Management of mixed dyslipidemia in patients with or at risk for cardiovascular disease: A role for combination fibrate therapy

Clinical Therapeutics/Volume 30, Number 2, 2008

Commentary Management of Mixed Dyslipidemia in Patients with or at Risk for Cardiovascular Disease: A Role for Combination Fibrate Therapy Sergio Fazio, MD Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee ABSTRACT Background: Lowering low-density lipoprotein cholesterol (LDL-C) is the primary focus of the management of dyslipidemia in patients with or at risk for cardiovascular disease. However, use of a statin alone may be insufficient for the treatment of mixed dyslipidemia, which is characterized by low levels of high-density lipoprotein cholesterol and elevated levels of triglycerides, with or without elevated levels of LDL-C. Objective: This report reviews the evidence for the efficacy and tolerability of different combination treatments for the management of mixed dyslipidemia, as supported by clinical-trial data and recommended by national guidelines. Methods: Using the terms lipid-modifying therapy,

combination therapy, combination statin-fibrate therapy, and mixed dyslipidemia, a search of PubMed was conducted (completed in April 2007, updated to October 2007) to identify English-language publications and pertinent studies of fibrate combination therapy in patients with mixed dyslipidemia, including those with diabetes or the metabolic syndrome. Results: National guidelines recommend the addition of either niacin (nicotinic acid) or a fibrate to statin therapy in patients with mixed dyslipidemia to achieve better overall lipid control. Fibrates do not have detrimental effects on uric acid levels or glycemic control in patients with diabetes or the metabolic syndrome. Based on data from the US Food and Drug Administration Adverse Event Reporting System indicating that gemfibrozil plus a statin was associated with a 15-fold higher risk of rhabdomyolysis than fenofibrate plus a statin, fenofibrate may be the fibrate of choice for use in combination with a statin. As reported by the Fenofibrate Intervention and Event Lowering in Diabetes study, fenofibrate treatment has also been associated with microvascular benefits in

294

patients with type 2 diabetes, which is consistent with preliminary evidence from the Diabetes Atherosclerosis Intervention Study. Conclusion: The addition of fenofibrate to statin therapy may be a useful strategy for the management of mixed dyslipidemia in patients with or at risk for cardiovascular disease. (Clin Tbe~: 2008;30:294-306) O 2008 Excerpta Medica Inc. Key words: mixed dyslipidemia, fibrate, fenofibrate, combination lipid therapy, residual cardiovascular risk.

INTRODUCTION There is extensive evidence that elevated low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular (CV) disease. In the Framingham Heart Study, 1 a 1% increase in LDL-C was associated with a >2% increase in coronary artery disease over 6 years. Lowering LDL-C is the main focus of the management of dyslipidemia in patients at high risk for CV disease, defined by the National Cholesterol Education Program Adult Treatment Panel III 2 (NCEP ATP III) as >20% risk of an event per 10 years. Treatment guidelines from the NCEP ATP III 2 and various professional groups 3-6 are supported by an extensive evidence base. A 2005 meta-analysis from the Cholesterol Treatment Trialists' Collaboration that included 90,056 patients at varying risk levels (18,686 with diabetes) enrolled in 14 randomized controlled trials of statins reported that statin therapy was associated with a 21% relative reduction in major Accepted for pubficafion December 18, 200Z doi:l 0.1016/j.clinthera.2008.02.004

0149-2918/$32.00 O 2008 Excerpta Medica Inc. All rights reserved.

