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Reducing Residual Risk for Patients on Statin Therapy: The Potential Role of Combination Therapy
Reducing Residual Risk for Patients on Statin Therapy: The Potential Role of Combination Therapy Michael H. Davidson, MD Cholesterol-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, has been established as an effective method of reducing death and myocardial infarction among patients with coronary artery disease (CAD). However, a significant number of patients receiving statin therapy continue to have high residual risk. An important clinical challenge exists in reducing residual CAD risk with optimal therapies without increasing adverse effects. Combination therapy appears most appropriate for patients with a high rate of events of residual risk despite optimal statin therapy. This article discusses the role of combination therapy in managing CAD and in achieving optional targets in high-risk patient populations. © 2005 Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96[suppl]:3K–13K)
Outcome trials of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have proved conclusively that lowering low-density lipoprotein (LDL) cholesterol results in significant improvement in cardiovascular morbidity and mortality. Additionally, primary and secondary prevention studies using statins have established the safety and efficacy of this class of pharmacologic agents. The relation between LDL cholesterol and coronary artery disease (CAD) events appears to be linear, with considerable evidence supporting the “lower is better” hypothesis. However, even with low LDL levels, the residual risk for subsets of high-risk patients continues to be elevated. In the Treating to New Targets trial, patients taking atorvastatin 80 mg (mean LDL cholesterol 77 mg/dL) had a 28% cardiovascular event rate compared with a 33% event rate for patients taking atorvastatin 10 mg (mean LDL cholesterol 101 mg/dL), a 22% relative risk reduction.1 Therefore, approximately 70% of the events were not avoided despite significant LDL cholesterol reduction. The 80-mg atorvastatin therapy also was associated with a slightly elevated rate of increased transaminase levels (0.2% vs 1.2%).1 Therefore, an important clinical challenge remains to further reduce the residual CAD risk in patients taking optimal statin therapy without adversely affecting patient safety.
Statin Therapy for Patients at High Risk for Coronary Artery Disease Events Post hoc and prespecified analyses of statin outcome trials demonstrate higher CAD event rates for patients with adRush Medical College, Rush University Medical Center, Chicago, Illinois, USA. Address for reprints: Michael H. Davidson, MD, Rush Medical College, Rush University Medical Center, 515 North State Street, Suite 2700, Chicago, Illinois 60610. E-mail address: [email protected]. 0002-9149/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.08.002
ditional risk factors. Of the modifiable risk factors, the presence of diabetes mellitus, cigarette smoking, the metabolic syndrome, and elevated high-sensitivity C-reactive protein (hs-CRP) predicts a high residual risk. The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guideline update on the implication of recent clinical trials recommends an optional LDL cholesterol goal of ⬍70 mg/dL and a non– high-density lipoprotein (HDL) goal of ⬍100 mg/dL for patients at very high risk.2 The definition of “very high risk” includes patients with cardiovascular disease with diabetes, cigarette smoking, or factors associated with the metabolic syndrome (Table 1).3 A recent survey documents that 75% of patients with CAD would meet this definition of very high risk. Therefore, pragmatically, most patients with CAD should be considered appropriate for the optional LDL goal of ⬍70 mg/dL. In the Heart Protection Study (HPS), statin therapy (simvastatin 40 mg/day) resulted in highly significant reductions in coronary mortality rate (18%), an incidence rate of first nonfatal myocardial infarction (38%), stroke incidence (25%), and incidence of coronary revascularization (30%),4 but patients with diabetes who had CAD and who were receiving statin therapy had an event rate of 31% compared with a placebo event rate of 25% in nondiabetic patients with CAD. In the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, intensive (atorvastatin 80 mg/dL) versus moderate (pravastatin 40 mg/dL) lipid lowering resulted in greater reductions in LDL cholesterol to mean levels of 78.9 and 110.4 mg/dL, respectively (p ⬍0.001). In addition, intensive lipid-lowering intervention resulted in a significantly lower progression rate in the percent change in atheroma volume (p ⫽ 0.02).5 However, the diabetic subset taking aggressive lipid-lowering therapy of atorvastatin 80 mg continued to have marked progression of atheroma volume. In the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 trial, the diabetic subset also continwww.AJConline.org
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The American Journal of Cardiology (www.AJConline.org) Vol 96 (9A) November 7, 2005 Table 1 Summary of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines for dyslipidemia
Risk Level Low risk ⬍2 risk factors Moderate risk ⱖ2 risk factors Moderate high risk ⱖ2 risk factors; 10%–20% 10-yr risk High risk CAD, PAD, AAA ⬎50% carotid stenosis Diabetes† ⬎20% 10-yr risk Creatinine ⬎1.5 mg/dL‡ 10%–20% 10-yr risk plus hs-CRP ⬎2.0 mg/L§ Very high risk CAD plus Diabetes Metabolic syndrome Cigarette smoking Acute coronary syndrome
LDL-C Goal (mg/dL)
If TG ⬎200 mg/ dL, Non-HDL-C Goal (mg/dL)
⬍160
⬍190
⬍130
⬍160
⬍100* ⬍100
⬍130 ⬍130
⬍70†
⬍100*
AAA ⫽ abdominal aortic aneurysm; CAD ⫽ coronary artery disease; HDL-C ⫽ high-density lipoprotein cholesterol; hs-CRP ⫽ high-sensitivity C-reactive protein; LDL-C ⫽ low-density lipoprotein cholesterol; PAD ⫽ pulmonary artery disease; TG ⫽ triglycerides. * NCEP ATP III optional goal. † The American Diabetes Association recommends that all patients with type 2 diabetes mellitus aged ⬎80 years should lower LDL-C by ⱖ 30%, even if baseline LDL-C is ⬍100 mg/dL. ‡ High risk by National Kidney Foundation guidelines. § High risk by American Heart Association/Centers for Disease Control and Prevention guidelines. Adapted from: JAMA.3 Table 2 Event rates in statin trials Without Diabetes Trial 4
HPS (CAD patients)* CARE†7 LIPID*8 PROSPER*9 ASCOT*10
HPS*4 CARE/LIPID*†7,8 PROSPER*9
With Diabetes
On Statin
On Placebo
On Statin
On Placebo
19.8% 19.6% 11.7% 13.1% 4.9%
25.7% 24.6% 15.2% 16% 8.7%
33.4% 28.7% 19.7% 23.1% 9.6%
37.8% 36.8% 22.8% 18.4% 11.4%
High HDL-C on Statin
High HDL-C on Placebo
Low HDL-C on Statin
Low HDL-C on Placebo
17% 18.5% 12.8%
20.9% 22.4% 11.6%
22.0% 25% 13%
29.9% 30.8% 19.3%
ASCOT ⫽ Anglo-Scandinavian Cardiac Outcomes Trial; CARE ⫽ Cholesterol and Recurrent Events; HDL-C ⫽ high-density lipoprotein cholesterol; HPS ⫽ Heart Protection Study; LIPID ⫽ Long-Term Prevention with Pravastatin in Ischaemic Disease; PROSPER ⫽ Prospective Study of Pravastatin in the Elderly at Risk. * Coronary artery disease (CAD) death, nonfatal myocardial infarction, coronary or noncoronary revascularization, stroke. † CAD death and nonfatal myocardial infarction.
ued to have progression of intima-media thickness despite statin therapy.6 A review of patients with diabetes or patients with low HDL in statin event trials demonstrates a
greatly elevated rate of residual events even with statin treatment (Table 2).4,7–10 In fact, the statin event rate in patients with diabetes or low HDL is higher than the pla-
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Figure 1. Heart Protection Study (HPS): Major vascular event by high-density lipoprotein cholesterol (HDL-C) and triglycerides. CI ⫽ confidence interval. (Adapted from Lancet.4)
cebo event rate for patients without diabetes or low HDL. Therefore, even with an LDL cholesterol ⬍70 mg/dL, a patient with CAD who has diabetes is likely to have a high recurrent event rate. In the HPS trial, the subgroup of patients with low HDL significantly benefited from simvastatin therapy. CAD events decreased from 29.9% to 22.6%, but patients receiving statin therapy still had a higher event rate than placebo-treated patients in the subgroup with a higher HDL (Figure 1).4 A similar relation exists for patients in the HPS trial with elevated triglyceride levels. Because hs-CRP correlates with the metabolic syndrome, an elevated hs-CRP (⬎2.0 mg/L) may represent an important marker of enhanced residual risk. Other high-risk subsets for recurrent events in patients taking statin therapy potentially include those with aspirin or clopidogrel resistance and other prothrombotic states. Plant sterol levels are not reduced with statin therapy, and, if elevated, may therefore also be a potential cause of recurrent events. Whether the prevalence of increased plant sterol levels in a population with CAD confers a marked increased risk is unclear.
Potential New Targets With recognition that the residual risk is significantly elevated in patients at very high risk, the NCEP ATP III panel recommended the therapeutic optional goals of LDL ⬍70 mg/dL and non-HDL ⬍100 mg/dL.2 However, other target goals have also been advocated in published reports. Based on the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT)11 and REVERSAL5 trials documenting hs-CRP as an independent predictor of events, even with a low LDL, a dual goal of LDL ⬍70 mg/dL and an hs-CRP ⬍2.0 mg/L (or potentially ⬍1.0 mg/L) has been put forward as a therapeutic target. However, because hs-CRP and the metabolic syndrome are closely correlated, an elevated hs-
CRP may not enhance the risk prediction beyond the more aggressive optional targets already advocated for patients with the metabolic syndrome by updated treatment guidelines. An elevated hs-CRP may be a relatively accessible biologic marker that will encourage more aggressive risk factor modification. Consensus regarding hs-CRP as a goal in conjunction with LDL will likely await the outcome of the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER).12 Apolipoprotein (apo) B has been shown to be a better predictor of CAD events than LDL in patients on statin therapy, and therefore an ApoB goal of ⬍90 mg/dL has been mentioned as an alternative to LDL as a goal of therapy. In the REVERSAL trial,5 intensive (atorvastatin 80 mg/dL) versus moderate (pravastatin 40 mg/dL) lipid-lowering intervention resulted in greater reductions in apoB to mean levels of 91.8 and 118.1 mg/dL, respectively.
