Expert Commentary

John B. Buse, MD, PhD, CDE, FACE, Associate Professor of Medicine, Chief, Division of General Internal Medicine and Clinical Epidemiology, Director, Diabetes Care Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina

Individuals with type 2 diabetes have a 2- to 4-fold increase in major cardiovascular events and cardiovascular death compared to persons without diabetes.¹ In fact, it has been well established that their risk is equal to that of persons with a prior myocardial infarction. Thus, diabetes is a "cardiovascular risk equivalent".^1,2 Even in the setting of insulin resistance or metabolic syndrome without diabetes, increased cardiovascular risk has been documented.³ The need is great to address the underlying cardiovascular risk factors in these patients. Recent guidelines from the third report of the National Cholesterol Education Project Adult Treatment Panel (NCEP ATP III) placed particular emphasis on the value of aggressive lipid modification in patients with diabetes or the metabolic syndrome.⁴ Typically, these individuals demonstrate a constellation of lipid abnormalities characterized by low high-density lipoprotein (HDL)-cholesterol, elevated triglycerides, and often normal or near-normal low-density lipoprotein (LDL)-cholesterol levels. This profile is frequently referred to as atherogenic, or mixed, dyslipidemia.

Such patients are usually prescribed HMG-CoA reductase inhibitors (statins), which primarily lower LDL-cholesterol. But in people with diabetes, elevated LDL-cholesterol is not the only concern or even the primary lipid abnormality. It has become clear that lowering LDL-cholesterol alone with statins is not sufficient to meet American Diabetes Association treatment guidelines for many patients with atherogenic dyslipidemia.^5,6 In addition to statins, interventions that increase HDL-cholesterol and lower triglycerides are a high priority. A variety of these adjunctive approaches are at the clinician's disposal including diet and exercise, fibrates, niacin, fish oils and pioglitazone. As is true in our efforts to reach glycemic targets and blood pressure targets in the management of patients with diabetes, reaching lipid targets often requires a combination of approaches—lifestyle therapy as well as generally one or more lipid modifying agents.

Results from an extensive number of clinical trials indicate that both statins and fibrates are effective in modulating these lipid abnormalities as well as in reducing excessive cardiovascular risk. Fibrates are an excellent choice for targeting low HDL-cholesterol and elevated triglycerides, especially in mixed dyslipidemia. While there is more limited clinical data available to support combination statin/fibrate therapy, this dual approach is being prescribed in patients with dyslipidemia with or without type 2 diabetes. While the available fibrates when combined with statins may be equally effective in meeting this goal, there are some additional safety concerns when gemfibrozil is combined with statins. Most notably, among the 31 fatal cases of rhabdomyolysis reported with cerivastatin use,⁷ gemfibrozil was used concomitantly in 12, according to the FDA's Adverse Events Reporting System for January 1998 to March 2002.⁷ It appears that this interaction is unique to gemfibrozil, as it has not been observed with combination fenofibrate/cerivastatin therapy.

Thus, for mixed dyslipidemia, fenofibrate may be a preferred option, according to speakers at a Satellite Symposium held during the 63rd Scientific Sessions of the American Diabetes Association. At this Symposium, which is summarized in this Cardiology Express Report, lipid specialists sorted through the treatment options and advised clinicians on the safest and most effective use of lipid-modifying agents.

High Risk Associated with Diabetes and the Metabolic Syndrome

The metabolic syndrome is diagnosed by the presence of three or more of the following features⁴:

• Triglycerides ≥150 mg/dL
• HDL-cholesterol ≤40 mg/dL in men and ≤50 mg/dL in women
• Waist >40 inches in men or >35 inches in women
• Systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥85 mm Hg
• Fasting plasma glucose ≥110 mg/dL

Each potential component of the metabolic syndrome is associated with increased risk for cardiovascular disease. In fact, presence of the metabolic syndrome imposes a 3.5-fold increased risk for cardiovascular mortality compared with individuals without the disorder,^[3] explained John B. Buse, MD, PhD, CDE, FACE, Associate Professor of Medicine, Chief, Division of General Internal Medicine and Clinical Epidemiology, Director, Diabetes Care Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.⁸

"There is now a clear mandate for maximizing the treatment of the atherogenic dyslipidemia associated with the metabolic syndrome and its related disorder, type 2 diabetes to minimize cardiovascular risk," stated Dr. Buse.