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S. Fazio vascular events per mmol/L reduction in LDL-C (corresponding to a reduction in risk of -5.4% per 10-mg/dL reduction in LDL-C) over a mean of 5 years of treatment. 7 However, most of these statin-treated patients remained at risk for further events. Notably, 21.2% of statin-treated patients with preexisting coronary heart disease (CHD) had further CV events over 5 years. Even though further reduction of LDL-C beyond target levels of 100 mg/dL increases the efficiency of therapy, patients remain at risk for CV events. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction (PROVE IT-TIMI) 22 study, 8 i in 5 patients with a history of acute coronary syndromes died within 30 months, despite the fact that LDL-C levels had been lowered to <70 mg/dL with atorvastatin 80 mg/d. Subgroup analyses of the Treating to New Targets (TNT) study found incremental benefit with intensive statin therapy in patients with CHD and diabetes (n = 1501) or the metabolic syndrome (n = 5584), with a relative risk reduction (RRR) for CV events of 25% (P = 0.026) and 29% (P < 0.001), respectively, with atorvastatin 80 mg/d compared with atorvastatin 10 mg/d. Nonetheless, the level of residual CV risk in both patient groups remained high (65%-75%). 9,1° The NCEP ATP III has proposed the existence of a log-linear relationship between LDL-C and CV risk.ll Within this model, the relative reduction in CV risk is constant in a log-linear association with LDL-C reduction; thus, risk rises more steeply with increasing LDL-C concentrations. In contrast, absolute risk reduction shows a diminishing return. As illustrated in Figure 1, the absolute risk reduction is much greater when LDL-C is reduced from 220 to 190 mg/dL than when it is reduced from 100 to 70 mg/dL. 12 However, this model fails to take into account changes in other lipid parameters, such as high-density lipoprotein cholesterol (HDL-C), that are predictive of CV risk.13 Patients with CHD or CHD risk equivalents (as defined by NCEP ATP III2), often have other lipid abnormalities, in particular low HDL-C and elevated triglycerides. In 8500 men with known CHD who were screened for the Veterans Affairs HDL Intervention Trial (VA-HIT), 33% had elevated triglycerides (>200 mg/dL) and 64% had low HDL-C (<40 mg/dL), in addition to elevated LDL-C (>100 mg/dL). 14 More recent US data indicated that approximately two thirds of statin-treated patients with CHD or CHD risk equivalents and wellFebruary 2008

LDL-C Reduction (mg/dL) From 100 to 70

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_

_

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Figure 1. Diminishing returns in absolute reduction of cardiovascular risk associated with lowering low-density lipoprotein

cholesterol (LDL-C).12

controlled LDL-C levels had low HDL-C levels (<40 mg/dL in men, <50 mg/dL in women), is Data from the Third National Health and Nutrition Examination Survey indicated that -30% of US adults have elevated triglycerides based on the NCEP ATP HI definition (>150 mg/dL), 16 with a higher prevalence (up to 75%) among those with the metabolic syndrome. 17 Both low HDL-C and elevated triglycerides are associated with increased CV risk. 18-2° Data from the Framingham Heart Study indicated a clear prognostic relationship between low HDL-C levels and increased CV morbidity and mortality, irrespective of LDL-C levels.18 The incidence of CHD was >8-fold higher in individuals with HDL-C levels <35 mg/dL compared with those with HDL-C levels >65 mg/dL. As HDL-C levels increased, there was a progressive reduction in CHD risk. Furthermore, in a meta-analysis of 4 large prospective studies (Framingham Heart Study, Lipid Research Clinics [LRC] Prevalence Mortality Followup Study, LRC Coronary Primary Prevention Trial, and Multiple Risk Factor Intervention Trial [MRFIT]), 19 for every 1-mg/dL decrease in HDL-C, there was a consistent 2% to 3% increased risk of CHD, independent of other risk factors, including plasma LDL-C concentrations. There is extensive epidemiologic evidence to support elevated triglycerides as an independent coronary 295

