’s ability to metabolize the statins, resulting in much higher systemic levels. Therefore, if the hepatotoxicity rate is low, the myopathy incidence should be exceedingly low; this relationship is supported by the clinical trial data and the postmarketing surveillance information regarding extended-release niacin. This excellent safety record of A SYMPOSIUM: COMBINATION THERAPY FOR DYSLIPIDEMIA
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extended-release niacin can be maintained by avoiding doses above the approved FDA limit of 2,000 mg/day or giving the drug more than once per day.
SAFETY OF STATIN-FIBRATE COMBINATION THERAPY There have been a number of relatively small controlled clinical trials that have evaluated the lipoprotein effects of statin and fibrate combination therapy.45,46 Fibrate treatment alone appears to be associated with some (probably similar) risk of myopathy. Of the nearly 600 subjects who have participated in controlled clinical trials of a statin and fibrate combination, 1% have experienced a creatinine phosphokinase level ⬎3 times the upper limit of normal without muscle symptoms, and 1% have been withdrawn from therapy because of muscle discomfort.5,47–51 None of these findings were considered serious by the trial investigators. No cases of rhabdomyolysis or myoglobinuria have been encountered in these clinical trials. The experience in these trials is predominantly with lovastatin and gemfibrozil, but it is reasonable to believe that the experiences with other statin-fibrate combinations would be similar. Most references regarding the safety of statins in combination with fibrates discuss fibrates as a class of drugs that should be avoided or used cautiously with a statin. In the FDA labeling of all statins, caution is advised for combination therapy with a fibrate. However, controlled clinical trials may markedly underestimate the risk of myopathy, because patients with confounding illness, such as hypertension, diabetes with altered renal function, or the elderly, are excluded. However, there are compelling data that fibrates differ in their effects on statin pharmacokinetics and safety. Gemfibrozil, which affects statin pharmacokinetics, has been associated with a high rate of myopathy when combined with a statin, especially cerivastatin.27 However, the incidence rate with fenofibrate is much less frequently reported. Based on the AERS of the FDA, pharmacokinetic studies, and clinical trial data, although not yet conclusive, fenofibrate used in combination with a statin does appear to have less risk of myopathy than does gemfibrozil.
REGULATORY CONSIDERATIONS The noted myotoxicity and subsequent withdrawal of cerivastatin from the worldwide markets has heightened the awareness of regulatory agencies for the safety of statins and combination therapy. Several important lessons were learned from the cerivastatin experience. The safety of statins is not a class effect. Statins of comparable efficacy may have different safety profiles, whereby the degree of LDL lowering and toxicity are not necessarily linked. In the future, statins that have a level of risk that exceeds that of the existing approved statin without significant enhanced efficacy will not receive regulatory clearance. Simvastatin 80 mg, with a myopathy rate of 0.3% to 0.5%, and atorvastatin 80 mg, with a liver function abnormality incidence of 2.5% to 3%, probably represent the thresholds by which lipid-lowering therapies will 58K THE AMERICAN JOURNAL OF CARDIOLOGY姞
be judged for approval. These thresholds, however, may be exceeded if a lipid-altering or antiatherosclerotic compound has a documented enhanced clinical benefit. A pharmacokinetic evaluation of cerivastatin has identified a number of factors that may explain the greater myotoxicity rate. Cerivastatin is by far the most potent statin per milligram of drug. The drug is also the most lipophilic and bioavailable with significant renal clearance. Therefore, several factors could lead to higher systemic levels, such as renal impairment or coadministration of a drug such as gemfibrozil, and the higher potency and/or lipophilicity of cerivastatin resulted in greater muscle toxicity (Table 1).25 Therefore, statins that are less lipophilic with fewer drug interactions and lower rates of renal excretion may be less prone to myotoxicity. In the preapproval data base, cerivastatin 0.8 mg had an overall myopathy rate of 1.3% and a 5.6% rate in elderly women. The FDA has acknowledged that this was a signal that cerivastatin was more myotoxic than other statins and that the elderly population, who are often not included in significant numbers in a preapproval regulatory submission, represent a group at higher risk for safety problems. Rosuvastatin is the first statin submitted for regulatory approval for which a large number of elderly patients were included in the New Drug Application. In the future, regulatory agencies are likely to require the inclusion of more elderly patients and pharmacokinetic studies of frequently coadministered drugs to assess safety. Although the coadministration of cerivastatin with gemfibrozil was contraindicated in the package labeling information starting in December 1999, clinicians continued to prescribe the 2 drugs together, which resulted in a number of serious and fatal cases of rhabdomyolysis. This experience underscores the inability of package labeling alone to completely prevent serious iatrogenic drug interactions. Many of the cases of cerivastatin-gemfibrozil–induced myopathy are the result of managed care plans advocating the switching of the prescribed statin to cerivastatin based on cost considerations. Therefore, regulatory agencies have learned that labeling alone is insufficient to prevent drug interactions, and it is incumbent upon them to not approve drugs if frequent serious drug interactions may occur. A combination tablet of lovastatin and extendedrelease niacin (Advicor) was approved by the FDA in 2001, and a combination of simvastatin and ezetimibe is in clinical development. This trend in combination tablet approval is likely to continue, but there will be increasing demands by regulatory agencies for sponsors to ascertain the safety of these therapies. A potential option for a combination therapy is fenofibrate and a statin in a single tablet. Although the risk of myopathy with fenofibrate and a statin is perhaps lower than gemfibrozil, the difficulty of defining the incidence of risk may be significant. The FDA has acknowledged that assessing the safety of these combinations is very difficult.13 Because the myopathy rate of statin monotherapy is approximately 1 in
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1,000, the average patient exposure for a lipid-lowering drug during development (3,000 to 4,000 patients) will have about a 95% likelihood of seeing 1 case. Therefore, agencies may require a significant number of patients (⬎10,000) to be evaluated in clinical development to assess whether there is an increased risk of myopathy with combination therapy over monotherapy.
CONCLUSIONS In our appropriate zeal to reduce the risk of CAD with lipid-lowering therapy, the trend to aggressively treat all lipoprotein abnormalities will continue. This more aggressive approach will require the use of higher doses of statins and combination therapy. A balance of efficacy and safety will be necessary to maximize the overall benefits of treatment. The withdrawal of cerivastatin has heightened the concern of both patients and physicians regarding the safety of lipid-lowering therapy. However, with recent information regarding the benefits of lipid-lowering therapy, such as the HPS, a new appreciation of at-risk subpopulations of patients, and a better understanding of potential drug interactions, physicians have the enhanced knowledge they need to maximize the risk: benefit ratio of drug therapy for dyslipidemia.
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