This report was reviewed for medical and scientific accuracy by Avedis K. Khachadurian, MD, Professor of Medicine, Division of Endocrinology, Metabolism and Nutrition, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Multiple large clinical trials have demonstrated that reducing levels of low-density lipoprotein cholesterol (LDL-C) significantly lowers morbidity and mortality associated with coronary atherosclerosis.^1-5 Ironically, most of the landmark trials of lipid-lowering pharmacotherapy included relatively few diabetic patients, a population recognized as possessing exceptionally high cardiovascular risk factors compared to the general population; particularly atherosclerotic coronary heart disease (CHD). However, the data from these studies have indicated that diabetic patients derived substantial benefit from treatment of dyslipidemia.⁶

At least part of the explanation for the lack of diabetic representation in major clinical trials of lipid-lowering pharmacotherapy relates to the focus on LDL-C. Diabetic dyslipidemia typically involves low levels of high-density lipoprotein cholesterol (HDL-C) with correspondingly elevated triglycerides indicating the presence of atherogenic triglyceride-rich intermediate-density lipoproteins.⁷ Type 2 diabetic patients typically have a preponderance of smaller, denser LDL particles, which possibly increases atherogenicity even if the absolute concentration of LDL-C is not significantly increased. Therefore, primary emphasis solely on LDL-C as it relates to the reduction of cardiovascular risk factors is inappropriate in the type 2 diabetic patient. The clinical trial focus on LDL-C has overshadowed the long-recognized fact that low HDL-C is a potent and independent coronary risk factor.⁸ Most major clinical trials employed HMG-CoA reductase inhibitors (statins) for lipid-lowering pharmacotherapy. However, statins act primarily on LDL-C and induce only modest increases in HDL-C.

The Veterans Affairs HDL Intervention Trial (VA-HIT) represented a new approach to clinical trials of lipid modification.⁹ The trial enrolled patients whose primary lipid abnormality was low HDL-C. The therapeutic agent employed was gemfibrozil (Lopid, Parke-Davis/Pfizer), a fibric acid derivative (fibrate). As a class, fibrates have a more robust impact on HDL-C, compared to statins, and induce substantial reductions in triglycerides. More than 30% of the VA-HIT patients were diabetic, including 25% at enrollment and an additional 6% who developed diabetes during the study. Many other patients had prediabetic characteristics, including elevated insulin levels, obesity, and hypertension.

VA-HIT tested the hypothesis that raising HDL-C levels, in the absence of an effect on LDL-C, would reduce the cardiovascular event rate in high-risk patients. The principal finding was a 22% reduction in cardiovascular events in patients treated with the fibrate, which compared favorably with results of the statin trials. Diabetic patients derived even greater benefit from treatment, a 27% overall reduction in events, including a 41% reduction in cardiovascular mortality.

The Diabetes Atherosclerosis Intervention Study (DAIS) went a step further and specifically limited enrollment to diabetic patients.¹⁰ This angiographic trial tested the ability of fenofibrate (Tricor, Abbott Laboratories) to slow the progression of atherosclerosis. At the end of the study, patients treated with fenofibrate had a 40% improvement in minimum lumen diameter, 43% improvement in minimum segment diameter, and 25% improvement in mean percentage stenosis, compared to patients randomized to placebo. Although not powered to show statistical significance, this trial showed a 23% reduction in cardiovascular events in the fenofibrate treatment arm.

The 2001 update to the National Cholesterol Education Program (NCEP) clinical guidelines has increased emphasis on both HDL-C and the diabetic patient.¹¹ The threshold for HDL-C has been raised from 35 mg/dL to 40 mg/dL. The NCEP guidelines recognize diabetes as a CHD equivalent, reflecting the recognition that a diabetic patient without CHD faces the same risk as a nondiabetic patient with CHD.

The new NCEP guidelines substantially increase the number of patients who qualify for drug therapy to correct lipid abnormalities. However, available evidence suggests that current treatment strategies (eg, statin monotherapy) fail to achieve NCEP-specified lipid goals in a majority of patients eligible for drug therapy. The Lipid Treatment Assessment Project (L-TAP), a community based assessment of lipid-lowering pharmacotherapy, showed that only 38% of treated patients achieved target lipid levels.¹² Worse yet, among high-risk individuals, treatment to target lipid values occurred only 18% of the time.