Clinical Therapeutics

risk factor. A recent meta-analysis of 29 prospective studies enrolling 262,525 subjects, including 10,158 with CHD, reported an odds ratio (adjusted for baseline values for risk factors, including HDL-C) of 1.72 for individuals in the top third of log-triglyceride values compared with those in the bottom third (95% CI, 1.56-1.90). '-° Moreover, the impact of triglycerides on CHD risk appeared to be similar in women and men. Although adjustment for HDL-C level attenuated the magnitude of the association (Z'- = 6.4; P = 0.01), this analysis still indicated a strong and highly significant association between triglyceride values and CHD risk. The NCEP ATP III recognized both low HDL-C (<40 mg/dL) and elevated triglycerides (>150 mg/dL) as markers of increased CV risk."- Furthermore, nonHDL-C (ie, the difference between total cholesterol and HDL-C), which has an atherogenic potential associated with partially delipidated triglyceride-rich lipoproteins (remnants), is recommended as a secondary target. '-,11 Non-HDL-C has been reported to be a stronger predictor of CV risk than LDL-C. '-1,'-'- The goal for non-HDL-C at any level of risk is 30 mg/dL higher than the LDL-C treatment goal. Thus, in patients at very high risk (ie, with CV disease and diabetes or the metabolic syndrome"-), who have an LDL-C goal of 70 mg/dL, the non-HDL-C goal is 100 mg/dL. 3,11 Mixed dyslipidemia, which is characterized by elevated triglycerides (>150 mg/dL) and low HDL-C levels (<40 mg/dL in men, <50 mg/dL in women), is typical of patients with type 2 diabetes or the metabolic syndrome.'-3J-4 Although plasma levels of LDL-C may be normal or only slightly above target levels (100 mg/dL), compositional changes in LDL particles have been reported to result in an increase in small, dense LDL particles. '-5 Elevated triglycerides appear to be a key factor in the production of these small, dense LDL particles. '-6 In addition, elevated triglycerides are implicated in the production of functionally defective HDL particles, which have a reduced capacity for cellular cholesterol efflux and protection of LDL against oxidative modification. '-7 Data from a study in 750 CHD patients with normal fasting glucose (n = 272), impaired fasting glucose (n = 314), or type 2 diabetes (n = 164) highlighted the association between atherogenic mixed dyslipidemia and the risk of developing coronary atherosclerosis in patients with insulin resistance. '-8 In this study, factor analysis indicated that an HDLrelated factor that combined triglycerides, HDL-C, 296

apolipoprotein A1, and LDL particle diameter was significantly associated with coronary stenoses of >50% in patients with type 2 diabetes (P = 0.011). However, there was no significant association between stenosis and an LDL-related factor that combined total cholesterol, LDL-C, and apolipoprotein in these patients. The HDL-related factor, but not the LDL-related factor, was also significantly predictive of vascular events in patients with type 2 diabetes (P = 0.044). Statin therapy is recommended as the primary lipidmodifying intervention in patients with mixed dyslipidemia. '-,4-6 Although evidence from clinical studies indicates that statins are efficacious in reducing CV risk in patients with diabetes >-3'- or the metabolic syndrome,>3° there remains a residual risk for CV events. Thus, there is an unmet clinical need in the management of these patients, for whom the gap between effective preventive measures and appropriate therapeutic interventions is at its widest. While statins are clearly effective in lowering LDL-C levels, they appear to have more modest effects in terms of raising HDL-C and lowering triglycerides. Statins have been reported to raise HDL-C levels by 5% to 15% and to lower triglycerides by 7% to 30%.'- In clinical trials, statin treatment has been associated with increases in HDL-C of <10%, even with intensive therapy. -~-~-36In a post hoc analysis of data from 1455 patients enrolled in 4 prospective studies (REVERSAL [Reversal of Atherosclerosis with Aggressive Lipid Lowering], CAMELOT [Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis], ACTIVATE [ACAT IntraVascular Atherosclerosis Treatment], and ASTEROID [A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden]) that used serial intravascular ultrasound imaging to evaluate the effects of up to 24 months of statin therapy on coronary atheroma burden, 36 raising HDL-C by at least 7.5%, along with intensive lowering of LDL-C (mean levels of 87.5 mg/dL), was found to predict regression of atherosclerosis. This finding supports the rationale for combining a statin with an agent having a synergistic or additive mode of action against all 3 lipid abnormalities in the management of patients at high CV risk according to the NCEP ATP III definition."This report reviews the evidence for the efficacy and tolerability of different combination treatments for the management of mixed dyslipidemia, as supVolume 30 Number 2

