Fibrate Activation of PPARα: Clinical Implications for the Dyslipidemic Patient
The ability of pharmacologic agents to reduce cardiovascular events by lowering low-density lipoprotein (LDL)-cholesterol levels and raising high-density lipoprotein (HDL)-cholesterol levels is well known. In addition to hypercholesterolemia, adequate treatment of hypertension, diabetes, obesity, and cessation of smoking similarly lead to a reduction in cardiovascular events. There is growing evidence that other risk factors, such as vascular inflammation and infectious agents (eg, cytomegalovirus) may be of equal importance in increasing the risk of cardiovascular events. Recent evidence suggests that the identification of inflammatory markers associated with vascular inflammation, can predict increased risk for cardiovascular events.1
Data presented at a satellite symposium held during the American Heart Association Scientific Sessions 2003 described the role of peroxisome proliferator-activated receptor α (PPARα) activators, such as fibrates in reducing inflammatory markers. It has been suggested that the anti-inflammatory effects of fibrates may be as important as their beneficial effects on lipid parameters in preventing coronary artery disease. Data was also presented that compared the efficacy of currently available cholesterol-lowering agents and the superior safety and efficacy of fenofibrate compared with gemfibrozil, both as single-agent fibrate therapy and in combination with HMG-CoA reductase inhibitors (statins).
This Cardiology Express Report emphasizes the importance in identification of all risk factors within patients at risk for coronary heart disease and the appropriate use of pharmacologic agents to reduce such risk factors safely and effectively.
Mechanisms of PPARα Action in the Modulation of the Inflammatory Process
The role of inflammation in the development of coronary heart disease has become a major area of clinical interest. Inflammation has been identified as a key non-lipid coronary heart disease risk factor, as atherosclerosis is now recognized as an inflammatory process. It is not surprising, then, to find that standard lipid-lowering therapies such as statins and fibrates have anti-inflammatory effects on the vasculature that partially explain the benefits of these treatments observed in primary and secondary prevention of coronary heart disease, explained Jean-Charles Fruchart, PharmD, PhD, Department of Atherosclerosis, Pasteur Institute of Lille, University of Lille, Lille, France.2
Dr. Fruchart explained that PPARα is a unique protein involved in the vascular inflammatory process that is present in the cells of the artery, heart, liver, and skeletal muscle.3 Administration of a fibrate activates PPARα, resulting in transcription activation of many genes including Apo A-I and Apo A-II,4 which are involved in HDL-cholesterol production, as well as genes involved in transcriptional repression of NFκB and AP-I,5,6 factors that orchestrate inflammation. PPARα activators also inhibit secretion of hepatic interleukin-1 which stimulates C-reactive protein secretion (a marker of inflammation) and C-reactive protein promoter activity.7 Inhibition of these factors by PPARα activation has a direct anti-inflammatory effect on the vasculature resulting in decreased thrombosis, decreased vasoconstriction, decreased cell migration, cell recruitment and activation, decreased foam cell formation, and increased cholesterol efflux. Similarly, the anti-inflammatory effects of fibrates achieved through PPARα activation include decreased vascular inflammation and immunoregulation, plaque stability, and lipid and glucose homeostasis.8 Dr. Fruchart stated that statins as well as fibrates appear to induce PPARα activation, but statins do so indirectly.
Dr. Fruchart went on to cite a study that illustrated how fibrate therapy exerted its anti-inflammatory effects in patients with coronary artery disease. Results of that study showed after four weeks of fenofibrate therapy, plasma interleukin-6 and C-reactive protein levels were reduced in dyslipidemic patients with coronary artery disease.5 Other studies show that there are differences among the two available fibrates in attenuating anti-inflammatory effects; for example, fenofibrate reduces fibrinogen while this effect is not seen with gemfibrozil, Dr. Fruchart indicated.
Highlighting the results of his research, Dr. Fruchart discussed the effects of PPARα activation in the ApoE2 knock in (KI) mouse model of mixed dyslipidemia and atherosclerosis.9 Animals treated with fenofibrate exhibited decreased vascular inflammation and after two to three months of fenofibrate therapy, the size of atherosclerotic lesions was greatly reduced. These results suggest that fibrates have direct anti-inflammatory and anti-atherogenic effect on the vessel wall, Dr. Fruchart advised.