Ratio Goals A total cholesterol to HDL goal has been advocated by Canadian guidelines (Table 3).13 These guidelines are similar to the NCEP ATP III recommendation, in that goals for LDL cholesterol are more aggressive according to risk classification. However, rather than non-HDL targets, Canadian guidelines have a total cholesterol to HDL ratio of ⬍4.0. The advantage of this approach is that for patients with low HDL, more aggressive LDL lowering or HDL raising, or both, may be necessary to achieve both targets. Because greater reductions in LDL cholesterol are usually easier to achieve with current therapies than significant increases in HDL, a ratio target of ⬍4.0 may frequently require reducing LDL levels to ⬍70 mg/dL in patients with low HDL. For example, a patient with an HDL of 30 mg/dL and triglycerides of 150 mg/dL would require a target total cholesterol
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of 120 mg/dL and an LDL cholesterol of 60 mg/dL. For patients with higher HDL levels, an LDL level ⬍100 mg/dL would likely result in a ratio goal of ⬍4.0. Therefore, by including a ratio target, Canadian guidelines appropriately require more aggressive LDL lowering in patients with low HDL based on clinical trials demonstrating that this subpopulation has a significantly higher residual risk of events with statin therapy. The ratio has been shown to be a better epidemiologic predictor of cardiovascular events than LDL and also appears to improve significantly event prediction with statin therapy. Therefore, rather than have a more aggressive LDL goal for all patients at risk, a ratio goal of ⬍4.0 in conjunction with an LDL cholesterol goal of ⬍100 mg/dL may sufficiently identify higher-risk patients who require more aggressive lipid-altering interventions. The argument against a ratio target is based on a lack of evidence supporting an increase in HDL as a therapeutic target, and therefore there is a concern that a ratio target would inappropriately emphasize the benefits of increasing HDL. However, because raising HDL by ⬎25% with existing therapies is difficult, the best means to achieve a ratio goal of ⬍4.0 would still require more aggressive LDL reduction. Another ratio target that has been evaluated is the apoAB– apoA1 ratio. apoAB–apoA1 is a better predictor of events in large observational trials such as the Apolipoprotein-related Mortality Risk Study (AMORIS),14 and the best predictor of events in patients on statin therapy according to the Air Force/ Texas Coronary Atherosclerosis Prevention Study (AFCAPS/ TexCAPS).15 Based on data from AMORIS14 and the INTERHEART16 study, an apoAB–apoA1 ratio of ⬍0.7 may be an appropriate target. ApoB measurements are most useful in patients with hypertriglyceridemia because they incorporate all atherogenic lipoproteins. Non-HDL correlates better with apoB than LDL, especially in patients with hypertriglyceridemia. The main reason the apoB–apoA1 ratio is better in predicting CAD events than total cholesterol to HDL is that in the hypertriglyceridemic population and in those with small dense LDL (apoB–LDL ⬎1.0), the apoB level is significantly more predictive of cardiovascular events than total cholesterol levels. Apolipoprotein measurements are not universally available and are more expensive than determining a standard lipid profile that includes the total cholesterol to HDL ratio, and therefore the use of the apoB–apoA1 ratio on a therapeutic target would require additional justification based on a cost– benefit analysis. However, to define a therapeutic benefit of a lipid-altering treatment, putative changes in the apoB–apoA1 ratio may be useful in demonstrating an enhanced benefit of a therapy, and may provide a helpful lipid surrogate end point for regulatory approval for novel therapies. Therapeutic Global Risk Goal A modified form of the Framingham risk score is used with multiple international guidelines to stratify patients into risk groups to determine thresholds for initiating therapy and goals of treatment. The Framingham score as a therapeutic
target is problematic for 2 reasons. First, this global risk formula was based on observational data, and although some intervention trials have shown good correlation with the Framingham equation, there is concern that the score may not assess risk adequately for patients receiving treatment. Second, age and sex are powerful contributors to the overall Framingham score, and these nonmodifiable risk factors therefore make the Framingham score difficult to use clinically. An alternative is a global risk score that attempts to incorporate the divergent guidelines established in the United States for the various risk factors. A hypothetical global risk score that includes the recommendations of the NCEP ATP III,3 the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (Joint National Committee 7),17 and the American Diabetes Association (ADA) is determined by the following equation: Hypothetical global risk score ⫽ total cholesterol/HDL ⫹ 共hemoglobin A1c ⫺ 7.0兲 ⫹ 共systolic blood pressure ⫺ 130⁄10兲 ⫹ Cigarette packs⁄day This hypothetical global risk score, with a goal of ⬍4.0, has the advantage of targeting all major modifiable risk factors (lipid level, blood pressure, and glucose control targets) simultaneously, as opposed to an isolated approach for each risk factor. Due to the influence of separate risk factor treatment guidelines and the marketing of drugs for individual risk factors, the therapeutic approach of risk factor modification has become a silo phenomenon. A global risk score would encourage clinicians to escalate and treat major risk factors in a more united fashion to achieve an overall therapeutic target. The proposed hypothetical global risk score would also encourage more aggressive lipid control of the total cholesterol to HDL ratio if a patient continues to smoke despite all efforts for cessation, or has a hemoglobin A1c that remains elevated to ⬎7.0 mg/dL after maximal therapy. A global risk score may be impossible to achieve in a significant percentage of high-risk populations, but this concept is an attempt to better coordinate management of all major modifiable risk factors.
Clinical Significance of Statin Pleiotropic Effects The word pleiotropic (which is usually applied to genetics) refers to the multiple actions of a single gene. With respect to drug therapy for dyslipidemia, the term has become synonymous with clinical benefits beyond the effects of the drug on lipoproteins. Statins have been evaluated extensively for effects independent of lipid alterations. Mice and rats are relatively good models to evaluate potential pleiotropic effects of statins, because they do not lower circulating cholesterol concentrations in these species. The administration of statins has been demonstrated to result in greater
Davidson/Combination Therapy to Reduce Residual Risks of Statins Table 3 Canadian Dyslipidemia Guidelines Target Level Risk Category High* (10-yr risk of CAD ⱖ20%, or history of diabetes mellitus† or any atherosclerotic disease) Moderate (10-yr risk, 11%–19%) Low‡
LDL-C Level (mmol/L)
TC: HDL-C Ratio
⬍2.5 and
⬍4.0
⬍3.5 and
⬍5.0
⬍4.5 and
⬍6.0
HDL-C ⫽ high-density lipoprotein cholesterol; LDL-C ⫽ low-density lipoprotein cholesterol; TC ⫽ total cholesterol. * Apolipoprotein B can be used as an alternative measurement, particularly for patients treated with statins. An optimal level of apolipoprotein B in a patient at high risk is ⬍0.9 g/L, in a patient at moderate risk ⬍1.05 g/L, and in a patient at low risk ⬍1.2 g/L. † Includes patients with chronic kidney disease and those undergoing long-term dialysis. ‡ In the very low risk stratum, treatment may be deferred if the 10-year estimate of cardiovascular disease is ⬍5% and the LDL level is ⬍5.0 mmol/L. Adapted from CMAJ.13
nitric oxide bioavailability, increased ability to recruit endothelial progenitor cells, inhibition of cardiac hypertrophy, and reductions in the size and severity of strokes.18 However, despite a failure to lower blood cholesterol, these drugs may influence cell membrane lipid levels. In rodent models, statins have been shown to decrease mitogen-activated protein kinase activation, enhance nitric oxide synthase expression, and reduce lipoxygenase-1 transcription by reducing oxidized LDL uptake in endothelial cell membranes.19 As a result, the pleiotropic effects in animals may not be independent of cellular uptake of lipids. The purported clinical benefits of statins in humans have ranged from improved bone density to reduction of Alzheimer disease, as well as enhanced cardiovascular benefits beyond blood lipid modification. Numerous studies have demonstrated that statins improve endothelial function, most likely by increasing nitric oxide bioavailability and reducing oxidant stress. Statins may also have “negative pleiotropic” effects, because they may downregulate cholesterol efflux from nonloaded human macrophages by inhibiting synthesis of an oxysterol ligand for liver X receptor.20 Historically speaking, the hypothesis that statins may reduce CAD events to a degree greater than expected from lipoprotein modification was first suggested by the results of the West of Scotland Coronary Prevention Study (WOSCOPS) group trial.21 Event rates were compared among patients taking pravastatin or placebo, and whose on-trial LDL cholesterol values were in a range that occurred with high frequency in both groups (3.62 to 4.65 mmol/L [140 to 180 mg/dL]). A significant reduction in event rates associated with pravastatin therapy was found after adjustment for lipoprotein cholesterol and triglyceride
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levels during treatment.21 Similar findings were demonstrated in the AFCAPS/TexCAPS, although, after correction for apoB and apoA1 levels,22 there was no difference in event rate for subjects taking lovastatin versus placebo. Owing to the lack of available outcome trial results for all statins at the time, the use of statins with proven benefits on event rates—including pravastatin, lovastatin, and simvastatin (all fungal metabolites or “natural statins”)—was advocated in part for their presumed ability to provide additional clinical benefits because of their pleiotropic effects.23 Based on the findings of additional outcomes trials, it has become obvious that all statins, whether fungal metabolites or synthetic, confer similar CAD event reduction if adjusted for differences in lipid changes (Figure 2). These additional trials, especially the HPS4 and PROVE-IT,11 also verified the hypothesis that lower is better regarding LDL cholesterol, especially for patients at high risk for CAD. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),25 although flawed owing to a high frequency of crossover between treatments, failed to demonstrate a clinical benefit for pravastatin beyond lipid lowering. This effectively ended the hypothesis that pravastatin provided unique pleiotropic benefits different from other statins. Additional lipid-altering drugs such as bile-acid sequestrants, niacin, and fibrates have been demonstrated to lower CAD events to an extent similar to statin therapy when adjusted for cholesterol lowering, although this provides only indirect evidence against clinical pleiotropic benefits of the statin drugs. Statins have been shown to lower inflammatory markers such as CRP, but the degree of CRP reduction correlates with the extent of lipid lowering, and this effect is not unique to statins. The cholesterol absorption inhibitor, ezetimibe, enhances CRP reduction when added to a statin, and equal lowering of LDL cholesterol by a low-dose statin plus ezetimibe or a high-dose statin provides equivalent CRP reduction.26 According to pleiotropic statin enthusiasts, clinical event reductions appear more rapidly in statin than in nonstatin trials. In the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL)27 trial and in PROVE-IT,11 significant benefits occurred within the first month of treatment and were attributed to reductions in the incidence of unstable angina. In comparison, in nonstatin trials, the clinical benefits required multiple years for the Kaplan-Meier curves to separate. Yet the MIRACL trial27 and PROVE-IT11 enrolled patients with acute coronary syndromes who had much higher event rates than subjects in the nonstatin trials. Whereas significant stroke reduction is present in statin trials, the nonstatin trials also trended toward stroke reduction, but with less cholesterol reduction. As a result, the idea that statins provide unique benefits attributable to factors other than modification of the lipoprotein profile compared with other classes of lipid-altering medications remains speculative.