S. Fazio

ported by clinical-trial data and recommended by national guidelines. M ETHODS

Using the terms lipid-modifying therapy, combination therapy, combination statin-fibrate therapy, and mixed dyslipidemia, a search of PubMed was conducted (completed in April 2007, updated to October 2007) to identify English-language publications and pertinent studies of fibrate combination therapy in patients with mixed dyslipidemia, including those with diabetes or the metabolic syndrome. Clinical studies that were selected for this review were randomized controlled trials. Subgroup analyses of these studies and consensus guideline reviews were also included. COMBINATION THERAPY

National guidelines recommend both niacin (nicotinic acid) and fibrates as additions to statin therapy in highrisk patients (as defined by the NCEP ATP 1111) with persistently low levels of HDL-C (<40 mg/dL in men, <50 mg/dL in women) and elevated triglycerides (>150 mg/dL). ~-s A meta-analysis of 53 trials of fibrates and 30 trials of niacin found that fibrates were associated with a numerically greater decrease in triglycerides compared with niacin (decrease from baseline: 36% [70.5 mg/dL; 95% CI,-79.78 to -61.22; P < 0.001] and 20% [47.0 mg/dL; 95% CI,-60.72 to 34.67; P < 0.001], respectively), whereas niacin was associated with a numerically greater increase in HDL-C compared with fibrates (increase from baseline: 16% [6.7 mg/dL; 95% CI, 5.10 to 8.44; P < 0.001] and 10% [4.1 mg/dL; 95% CI, 3.34 to 4.91; P < 0.001], respectively). 37 Updated guidelines from the NCEP ATP III recognize the potential of these agents used in combination with a statin in patients with mixed dyslipidemia and CHD or CHD risk equivalents. 38 Fibrates may offer potential advantages over niacin in some types of patients. In clinical studies, fenofibrate has been reported to modify the quality of lipoprotein particles by promoting a shift from small, dense LDL particles toward larger, more buoyant particles having an increased binding affinity for the LDL receptor. 39,4° In addition, as a consequence of their role as agonists of the peroxisome proliferator-activated receptor 0%fibrates may have other pleiotropic effects that have potential value in atherosclerosis. Experimental and in vitro studies have found that fibrates

February 2008

attenuated the production of proinflammatory substances such as interleukin-6, as well as expression of inflammatory proteins of the acute phase, including fibrinogen and C-reactive protein. 41 Furthermore, in vitro studies found that fibrates had favorable effects on the coagulation and fibrinolytic systems, reducing fibrinogen levels, increasing fibrinolysis, and attenuating platelet hyperaggregability. 41 This pharmacologic profile suggests that fibrate-statin combination therapy may be useful in the management of mixed dyslipidemia associated with type 2 diabetes or the metabolic syndrome. Clinical data support the use of fibrate therapy in high-risk patients (NCEP ATP III definition s), including those with diabetes (Table I). 4247 In VA-HIT, treatment with gemfibrozil was associated with significant reductions in the primary combined end point of CHD death or nonfatal myocardial infarction (MI) (RRR = 22%; P = 0.006), nonfatal MI alone (RRR = 23%; P = 0.02), and investigator-designated stroke (RRR = 29%; P = 0.04), as well as a nonsignificant reduction in CHD mortality (RRR = 22%). 4~ A recent meta-analysis involving 36,489 patients from 10 randomized, placebocontrolled studies reported that fibrates significantly reduced the risk of nonfatal MI by 22% (P < 0.001), with no evidence of an excess risk of all-cause mortality. 48 Until recently, evaluation of the clinical benefits of fibrates in patients with diabetes had been limited to subgroup analyses of clinical-study cohorts. 4s,46 In an analysis of VA-HIT involving 769 patients with diabetes and CHD (30% of the total study population), 4s significantly greater benefits were reported in patients with diabetes compared with those without diabetes with respect to the composite end point of CHD death, MI, and stroke (RRR = 32% vs 18%, respectively; P = 0.004), CHD mortality (RRR = 41% vs 3%; P = 0.02), and stroke (RRR = 40% vs 10%; P = 0.046). The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5-year, randomized, placebocontrolled, double-blind study of the efficacy and tolerability of fenofibrate 200 mg/d in 9795 patients with type 2 diabetes recruited in both primary and secondary prevention settings. 4° Fenofibrate treatment did not have a significant effect on the primary end point of first nonfatal MI or CHD death (RRR = 11%). There was, however, a significant reduction in the secondary end point of total CV events (RRR = 11%; P = 0.035), largely driven by significant reductions in nonfatal MI (RRR = 24%; P = 0.01) and coronary revascularization (RRR =

