Editorial

Michael Davidson, MD, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois

Recent publications and guidelines have raised awareness of the need to aggressively treat dyslipidemia to reduce cardiovascular risks in patients with diabetes or metabolic syndrome. However, the best way to approach pharmacologic therapy in these patients remains the subject of much study and debate. While some of these patients have isolated elevated low-density lipoprotein (LDL)-cholesterol, many have combined dyslipidemia, which is characterized by elevated triglyceride levels and low high-density lipoprotein (HDL)-cholesterol levels in addition to increased levels of small, dense LDL-cholesterol particles.

Statins remain the mainstay of therapy for most patients with hyperlipidemia. For those patients who do not achieve target lipid goals with standard statin doses, pharmacologic treatment options include high-dose statin therapy or statin combination therapy with ezetimibe, niacin, or fibrates. High-dose statin therapy is associated with greater reductions in LDL-cholesterol and cardiovascular risks than standard doses; however, it is also associated with an increased risk for serious side effects (myopathy and/or liver function abnormalities). Combination statin-ezetimibe therapy appears to provide similar improvements in LDL-cholesterol without safety concerns; however the lack of effect on HDL-cholesterol and triglycerides may limit the utility of this combination in patients with diabetes or metabolic syndrome. Combination statin-niacin therapy improves HDL-cholesterol, but is associated with worsening of hyperglycemia.

Combination statin-fibrate therapy may be the best pharmacologic option for patients with diabetes or metabolic syndrome not achieving target lipid goals with single-agent statin therapy. Statin-fibrate combinations improve patients' overall lipid profiles (reduce LDL-cholesterol and triglycerides and increase HDL-cholesterol). Furthermore, the effects of fibrates on non-lipid parameters (inflammation and thrombotic processes) may enhance the overall efficacy of these combinations in reducing cardiovascular risks. Differences in the pharmacokinetic profiles of the fibrates suggest that the combination of statin-fenofibrate may be safer than the combination of statin-gemfibrozil, as fenofibrate is less likely to alter the metabolism of statins through both the cytochrome P450 and glucuronidation pathways.

Perspective

Type 2 diabetes is associated with considerable cardiovascular morbidity and mortality. Patients with type 2 diabetes have a 2- to 4-fold increase in major cardiovascular events compared to individuals without diabetes.¹ For this reason, the American Diabetes Association (ADA)² and the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP III)³ have advocated aggressive treatment of dyslipidemia in patients with type 2 diabetes or metabolic syndrome. The relationship between type 2 diabetes and cardiovascular risks is of particular interest to clinicians in the United States, as a dramatic increase in the prevalence of diabetes and obesity has been reported.⁴

Diabetes has been associated with 2 lipid disorders. The first is isolated elevation of LDL-cholesterol levels, which are associated with atherogenesis and the rupture of coronary plaque. More commonly, patients with type 2 diabetes have atherogenic dyslipidemia, or combined dyslipidemia. This disorder is characterized by an increased number of small, dense LDL-cholesterol particles; elevated triglycerides; and low HDL-cholesterol levels.

It is widely accepted that both statins and fibrates reduce cardiovascular risks in patients with dyslipidemia. However, when used as single-agent therapy, these agents may not completely correct all lipid abnormalities in patients. New evidence suggests that combination therapy (statin plus fibrate) may provide the greatest benefit in high-risk patients with combined dyslipidemia associated with diabetes or metabolic syndrome.

Statins and Fibrates: Effects on Lipid Parameters

Whereas both statins and fibrates are known to reduce the risk for coronary artery disease associated with individual lipid parameters, they affect these parameters differently. Statins substantially reduce the risk of cardiovascular events through significant reductions in LDL-cholesterol and triglycerides and moderate increases in HDL-cholesterol. While statins have demonstrated the ability to reduce cardiovascular events in patients with low HDL-cholesterol, patients who continue to have low HDL-cholesterol while taking statins continue to have a greater risk of coronary artery disease than those with higher HDL-cholesterol levels.⁵

Fibrates produce reductions in cardiovascular risk through significant effects (increases) in HDL-cholesterol levels and are particularly effective in patients with low HDL-cholesterol and normal LDL-cholesterol levels. They also appear to provide beneficial cardiovascular effects that extend beyond those derived from changes in lipid parameters. In the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) subgroup analysis,⁶ the fibrate gemfibrozil (Lopid) significantly reduced the risk of major cardiovascular events (relative risk reduction 32%, hazard ratio 0.68; 95% Confidence Interval (CI), 0.53-0.88; P = .004; absolute risk reduction, 10%) in patients with low HDL-cholesterol, diabetes, and hyperinsulinemia (Figure 1). Clinical efficacy was greater in patients with diabetes than in patients without diabetes even though the effects on lipids were less pronounced.

