Expert Commentary

Michael Davidson, MD, Director of Preventive Cardiology, Associate Professor, Rush-Presbyterian St. Luke's Medical Center, Chicago, Illinois

Managing dyslipidemia in patients with diabetes or the metabolic syndrome is essential for preventing cardiovascular events, which are increased two- to four-fold in this population.¹ The most common pattern of dyslipidemia in type 2 diabetes is characterized by decreased high-density lipoprotein (HDL)-cholesterol and elevated triglyceride levels, with low-density lipoprotein (LDL)-cholesterol that is usually not significantly different from nondiabetic individuals. Initial therapy with a statin is recommended, but frequently adjunctive agents are necessary to normalize the constellation of lipid abnormalities.

According to the American Diabetes Association (ADA) and the National Cholesterol Education Project Adult Treatment Panel (NCEP ATP III) guidelines,^2,3 fibrates should be considered in addition to statins for patients with mixed dyslipidemia with inadequately controlled non-HDL-cholesterol and/or triglyceride levels. Of the two available fibrates in the United States, there is emerging evidence demonstrating their differences in regards to safety in combination with statins.

With the occurrence of rhabdomyolysis in patients taking cerivastatin⁴ or cerivastatin plus gemfibrozil,^5,6 concern heightened over the potential risk of combining statins with fibrates. However, data presented at the 63rd Scientific Sessions of the ADA, along with findings recently published in the medical literature, suggest that the available fibrates behave differently in combination with statins, and that the data support the safety of fenofibrate in combination with statin therapy.

Follow-up analysis from the Lipids in Diabetes Study (LDS),⁷ which evaluated cerivastatin and fenofibrate as single agents and in combination, found the combination to be superior in improving lipid profiles with no adverse events reported. Most importantly, there were no cases of myositis or rhabdomyolysis in this large trial of persons with type 2 diabetes.

Fenofibrate was recently differentiated from gemfibrozil in a laboratory study conducted by Merck investigators which aimed to elucidate the pharmacokinetic interactions between the fibrates and statins.⁸ Using human hepatocytes, the researchers performed sophisticated metabolic tests that revealed much about the interactions between the fibrates and various statins. Their findings suggested that the statins vary in their susceptibility to interactions with the fibrates, and that fenofibrate may alter statin metabolism less than gemfibrozil. Differences in these metabolic interactions may help explain the difference in the safety profile exhibited by gemfibrozil versus fenofibrate in combination with cerivastatin.

These recent studies provide some reassurance to clinicians that patients with type 2 diabetes can be safely and effectively treated with statin/fenofibrate combination therapy. This treatment appears to be the optimal approach for the atherogenic dyslipidemia that greatly raises cardiovascular risk in this population.

Lipids in Diabetes Study Confirms Safety and Efficacy of Statin/Fenofibrate

The LDS trial recruited 4,191 individuals with type 2 diabetes, with LDL-cholesterol <158 mg/dL and without known coronary heart disease, from 30 centers in the United Kingdom.⁷ Patients were randomized in a double-blind 2x2 factorial design to one of four treatment arms: micronised fenofibrate 200 mg in the morning plus cerivastatin 0.4 mg in the evening; micronised fenofibrate 200 mg in the morning plus placebo in the evening; placebo in the morning plus cerivastatin 0.4 mg in the evening; or placebo in the morning and evening.

Patients were to be evaluated every 4 months for 5 years for the first occurrence of a fatal myocardial infarction or sudden death, nonfatal myocardial infarction, or need for coronary or peripheral artery revascularization.

The study began in May 1999 but closed prematurely in August 2001 when cerivastatin was withdrawn from the United States marketplace.⁹ At that point, 1,949 patients had been followed for 1 year, and were included in the current analysis reported at ADA 2003.

The baseline lipid characteristics of the study population were total cholesterol of 189 mg/dL, LDL-cholesterol of 120 mg/dL, HDL-cholesterol of 46 mg/dL, and triglycerides of 133 mg/dL. Baseline body mass index (BMI) was 30.5 kg/m², while baseline blood pressure was 143/83 mm Hg with a median hemoglobin A_1c of 8.0%.

Combination therapy with cerivastatin plus fenofibrate produced additional benefits in lowering LDL-cholesterol and triglycerides, compared with either agent used alone. Most importantly, no myositis or rhabdomyolysis was reported in this large study population, according to Principal Investigator Andrew Neil, MD, Director of the Diabetes Trial Unit of the Oxford Centre for Diabetes, Endocrinology, and Metabolism, Oxford University, Oxford, United Kingdom.

"Our trial was halted early because of the market withdrawal of cerivastatin, so one has to be extremely cautious in interpreting the findings. But, our data suggest that with fenofibrate and cerivastatin in combination, we were less likely to observe the sort of side effects and adverse events observed when this statin was used with gemfibrozil," noted Dr. Neil.

"The combined agents produced a greater LDL-cholesterol and triglyceride reduction than either agent used alone. The additive effects of this combination might enhance the reduction in coronary heart disease, but we need to wait for additional clinical trial endpoint data to determine this," advised Dr. Neil.

With combination cerivastatin/fenofibrate therapy, the net reduction in LDL-cholesterol from baseline was 41 mg/dL (Table 1). In contrast, LDL-cholesterol was reduced by 36 mg/dL with single-agent cerivastatin, by 14 mg/dL with single-agent fenofibrate, and by 1.9 mg/dL with placebo, reported Dr. Neil.

Triglycerides were reduced by 56 mg/dL with the combination of cerivastatin and fenofibrate, and less so in the other treatment arms: reductions were 24 mg/dL and 42 mg/dL with single-agent cerivastatin and single-agent fenofibrate, respectively. Triglyceride levels increased by 3 mg/dL with placebo.