297

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Bezafibrate 400 mg/d vs placebo

Fenofibrate 200 mg/d vs placebo

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BIP 43,46

FIELD 49

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Men and w o m e n , 2131 w i t h a history o f cardiovascular disease

Men and w o m e n w i t h previous MI (HDL-C _<45 mg/dL; LDUC _<180 mg/dL) Subgroup w i t h elevated triglycerides (>200 mg/dL)

Men with CHD (low HDL-C and low LDL-C)

Patient Population

Total CV events

N o n f a t a l MI or C H D death

N o n f a t a l or fatal MI or sudden death

N o n f a t a l MI or C H D death or st ro ke

Nonfatal MI or CHD death

Point

Key End

9795

459

3090

2531

9795

516 (16.7)

769 (30.4)

Total No. No. with Diabetes of Patients (% of Total)

11 (P = 0.035)

(P = NS)

11.0

(P < 0.002)

39.5

7.3 (P = NS)

24.0 (P < 0.001)

22.0 (P = 0.006)

All Patients

11 (P = 0.035)

(P = NS)

11.0

4.9 (P = NS)

32.0 (P = 0.004)

24.0 (P = 0.05)

Patients w i t h Diabetes

VA-HIT = Veterans Affairs HDL Intervention Trial; HDUC = high-density lipoprotein cholesterol; LDUC = low-density lipoprotein cholesterol; MI = myocardial infarction; BIP = Bezafibrate Infarction Prevention; FIELD = Fenofibrate Intervention and Event Lowering in Diabetes; CV = cardiovascular.

Comparators

Trial

Risk Reduction Relative to Placebo, %

Table I. Summary of selected trials o f f i b r a t e s in >1000 patients with coronary heart disease (CHD) or CHD risk equivalents.

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21%; P = 0.003). 49 A significant reduction in unstable angina was also reported for fenofibrate compared with placebo (RRR = 18%; P = 0.04) (Figure 2). 50 The lack of significance for the primary end point may have been attributable to the greater use of statins in the placebo arm (mean use at the end of the study, 36% placebo, 19% fenofibrate). 49 FIELD also found potential benefits of lipid-modifying therapy in attenuating the progression of microvascular complications in patients with diabetes. Fenofibrate treatment was associated with significant reductions in the need for retinal laser therapy (RRR = 30%; P < 0.001) and decreased progression/increased regression of albuminuria (2.6% more patients allocated to fenofibrate regressed/did not progress vs placebo; P = 0.002). 49 The evidence of less progression of albuminuria in the FIELD study is consistent with preliminary evidence from the Diabetes Atherosclerosis Intervention

Study (DAIS). 51 A recent analysis by the FIELD investigators found that fenofibrate reduced the frequency of first laser treatment for macular edema by 31% (P = 0.002) and for proliferative diabetic retinopathy by 30% (P = 0.015). 52 The FIELD investigators also reported a significant 38 % reduction in the risk for nontraumatic amputations with fenofibrate (P = 0.011) (Figure 2). 50 T O L E R A B I L I T Y O F FI B R A T E - S T A T I N COM B INATIO N TH ERAPY