The VA-HIT investigators suggested that the additional effects of fibrates on non-lipid parameters (inflammatory and thrombotic processes) may have contributed to the clinical efficacy of gemfibrozil in patients with diabetes in this study.

Benefits and Risks of High-Dose Statin Therapy

Statins are commonly used to treat dyslipidemia in patients at risk for coronary artery disease. While statins provide safe and effective lipid control in most patients, some patients fail to achieve the target lipid goals with standard statin doses (Table 1).

Because the effectiveness of statins is dose-related, high-dose statin therapy has been proposed as one treatment option for these patients. However, the clinical utility of this approach is limited by side effects--myopathy and liver function abnormalities, while relatively uncommon, are also dose-related. A recent review in the American Journal of Cardiology discussed these benefits and risks.⁷ The author stated that assuming the benefits of statin therapy are linear, an additional 5% to 6% reduction in LDL-cholesterol should therefore result in an additional 1% reduction in clinical events. An increase in simvastatin or atorvastatin from 40 mg to 80 mg would also result in at least an additional 1% to 2% absolute incidence in myopathy and/or liver function abnormalities. Therefore, for the additional 1% reduction in cardiac events, there is also a 1% to 2% increase in risk of a serious side effect (Figure 2).

Combination Therapy

Another approach in treating patients not achieving target lipid goals with single-agent statin therapy is statin-based combination therapy. The addition of ezetimibe to statin therapy reduces LDL-cholesterol levels an additional 25% compared to statins alone.⁸ Moderate additional reductions in triglycerides and slight improvements in HDL-cholesterol have also been reported. This combination appears to be safe (the rates of adverse events and changes in liver function tests and creatinine phosphokinase [CPK] were similar to those observed with statins alone).⁷ However, given its relatively modest effects on triglycerides and HDL-cholesterol levels, statin-ezetimibe combination therapy may not be the optimum choice in patients with diabetes or metabolic syndrome that have elevated triglycerides and low HDL-cholesterol levels.

Niacin increases HDL-cholesterol levels and has been used in patients with diabetes and metabolic syndrome. According to the treatment guidelines published by the ADA,² the combination of a statin with niacin is extremely effective in modifying diabetic dyslipidemia, producing the greatest increases in HDL-cholesterol levels. However, combination statin-niacin therapy may significantly worsen hyperglycemia. It may also produce hepatotoxicity and, rarely, myopathy.⁷ The ADA recommends that this combination be used with extreme caution.² Clinicians employing this combination should consider low doses of niacin (≤1500 mg per day) and monitor glucose levels frequently.

The addition of a fibrate (fenofibrate (Tricor)) to statin therapy has been shown to reduce LDL-cholesterol, increase HDL-cholesterol levels, and decrease triglycerides.^9-11 In one study, the combination of atorvastatin and fenofibrate allowed 97.5%, 100%, and 60% of patients with diabetes to attain ADA LDL-cholesterol, HDL-cholesterol, and triglyceride target goals, respectively⁹ (Table 2).

The ability of statin-fibrate combinations to improve patients' overall lipid profiles would be expected to provide greater cardiovascular benefits than therapies affecting only 1 or 2 lipid parameters. Furthermore, the effects of fibrates on non-lipid parameters (vascular biology) may provide additional reduction of cardiovascular risks in patients with diabetes. In the atorvastatin-fenofibrate study described above, 10-year myocardial infarction risk was lower with combination therapy (4.2%) than with single-agent atorvastatin (7.5%) or single-agent fenofibrate (10.9%) (P<.05 for combination therapy vs each single-agent therapy).⁹

Safety of Statin and Fibrate Combinations

Concerns about the safety of statin-fibrate combinations have limited their use. Most of these concerns are based on safety data from studies and post-marketing reports of cerivastatin (Baycol) and gemfibrozil therapy.^12,13 Cerivastatin was withdrawn from the United States market following reports of rhabdomyolysis with this combination. Furthermore, class labeling for statins was instituted, urging caution with combination statin-fibrate therapy.