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Figure 2. Relation of reduction in triglyceride levels to reduction in cardiovascular (CV) events: statin and nonstatin therapy. Circles ⫽ nonstatin therapy; diamonds ⫽ statin therapy. A to Z ⫽ phase Z in the A to Z trial; AFCAPS ⫽ Air Force/Texas Coronary Atherosclerosis Prevention study; ALLHAT-LLT ⫽ Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack–Lipid-Lowering Trial; ASCOT-LLA ⫽ Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm; CABG ⫽ coronary artery bypass graft surgery; CARE ⫽ Cholesterol and Recurrent Events trial; CDP ⫽ Coronary Drug Project Study; CTL ⫽ control group; HHS ⫽ Helsinki Heart Study; HPS ⫽ Heart Protection Study; LIPID ⫽ Long-Term Intervention with Pravastatin in Ischaemic Disease trial; LIPS ⫽ Lescal Intervention Prevention Study; LRC-CPPT ⫽ Lipid Research Clinics Coronary Primary Prevention Trial; MI ⫽ myocardial infarction; POSCH ⫽ Program on the Surgical Control of Hyperlipidemias; PROVE-IT ⫽ Pravastatin or Atorvastatin Evaluation and Infection Therapy trial; TC ⫽ total cholesterol; TNT ⫽ Treating to New Targets trial; TRT ⫽ treatment; VA-HIT ⫽ Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial; WOSCOPS ⫽ West of Scotland Coronary Prevention Study. (Reprinted with permission from Circulation.24)
Clinical Significance of Nonstatin Pleiotropic Effects Nonstatin therapies also have a multitude of potential pleiotropic effects. Niacin lowers lipoprotein(a) and fibrinogen, while increasing HDL and modifying LDL particle size. Ezetimibe lowers plant sterol levels and alters the cholesterol composition of postprandial chylomicrons. Both bile acid sequestrants and ezetimibe may affect farnesoid X receptor or liver X receptor, or both, by altering bile salts/ biliary cholesterol absorption. Fibrates, as peroxisome proliferator-activated receptor–␣ (PPAR-␣) agonists, affect the expression of numerous genes that alter lipoprotein metabolism or the development of atherosclerosis (Figure 3). PPAR-␣ agonism upregulates the genes involved in reverse cholesterol transport. Fenofibrate has been shown to upregulate macrophage ABCA1, which increases efflux of free cholesterol into nascent HDL and enhances the uptake of HDL by the hepatic SRBI receptors, which results in increased biliary cholesterol excretion. PPAR-␣ agonists also appear to have numerous anti-inflammatory and antithrombotic effects that may reduce plaque rupture vulnerability to induce clinical events (Figure 4). Although the clinical benefits of these pleiotropic effects of nonstatin therapies remains speculative, there are intriguing post hoc analyses from fibrate trials that support additional clinical benefits of PPAR-␣ agonism in patients with the metabolic syndrome or diabetes. In the fibrate outcomes trials, the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT)28 and the Helsinki Heart Study (HHS),29 the subset of patients with diabetes had a greater risk reduction than patients
without diabetes (Figure 5). In VA-HIT28 the occurrence of new cardiovascular events and the benefit of fibrate therapy were much less dependent on levels of HDL cholesterol or triglycerides than on the presence or absence of insulin resistance.
Rationale of Combination Therapy In light of the residual risk of CAD events in statin trials within certain subgroups, combination therapy appears most appropriate in patients with a high rate of events despite optimal statin treatment. These subgroups include patients with LDL cholesterol levels ⬎70 mg/dL, patients with diabetes, those with the metabolic syndrome, those with elevated hs-CRP, and cigarette smokers. A recent survey demonstrated that 75% of patients with CAD met the definition of “very high risk” according to the NCEP ATP III update report.30 In this survey, only 18% of patients at very high risk had an LDL level ⬍70 mg/dL, and only 4% had an LDL level ⬍70 mg/dL and a non-HDL level ⬍100 mg/dL when triglycerides were ⬎200 mg/dL. These data support the use of more aggressive statin therapy and implementation of combination therapy as necessary to achieve these optional targets in the very high risk patient population. Whereas further LDL cholesterol lowering may provide additional clinical benefits in patients with diabetes or the metabolic syndrome, or both, the post hoc analysis of clinical trials has demonstrated a very high residual risk, even with low LDL cholesterol levels. Surrogate end point trials also demonstrate significant atherosclerotic progression in
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Figure 3. Peroxisome proliferator-activated receptor–␣ (PPAR-␣) expression in monocytes/macrophages and the liver. ApoA ⫽ apolipoprotein A; HDL ⫽ high-density lipoprotein cholesterol; LCAT ⫽ lecithin-cholesterol acyltransferase; LDL ⫽ low-density lipoprotein cholesterol; PLTP ⫽ phospholipid transfer protein; RXR ⫽ retinoid X receptor; VLDL ⫽ very-low-density lipoprotein.
patients with diabetes taking statins or a combination of statins and niacin. Because fibrates appear to have unique benefits in patients with insulin resistance, the combination of a statin and a fibrate is potentially most appropriate in this patient population. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial31 will be testing this hypothesis in approximately 10,000 patients with diabetes taking simvastatin randomized to fenofibrate or placebo to evaluate CAD outcomes. The additive effects of simvastatin and fenofibrate on lipid parameters have been documented in the Simvastatin Plus Fenofibrate for Combined Hyperlipidemia (SAFARI) trial.32 Simvastatin monotherapy (20 mg/day) was compared with combination therapy (simvastatin 20 mg/day plus fenofibrate 160 mg/day) in patients with combined hyperlipidemia (fasting triglyceride levels ⱖ150 and ⱕ500 mg/dL and LDL cholesterol ⬎130 mg/dL). Mean LDL levels significantly decreased with combination therapy when compared with monotherapy (31.2% and 25.8%, respectively; p ⬍0.001). In addition, mean HDL cholesterol levels significantly increased with combination therapy when compared with monotherapy (18.6% and 9.7%, respectively; p ⬍0.001), and no drug-related serious adverse events occurred.32 Safety of Combination Therapy Although combination therapy is widely used and, in fact, is recommended by expert panels for managing hypertension
and diabetes and for treating dyslipidemia, combination treatment is seldom clinically applied in practice. In the NCEP Evaluation Project Utilizing Novel E-Technology30 survey, only 5% of treated patients were receiving combination therapy. The major reason combination therapy has not been used widely in practice is the perception of adverse safety associated with combining a statin with niacin or a fibrate. On the labels of all statins are cautionary notes regarding the combination with niacin or a fibrate, stating that the benefits should outweigh the increased risk of myopathy. The concern regarding the combination of niacin with a statin is based on early case reports documenting myopathy with lovastatin in combination with high doses of niacin (ⱖ2.5 g/day). Because niacin does not alter the pharmacokinetics of lovastatin and excessive doses of niacin have documented hepatotoxicity, the most likely explanation for the cases of myopathy associated with combination statin–niacin therapy is that the liver impairment associated with niacin toxicity results in delayed clearance of the statin, leading to an increased risk of myopathy. Statin-induced myopathy is almost always associated with factors that increase the area under the curve (AUC), such as increased dosage, hypothyroidism, renal or hepatic impairment, or drugs that interfere with statin metabolism such as cytochrome P450 (CYP) 3A4 inhibitors. In the absence of hepatotoxicity, it is unlikely that niacin would increase the risk of statin myopathy, and since the first 2 reports of niacin and lovastatin myopathy, there have been no additional pub-
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Figure 4. Anti-inflammatory effects of peroxisome proliferator-activated receptor (PPARs) and the potential anti-atherosclerotic effects promoting plaque stabilization. ABCA1 ⫽ ATP-binding cassette transporter A1; CCR-2 ⫽ CC chemokines receptor–2; CRP ⫽ C-reactive protein; COX-2 ⫽ cyclooxygenase-2; ET-1 ⫽ endothelin-1; ICAM-1 ⫽ intercellular adhesion molecule–1; MCP-1 monocyte chemotactic protein–1; MMP ⫽ matrix metalloproteinase; PAF ⫽ platelet-activating factor; sPLA2 ⫽ secretory phospholipase A2; SR ⫽ steroidogenic receptor; TF ⫽ tissue factor; TNF-␣ ⫽ tumor necrosis factor-␣; TXS ⫽ thromboxane synthase; VACM-1 ⫽ vascular cell adhesion molecule–1.