Given the complementary pharmacologic profiles of fibrates and statins, greater clinical benefit may be expected with combination therapy than with monotherapy. However, both statins and fibrates have been reported to cause myopathy when administered as monotherapy. 52-55 Therefore, there is a perception that combining agents from these 2 classes may exacerbate the

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Figure 2. Summary o f the macrovascular and microvascular outcomes in patients with type 2 diabetes treated with fenofibrate 200 mg/d in the Fenofibrate Intervention and Event Lowering in Diabetes study.49, s0

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risk of myopathy. However, the available evidence indicates that there may be differences in myopathy risk between fibrates. An evaluation of safety surveillance data from the US Food and Drug Administration Adverse Event Reporting System over the period 19982002 indicated that gemfibrozil in combination with any statin (other than cerivastatin, which has been withdrawn from the market) was associated with a 15-fold higher risk of rhabdomyolysis than fenofibrate plus any statin (8.6 vs 0.58 cases per million prescriptions dispensed, respectively) (Table II). 56 Furthermore, the FIELD investigators found that none of the -1000 patients receiving fenofibrate-statin combination therapy developed myopathy or rhabdomyolysis.49 In addition, there were no significant increases in liver enzymes, creatine phosphokinase, or newly diagnosed cancer or renal disease in patients treated with fenofibrate, either alone or in combination with a statin, compared with the placebo arm. Statins are metabolized primarily via cytochrome P450 (CYP) enzymes in the liver (CYP3A4, CYP2Cg, and CYP2C8) and have a potential for drug interactions when coadministered with potential inhibitors of these enzymes. Not only has gemfibrozil been reported to be a potent inhibitor of CYP2C9 and CYP2C, 9 S but in vitro studies have found that gemfibrozil interacts with the same family of glucuronidation enzymes that are involved in statin biotransformation (Figure 3). 58 This may

explain findings from clinical pharmacokinetic studies in which coadministration of gemfibrozil and a statin was associated with a 2- to 6-fold increase in the statin AUC and, hence, drug exposure. > In contrast, in vitro studies found that fenofibrate produced less inhibition of CYP2C9 than gemfibrozil, and was metabolized by different glucuronidation enzymes than those involved in statin metabolism (Figure 3).58,59 Despite the limitations of in vitro data for identifying potential interactions and translating the results into clinical practice, studies in healthy human volunteers have not identified any significant effects of fenofibrate on the pharmacokinetics of a range of statins, including pravastatin, rosuvastatin, simvastatin, and atorvastatin. 6°-63 The evidence suggesting that fenofibrate may be the preferred fibrate for use in combination with a statin has led to revision of the prescribing information for simvastatin, fluvastatin, and rosuvastatin to allow use of all doses of these agents with fenofibrate. 64 National consensus guidelines recommend fenofibrate as the fibrate of choice for statin-treated patients with mixed dyslipidemia and CHD or CHD risk equivalents. <6 However, given that fenofibrate has been reported to be independently associated with an increased risk for myopathy, it is advisable not to use the maximal statin dose in combination therapy. 64 The fact that there has been no reported evidence of significant pharmacokinetic interactions between feno-

Table II. Number of" reports of- rhabdomyolysis with fibrate-statin combination therapy in the US Food and Drug Administration Adverse Event Reporting System f-rom January 1, 1998, to March 31, 2002.