The NCEP recommends a target LDL-C level of less than 100 mg/dL for all diabetic patients, the same as lipid-lowering in the setting of secondary prevention. The stricter criteria for lipid control, including the higher threshold for low HDL-C, make the management of diabetic dyslipidemia more challenging than ever. It should by noted that the revised NCEP guidelines, as a prelude to pharmacologic therapy, emphasize changes in lifestyle that can lead to CHD risk reduction. These therapeutic lifestyle changes involve diet, weight reduction, and physical activity.

One strategy to meet the challenge of managing diabetic dyslipidemia would be combination therapy with a statin and a fibrate. Because of their complementary effects on lipid parameters, statin and fibrate combination therapy offers the potential to achieve a better overall lipid profile compared to either agent used alone. However, combination therapy with these agents has been attenuated by concern emanating from reports of treatment-induced myopathy with the combination of lovastatin and gemfibrozil¹³, and more recently, myopathy-rhabdomyolysis reported with cerivastatin and gemfibrozil.^14,15 A recent review of published clinical trials showed a 0.12% incidence of myopathy in patients treated with statin-fibrate combinations.¹⁶ The authors concluded the small risk of myopathy rarely outweighs the established morbidity and mortality benefits in achieving lipid goals and advised an examination of predisposing risk factors (eg, renal or liver disease, diabetes, hypothyroidism, debilitated status) to insure appropriate patient selection and patient counseling after careful risk-benefit analysis.

The recognition that HDL-C is an independent risk factor for cardiovascular disease combined with the renewed emphasis on total lipid management by the medical community as defined by NCEP has led to extensive research in hopes of establishing the most efficacious lipid-lowering therapy. The ultimate question is which regimen is most appropriate for the patient being treated; single-agent statin or fibrate therapy or a combination of both?

Fibrate vs Statin: Comparative Efficacy in Low HDL-C

Investigators recently reported results from a multicenter clinical trial designed to compare the effects of fenofibrate and atorvastatin on lipid parameters of patients with low HDL-C levels.¹⁷ The trial involved 181 patients with mean baseline of HDL-C of 36.6 mg/dL, total cholesterol of 241.1 mg/dL, LDL-C of 162.6 mg/dL, and triglyceride level of 211.9 mg/dL.

The patients were randomized to fenofibrate 200 mg/day (n = 79) or atorvastatin 10 mg/day (n = 86) and followed for 12 weeks. The primary clinical endpoint was the percentage change in HDL-C after 12 weeks of randomized treatment.

The results showed a highly significant advantage for treatment with fenofibrate (see Figure 1). The mean HDL-C level increased by 13.3% in the fenofibrate group, compared to 5.3% in patients treated with atorvastatin (P = .0003). In fenofibrate-treated patients, the magnitude of the treatment effect on HDL-C was inversely related to baseline HDL-C values, meaning that patients with the lowest baseline HDL-C derived the greatest benefit. No such relationship was seen in atorvastatin-treated patients. Moreover, 29 of 57 fenofibrate-treated patients (50.9%), with baseline HDL-C values of less than 40 mg/dL had 12-week values in excess of 40 mg/dL, compared to 19 of 68 (27.9%) in atorvastatin-treated patients (P = .01). Fenofibrate also resulted in a significantly greater decrease in triglycerides, whereas atorvastatin achieved significantly greater declines in total cholesterol and LDL-C.

The investigators concluded the greater impact of fenofibrate on HDL-C makes fibrate treatment a viable treatment option for dyslipidemic patients who have low HDL-C and moderately elevated LDL-C.

