Due to their beneficial effects on glucose and lipid metabolism, PPAR's alpha agonists (fibrates) are good potential candidates for reducing the risk of myocardial infarction (MI) in subjects with metabolic syndrome and diabetes [
10‐
12]. Although less clinical intervention studies have been performed with fibrates than with statins, there are evidences indicating that fibrates may reduce risk of cardiovascular disease and particularly non-fatal MI [
13‐
19]. Interestingly, reduction of cardiovascular disease with two of the fibric acid derivates – gemfibrozil and bezafibrate – was more pronounced in patients displaying baseline characteristics very similar to metabolic syndrome definitions [
13,
14,
20].
There have been no direct head-to-head comparisons of a statin with a fibrate in any clinical endpoint trial. However, compared with statins, fibrates appear to more selectively target the therapeutic goals in obese individuals with features of insulin resistance and metabolic syndrome (i.e. with near-goal LDL-cholesterol and inappropriate HDL-cholesterol and triglyceride levels).
Gemfibrozil: confirmed long-term efficacy
The primary-prevention trial Helsinki Heart Study (HHS) showed that treatment with gemfibrozil led to a significant reduction in major cardiovascular events [
13]. Regarding secondary prevention, in the VA-HIT study (Veterans Affairs High-density lipoprotein cholesterol Intervention Trial) – which included 30% of diabetic patients – gemfibrozil reduced the occurrence of major cardiovascular events by 22 % [
14]. Similarly, reduction of cardiovascular disease with gemfibrozil was more pronounced in patients displaying above three of the features of metabolic syndrome [
21,
22].
The 18-year results from the Helsinki Heart Study shows that patients in the original gemfibrozil group had a 23% lower risk of CAD mortality compared with the original placebo group. But those in the highest tertile of both body-mass index and triglyceride level at baseline had the most dramatic risk reductions with gemfibrozil – 71% for CAD mortality and 33% for all-cause mortality [
23].
These results are entirely consistent with the original positive results of HHS and are strongly supported by the findings of VA-HIT.
Fenofibrate: disappointing results of the FIELD
The recent Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study (24 investigated the effects of fenofibrate on cardiovascular events in type 2 diabetes patients. This was a multinational, randomized, double-blind, placebo-controlled trial in 9795 subjects aged 50 to 75 years of age with type 2 diabetes who were not prescribed statin therapy at study entry. The primary endpoint was coronary events (CAD death or nonfatal MI). The prespecified endpoint for subgroup analyses was cardiovascular events (cardiovascular death, MI, stroke, and coronary and carotid revascularization procedures). After 5 years, fenofibrate-treated patients had a nonsignificant 11% reduction in the incidence of the primary endpoint, nonfatal myocardial infarction, or CAD death (5.2% event rate for the fenofibrate group compared with 5.9% for the placebo group; P = 0.16). Fenofibrate treatment did, however, reduce the incidence of the broader total cardiovascular events endpoint (a prespecified secondary endpoint) by 11% (P = 0.035). Fenofibrate reduced the incidence of most other prespecified endpoints of macrovascular disease, including nonfatal MI events by 24% (P = 0.01), coronary revascularizations by 21% (P = 0.003), and all revascularizations by 20% (P = 0.001). Fenofibrate treatment had a particularly beneficial effect in patients that had no prior CAD. In this primary prevention population (78% of the total population), fenofibrate reduced the incidence of the primary endpoint (CAD events) by 25% (P = 0.014) and the incidence of total cardiovascular events by 19% (P = 0.004). In addition, fenofibrate unexpectedly showed statistically significant reductions in several endpoints, suggesting that microvascular benefit was provided by this treatment. These included a reduction in the requirement for laser retinopathy (5.2% vs. 3.6%, for a 30% reduction; P = 0.0003) and a reduction in albuminuria (2.5% absolute reduction and 1.2% regression; P = 0.002).
The FIELD study design allowed for statin therapy or other lipid-lowering drugs to be added at any time after randomization to either the fenofibrate arm or the placebo arm. The average use of other lipid-lowering therapies (mainly statins) was 17% in the placebo patients and 8% in the fenofibrate patients (P < 0.0001). Significant differences existed also in the use of other in-treatment therapies between the two treatment arms, including angiotensin- converting enzyme (ACE) inhibitors (P = 0.003), beta-blockers (P = 0.01), diuretics (P = 0.006), and coronary revascularization procedures (P = 0.003), with the greater use always occurring in placebo patients. There was a continual increase in statin use through the course of the study, and by the end of the study the statin drop-in rate was 36% in the placebo patients and 19% in the fenofibrate patients. Initiation of statin therapy and other secondary preventive therapies such as aspirin, ACE inhibitors, and beta-blockers also occurred at higher rates in patients with a prior history of CAD compared with patients with no prior history of CAD. The differential use of statins and other evidence-based therapies significantly attenuated the benefits of fenofibrate therapy. Adjustment for statin use revealed a pronounced reduction of total cardiovascular events.
A second explanation for the negative outcome of FIELD related to the change in lipids with fenofibrate, which was considerably less than expected for HDL cholesterol: it was increased by just 5% (compare, for example, with 18% increasing of HDL cholesterol by bezafibrate in the Bezafibrate Infarction Prevention (BIP) trial)).