Treatment Fenofibrate + Cerivastatin* + Other statin + Any statin Gemfibrozil + Cerivastatin * + Other statin + Any statin

Cases of Rhabdomyolysis

Prescriptions Dispensed

No. of Cases per Million Prescriptions

16

100,000 3,419,000 3,519,000

140 0.58 4.50

533 57 590

116,000 6,641,000 6,757,000

4600 8.60 87

14 2

*Subsequently withdrawn. Adapted with permission From Jones and Davidson. 56

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3000

•

Gemfibrozil

[ ] Fenofi brat:e

2500 2000 1500

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40 30 20 10

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1A9

2B7

2B15

Pathways

Figure 3. Glucuronidation pathways involved in the metabolism ofgemfibrozil and fenofibrate. It has been reported that gemfibrozil and the statins share the UDP-glucuronosyltransferase (UGT) 1A1 and UGT 1A3 pathways, whereas fenofibrate mainly uses UGT 1A9 and 2BZ These differences may account for the competitive inhibition ofstatin metabolism seen in the presence ofgemfibrozil but not fenofibrate. HLM = human liver microsomes. Reproduced with permission from Prueksaritanont et al. s8

fibrate and ezetimibe, a cholesterol-absorption inhibitor, 65'66 suggests that this combination may be useful in patients who are unable to tolerate statin therapy. T H E ROLE O F C O M B I N A T I O N FENOFIBRATESTATIN T H E R A P Y IN H I G H - R I S K P A T I E N T S

Clinical studies have reported that the combination of fenofibrate and low to moderate doses of a statin resuited in better overall lipid control than statin monotherapy in patients with mixed dyslipidemia, including those with diabetes or the metabolic syndrome. 67,68 In the Simvastatin plus Fenofibrate for Combined Hyperlipidemia (SAFARI) trial, 67 618 patients with mixed dyslipidemia (triglycerides 150-500 mg/dL and LDL-C >130 mg/dL) were treated with either simvastatin 20 mg/d (n = 207) or the combination of simvastatin 20 mg/d plus fenofibrate 160 mg/d (n = 411) for 12 weeks (after a 6-week diet-plus-placebo run-in period). Treatment with the combination of simvastatin

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plus fenofibrate was associated with significantly greater changes compared with simvastatin alone in triglycerides (-43.0% vs -20.1%, respectively; treatment difference,-23.6%; P < 0.001), LDL-C (-31.2% vs -25.8%; treatment difference,-5.4%; P < 0.001), and HDL-C (18.6% vs 9.7%; treatment difference, 8.8%; P < 0.001). In addition, a significant shift was found in the LDL subclass profile from small, dense LDL particles to larger, more buoyant LDL particles with combination therapy (P < 0.001). The results of clinical studies support the efficacy of combination fenofibrate-statin therapy in patients with type 2 diabetes or the metabolic syndrome. 68-7° In a study in 120 patients with type 2 diabetes and no preexisting CHD, 24 weeks of treatment with the combination of atorvastatin 20 mg/d plus fenofibrate 200 mg/d (n = 40) reduced LDL-C by 46%, reduced triglycerides by 50%, and increased HDL-C by 22% (all, P < 0.001 vs baseline). 68 These changes were all

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significantly better than those observed with either monotherapy (P < 0.001 for each lipid parameter) (Figure 4). Moreover, 97.5% of patients attained an LDL-C goal of <100 mg/dL, 100% achieved triglyceride levels of <200 mg/dL, and 60% achieved HDL-C levels of >45 mg/dL. In a randomized, placebo-controlled, crossover trial in which patients with combined dyslipidemia and metabolic syndrome received simvastatin 10 mg/d for 3 months followed by simvastatin 10 mg/d plus fenofibrate 200 mg/d for 3 months, 69 combination therapy was reported to improve atherogenic dyslipidemia (very-low-density lipoprotein, intermediatedensity lipoprotein, and apolipoprotein B) to a significantly greater extent than simvastatin monotherapy (P < 0.05). In another study in 48 patients with combined dyslipidemia, type 2 diabetes, and CHD, 7° treatment with the combination of fenofibrate 200 mg/d plus fluvastatin 80 mg/d for 1 year was associated with significantly greater improvement in lipid parameters than monotherapy with fluvastatin 80 mg/d (LDL-C: -35% vs -25%, respectively; HDL-C: 34% vs 14%; triglycerides: -32% vs -17%; all, P < 0.05).