Combination vs Monotherapy in Type 2 Diabetes

Athyros et al recently reported results comparing the efficacy of single-agent therapy with fenofibrate or atorvastatin against the combination of the two drugs in type 2 diabetic patients with combined hyperlipidemia.¹⁸ The study involved 120 patients with type 2 diabetes and no history of CHD at enrollment. Mean baseline lipid values for the three treatment arms included total cholesterol of 252-255 mg/dL, LDL-C of 161-163 mg/dL, HDL-C of 34.6-35.1 mg/dL, and triglycerides of 278-281 mg/dL (see Table 1). Notably, the patients had an estimated 10-year risk for myocardial infarction [PROCAM CAD¹⁹] assessed at baseline of 21.6%, placing them in the NCEP high-risk category.¹¹ Glycohemoglobin levels averaged about 8% at baseline, and a majority of the patients were receiving insulin.

The patients were randomized to one of three treatment groups: atorvastatin 20 mg/day; fenofibrate 200 mg/day; or the combination of the two drugs at the monotherapy dosages. Randomized therapy continued for 24 weeks, and the principal objective was the impact of treatment on overall lipid profile. Therapeutic efficacy was evaluated within the context of optimal lipid goals established by the American Diabetes Association (ADA, Diabetes Care, 2001): an LDL-C of less than 100 mg/dL, triglycerides of less than 200 mg/dL, and an HDL-C greater than 45 mg/dL.

In these high-risk patients, with high LDL-C, elevated triglycerides and low HDL-C, single-agent therapy with fenofibrate or atorvastatin led to significant improvement in different aspects of patients' lipid profiles. However, combination therapy achieved the best results. The combination reduced total cholesterol and LDL-C levels to a greater extent than did single-agent atorvastatin. Additionally, combination therapy achieved a greater decrease in triglycerides and a greater increase in HDL-C compared to single-agent fenofibrate.

With combination therapy, 97.5% of patients attained the ADA goal for LDL-C, compared to 80% with single-agent atorvastatin, and 5% with single-agent fenofibrate. All 40 patients treated with the combination achieved the ADA goal for triglycerides, as did 92.7% of the patients with single-agent fenofibrate, and 75% of the patients with single-agent atorvastatin. The ADA's optimal value for HDL-C was achieved by 60% of patients in the combination group, 30% of single-agent fenofibrate patients, and 17.5% of single-agent atorvastatin patients.

All three treatment groups had significant reductions in 10-year myocardial infarction (MI) risk, but patients treated with the combination of fenofibrate and atorvastatin fared the best (see Figure 2). The 10-year estimated risk for MI declined to 4.2% with combination therapy (P <.05 vs single-agent therapy), compared to 7.5% with atorvastatin (P <.05 vs fenofibrate), and 10.9% with fenofibrate (P <.001 vs baseline).

Single-agent fenofibrate and combination therapy also led to significant 20-21% reductions in plasma fibrinogen levels, whereas fibrinogen did not change appreciably with single-agent atorvastatin. Uric acid levels declined with single-agent atorvastatin and combination groups.

Providing reassurance about the safety of combination therapy, no patient withdrew from the study because of side effects. In particular, no patient in any of the groups presented with myalgia or a creatine kinase level exceeding 10 times baseline values. Patients in the combination therapy arm experienced a nonsignificant increase in serum transaminase values.

The investigators concluded that combination therapy with fenofibrate and atorvastatin "is a very effective therapeutic approach (for) patients with type 2 diabetes and combined hyperlipidemia. It has a clear beneficial effect on all lipid parameters and plasma fibrinogen concentrations. These properties reduce coronary artery disease risk, expand the spectrum of therapeutic choices, and enhance the individualization of hypolipidemic treatment in patients with type 2 diabetes."

Summary

The new NCEP guidelines recognize diabetes as a CHD risk equivalent and emphasize that treatment beyond LDL-C may be necessary for these patients. Specifically, emphasis is placed on patients with low HDL-C and high triglycerides, as well as on the risk associated with features of the metabolic syndrome. Diabetic dyslipidemia is typified by low HDL-C and elevated triglycerides, usually accompanied by normal or moderately elevated LDL-C levels. Statin-based pharmacotherapy primarily targets LDL-C, and results in only modest increases in HDL-C.