lished reports. Adverse event reports (AERs) under the Med Watch program of the US Food and Drug Administration (FDA) have also documented a very low incidence of statin myopathy associated with niacin.33 Extended-release niacin, which has a very low rate of hepatotoxicity, especially when compared with sustained-release niacin, has very few reports of myopathy in the AER database, despite several hundred thousand prescriptions written in combination with a statin. Therefore, the AER data, although not conclusive, support the safety of doses of extended-release niacin up to 2 g/day in combination with a statin. With regard to fibrate therapy, there appears to be a clinically significant difference in safety in the combination of gemfibrozil plus a statin versus fenofibrate and a statin. There are ⱖ60 case reports of gemfibrozil-statin myopathy in published data compared with 2 cases of fenofibrate in combination with a statin. Recent reviews of the FDA’s AER database have documented that, after correcting for prescription use, the rate of myopathy for gemfibrozil with a statin is ⬎30 times the rate for combination therapy with fenofibrate (Table 4).34,35 Cerivastatin combined with gemfibrozil was associated with ⬎4,000 times the rate of rhabdomyolysis compared with statin therapy alone, and numer-
ous fatalities were reported, resulting in the removal of cerivastatin from the worldwide market. An analysis of several managed care prescription and hospitalization event data has estimated that the rate of rhabdomyolysis requiring hospitalization from cerivastatin combined with gemfibrozil was at least 1 in 10 patients. The Lipid in Diabetes Study (LDS),36 a 2 ⫻ 2 factorial design, used cerivastatin-fenofibrate combination therapy or placebo in patients with diabetes; the study enrolled ⬎2,000 patients (⬎1,000 for ⬎12 weeks) taking cerivastatin and fenofibrate before the study was discontinued when cerivastatin was withdrawn from the market. In the ⬎2,000 patients taking the combination of cerivastatin and fenofibrate, there were no case reports of myopathy. In a Veterans Administration database evaluation during a 2-year period (October 1, 2002, to September 30, 2003), 93,677 patients took a combination of gemfibrozil and a statin and 1,830 patients took fenofibrate with a statin during the evaluation period. During the 2 years evaluated, there were 149 cases of rhabdomyolysis or acute tubular necrosis in the 93,677 patients taking gemfibrozil with any statin, for an overall rate of 0.16%. There were no cases of rhabdomyolysis or acute tubular necrosis in 1,830 patients taking a fenofibrate with any statin.37 Therefore, the
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Figure 5. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) cardiovascular disease (CVD) risk reduction in patients with diabetes compared with those without diabetes. CAD ⫽ coronary artery disease; DM ⫽ diabetes mellitus; MI ⫽ myocardial infarction. (Adapted from N Engl J Med.28)
Table 4 Reported cases of rhabdomyolysis with fenofibrate ⫹ statin versus gemfibrozil ⫹ statin Medication Fenofibrate ⫹ any statin Fenofibrate ⫹ cerivastatin Fenofibrate ⫹ other statins Gemfibrozil ⫹ any statin Gemfibrozil ⫹ cerivastatin Gemfibrozil ⫹ other statins
No. Cases Reported 16 14 2 590 533 57
No. Prescriptions Dispensed 3,519,000 100,000 3,419,000 6,757,000 116,000 6,641,000
No. Cases Reported per Million 4.55 140.00 0.58 87.32 4,594.83 8.58
Data from: Am J Cardiol.34,35
AER data or the information from LDS support a much greater safety margin for combining a statin with fenofibrate than with gemfibrozil. The reason for the much greater propensity for gemfibrozil to increase the risk for myopathy with a statin is likely due to the difference in the pharmacokinetic interactions between the 2 fibrates. Lipophilic statins are hydrolyzed by the CYP450 enzymes to increase water solubility for renal excretion. Statins also are metabolized by another secondary pathway known as glucuronidation. Gemfibrozil uses the same family of glucuronidation enzymes as the statins, but fenofibrate uses a different enzyme family. This explains the marked increase in the AUC for statins in conjunction with gemfibrozil, whereas fenofibrate has no significant effects on statin blood levels. Gemfibrozil is also a potent CYP2C8 inhibitor, which is a metabolic pathway for cerivastatin. The more prominent increase in the AUC for gemfibrozil and cerivastatin may be due to the effect of both CYP2C8 and glucuronidation. Rosiglitazone and repaglinide are also CYP2C8 metabolized, and blood levels are increased in combination with gemfibrozil but not with fenofibrate. Therefore, gemfibrozil is problematic not only for combi-
nation therapy with statins but also for use with antidiabetic drugs that use the CYP2C8 pathway. In patients with diabetes who have documented benefits from statin therapy but a high residual risk, combination therapy with fenofibrate appears the most appropriate additional treatment to improve the lipid profile further, if necessary, and to avoid the significant safety problems associated with gemfibrozil therapy. The ACCORD trial is underway to determine the enhanced clinical benefit of adding fenofibrate to patients receiving simvastatin therapy, and the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) trial will be evaluating the potential clinical benefits of increasing HDL cholesterol with niacin in patients with CAD and the metabolic syndrome.
Conclusion Reducing the residual CAD risk in patients on statin therapy remains an important clinical challenge. The “lower is better” hypothesis has been well documented by clinical trials,
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but even with low levels of LDL cholesterol, patients with diabetes, the metabolic syndrome, and other uncontrolled risk factors continue to have a relatively high cardiovascular event rate. Combination therapy that further improves the lipid profile appears to be frequently necessary for very high risk patients who have not yet achieved the optional therapeutic target. The use of combination therapy has been tainted by the history of increased risk of myopathy with gemfibrozil in combination with a statin. However, other lipid-altering agents such as bile-acid sequestrants, extendedrelease niacin, ezetimibe, and fenofibrate do not have a pharmacokinetic interaction with statins and appear to have a low risk for increasing statin-related adverse effects. The improved safety of these agents with a statin has stimulated a new era of clinical trials evaluating the potential clinical benefits of combination therapy. 1. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK, for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425–1435. 2. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004;110:227–239. 3. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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. 4. Heart Protection Study Collaborative Group. 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. 5. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, Grines CL, DeMaria AN. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291:1071–1080. 6. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004;110:3512– 3517. 7. Sacks FM, Rouleau JL, Moye LA, Pfeffer MA, Warnica JW, Arnold JM, Nash DT, Brown LE, Sestier F, Rutherford J, et al. Baseline characteristics in the Cholesterol and Recurrent Events (CARE) trial of secondary prevention in patients with average serum cholesterol levels. Am J Cardiol 1995;75:621– 623. 8. Lipid Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels: the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339: 1349 –1357. 9. Shepherd J, Blauw GJ, Murphy MB, Bollen ELEM, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623–1630. 10. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, et al, for the ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-
11.
12.
13.
14.
15.
16.
17.
18. 19.
20.
21.
22.
23. 24. 25. 26.
average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149 –1158. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495–1504. Ridker PM, for the JUPITER Study Group. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation 2003;108:2292–2297. Genest J, Frohlich J, Fodor G, McPherson R, for the Working Group on Hypercholesterolemia and Other Dyslipidemias. Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: summary of the 2003 update. CMAJ 2003;169:921–924. Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet 2001;358:2026 –2033. Downs JR, Clearfield M, Weiss S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM, for the AFCAPS/ TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. JAMA 1998;279:1615–1622. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L, for the INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937–952. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ, for the National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 2003;289:2560 –2571. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004;109(suppl III):III-39 –III-43. Li D, Singh RM, Liu L, Chen H, Singh BM, Kazzaz N, Mehta JL. Oxidized-LDL through LOX-1 increases the expression of angiotensin converting enzyme in human coronary artery endothelial cells. Cardiovasc Res 2003;57:238 –243. Wong J, Quinn CM, Brown AJ. Statins inhibit synthesis of an oxysterol ligand for the liver x receptor in human macrophages with consequences for cholesterol flux. Arterioscler Thromb Vasc Biol 2004;24:2365–2371. West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 1998;97:1436 – 1439. Gotto AM Jr, Whitney E, Stein EA, Shapiro DR, Clearfield M, Weis S, Jou JY, Langendorfer A, Beere PA, Watson DJ, Downs JR, de Cani JS. Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation 2000;101:477– 484. Furberg CD. Natural statins and stroke risk. Circulation 1999;99:185– 188. Davidson MH. Clinical significance of statin pleotropic effects: hypotheses vs. evidence. Circulation 2005;111:2280 –2281. Pasternak RC. The ALLHAT lipid lowering trial—less is less. JAMA 2002;288:3042–3044. Sager PT, Melani L, Lipka L, Strony J, Yang B, Suresh R, Veltri E, for the Ezetimibe Study Group. Effect of coadministration of ezetimibe
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27.
28.
29.
30.
and simvastatin on high-sensitivity C-reactive protein. Am J Cardiol 2003;92:1414 –1418. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T, for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001;285:1711–1718. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410 – 418. Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Manttari M, Heinonen OP, Frick MH. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: implications for treatment. Circulation 1992;85:37– 45. Davidson MH, Maki KC, Pearson TA, Pasternak RC, Deedwania PC, McKenney JM, Fonarow GC, Maron DJ, Ansell BJ, Clark LT, Ballantyne CM. Results of the National Cholesterol Education Program (NCEP) Evaluation Project Utilizing Novel E-Technology (NEP-
31.
32.
33. 34.
35. 36.
37.
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TUNE) II Survey: implications for treatment under the recent NCEP Writing Group recommendations. Am J Cardiol 2005;96:556 –563. Action to control cardiovascular risk in diabetes (ACCORD). Available at: http://www.accordtrial.org/public/index.cfm. Accessed June 3, 2005. Grundy SM, Vega LG, Yuan Z, Battisti WP, Brady WD, Palmisano J. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial). Am J Cardiol 2005;95:462– 468. Alsheikh-Ali AA, Karas RH. Circulation 2004;110(suppl III):III– 813. Abstract 3754. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate ⫹ statin versus gemfibrozil ⫹ any statin. Am J Cardiol 2005;95:120 –122. Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with fibrates. Am J Cardiol 2004;94:935–938. University of Oxford Diabetes Trials Unit. Combination statin and fibrate therapy in type 2 diabetes: results from the Lipids in Diabetes Study [abstract]. Diabetes 2003;52:A74. US Department of Veterans Affairs. Pharmacy Benefits Management Strategic Healthcare Group. Statin fibrate safety report. Available at: http://www.vapbm.org/Safety%20Reports/87ry38statin-fibrate-Final.pdf. Accessed August 5, 2005.