30

20

In a study in patients with mixed dyslipidemia and preexisting CHD or at least 3 risk factors for CHD, 71 treatment with fenofibrate 300 mg/d or fenofibrate micronized formulation 200 mg/d plus either pravastatin 20 mg/d (n = 63) or simvastatin 10 mg/d (n = 17) for 2 years was found to reduce triglycerides and LDL-C by 41% and 28 %, respectively, and to increase HDL-C by 22% (all, P < 0.001). Two patients in this study were reported to have increases in creatine kinase of between 3 and 6 times the upper limit of the normal reference range, although none of these events were associated with symptoms of myopathy. STUDY LIMITATIONS AND FUTURE DIRECTIONS

The limitations of PubMed searches for identifying all relevant published studies on a topic are acknowledged. In addition, there is a clear need for large, longterm, prospective, controlled studies to assess the benefits on clinical outcomes and tolerability of combination statin-fenofibrate therapy. The ongoing Action to Control Cardiovascular Risk in Diabetes

4~

[ ] A t o r v a s t a t i n 20 m g (n = 4 0 ) • Fenofibrate 200 mg(n = 40) [ ] A t o r v a s t a t i n 20 m g +

22 16[--

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Figure 4. Overall lipid-modifying efficacy offenofibrate 200 mg/d plus atorvastatin 20 mg/d compared with either monotherapy. 69 *P < 0.001 versus monotherapy. LDL-C = low-density lipoprotein cholesterol; TC = total cholesterol; TG = triglycerides; HDL-C = high-density lipoprotein cholesterol.

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(ACCORD) study was designed to independently test 3 medical strategies in 10,000 patients with type 2 diabetes and a history of or high risk for CV disease: intensive versus standard glycemic control (glycosylated hemoglobin <6.0% vs 7 . 0 % - 7 . 9 % ) ; intensive versus standard blood pressure control (systolic blood pressure goal <120 mm Hg vs <140 mm Hg); and overall lipid management versus LDL-C lowering alone, r2 The lipid arm, which will include - 5 5 0 0 patients, will evaluate whether adding fenofibrate to simvastatin reduces CV risk beyond the risk reduction with simvastatin alone. CONCLUSIONS

Lowering LDL-C is the primary focus of dyslipidemia management in patients with or at risk for CV disease. However, patients with mixed dyslipidemia who achieve LDL-C levels below currently recommended targets may still be at risk for CV events, largely as a result of elevated levels of triglycerides and low levels of HDL-C. Treatment guidelines recommend the use of combination treatment with a fibrate or niacin plus a statin for patients with mixed dyslipidemia, including those with type 2 diabetes or the metabolic syndrome. Clinical studies have reported overall lipid-modifying efficacy with fenofibrate-statin combination therapy compared with statin monotherapy in these patients. Data from prospective outcome studies are required to evaluate the benefits of this approach. ACKNOWLEDGMENTS

Abbott Laboratories, Abbott Park, Illinois, provided support for the preparation of this manuscript, but did not influence its content. The author had no direct or indirect contact with any company representative concerning this project. The author thanks Jane Stock, PhD, for assistance with the writing of this manuscript. The author has received funding for clinical trials from Merck & Co., Inc., Pfizer Inc., AstraZeneca Pharmaceuticals, and Takeda Pharmaceuticals, Inc. He is a lecturer or advisor for Merck & Co., Inc., ScheringPlough Corporation, AstraZeneca Pharmaceuticals, GlaxoSmithKline, and Abbott Laboratories.

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Address correspondence to: Sergio Fazio, MD, Division of Cardiovascular

Medicine, Vanderbilt University School of Medicine, 383 PRB, 2220 Pierce Avenue, Nashville, TN 37232. E-mail: [email protected] Volume 30 Number 2