Bezafibrate: emerged benefits in metabolic syndrome
Bezafibrate, in comparison with other fibrates, has an unique characteristic profile of action since it activates all three PPAR subtypes (alpha, gamma and delta) at comparable doses [
25‐
27]. Therefore, bezafibrate operates as a pan-agonist for all three PPAR isoforms. In two old studies bezafibrate decreased the rate of progression of coronary atherosclerosis and decreased coronary event rate [
15,
16]. In another large trial in 1568 men with lower extremity arterial disease, bezafibrate reduced the severity of intermittent claudication [
17]. In general, the incidence of coronary heart disease in patients on bezafibrate has tended to be lower, but this tendency did not reach statistical significance. However, bezafibrate had significantly reduced the incidence of non-fatal coronary events, particularly in those aged <65 years at entry, in whom all coronary events may also be reduced. In the BIP study an overall trend of a 9.4% reduction of the incidence of primary end point (fatal or non-fatal myocardial infarction or sudden death) was observed. The reduction in the primary end point in 459 patients with high baseline triglycerides (200 mg/dL) was significant [
18].
Most recent extensions of the BIP trial give further support to the hypothesis that patients with insulin-resistant syndromes such as diabetes or metabolic syndrome might be the ones to derive the most benefit from therapy with fibrates [
20,
28‐
30]. Bezafibrate can reduce the incidence of MI in patients with metabolic syndrome. Overall, bezafibrate treatment was associated with reduced risk of any MI and non-fatal MI with HR (CI) respectively 0.71 (0.54–0.95) and 0.67 (0.49–0.91). The cardiac mortality risk tended to be lower on bezafibrate (HR 0.74, CI 0.54–1.03). This trend persisted in patients with augmented features of metabolic syndrome(at least 4 risk factors for metabolic syndrome); of note, a marked reduction in cardiac mortality was observed among these patients on bezafibrate (HR 0.44, CI 0.25–0.80).
Measurements obtained during placebo treatment within BIP trial demonstrated a natural history of progressive increasing of insulin resistance over long-term follow-up [
28]). These unfavorable longitudinal changes were stopped when patients used bezafibrate. In addition, reduced incidence of type 2 diabetes in patients on bezafibrate has been demonstrated [
29,
30]. These new data raise the intriguing possibility that bezafibrate and other fibrates may eventually prove to be clinically useful for conditions other than dyslipidemia [
31].
The factor that dominates in overweight-related metabolic syndrome is the permanent elevation of plasma free fatty acids (FFA) and the predominant utilization of lipids by the muscle inducing a diminution of glucose uptake and insulin resistance. Currently, an insulin-resistant state – as the key phase of metabolic syndrome – constitutes the major risk factor for development of macrovascular complications [
32‐
35].
On the basis of the current concept of the evolution of adipogenesis via PPAR modulation toward insulin resistance and atherothrombotic macrovascular complications (including MI), the decreasing of plasma FFA and improving of insulin sensitization by PPAR agonists seems to be a logical and valuable goal for therapy.
It is important to note that on a whole-body level, lipid and glucose metabolisms interact intimately. Briefly, PPAR alpha is activated by fibric acids (e.g. bezafibrate) and form heterodimers with the 9-cis retinoic acid receptor (RXR). These heterodimers bind to peroxisome proliferator response elements, which are located in numerous gene promoters and increase the level of the expression of mRNAs encoded by PPAR alpha target genes. Bezafibrate reduces triglyceride plasma levels through increases in the expression of genes involved in fatty acid-beta oxidation and by decrease in apolipoprotein C-III gene expression. Fibric acids increase HDL-C partly by increasing apolipoprotein A-I and apolipoprotein A-II gene expression. Their triglyceride-lowering and HDL-C raising effects lead to decreased systemic availability of fatty acid, diminished fatty acid uptake by muscle with improvement of insulin sensitization and reduced plasma glucose level [
36‐
39].
Evidence also suggests that there is a 'fibrate effect' that mediates the reduction in CAD risk beyond the favorable impact of these agents on HDL-C levels. This last notion is consistent with the pleiotropic effects of fibrates which are known to be related to their mechanisms of action [
40]. Through PPAR alpha, fibrates have a significant impact on the synthesis of several apolipoproteins (apo) and enzymes of lipoprotein metabolism as well as on the expression of several genes involved in fibrinolysis and inflammation. Such changes contribute to improve the catabolism of triglyceride-rich lipoproteins, leading to a substantial increase in HDL-C levels accompanied by a shift in the size and density of LDL particles: from small, dense LDL particles to larger, more buoyant cholesteryl ester-rich LDL. These observations becomes particularly important given the dramatic increase in obesity, diabetes, and metabolic syndrome, conditions associated with low HDL and high triglyceride levels and small, dense LDL particles, the lipid profile for which fibrates would seem to be ideally suited [
31].
However, different fibrates may have a somewhat different spectrum of effects. Pooled together evidence suggests, that gemfibrozil and bezafibrate have optimum cardiovascular benefit in metabolic syndrome and/or other appearances of insulin resistance.