PPARα Agonists in Atherogenic Dyslipidemia

Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors that control a variety of cellular functions by modulating the expression of target genes. The activation of PPARs (PPARα, PPARβ, and PPARγ) by agonists promotes their activity.

PPARα, in particular, regulates lipoprotein metabolism through its effects on lipid transport and oxidation. By affecting the catabolism of fatty acids, PPARα reduces fatty acids and triglyceride particles in the plasma. Recently, PPARα was shown to act on the Apo AV gene locus,⁹ which contributes significantly to inter-individual variations in plasma triglyceride levels and very low-density lipoprotein (VLDL) mass.

"When we use a fibrate, which is a PPARα agonist, we increase the expression of Apo AV and we also normalize the structure of very low-density lipoprotein. Fibrates cause a shift of small atherosclerotic low-density lipoprotein particles to less atherogenic low-density lipoprotein, and reduce triglyceride levels," said Jean-Charles Fruchart, PharmD, PhD, Department of Atherosclerosis, Pasteur Institute of Lille, University of Lille, Lille, France.¹⁰

Additionally, PPARα agonists enhance cholesterol efflux from human macrophages, decrease thrombosis, and increase plaque stability. Fibrates also reduce modulators of inflammation in the vascular wall and lower plasma C-reactive protein expression. "If you treat a patient with fenofibrate, you get a very significant drop in C-reactive protein levels^[11]," advised Dr. Fruchart.

"But PPARα agonists—fibrates—are not all the same," Dr. Fruchart emphasized, describing a new concept called "selective PPAR modulation." In the treatment of dyslipidemia, the available fibrates (gemfibrozil and fenofibrate) have common pharmacologic activities in that they both reduce triglyceride and increase HDL-cholesterol levels, but they also have some distinct pharmacological actions, since gemfibrozil is only a partial PPARα agonist, according to Dr. Fruchart. "Fenofibrate reduces LDL-cholesterol, reduces fibrinogen, and increases Apo A-I, while gemfibrozil has no effect on LDL-cholesterol, fibrinogen or Apo A-I," Dr. Fruchart pointed out.

Statins can also induce PPARα activity, via inhibition of the geranylgeranyl-PP/RhoA signaling pathway, and can induce Apo A-I expression. "The combination of statins and PPARα activators, in fact, have a synergistic effect on Apo A-I and thus can increase HDL-cholesterol more significantly than either agent administered alone," noted Dr. Fruchart.

Evidence of Benefit with PPARα Agonists

Evidence for the use of PPARα agonists for coronary heart disease (CHD) prevention in patients with diabetes or the metabolic syndrome is based largely on the results of the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) undertaken with gemfibrozil.¹²

The study population included 2,531 men with documented CHD, low HDL-cholesterol (mean 32 mg/dL), low LDL-cholesterol (mean 111 mg/dL), and borderline-high triglycerides (mean 162 mg/dL) at baseline, who had a high prevalence of diabetes (31%) and hyperinsulinemia (33%). "In this population, gemfibrozil preferentially reduced coronary heart disease and strokes in persons with diabetes or hyperinsulinemia,^[13] but had no benefit in persons who did not have these conditions," stated Sander J. Robins, MD, Professor of Medicine, Boston University School of Medicine, Boston, Massachusetts and Co-principal Investigator of VA-HIT.

In diabetic patients, the reduction in CHD death was directly related to body mass index (BMI), with patients (39% with baseline BMI ≥30 kg/m²) in the highest BMI tertiles experiencing about a 50% reduction. "Gemfibrozil may have a greater effect in coronary heart disease as BMI increases," advised Dr. Robins, noting that this particular benefit seems true across the fibrate class of agents. Furthermore, benefit was seen early. "Deaths from coronary heart disease were reduced in a period as short as 3 years, which is unprecedented," exclaimed Dr. Robins.

In the VA-HIT diabetic population, gemfibrozil was associated with a 41% reduction in CHD death (hazard ratio, 0.59; 95% Confidence Interval (CI), 0.39-0.91; P = .02) and a 40% reduction in stroke risk (hazard ratio, 0.60; 95% CI, 0.37-0.99; P = 0.46). "This magnitude of benefit, especially for coronary heart disease deaths in diabetics with low-to-moderate LDL-cholesterol, was greater than seen in trials of statin therapy," noted Dr. Robins.

"Results of the VA-HIT,^[12] Helsinki Heart Study,^[14] and the Bezafibrate Infarction Prevention (BIP) study^[15] showed that gemfibrozil and bezafibrate preferentially reduce coronary heart disease events in those with the highest BMI, suggesting that fibrates optimally benefit patients with features of the metabolic syndrome," advised Dr. Robins.