Fenofibrate, as demonstrated by Despres et al, has a greater positive effect on HDL-C than atorvastatin, as well as leading to a greater reduction in triglycerides. As described by Sacks et al in the Expert Group Recommendations on HDL Cholesterol²⁰, fibrates may be particularly effective in the treatment of patients with the high-risk features of the metabolic syndrome, a group where dyslipidemia is typically characterized by low HDL-C, high triglycerides, and normal or only slightly elevated LDL-C. There is also a population of diabetic patients with severe mixed dyslipidemia. This population, as described by Athyros et al, has a very high 10-year risk of MI, and complex lipid therapy is often required to effectively manage risk. Athyros has convincingly shown that in order to control cardiovascular risk in these patients, combination therapy is often necessary, and the combination of fenofibrate and atorvastatin was able to lower overall cardiovascular risk more than either agent alone, with the combination patients realizing a reduction in their 10-year risk of MI from 21.6% to 4.2%, a risk reduction statistically superior to either agent used alone. In sum, it is clear that for high-risk patients with diabetes or the metabolic syndrome, fibrate therapy, either alone or in combination with a statin, should be considered for cardiovascular risk reduction.

References

1. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389.
2. Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301-1307.
3. Sacks FM, Pfeffer MA, Moye LA, et al, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001-1009.
4. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615-1622.
5. The Long-Term Intervention with Pravastatin in Ischemic Disease (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. N Engl J Med. 1998;339:1349-1357.
6. American Diabetes Association. Management of Dyslipidemia in Adults with Diabetes. Diabetes Care. 2002;25(suppl 1):S74-S77.
7. McLaughlin PR and Gladstone P. Diabetes Atherosclerosis Intervention Study (DAIS): Quantitative coronary angiographic analysis of coronary artery atherosclerosis. Cathet Cardiovasc Diagn. 1998;44:249-256.
8. Gordon T, Castelli WP, Hjortland MC, et al. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977;62:707-714.
9. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341:410-418.
10. Diabetes Atherosclerosis Intervention Study Investigators. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet. 2001;357:905-910.
11. 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.
12. Pearson TA, Laurora I, Chu H, Kafonek S. The Lipid Treatment Assessment Project (L-TAP). A multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein goals. Arch Intern Med. 2000;160:459-467.
13. Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA. 1990;264:71-75.
14. Alexandridis G, Pappas GA, Elisaf MS. Rhabdomyolysis due to combination therapy with cerivastatin and gemfibrozil. Am J Med. 2000;109:261-262.
15. Pogson GW, Kindred LH, Carper BG. Rhabdomyolysis and renal failure associated with cerivastatin-gemfibrozil combination therapy. Am J Cardiol. 1999;83:1146.
16. Shek A, Ferrill M. Statin-fibrate combination therapy. Ann Pharmacother. 2001;35:908-917.
17. Despres JP, Lemieux I, Salomon H, Delaval D. Effects of micronized fenofibrate versus atorvastatin in the treatment of dyslipidaemic patients with low plasma HDL-cholesterol levels: a 12-week randomized trial. J Intern Med. 2002;251:490-499.
18. Athyros VG, Papageorgiou AA, Athyrou VV, et al. Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidemia. Diabetes Care. 2002;25:1198-1202.
19. Assmann G, Cullen P, Schulte H. Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the Prospective Cardiovascular Munster (PROCAM) Study. Circulation. 2002;105:310-315.
20. Sacks F. The role of high-density lipoprotein cholesterol in the prevention and treatment of coronary heart disease: Expert Group Recommendations. [Editorial] Am J Cardiol. 2002;90:139-143.

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Disclosure
Avedis K. Khachadurian, MD
Has no significant relationships to disclose.

This report contains information on commercial products that is outside of current approved labeling or information on the investigational use of products not yet approved by the United States Food and Drug Administration. Approved labeling should be consulted prior to treating patients with products discussed herein.

This report is supported by an educational grant from Abbott Laboratories.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Cardiology Express Report(tm) includes discussion of treatment and indications outside of current approved labeling. This Cardiology Express Report(tm) was made possible through an educational grant from Abbott Laboratories.

© 2002 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education