Outcome trials of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have proved conclusively that lowering low-density lipoprotein (LDL) cholesterol results in significant improvement in cardiovascular morbidity and mortality. Additionally, primary and secondary prevention studies using statins have established the safety and efficacy of this class of pharmacologic agents. The relation between LDL cholesterol and coronary artery disease (CAD) events appears to be linear, with considerable evidence supporting the “lower is better” hypothesis. However, even with low LDL levels, the residual risk for subsets of high-risk patients continues to be elevated. In the Treating to New Targets trial, patients taking atorvastatin 80 mg (mean LDL cholesterol 77 mg/dL) had a 28% cardiovascular event rate compared with a 33% event rate for patients taking atorvastatin 10 mg (mean LDL cholesterol 101 mg/dL), a 22% relative risk reduction.1 Therefore, approximately 70% of the events were not avoided despite significant LDL cholesterol reduction. The 80-mg atorvastatin therapy also was associated with a slightly elevated rate of increased transaminase levels (0.2% vs 1.2%).1 Therefore, an important clinical challenge remains to further reduce the residual CAD risk in patients taking optimal statin therapy without adversely affecting patient safety.
Statin Therapy for Patients at High Risk for Coronary Artery Disease Events Post hoc and prespecified analyses of statin outcome trials demonstrate higher CAD event rates for patients with adRush Medical College, Rush University Medical Center, Chicago, Illinois, USA. Address for reprints: Michael H. Davidson, MD, Rush Medical College, Rush University Medical Center, 515 North State Street, Suite 2700, Chicago, Illinois 60610. E-mail address: [email protected]. 0002-9149/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.08.002
ditional risk factors. Of the modifiable risk factors, the presence of diabetes mellitus, cigarette smoking, the metabolic syndrome, and elevated high-sensitivity C-reactive protein (hs-CRP) predicts a high residual risk. The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guideline update on the implication of recent clinical trials recommends an optional LDL cholesterol goal of ⬍70 mg/dL and a non– high-density lipoprotein (HDL) goal of ⬍100 mg/dL for patients at very high risk.2 The definition of “very high risk” includes patients with cardiovascular disease with diabetes, cigarette smoking, or factors associated with the metabolic syndrome (Table 1).3 A recent survey documents that 75% of patients with CAD would meet this definition of very high risk. Therefore, pragmatically, most patients with CAD should be considered appropriate for the optional LDL goal of ⬍70 mg/dL. In the Heart Protection Study (HPS), statin therapy (simvastatin 40 mg/day) resulted in highly significant reductions in coronary mortality rate (18%), an incidence rate of first nonfatal myocardial infarction (38%), stroke incidence (25%), and incidence of coronary revascularization (30%),4 but patients with diabetes who had CAD and who were receiving statin therapy had an event rate of 31% compared with a placebo event rate of 25% in nondiabetic patients with CAD. In the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, intensive (atorvastatin 80 mg/dL) versus moderate (pravastatin 40 mg/dL) lipid lowering resulted in greater reductions in LDL cholesterol to mean levels of 78.9 and 110.4 mg/dL, respectively (p ⬍0.001). In addition, intensive lipid-lowering intervention resulted in a significantly lower progression rate in the percent change in atheroma volume (p ⫽ 0.02).5 However, the diabetic subset taking aggressive lipid-lowering therapy of atorvastatin 80 mg continued to have marked progression of atheroma volume. In the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 trial, the diabetic subset also continwww.AJConline.org
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The American Journal of Cardiology (www.AJConline.org) Vol 96 (9A) November 7, 2005 Table 1 Summary of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines for dyslipidemia
Risk Level Low risk ⬍2 risk factors Moderate risk ⱖ2 risk factors Moderate high risk ⱖ2 risk factors; 10%–20% 10-yr risk High risk CAD, PAD, AAA ⬎50% carotid stenosis Diabetes† ⬎20% 10-yr risk Creatinine ⬎1.5 mg/dL‡ 10%–20% 10-yr risk plus hs-CRP ⬎2.0 mg/L§ Very high risk CAD plus Diabetes Metabolic syndrome Cigarette smoking Acute coronary syndrome
LDL-C Goal (mg/dL)
If TG ⬎200 mg/ dL, Non-HDL-C Goal (mg/dL)
⬍160
⬍190
⬍130
⬍160
⬍100* ⬍100
⬍130 ⬍130
⬍70†
⬍100*
AAA ⫽ abdominal aortic aneurysm; CAD ⫽ coronary artery disease; HDL-C ⫽ high-density lipoprotein cholesterol; hs-CRP ⫽ high-sensitivity C-reactive protein; LDL-C ⫽ low-density lipoprotein cholesterol; PAD ⫽ pulmonary artery disease; TG ⫽ triglycerides. * NCEP ATP III optional goal. † The American Diabetes Association recommends that all patients with type 2 diabetes mellitus aged ⬎80 years should lower LDL-C by ⱖ 30%, even if baseline LDL-C is ⬍100 mg/dL. ‡ High risk by National Kidney Foundation guidelines. § High risk by American Heart Association/Centers for Disease Control and Prevention guidelines. Adapted from: JAMA.3 Table 2 Event rates in statin trials Without Diabetes Trial 4
HPS (CAD patients)* CARE†7 LIPID*8 PROSPER*9 ASCOT*10
HPS*4 CARE/LIPID*†7,8 PROSPER*9
With Diabetes
On Statin
On Placebo
On Statin
On Placebo
19.8% 19.6% 11.7% 13.1% 4.9%
25.7% 24.6% 15.2% 16% 8.7%
33.4% 28.7% 19.7% 23.1% 9.6%
37.8% 36.8% 22.8% 18.4% 11.4%
High HDL-C on Statin
High HDL-C on Placebo
Low HDL-C on Statin
Low HDL-C on Placebo
17% 18.5% 12.8%
20.9% 22.4% 11.6%
22.0% 25% 13%
29.9% 30.8% 19.3%
ASCOT ⫽ Anglo-Scandinavian Cardiac Outcomes Trial; CARE ⫽ Cholesterol and Recurrent Events; HDL-C ⫽ high-density lipoprotein cholesterol; HPS ⫽ Heart Protection Study; LIPID ⫽ Long-Term Prevention with Pravastatin in Ischaemic Disease; PROSPER ⫽ Prospective Study of Pravastatin in the Elderly at Risk. * Coronary artery disease (CAD) death, nonfatal myocardial infarction, coronary or noncoronary revascularization, stroke. † CAD death and nonfatal myocardial infarction.
ued to have progression of intima-media thickness despite statin therapy.6 A review of patients with diabetes or patients with low HDL in statin event trials demonstrates a
greatly elevated rate of residual events even with statin treatment (Table 2).4,7–10 In fact, the statin event rate in patients with diabetes or low HDL is higher than the pla-
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Figure 1. Heart Protection Study (HPS): Major vascular event by high-density lipoprotein cholesterol (HDL-C) and triglycerides. CI ⫽ confidence interval. (Adapted from Lancet.4)
cebo event rate for patients without diabetes or low HDL. Therefore, even with an LDL cholesterol ⬍70 mg/dL, a patient with CAD who has diabetes is likely to have a high recurrent event rate. In the HPS trial, the subgroup of patients with low HDL significantly benefited from simvastatin therapy. CAD events decreased from 29.9% to 22.6%, but patients receiving statin therapy still had a higher event rate than placebo-treated patients in the subgroup with a higher HDL (Figure 1).4 A similar relation exists for patients in the HPS trial with elevated triglyceride levels. Because hs-CRP correlates with the metabolic syndrome, an elevated hs-CRP (⬎2.0 mg/L) may represent an important marker of enhanced residual risk. Other high-risk subsets for recurrent events in patients taking statin therapy potentially include those with aspirin or clopidogrel resistance and other prothrombotic states. Plant sterol levels are not reduced with statin therapy, and, if elevated, may therefore also be a potential cause of recurrent events. Whether the prevalence of increased plant sterol levels in a population with CAD confers a marked increased risk is unclear.
Potential New Targets With recognition that the residual risk is significantly elevated in patients at very high risk, the NCEP ATP III panel recommended the therapeutic optional goals of LDL ⬍70 mg/dL and non-HDL ⬍100 mg/dL.2 However, other target goals have also been advocated in published reports. Based on the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT)11 and REVERSAL5 trials documenting hs-CRP as an independent predictor of events, even with a low LDL, a dual goal of LDL ⬍70 mg/dL and an hs-CRP ⬍2.0 mg/L (or potentially ⬍1.0 mg/L) has been put forward as a therapeutic target. However, because hs-CRP and the metabolic syndrome are closely correlated, an elevated hs-
CRP may not enhance the risk prediction beyond the more aggressive optional targets already advocated for patients with the metabolic syndrome by updated treatment guidelines. An elevated hs-CRP may be a relatively accessible biologic marker that will encourage more aggressive risk factor modification. Consensus regarding hs-CRP as a goal in conjunction with LDL will likely await the outcome of the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER).12 Apolipoprotein (apo) B has been shown to be a better predictor of CAD events than LDL in patients on statin therapy, and therefore an ApoB goal of ⬍90 mg/dL has been mentioned as an alternative to LDL as a goal of therapy. In the REVERSAL trial,5 intensive (atorvastatin 80 mg/dL) versus moderate (pravastatin 40 mg/dL) lipid-lowering intervention resulted in greater reductions in apoB to mean levels of 91.8 and 118.1 mg/dL, respectively.