Efficacy of Combination Therapy with PPARα Agonists and Statins for Mixed Dyslipidemia

In persons at high risk for CHD, statin monotherapy reduces relative risk by about 20-40% regardless of baseline LDL-cholesterol levels, according to results from the major clinical trials. However, statins are often not sufficient to bring patients to the recommended target lipid goals, especially in patients with mixed dyslipidemia. "The combination of a statin and a fibrate is often a very effective option," indicated Peter H. Jones, MD, Associate Professor of Medicine, Baylor College of Medicine, Houston, Texas.16

"Patients with combined dyslipidemias are a very high-risk group," stressed Dr. Jones. High CHD risk is associated with the atherogenic lipid "triad" of small, dense LDL-cholesterol, low HDL-cholesterol, and elevated triglycerides. Post-hoc analysis of statin trials (CARE,¹⁷ LIPID,¹⁸ 4S¹⁹) and fibrate trials (VA-HIT,¹² Helsinki Heart Study,¹⁴ BIP¹⁵) demonstrate a reduction of CHD events with treatment of the lipid triad, indicated Dr. Jones. "There are incredible benefits with the combination," Dr. Jones remarked.

Dr. Jones gave the following rationale for using a statin-plus-fibrate approach:

• Statins reduce the number of atherogenic (Apo-B-containing) lipoprotein particles through a hepatic LDL receptor-mediated process.
• Fibrates reduce triglyceride-rich lipoproteins and postprandial lipemia by PPARα-mediated enhanced clearance, and they increase LDL particle size.
• Both statins and fibrates can reduce VLDL production and increase Apo A-I production.

"These observations raise the possibility that combined drug therapy with fibrates and statins will offer a greater risk reduction than can be achieved by LDL-lowering alone," Dr. Jones advised.

Dr. Jones noted a recent study by Athyros et al,²⁰ in which 120 patients with type 2 diabetes and combined dyslipidemia showed "a clearly additive effect" of combined treatment with atorvastatin and fenofibrate, compared to either agent alone. Additional improvements were seen in all components of the dyslipidemic profile. Furthermore, more patients achieved the American Diabetes Association goals with combined atorvastatin plus fenofibrate therapy. The combination significantly reduced the 10-year probability of myocardial infarction (calculated using the PROCAM risk calculator²¹) over therapy with either agent alone (P<.05).

Safety Concerns with High-dose Statins and Fibrates in Combination

High-dose statins (80 mg atorvastatin or simvastatin) will also achieve moderately greater improvements in cardiovascular risk factors, compared to lower doses of statins, and the American Diabetes Association recommends this approach.⁶ But the additional LDL-lowering benefit of high-dose statins may be outweighed by as much as a 4-fold increased risk of elevated hepatic transaminases, compared to lower doses.²² "The higher doses also pose an increased risk for muscle symptoms, and possibly even rhabdomyolysis," advised Dr. Jones.

"Fibrates can also cause myopathy, so there have been concerns about using fibrates and statins together. However, there are certain situations in which the risk is increased, and mostly this involves gemfibrozil," Dr. Jones pointed out. The risk of myositis with combination statin and fibrate therapy is considered to be about 1%.²³ Noting that the vast majority of fatal rhabdomyolysis cases with cerivastatin occurred when this statin was used with gemfibrozil (12 of 31, 39%) led Dr. Jones to caution "Do not use gemfibrozil in combination with a statin."

Dr. Jones suggested a possible explanation for the difference in safety between fenofibrate and gemfibrozil may lie within the glucuronidation process. Glucuronidation is a pathway for the elimination of the active hydroxy acid metabolites of simvastatin, atorvastatin, and cerivastatin. Recent data suggest that gemfibrozil, but not fenofibrate, strongly inhibits glucuronidation, most prominently for cerivastatin.²² Additionally, in various studies, gemfibrozil has been shown to greatly enhance plasma concentrations of simvastatin and lovastatin,^24,25 while fenofibrate has shown no appreciable effect on the plasma concentrations of cerivastatin, pravastatin, or rosuvastatin.^26,27

"Interestingly, the significant effect of gemfibrozil on both glucuronidation and oxidation of cerivastatin seems to occur also with rosuvastatin, according to a study presented at the American Heart Association 2002 Annual Meeting [Abstract 926] and recently published,^[28] suggesting the potential for pharmacokinetic interaction between this new statin and gemfibrozil," added Dr. Jones.