According to Dr. Neil, all treatment approaches appeared very safe. There were no reports of myositis or rhabdomyolysis. "When gemfibrozil is used in combination with cerivastatin, there does seem to be a specific association leading to rhabdomyolysis. Although we only have 4,700 person-years of follow-up, this study suggests that fenofibrate is a safer drug to use in combination with statin therapy. I think the available data suggest that the side effect profile of fenofibrate may be very different from that of gemfibrozil when used in combination with a statin," commented Dr. Neil.

Effects of Fibrates on Metabolism of Statins

The increased risk for myopathy, including rhabdomyolysis, with the co-administration of fibrates and statins has generally been accepted as a class effect. However, this increased risk has been observed at varied incidences with different fibrates and statins. More documented cases for myopathy have been reported with the gemfibrozil-statin combination therapy than with other fibrate-statin combinations.^4,10

The increased risk of myopathy has been thought to stem primarily from a pharmacodynamic drug-drug interaction, but pharmacokinetic factors may also be involved. To further evaluate this issue, Prueksaritanont and colleagues investigated the effects of fibrates on all major metabolic pathways known to statin hydroxy acids, including beta-oxidation, glucuronidation (a newly identified common metabolic pathway for several statin hydroxy acids), and cytochrome P450-mediated oxidation, using human hepatocytes.8 Based on previous clinical studies, they were interested in determining whether gemfibrozil might interact similarly with other statins, as it does with cerivastatin, and whether fenofibrate would interact differently with the statins than gemfibrozil.

The results of the study suggested that statins differ in their susceptibility to metabolic interactions with gemfibrozil, and that there may be a difference between gemfibrozil and fenofibrate in their ability to alter the pharmacokinetics of statins.

The pharmacokinetic interaction observed between simvastatin and gemfibrozil was believed to be due not to the inhibitory effect of gemfibrozil on the beta-oxidation of simvastatin, but rather to an interaction via glucuronidation. Gemfibrozil modestly affected the formation of beta-oxidative products and CYP3A4-mediated oxidative metabolites of simvastatin hydroxy acid but markedly inhibited the glucuronidation-mediated lactonization of simvastatin hydroxy acid and the glucuronidation of a beta-oxidation product. In contrast, fenofibrate had a minimal effect on all the metabolic pathways of simvastatin hydroxy acid.

Gemfibrozil also significantly inhibited the oxidation of cerivastatin and rosuvastatin, but not of the CYP3A4 substrates simvastatin and atorvastatin, while effectively decreasing the lactonization of all three statins. Based on the studies with known cytochrome P450 inhibitors and a known substrate of CYP2C8, the observed inhibition of cerivastatin oxidation was attributed largely to the inhibitory effect of gemfibrozil on CYP2C8 activity.

The study suggests that gemfibrozil and fenofibrate may be different from each other in terms of their alteration of statin pharmacokinetics, and that statins vary in their susceptibility to pharmacokinetic interactions with gemfibrozil in humans.

The investigators concluded that "Additionally, considering that the exposure to fenofibrate...is much less than the exposure to gemfibrozil at their respective therapeutic doses, the present results suggest that fenofibrate would be less likely than gemfibrozil to inhibit simvastatin metabolism in humans." Furthermore, investigators noted that these results were supported by a clinical pharmacokinetic study that showed fenofibrate did not increase simvastatin exposure when administered with simvastatin (Merck Research Laboratories, manuscript in preparation).

Conclusion

Recent analysis of the Lipid in Diabetes Study from the United Kingdom demonstrated that the combination of cerivastatin (no longer marketed) and fenofibrate was superior to either agent used alone in improving the atherogenic profile of subjects with type 2 diabetes. Importantly, the combination was shown to be safe, with no reports of myositis or rhabdomyolysis with 4,700 person-years of follow-up. Other published studies have found that fenofibrate interacts differently with statins than gemfibrozil, and that statins vary in their susceptibility to pharmacokinetic interactions with gemfibrozil. Together, the results point to a more favorable safety profile when fenofibrate, rather than gemfibrozil, is used in combination with a statin.

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 or without prior myocardial infraction. N Engl J Med. 1998;339:229-234.
2. American Diabetes Association. Management of dyslipidemia in adults with diabetes. 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. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002;346:539-540.
5. Alexandridis G, Pappas GA, Elisaf MS. Rhabdomyolysis due to combination therapy with cerivastatin and gemfibrozil. Am J Med. 2000;109:261-262.
6. Pogson GW, Kindred LH, Carper BG. Rhabdomyolysis and renal failure associated with cerivastatin-gemfibrozil combination therapy. Am J Cardiol. 1999;83:1146.
7. Neil A, Wheeler F, Cull CA, Manley SE, Keenan J, Holman RR. Combination statin and fibrate therapy in type 2 diabetes: results from the Lipids in Diabetes Study. Presented at the 63rd Annual Scientific Sessions of the American Diabetes Association, June 13-17, 2003, New Orleans, Louisiana. Abstract 317-OR.
8. Prueksaritanont T, Tang C, Qiu Y, Mu L, SubramanianR, Lin JG. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Disp. 2002;30:1280-1287.
9. U.S. Food and Drug Administration, FDA Talk Paper, T01-34, August 8, 2001, Bayer Voluntarily Withdraws Baycol. Available at http://www.fda.gov/bbs/topics/ANSWERS/2001/ANS01095.html. Accessed June 25, 2003.
10. Shek A, Ferrill MJ. Statin-fibrate combination therapy. Ann Pharmacother. 2001;35:908-917.