Ratio Goals A total cholesterol to HDL goal has been advocated by Canadian guidelines (Table 3).13 These guidelines are similar to the NCEP ATP III recommendation, in that goals for LDL cholesterol are more aggressive according to risk classification. However, rather than non-HDL targets, Canadian guidelines have a total cholesterol to HDL ratio of ⬍4.0. The advantage of this approach is that for patients with low HDL, more aggressive LDL lowering or HDL raising, or both, may be necessary to achieve both targets. Because greater reductions in LDL cholesterol are usually easier to achieve with current therapies than significant increases in HDL, a ratio target of ⬍4.0 may frequently require reducing LDL levels to ⬍70 mg/dL in patients with low HDL. For example, a patient with an HDL of 30 mg/dL and triglycerides of 150 mg/dL would require a target total cholesterol
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of 120 mg/dL and an LDL cholesterol of 60 mg/dL. For patients with higher HDL levels, an LDL level ⬍100 mg/dL would likely result in a ratio goal of ⬍4.0. Therefore, by including a ratio target, Canadian guidelines appropriately require more aggressive LDL lowering in patients with low HDL based on clinical trials demonstrating that this subpopulation has a significantly higher residual risk of events with statin therapy. The ratio has been shown to be a better epidemiologic predictor of cardiovascular events than LDL and also appears to improve significantly event prediction with statin therapy. Therefore, rather than have a more aggressive LDL goal for all patients at risk, a ratio goal of ⬍4.0 in conjunction with an LDL cholesterol goal of ⬍100 mg/dL may sufficiently identify higher-risk patients who require more aggressive lipid-altering interventions. The argument against a ratio target is based on a lack of evidence supporting an increase in HDL as a therapeutic target, and therefore there is a concern that a ratio target would inappropriately emphasize the benefits of increasing HDL. However, because raising HDL by ⬎25% with existing therapies is difficult, the best means to achieve a ratio goal of ⬍4.0 would still require more aggressive LDL reduction. Another ratio target that has been evaluated is the apoAB– apoA1 ratio. apoAB–apoA1 is a better predictor of events in large observational trials such as the Apolipoprotein-related Mortality Risk Study (AMORIS),14 and the best predictor of events in patients on statin therapy according to the Air Force/ Texas Coronary Atherosclerosis Prevention Study (AFCAPS/ TexCAPS).15 Based on data from AMORIS14 and the INTERHEART16 study, an apoAB–apoA1 ratio of ⬍0.7 may be an appropriate target. ApoB measurements are most useful in patients with hypertriglyceridemia because they incorporate all atherogenic lipoproteins. Non-HDL correlates better with apoB than LDL, especially in patients with hypertriglyceridemia. The main reason the apoB–apoA1 ratio is better in predicting CAD events than total cholesterol to HDL is that in the hypertriglyceridemic population and in those with small dense LDL (apoB–LDL ⬎1.0), the apoB level is significantly more predictive of cardiovascular events than total cholesterol levels. Apolipoprotein measurements are not universally available and are more expensive than determining a standard lipid profile that includes the total cholesterol to HDL ratio, and therefore the use of the apoB–apoA1 ratio on a therapeutic target would require additional justification based on a cost– benefit analysis. However, to define a therapeutic benefit of a lipid-altering treatment, putative changes in the apoB–apoA1 ratio may be useful in demonstrating an enhanced benefit of a therapy, and may provide a helpful lipid surrogate end point for regulatory approval for novel therapies. Therapeutic Global Risk Goal A modified form of the Framingham risk score is used with multiple international guidelines to stratify patients into risk groups to determine thresholds for initiating therapy and goals of treatment. The Framingham score as a therapeutic
target is problematic for 2 reasons. First, this global risk formula was based on observational data, and although some intervention trials have shown good correlation with the Framingham equation, there is concern that the score may not assess risk adequately for patients receiving treatment. Second, age and sex are powerful contributors to the overall Framingham score, and these nonmodifiable risk factors therefore make the Framingham score difficult to use clinically. An alternative is a global risk score that attempts to incorporate the divergent guidelines established in the United States for the various risk factors. A hypothetical global risk score that includes the recommendations of the NCEP ATP III,3 the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (Joint National Committee 7),17 and the American Diabetes Association (ADA) is determined by the following equation: Hypothetical global risk score ⫽ total cholesterol/HDL ⫹ 共hemoglobin A1c ⫺ 7.0兲 ⫹ 共systolic blood pressure ⫺ 130⁄10兲 ⫹ Cigarette packs⁄day This hypothetical global risk score, with a goal of ⬍4.0, has the advantage of targeting all major modifiable risk factors (lipid level, blood pressure, and glucose control targets) simultaneously, as opposed to an isolated approach for each risk factor. Due to the influence of separate risk factor treatment guidelines and the marketing of drugs for individual risk factors, the therapeutic approach of risk factor modification has become a silo phenomenon. A global risk score would encourage clinicians to escalate and treat major risk factors in a more united fashion to achieve an overall therapeutic target. The proposed hypothetical global risk score would also encourage more aggressive lipid control of the total cholesterol to HDL ratio if a patient continues to smoke despite all efforts for cessation, or has a hemoglobin A1c that remains elevated to ⬎7.0 mg/dL after maximal therapy. A global risk score may be impossible to achieve in a significant percentage of high-risk populations, but this concept is an attempt to better coordinate management of all major modifiable risk factors.
Clinical Significance of Statin Pleiotropic Effects The word pleiotropic (which is usually applied to genetics) refers to the multiple actions of a single gene. With respect to drug therapy for dyslipidemia, the term has become synonymous with clinical benefits beyond the effects of the drug on lipoproteins. Statins have been evaluated extensively for effects independent of lipid alterations. Mice and rats are relatively good models to evaluate potential pleiotropic effects of statins, because they do not lower circulating cholesterol concentrations in these species. The administration of statins has been demonstrated to result in greater
Davidson/Combination Therapy to Reduce Residual Risks of Statins Table 3 Canadian Dyslipidemia Guidelines Target Level Risk Category High* (10-yr risk of CAD ⱖ20%, or history of diabetes mellitus† or any atherosclerotic disease) Moderate (10-yr risk, 11%–19%) Low‡
LDL-C Level (mmol/L)
TC: HDL-C Ratio
⬍2.5 and
⬍4.0
⬍3.5 and
⬍5.0
⬍4.5 and
⬍6.0
HDL-C ⫽ high-density lipoprotein cholesterol; LDL-C ⫽ low-density lipoprotein cholesterol; TC ⫽ total cholesterol. * Apolipoprotein B can be used as an alternative measurement, particularly for patients treated with statins. An optimal level of apolipoprotein B in a patient at high risk is ⬍0.9 g/L, in a patient at moderate risk ⬍1.05 g/L, and in a patient at low risk ⬍1.2 g/L. † Includes patients with chronic kidney disease and those undergoing long-term dialysis. ‡ In the very low risk stratum, treatment may be deferred if the 10-year estimate of cardiovascular disease is ⬍5% and the LDL level is ⬍5.0 mmol/L. Adapted from CMAJ.13
nitric oxide bioavailability, increased ability to recruit endothelial progenitor cells, inhibition of cardiac hypertrophy, and reductions in the size and severity of strokes.18 However, despite a failure to lower blood cholesterol, these drugs may influence cell membrane lipid levels. In rodent models, statins have been shown to decrease mitogen-activated protein kinase activation, enhance nitric oxide synthase expression, and reduce lipoxygenase-1 transcription by reducing oxidized LDL uptake in endothelial cell membranes.19 As a result, the pleiotropic effects in animals may not be independent of cellular uptake of lipids. The purported clinical benefits of statins in humans have ranged from improved bone density to reduction of Alzheimer disease, as well as enhanced cardiovascular benefits beyond blood lipid modification. Numerous studies have demonstrated that statins improve endothelial function, most likely by increasing nitric oxide bioavailability and reducing oxidant stress. Statins may also have “negative pleiotropic” effects, because they may downregulate cholesterol efflux from nonloaded human macrophages by inhibiting synthesis of an oxysterol ligand for liver X receptor.20 Historically speaking, the hypothesis that statins may reduce CAD events to a degree greater than expected from lipoprotein modification was first suggested by the results of the West of Scotland Coronary Prevention Study (WOSCOPS) group trial.21 Event rates were compared among patients taking pravastatin or placebo, and whose on-trial LDL cholesterol values were in a range that occurred with high frequency in both groups (3.62 to 4.65 mmol/L [140 to 180 mg/dL]). A significant reduction in event rates associated with pravastatin therapy was found after adjustment for lipoprotein cholesterol and triglyceride
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levels during treatment.21 Similar findings were demonstrated in the AFCAPS/TexCAPS, although, after correction for apoB and apoA1 levels,22 there was no difference in event rate for subjects taking lovastatin versus placebo. Owing to the lack of available outcome trial results for all statins at the time, the use of statins with proven benefits on event rates—including pravastatin, lovastatin, and simvastatin (all fungal metabolites or “natural statins”)—was advocated in part for their presumed ability to provide additional clinical benefits because of their pleiotropic effects.23 Based on the findings of additional outcomes trials, it has become obvious that all statins, whether fungal metabolites or synthetic, confer similar CAD event reduction if adjusted for differences in lipid changes (Figure 2). These additional trials, especially the HPS4 and PROVE-IT,11 also verified the hypothesis that lower is better regarding LDL cholesterol, especially for patients at high risk for CAD. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),25 although flawed owing to a high frequency of crossover between treatments, failed to demonstrate a clinical benefit for pravastatin beyond lipid lowering. This effectively ended the hypothesis that pravastatin provided unique pleiotropic benefits different from other statins. Additional lipid-altering drugs such as bile-acid sequestrants, niacin, and fibrates have been demonstrated to lower CAD events to an extent similar to statin therapy when adjusted for cholesterol lowering, although this provides only indirect evidence against clinical pleiotropic benefits of the statin drugs. Statins have been shown to lower inflammatory markers such as CRP, but the degree of CRP reduction correlates with the extent of lipid lowering, and this effect is not unique to statins. The cholesterol absorption inhibitor, ezetimibe, enhances CRP reduction when added to a statin, and equal lowering of LDL cholesterol by a low-dose statin plus ezetimibe or a high-dose statin provides equivalent CRP reduction.26 According to pleiotropic statin enthusiasts, clinical event reductions appear more rapidly in statin than in nonstatin trials. In the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL)27 trial and in PROVE-IT,11 significant benefits occurred within the first month of treatment and were attributed to reductions in the incidence of unstable angina. In comparison, in nonstatin trials, the clinical benefits required multiple years for the Kaplan-Meier curves to separate. Yet the MIRACL trial27 and PROVE-IT11 enrolled patients with acute coronary syndromes who had much higher event rates than subjects in the nonstatin trials. Whereas significant stroke reduction is present in statin trials, the nonstatin trials also trended toward stroke reduction, but with less cholesterol reduction. As a result, the idea that statins provide unique benefits attributable to factors other than modification of the lipoprotein profile compared with other classes of lipid-altering medications remains speculative.