Clinical Effects of Lipid-lowering Agents on C-reactive Protein
Elevated C-reactive protein is recognized as a stronger predictor of cardiovascular events than LDL-cholesterol and adds prognostic information to that conveyed by the Framingham risk score.10 Moreover, high-sensitivity C-reactive protein has been acknowledged by the American Heart Association as an independent cardiovascular risk factor to be used at the discretion of the physician as part of global risk assessment in adults with no known cardiovascular disease.11
Vascular inflammation, as reflected by elevated C-reactive protein, provides a partial explanation for the occurrence of myocardial infarction in persons with normal cholesterol levels, which represents about 50% of patients who have a myocardial infarction, noted Paul M. Ridker, MD, Eugene Braunwald Professor Medicine, Harvard Medical School; Director, Center for Cardiovascular Disease Prevention, Brigham & Women's Hospital, Boston, Massachusetts.12
Dr. Ridker emphasized that LDL-cholesterol remains an extremely important predictor of cardiovascular events that should be treated aggressively. C-reactive protein level does not replace LDL-cholesterol as a prognostic marker, but should be considered supplemental information in formulating clinical management strategies. Moreover, no correlation between the magnitude of reduction of LDL-cholesterol and C-reactive protein level has been observed.13 This "disconnect" suggests that C-reactive protein and LDL-cholesterol are independent of one another, Dr. Ridker noted. Patients with elevated LDL-cholesterol levels and elevated C-reactive protein levels are at high risk for future cardiovascular events. Clinical management of these patients is made more complex since currently utilized lipid screenings do not include an assessment of C-reactive protein.
According to Dr. Ridker, the broader issue is whether C-reactive protein screening combined with current lipid screenings will lead to improved targeted therapy in the primary prevention of cardiovascular disease. Analysis of the Air Force/Texas Coronary Prevention Study (AFCAPS/TexCAPS) showed that statin therapy was effective in patients with low LDL-cholesterol and high C-reactive protein, high LDL-cholesterol/low C-reactive protein, and high levels of both risk factors.14 No effect of statins was found in patients with low levels of both markers.
Clinical trial data in patients with combined hyperlipidemia suggest that both fenofibrate15 and bezafibrate16 lower C-reactive protein level as well, noted Dr. Ridker.
Anti-inflammatory Effects of Fibrate Therapy
The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) was the first lipid intervention trial designed to show that raising HDL-cholesterol concentrations while not decreasing LDL-cholesterol in patients with established coronary heart disease would significantly reduce the incidence of major coronary events.17 VA-HIT evaluated a total of 2,531 men with low HDL-cholesterol, low LDL-cholesterol, and moderately high triglycerides. Fibrate therapy was associated with a 22% relative risk reduction in coronary heart disease death and nonfatal myocardial infarction (95% Confidence Interval (CI), 7%-35%; P = .006) and a 24% relative risk reduction in the expanded endpoint of coronary heart disease death, nonfatal myocardial infarction, and confirmed stroke (95% CI, 11%-36%; P<.001).
Sander Robins, MD, Professor of Medicine, Boston University School of Medicine, Boston, Massachusetts, Co-Principal Investigator of VA-HIT,18 pointed out that the lipid changes achieved with fibrate therapy accounted for only 23% of the treatment benefit.19 This led investigators to look for other effects that might have led to the risk reduction in cardiovascular events observed in the trial.
The study population had a high prevalence of diabetes (31%), hyperinsulinemia, a surrogate marker for insulin resistance (33%), obesity (39%), and other features consistent with the metabolic syndrome. Patients with diabetes experienced a 41% reduction in coronary heart disease death (hazard ratio, 0.59; 95% CI, 0.39-0.91; P = .02) and a 40% reduction in stroke (hazard ratio, 0.60; 95% CI, 0.37-0.99; P = .046) with fibrate therapy.20
An intention-to-treat subanalysis of VA-HIT was conducted to better understand the effects of fibrate therapy on the incidence of major cardiovascular events in the presence of insulin resistance. With insulin resistance, there was a significantly higher relative risk of a cardiovascular event with diabetes (relative risk, 1.62; 95% CI, 1.28-2.06) and without diabetes (relative risk, 1.43; 95% CI, 1.03-1.98) than without insulin resistance.21 Throughout both lower and higher ranges of HDL-cholesterol and triglycerides, the rate of new cardiovascular events and the reduction of events with fibrate therapy were greater in subjects with insulin resistance than without.