Dr. Jones summarized his advice regarding using a safe combination therapy for dyslipidemia in diabetes, "The most important thing is to keep plasma levels of statins low. Don't use the maximum doses, don't interfere with the metabolism of the statins [through drugs that interact], and use fenofibrate rather than gemfibrozil."

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 infarction. N Engl J Med. 1998; 339:229-234.
2. Mukamal KJ, Nesto RW, Cohen MC, et al. Impact of diabetes on long-term survival after acute myocardial infarction. Comparability of risk with prior myocardial infarction. Diabetes Care. 2001;24:1422-1427.
3. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002; 288:2709-2716.
4. 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.
5. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2003;26(suppl 1):S33-S50.
6. American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care. 2003;26(suppl 1):S83-S86.
7. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Eng J Med. 2002;346:539-540.
8. Buse J. The High Risk Associated with Patients with Diabetes or the Metabolic Syndrome. Presented in the Satellite Symposium "PPARα: Is it the Key to Unlock Greater Cardiovascular Risk Reduction in the Diabetic?" during the 63rd Scientific Sessions of the American Diabetes Association, June 13, 2003, New Orleans, Louisiana.
9. Pennacchio LA, Olivier M, Hubacek JA, et al. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science. 2001;294:169-173.
10. Fruchart JC. Unique Properties of PPARα Compounds and Their Relationship to Patients with Diabetes and the Metabolic Syndrome. Presented in the Satellite Symposium "PPARα: Is it the Key to Unlock Greater Cardiovascular Risk Reduction in the Diabetic?" during the 63rd Scientific Sessions of the American Diabetes Association, June 13, 2003, New Orleans, Louisiana.
11. Staels B, Koenig W, Habib A, et al. Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not PPARgamma activators. Nature. 1998;393:790-793.
12. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low-density lipoprotein cholesterol. Veterans High-Density Lipoprotein Intervention Trial Study Group. N Engl J Med. 1999;341:410-418.
13. 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 Int Med. 2002;162:2597-2604.
14. Tenkanen L, Mantarri M, Manninen V. Some coronary risk factors related to the insulin resistance syndrome and treatment with gemfibrozil: experience from the Helsinki Heart Study. Circulation. 1995;92:1779-1785.
15. The BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) Study. Circulation. 2000;102:21-27.
16. Jones PH. The Safety of Combination Therapy with PPARα Agonists and HMG-CoA Reductase Inhibitors for Mixed Dyslipidemia. Presented in the Satellite Symposium "PPARα: Is it the Key to Unlock Greater Cardiovascular Risk Reduction in the Diabetic?" during the 63rd Scientific Sessions of the American Diabetes Association, June 13, 2003, New Orleans, Louisiana.
17. 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.
18. 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 Ischemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349-1357.
19. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344:1383-1389.
20. Athyros VG, Papageorgiou AA, Athyrou VV, Demitriadis DS, Kontopoulos AG. Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidemia. Diabetes Care. 2002;25:1198-1202.
21. 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.
22. Davidson MH. Combination therapy for dyslipidemia: safety and regulatory considerations. Am J Cardiol. 2002;90(suppl):50K-60K.
23. Pasternak RC, Smith SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. American College of Cardiology; American Heart Association; National Heart, Lung and Blood Institute. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol. 2002;40:567-572.
24. Backman JT, Kyrklund C, Kivisto KT, Wang JS, Neuvonen PJ. Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther. 2000;66:122-129.
25. Kyrklund C, Backman JT, Kivisto KT, Neuvonen M, Laitila J, Neuvonen PJ. Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate. Clin Pharmacol Ther. 2001;69:340-345.
26. Pan WJ, Gustavson LE, Achari R, et al. Lack of a clinically significant pharmacokinetic interaction between fenofibrate and pravastatin in healthy volunteers. J Clin Pharmacol. 2000;40:316-323.
27. Martin PD, Dane AL, Schneck DW, Warwick MJ. An open-label, randomized, three-way crossover trial of the effects of coadministration of rosuvastatin and fenofibrate on the pharmacokinetic properties of rosuvastatin and fenofibric acid in healthy male volunteers. Clin Ther. 2003;25:459-471.
28. Prueksaritanont T, Tang C, Qiu Y, Mu L, Subramanian R, Lin JH. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos. 2002;30:1280-1287.