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Figure 2. Relation of reduction in triglyceride levels to reduction in cardiovascular (CV) events: statin and nonstatin therapy. Circles ⫽ nonstatin therapy; diamonds ⫽ statin therapy. A to Z ⫽ phase Z in the A to Z trial; AFCAPS ⫽ Air Force/Texas Coronary Atherosclerosis Prevention study; ALLHAT-LLT ⫽ Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack–Lipid-Lowering Trial; ASCOT-LLA ⫽ Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm; CABG ⫽ coronary artery bypass graft surgery; CARE ⫽ Cholesterol and Recurrent Events trial; CDP ⫽ Coronary Drug Project Study; CTL ⫽ control group; HHS ⫽ Helsinki Heart Study; HPS ⫽ Heart Protection Study; LIPID ⫽ Long-Term Intervention with Pravastatin in Ischaemic Disease trial; LIPS ⫽ Lescal Intervention Prevention Study; LRC-CPPT ⫽ Lipid Research Clinics Coronary Primary Prevention Trial; MI ⫽ myocardial infarction; POSCH ⫽ Program on the Surgical Control of Hyperlipidemias; PROVE-IT ⫽ Pravastatin or Atorvastatin Evaluation and Infection Therapy trial; TC ⫽ total cholesterol; TNT ⫽ Treating to New Targets trial; TRT ⫽ treatment; VA-HIT ⫽ Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial; WOSCOPS ⫽ West of Scotland Coronary Prevention Study. (Reprinted with permission from Circulation.24)
Clinical Significance of Nonstatin Pleiotropic Effects Nonstatin therapies also have a multitude of potential pleiotropic effects. Niacin lowers lipoprotein(a) and fibrinogen, while increasing HDL and modifying LDL particle size. Ezetimibe lowers plant sterol levels and alters the cholesterol composition of postprandial chylomicrons. Both bile acid sequestrants and ezetimibe may affect farnesoid X receptor or liver X receptor, or both, by altering bile salts/ biliary cholesterol absorption. Fibrates, as peroxisome proliferator-activated receptor–␣ (PPAR-␣) agonists, affect the expression of numerous genes that alter lipoprotein metabolism or the development of atherosclerosis (Figure 3). PPAR-␣ agonism upregulates the genes involved in reverse cholesterol transport. Fenofibrate has been shown to upregulate macrophage ABCA1, which increases efflux of free cholesterol into nascent HDL and enhances the uptake of HDL by the hepatic SRBI receptors, which results in increased biliary cholesterol excretion. PPAR-␣ agonists also appear to have numerous anti-inflammatory and antithrombotic effects that may reduce plaque rupture vulnerability to induce clinical events (Figure 4). Although the clinical benefits of these pleiotropic effects of nonstatin therapies remains speculative, there are intriguing post hoc analyses from fibrate trials that support additional clinical benefits of PPAR-␣ agonism in patients with the metabolic syndrome or diabetes. In the fibrate outcomes trials, the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT)28 and the Helsinki Heart Study (HHS),29 the subset of patients with diabetes had a greater risk reduction than patients
without diabetes (Figure 5). In VA-HIT28 the occurrence of new cardiovascular events and the benefit of fibrate therapy were much less dependent on levels of HDL cholesterol or triglycerides than on the presence or absence of insulin resistance.
Rationale of Combination Therapy In light of the residual risk of CAD events in statin trials within certain subgroups, combination therapy appears most appropriate in patients with a high rate of events despite optimal statin treatment. These subgroups include patients with LDL cholesterol levels ⬎70 mg/dL, patients with diabetes, those with the metabolic syndrome, those with elevated hs-CRP, and cigarette smokers. A recent survey demonstrated that 75% of patients with CAD met the definition of “very high risk” according to the NCEP ATP III update report.30 In this survey, only 18% of patients at very high risk had an LDL level ⬍70 mg/dL, and only 4% had an LDL level ⬍70 mg/dL and a non-HDL level ⬍100 mg/dL when triglycerides were ⬎200 mg/dL. These data support the use of more aggressive statin therapy and implementation of combination therapy as necessary to achieve these optional targets in the very high risk patient population. Whereas further LDL cholesterol lowering may provide additional clinical benefits in patients with diabetes or the metabolic syndrome, or both, the post hoc analysis of clinical trials has demonstrated a very high residual risk, even with low LDL cholesterol levels. Surrogate end point trials also demonstrate significant atherosclerotic progression in
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Figure 3. Peroxisome proliferator-activated receptor–␣ (PPAR-␣) expression in monocytes/macrophages and the liver. ApoA ⫽ apolipoprotein A; HDL ⫽ high-density lipoprotein cholesterol; LCAT ⫽ lecithin-cholesterol acyltransferase; LDL ⫽ low-density lipoprotein cholesterol; PLTP ⫽ phospholipid transfer protein; RXR ⫽ retinoid X receptor; VLDL ⫽ very-low-density lipoprotein.
patients with diabetes taking statins or a combination of statins and niacin. Because fibrates appear to have unique benefits in patients with insulin resistance, the combination of a statin and a fibrate is potentially most appropriate in this patient population. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial31 will be testing this hypothesis in approximately 10,000 patients with diabetes taking simvastatin randomized to fenofibrate or placebo to evaluate CAD outcomes. The additive effects of simvastatin and fenofibrate on lipid parameters have been documented in the Simvastatin Plus Fenofibrate for Combined Hyperlipidemia (SAFARI) trial.32 Simvastatin monotherapy (20 mg/day) was compared with combination therapy (simvastatin 20 mg/day plus fenofibrate 160 mg/day) in patients with combined hyperlipidemia (fasting triglyceride levels ⱖ150 and ⱕ500 mg/dL and LDL cholesterol ⬎130 mg/dL). Mean LDL levels significantly decreased with combination therapy when compared with monotherapy (31.2% and 25.8%, respectively; p ⬍0.001). In addition, mean HDL cholesterol levels significantly increased with combination therapy when compared with monotherapy (18.6% and 9.7%, respectively; p ⬍0.001), and no drug-related serious adverse events occurred.32 Safety of Combination Therapy Although combination therapy is widely used and, in fact, is recommended by expert panels for managing hypertension
and diabetes and for treating dyslipidemia, combination treatment is seldom clinically applied in practice. In the NCEP Evaluation Project Utilizing Novel E-Technology30 survey, only 5% of treated patients were receiving combination therapy. The major reason combination therapy has not been used widely in practice is the perception of adverse safety associated with combining a statin with niacin or a fibrate. On the labels of all statins are cautionary notes regarding the combination with niacin or a fibrate, stating that the benefits should outweigh the increased risk of myopathy. The concern regarding the combination of niacin with a statin is based on early case reports documenting myopathy with lovastatin in combination with high doses of niacin (ⱖ2.5 g/day). Because niacin does not alter the pharmacokinetics of lovastatin and excessive doses of niacin have documented hepatotoxicity, the most likely explanation for the cases of myopathy associated with combination statin–niacin therapy is that the liver impairment associated with niacin toxicity results in delayed clearance of the statin, leading to an increased risk of myopathy. Statin-induced myopathy is almost always associated with factors that increase the area under the curve (AUC), such as increased dosage, hypothyroidism, renal or hepatic impairment, or drugs that interfere with statin metabolism such as cytochrome P450 (CYP) 3A4 inhibitors. In the absence of hepatotoxicity, it is unlikely that niacin would increase the risk of statin myopathy, and since the first 2 reports of niacin and lovastatin myopathy, there have been no additional pub-
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Figure 4. Anti-inflammatory effects of peroxisome proliferator-activated receptor (PPARs) and the potential anti-atherosclerotic effects promoting plaque stabilization. ABCA1 ⫽ ATP-binding cassette transporter A1; CCR-2 ⫽ CC chemokines receptor–2; CRP ⫽ C-reactive protein; COX-2 ⫽ cyclooxygenase-2; ET-1 ⫽ endothelin-1; ICAM-1 ⫽ intercellular adhesion molecule–1; MCP-1 monocyte chemotactic protein–1; MMP ⫽ matrix metalloproteinase; PAF ⫽ platelet-activating factor; sPLA2 ⫽ secretory phospholipase A2; SR ⫽ steroidogenic receptor; TF ⫽ tissue factor; TNF-␣ ⫽ tumor necrosis factor-␣; TXS ⫽ thromboxane synthase; VACM-1 ⫽ vascular cell adhesion molecule–1.