However, important differences in the fibrate pharmacokinetic profiles result in diverse effects on concomitant statin therapy.⁷ Gemfibrozil affects the pharmacokinetics of all the statins except fluvastatin. All the statin-gemfibrozil combinations (with the exception of fluvastatin) are associated with elevated myopathy rates. In contrast, fenofibrate, does not appear to interact significantly with simvastatin, pravastatin, or rosuvastatin (Table 3). Based on published reports and the FDA Adverse Event Reporting System (AERS), the risk of interaction appears to be less with statin-fenofibrate combinations than with statin-gemfibrozil combination therapy.⁷

Originally, the adverse effects observed with the statin-fibrate combinations were thought to result from competitive inhibition of statin metabolism through the cytochrome P450 3A4 (CYP3A4) pathway. However, recent research suggests that competition between statins and fibrates for metabolism by glucuronidation pathways, not CYP3A4, is what leads to the occurrence of adverse effects such as myositis and rhabdomyolysis.

Glucuronidation is responsible for the metabolism of the active hydroxy acids of simvastatin, atorvastatin, and cerivastatin by uridine diphosphate glucuronosyl transferase (UGT) enzymes. Reduced statin glucuronidation leads to accumulation of statins in the tissues and may result in myositis and rhabdomyolysis. While gemfibrozil and fenofibrate both undergo extensive glucuronidation, the UGT isoforms responsible for the glucuronidation of these agents are different. Importantly, the UGT isoforms responsible for the glucuronidation of the statins, UGT1A1 and UGT 1A3, seem to be less involved in the glucuronidation of fenofibric acid (the major metabolite of fenofibrate) than gemfibrozil. These differences in their metabolism may provide an explanation of the differences in the ability of gemfibrozil and fenofibrate to alter the pharmacokinetics of the statins. This in turn may explain the greater incidence of adverse effects observed with statin-gemfibrozil combinations compared with those of statin-fenofibrate combinations.

Conclusion

Patients with type 2 diabetes or metabolic syndrome are at high risk for cardiovascular morbidity and mortality. The most common pattern of dyslipidemia observed among patients with type 2 diabetes is increased numbers of small, dense LDL-cholesterol particles, elevated triglycerides, and low HDL-cholesterol levels. Combination therapy designed to therapeutically target all 3 of these lipid abnormalities may provide greater cardiovascular risk reduction than that which can be achieved by lowering LDL-cholesterol levels alone. Indeed, evidence suggests that combination statin-fibrate therapy appears to improve all 3 lipid parameters and reduce cardiovascular risk. The risks associated with these combinations appear to be less than previously thought. A clearer understanding of the interactions between statins and fibrates should help guide clinicians when choosing combination therapy.

References

1. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infraction. N Engl J Med. 1998;339:229-234.
2. Management of dyslipidemia in adults with diabetes. American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S83-S86.
3. 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. Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP. The continuing epidemics of obesity and diabetes in the United States. JAMA. 2001;286:1195-1200.
5. Sacks FM for the Expert Group on HDL Cholesterol. The role of high-density lipoprotein (HDL) cholesterol in the prevention and treatment of coronary heart disease: expert group recommendations. Am J Cardiol. 2002;90:139-143.
6. Rubins HB, Robins SJ, Collins D, et al for the VA-HIT Study group. Diabetes, plasma insulin and cardiovascular disease. Subgroup analysis from the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT). Arch Intern Med. 2002;162:2597-2604.
7. Davidson MH. Combination therapy for dyslipidemia: safety and regulatory considerations. Am J Cardiol. 2002;90(suppl):50K-60K.
8. Gagne C, Bays HE, Weiss SR, et al for the Ezetimibe Study Group. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol. 2002;90:1084-1091.
9. 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.
10. Ellen RLB, McPherson R. Long-term efficacy and safety of fenofibrate and a statin in the treatment of combined hyperlipidemia. Am J Cardiol. 1998;81(suppl B):60S-65S.
11. Kiortisis DN, Millionis H, Bairaktari E, Elisaf MS. Efficacy of combination of atorvastatin and micronised fenofibrate in the treatment of severe mixed hyperlipidemia. Eur J Clin Pharmacol. 2000;56:631-635.
12. Alexandridis G, Pappas GA, Elisaf MS. Rhabdomyolysis due to combination therapy with cerivastatin and gemfibrozil. Am J Med. 2000;109:261-262.
13. Pogson GW, Kindred LH, Carper BG. Rhabdomyolysis and renal failure associated with cerivastatin-gemfibrozil combination therapy. Am J Cardiol. 1999;83:1146.