Although VA-HIT was undertaken with the premise that increasing a low HDL-cholesterol would reduce cardiovascular events, Dr. Robins pointed out that in the subgroup of individuals with insulin resistance where event reduction with gemfibrozil was substantial, there was only a small increase in HDL-cholesterol (on the order of 1 to 2%). However, in contrast to this small change in HDL-cholesterol, new and as yet unpublished data shows that with fibrate therapy in VA-HIT, there was a highly significant reduction in levels of C-reactive protein (on the order of 40%) that was selectively greater in those with insulin resistance than without insulin resistance. Moreover, in the subgroup with insulin resistance, the reduction in C-reactive protein was found to predict a significant reduction in cardiovascular events.
Dr. Robins concluded by saying that while a low HDL-cholesterol (in addition to other features of the metabolic syndrome) defined the population at risk who were most likely to benefit from fibrate therapy, the benefit of fibrate therapy appeared to be more related to a reduction in inflammation than to an increase in HDL-cholesterol concentration.
The Safety of Statin and Fibrate Combination Therapy
"With the support of treatment guidelines, physicians should now be targeting dyslipidemia aggressively," advised Michael H. Davidson, MD, FACC, Associate Professor of Medicine, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois.22 Statins effectively lower LDL-cholesterol but have a modest effect on raising HDL-cholesterol while fibrates raise HDL-cholesterol and lower triglycerides. These properties offer an attractive option for combination therapy in the total lipid management of patients with dyslipidemia, such as diabetics or those with metabolic syndrome. Emphasizing the opportunity for combination therapy, Dr. Davidson pointed out that even though target LDL-cholesterol goals may be achieved with statin therapy, a significant residual risk of cardiovascular events persists in the patient with elevated non-HDL-cholesterol and hypertriglyceridemia.23
"Alternatively, statins could be uptitrated to achieve further reductions in lipids, but several studies have raised safety concerns related myopathy in association with high-dose statin therapy," stated Dr. Davidson. Myopathy appears to be a dose-related phenomenon and is generally not observed when approved doses of statins are used. The risk/benefit ratio needs to be considered when increasing doses of statins. In the Myocardial Ischemia Reduction with Acute Cholesterol Lowering (MIRACL) trial, absolute reduction in risk of cardiovascular events was 2% with atorvastatin 80 mg daily with a corresponding absolute increase of 2% in abnormal liver transaminases (>3 times upper limit of normal) (P<.001).24
Looking to differentiate the available fibrates, Dr. Davidson noted that peak levels of simvastatin were increased with concomitant gemfibrozil.25 When cerivastatin (withdrawn from the US market26) was combined with gemfibrozil, a number of cases of rhabdomyolysis and death were reported,27-29 presumably due to marked increases in levels of cerivastatin.30 Important differences in the pharmacokinetic profiles of gemfibrozil and fenofibrate result in diverse effects on concomitant statin therapy.31 Although gemfibrozil has been shown to increase plasma levels of many statins, studies show that fenofibrate does not increase levels of pravastatin, cerivastatin, simvastatin, or rosuvastatin.31
Glucuronidation provides an explanation for the difference between fibrates, Dr. Davidson explained. Gemfibrozil affects glucuronidation (a pathway for the elimination of the active hydroxy acid metabolites of simvastatin, atorvastatin, and cerivastatin) where fenofibrate does not.
Evidence for the safety of fenofibrate and statin combinations comes from the Lipids in Diabetes Study (LDS),32 a study which evaluated fenofibrate and cerivastatin as single agents and in combination. No increase in risk of rhabdomyolysis and a low-risk of myopathy was observed in more than 1,000 patients treated with the combination of fenofibrate and cerivastatin. However, the trial was terminated upon the market withdrawal of cerivastatin.
The role of inflammatory markers as predictors of cardiovascular risk will continue to evolve as the relationship between the inflammatory process and the development of coronary heart disease is more clearly defined. Fibrates have been shown to reduce inflammatory markers through PPARα activation and thereby reduce cardiovascular events in the patient with dyslipidemia. Data shows that single-agent fenofibrate, or in combination with statins, can safely and effectively treat such patients.
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32. 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.