lished reports. Adverse event reports (AERs) under the Med Watch program of the US Food and Drug Administration (FDA) have also documented a very low incidence of statin myopathy associated with niacin.33 Extended-release niacin, which has a very low rate of hepatotoxicity, especially when compared with sustained-release niacin, has very few reports of myopathy in the AER database, despite several hundred thousand prescriptions written in combination with a statin. Therefore, the AER data, although not conclusive, support the safety of doses of extended-release niacin up to 2 g/day in combination with a statin. With regard to fibrate therapy, there appears to be a clinically significant difference in safety in the combination of gemfibrozil plus a statin versus fenofibrate and a statin. There are ⱖ60 case reports of gemfibrozil-statin myopathy in published data compared with 2 cases of fenofibrate in combination with a statin. Recent reviews of the FDA’s AER database have documented that, after correcting for prescription use, the rate of myopathy for gemfibrozil with a statin is ⬎30 times the rate for combination therapy with fenofibrate (Table 4).34,35 Cerivastatin combined with gemfibrozil was associated with ⬎4,000 times the rate of rhabdomyolysis compared with statin therapy alone, and numer-
ous fatalities were reported, resulting in the removal of cerivastatin from the worldwide market. An analysis of several managed care prescription and hospitalization event data has estimated that the rate of rhabdomyolysis requiring hospitalization from cerivastatin combined with gemfibrozil was at least 1 in 10 patients. The Lipid in Diabetes Study (LDS),36 a 2 ⫻ 2 factorial design, used cerivastatin-fenofibrate combination therapy or placebo in patients with diabetes; the study enrolled ⬎2,000 patients (⬎1,000 for ⬎12 weeks) taking cerivastatin and fenofibrate before the study was discontinued when cerivastatin was withdrawn from the market. In the ⬎2,000 patients taking the combination of cerivastatin and fenofibrate, there were no case reports of myopathy. In a Veterans Administration database evaluation during a 2-year period (October 1, 2002, to September 30, 2003), 93,677 patients took a combination of gemfibrozil and a statin and 1,830 patients took fenofibrate with a statin during the evaluation period. During the 2 years evaluated, there were 149 cases of rhabdomyolysis or acute tubular necrosis in the 93,677 patients taking gemfibrozil with any statin, for an overall rate of 0.16%. There were no cases of rhabdomyolysis or acute tubular necrosis in 1,830 patients taking a fenofibrate with any statin.37 Therefore, the
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Figure 5. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) cardiovascular disease (CVD) risk reduction in patients with diabetes compared with those without diabetes. CAD ⫽ coronary artery disease; DM ⫽ diabetes mellitus; MI ⫽ myocardial infarction. (Adapted from N Engl J Med.28)
Table 4 Reported cases of rhabdomyolysis with fenofibrate ⫹ statin versus gemfibrozil ⫹ statin Medication Fenofibrate ⫹ any statin Fenofibrate ⫹ cerivastatin Fenofibrate ⫹ other statins Gemfibrozil ⫹ any statin Gemfibrozil ⫹ cerivastatin Gemfibrozil ⫹ other statins
No. Cases Reported 16 14 2 590 533 57
No. Prescriptions Dispensed 3,519,000 100,000 3,419,000 6,757,000 116,000 6,641,000
No. Cases Reported per Million 4.55 140.00 0.58 87.32 4,594.83 8.58
Data from: Am J Cardiol.34,35
AER data or the information from LDS support a much greater safety margin for combining a statin with fenofibrate than with gemfibrozil. The reason for the much greater propensity for gemfibrozil to increase the risk for myopathy with a statin is likely due to the difference in the pharmacokinetic interactions between the 2 fibrates. Lipophilic statins are hydrolyzed by the CYP450 enzymes to increase water solubility for renal excretion. Statins also are metabolized by another secondary pathway known as glucuronidation. Gemfibrozil uses the same family of glucuronidation enzymes as the statins, but fenofibrate uses a different enzyme family. This explains the marked increase in the AUC for statins in conjunction with gemfibrozil, whereas fenofibrate has no significant effects on statin blood levels. Gemfibrozil is also a potent CYP2C8 inhibitor, which is a metabolic pathway for cerivastatin. The more prominent increase in the AUC for gemfibrozil and cerivastatin may be due to the effect of both CYP2C8 and glucuronidation. Rosiglitazone and repaglinide are also CYP2C8 metabolized, and blood levels are increased in combination with gemfibrozil but not with fenofibrate. Therefore, gemfibrozil is problematic not only for combi-
nation therapy with statins but also for use with antidiabetic drugs that use the CYP2C8 pathway. In patients with diabetes who have documented benefits from statin therapy but a high residual risk, combination therapy with fenofibrate appears the most appropriate additional treatment to improve the lipid profile further, if necessary, and to avoid the significant safety problems associated with gemfibrozil therapy. The ACCORD trial is underway to determine the enhanced clinical benefit of adding fenofibrate to patients receiving simvastatin therapy, and the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) trial will be evaluating the potential clinical benefits of increasing HDL cholesterol with niacin in patients with CAD and the metabolic syndrome.
Conclusion Reducing the residual CAD risk in patients on statin therapy remains an important clinical challenge. The “lower is better” hypothesis has been well documented by clinical trials,
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but even with low levels of LDL cholesterol, patients with diabetes, the metabolic syndrome, and other uncontrolled risk factors continue to have a relatively high cardiovascular event rate. Combination therapy that further improves the lipid profile appears to be frequently necessary for very high risk patients who have not yet achieved the optional therapeutic target. The use of combination therapy has been tainted by the history of increased risk of myopathy with gemfibrozil in combination with a statin. However, other lipid-altering agents such as bile-acid sequestrants, extendedrelease niacin, ezetimibe, and fenofibrate do not have a pharmacokinetic interaction with statins and appear to have a low risk for increasing statin-related adverse effects. The improved safety of these agents with a statin has stimulated a new era of clinical trials evaluating the potential clinical benefits of combination therapy. 1. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK, for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425–1435. 2. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004;110:227–239. 3. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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. 4. Heart Protection Study Collaborative Group. 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. 5. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, Grines CL, DeMaria AN. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291:1071–1080. 6. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004;110:3512– 3517. 7. Sacks FM, Rouleau JL, Moye LA, Pfeffer MA, Warnica JW, Arnold JM, Nash DT, Brown LE, Sestier F, Rutherford J, et al. Baseline characteristics in the Cholesterol and Recurrent Events (CARE) trial of secondary prevention in patients with average serum cholesterol levels. Am J Cardiol 1995;75:621– 623. 8. Lipid Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels: the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339: 1349 –1357. 9. Shepherd J, Blauw GJ, Murphy MB, Bollen ELEM, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623–1630. 10. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, et al, for the ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-
11.
12.
13.
14.
15.
16.
17.
18. 19.
20.
21.
22.
23. 24. 25. 26.
average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149 –1158. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495–1504. Ridker PM, for the JUPITER Study Group. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation 2003;108:2292–2297. Genest J, Frohlich J, Fodor G, McPherson R, for the Working Group on Hypercholesterolemia and Other Dyslipidemias. Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: summary of the 2003 update. CMAJ 2003;169:921–924. Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet 2001;358:2026 –2033. Downs JR, Clearfield M, Weiss S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM, for the AFCAPS/ TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. JAMA 1998;279:1615–1622. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L, for the INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937–952. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ, for the National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 2003;289:2560 –2571. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004;109(suppl III):III-39 –III-43. Li D, Singh RM, Liu L, Chen H, Singh BM, Kazzaz N, Mehta JL. Oxidized-LDL through LOX-1 increases the expression of angiotensin converting enzyme in human coronary artery endothelial cells. Cardiovasc Res 2003;57:238 –243. Wong J, Quinn CM, Brown AJ. Statins inhibit synthesis of an oxysterol ligand for the liver x receptor in human macrophages with consequences for cholesterol flux. Arterioscler Thromb Vasc Biol 2004;24:2365–2371. West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 1998;97:1436 – 1439. Gotto AM Jr, Whitney E, Stein EA, Shapiro DR, Clearfield M, Weis S, Jou JY, Langendorfer A, Beere PA, Watson DJ, Downs JR, de Cani JS. Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation 2000;101:477– 484. Furberg CD. Natural statins and stroke risk. Circulation 1999;99:185– 188. Davidson MH. Clinical significance of statin pleotropic effects: hypotheses vs. evidence. Circulation 2005;111:2280 –2281. Pasternak RC. The ALLHAT lipid lowering trial—less is less. JAMA 2002;288:3042–3044. Sager PT, Melani L, Lipka L, Strony J, Yang B, Suresh R, Veltri E, for the Ezetimibe Study Group. Effect of coadministration of ezetimibe
Davidson/Combination Therapy to Reduce Residual Risks of Statins
27.
28.
29.
30.
and simvastatin on high-sensitivity C-reactive protein. Am J Cardiol 2003;92:1414 –1418. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T, for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001;285:1711–1718. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410 – 418. Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Manttari M, Heinonen OP, Frick MH. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: implications for treatment. Circulation 1992;85:37– 45. Davidson MH, Maki KC, Pearson TA, Pasternak RC, Deedwania PC, McKenney JM, Fonarow GC, Maron DJ, Ansell BJ, Clark LT, Ballantyne CM. Results of the National Cholesterol Education Program (NCEP) Evaluation Project Utilizing Novel E-Technology (NEP-
31.
32.
33. 34.
35. 36.
37.
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TUNE) II Survey: implications for treatment under the recent NCEP Writing Group recommendations. Am J Cardiol 2005;96:556 –563. Action to control cardiovascular risk in diabetes (ACCORD). Available at: http://www.accordtrial.org/public/index.cfm. Accessed June 3, 2005. Grundy SM, Vega LG, Yuan Z, Battisti WP, Brady WD, Palmisano J. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial). Am J Cardiol 2005;95:462– 468. Alsheikh-Ali AA, Karas RH. Circulation 2004;110(suppl III):III– 813. Abstract 3754. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate ⫹ statin versus gemfibrozil ⫹ any statin. Am J Cardiol 2005;95:120 –122. Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with fibrates. Am J Cardiol 2004;94:935–938. University of Oxford Diabetes Trials Unit. Combination statin and fibrate therapy in type 2 diabetes: results from the Lipids in Diabetes Study [abstract]. Diabetes 2003;52:A74. US Department of Veterans Affairs. Pharmacy Benefits Management Strategic Healthcare Group. Statin fibrate safety report. Available at: http://www.vapbm.org/Safety%20Reports/87ry38statin-fibrate-Final.pdf. Accessed August 5, 2005.