Understanding the mechanism of action of fibrates itself took 30 years. The basic mechanism was identified only in the 1990s, when a new superfamily of nuclear receptors was discovered, different from the previously known steroid receptors, whose ligands may include a large group of compounds such as fatty acids and fibrates [1]. The receptors mediate the proliferative response of peroxisomes, and thus their name – peroxisome proliferator-activated receptors (PPARs) [2–5]. Today, three groups of the receptors – PPARα (NR1C1), PPARβ/δ (NR1C2) and PPARγ (NR1C3) – have been identified [3]. PPARα are located primarily in mitochondria-rich cells – in the liver, kidneys and heart as well as in the mucous membrane of intestines – while the two other types are expressed throughout the entire body [3–5]. Fibrates act as ligands primarily for PPARα (only bezafibrate activates α, β/δ and γ receptors to the same degree) [6–8]. An activated receptor recognises and binds to strictly defined DNA sites, thus causing activation or inhibition of a relevant gene – in the case of fibrates, it has been proven that binding to PPARα induces the expression of genes which are involved in intracellular processes of metabolism of fatty acids and genes controlling protein synthesis (enzymes and apolipoproteins [Apos]), connected with the metabolism of lipids and lipoproteins [9, 10].

The beneficial effect of fibrates on lipid levels is exerted via several mechanisms: (1) they enhance lipolysis by increasing the activity of lipoprotein lipase [11] and reduce hepatic production of Apo C-III, a component of very large density lipoprotein (VLDL), which inhibits the enzyme [12]; (2) they increase hepatic beta-oxidation of fatty acids, which are precursors of triglycerides (TGs) – reduction in the concentration of substrates for the production of TGs results in reduced production of TG-rich VLDL particles in the liver [13, 14]; (3) they increase the elimination of LDL particles – during therapy with fibrates, LDL lipoproteins having increased affinity for LDL receptor are formed, which significantly facilities and hastens their catabolism [15]. This leads to changes in LDL-C subfractions – mainly small dense lipoproteins are reduced, while the subfraction of larger LDL particles increases [15–17]; (4) they reduce the production of TG-rich lipoproteins by reducing the exchange of TGs and cholesterol esters between high-density lipoprotein (HDL) particles and VLDL particles [18]; (5) they increase the production of HDL-C – fibrates have the ability to increase the production of Apos A-I and A-II in the liver, which results in increased plasma levels of HDL-C and more efficient transfer of cholesterol from peripheral tissues [19, 20] and is associated with decreased concentration of Lp-AI (HDL subfraction containing Apo A-I without Apo A-II) and increased concentration of Lp-AI:AII [21, 22]. Recently, it has been postulated that favourable modification of the HDL subfraction towards larger particles might be possible, although the results are not unequivocal [23, 24].

In the light of the mechanisms described above, the clinical effects of fibrates are as the following: they reduce plasma levels of TG by 30–50 % and increase HDL-C levels by 2–20 %; however, their effect on LDL cholesterol levels is relatively weak – from even no effect (less than 5 %) to a 10–20 % reduction [7, 25, 26].

The most important studies of fibrates include the Helsinki Heart Study (HHS) [27] and the Veterans Affairs high-density lipoprotein cholesterol intervention trial (VA-HIT) [28] – both with gemfibrozil – the Bezafibrate Infarction Prevention (BIP) [29] and the Lower Extremity Arterial Disease Event Reduction (LEADER) [30] – both with bezafibrate – and two large studies with fenofibrate: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) [31] and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial [32].

Taking into account the fact that in many European countries only fenofibrate is available, the authors of this chapter have focused on the studies/trials dedicated to this fibrate. However, it is worth emphasising that in the light of high prevalence of dyslipidaemias and lack of efficacy of residual risk reduction, accessibility of such potent fibrates like gemfibrozil and bezafibrate would be much expected.

The FIELD was a multi-centre, double-blind, and randomised study that was aimed at determining whether therapy with fibrate, compared with placebo, reduces the risk of cardiovascular (CV) incidents in patients with type 2 diabetes (DMt2). The primary end point was either coronary heart disease (CHD) death or non-fatal myocardial infarction (MI) or both events combined [31]. Participants had to meet at least one of the following lipid criteria: serum total cholesterol (TC) levels 3.0–6.5 mmol/L (115–250 mg/dL) and/or TC-to-HDL-C ratio ≥4 or TG level 1–5 mmol/L (90–445 mg/dL). Individuals were not eligible if they: had indications for the use of other hypolipidemic agents (although the use of such agents during the study was allowed), had a CV event in the last 3 months or suffered from chronic kidney disease (CKD; creatinine >130 μmol/L) or chronic liver disease or symptomatic gallbladder disease [31].

The study finally involved 9,795 patients, mean time from the diagnosis of DMt2 was 5 years, the subjects were aged 50–75 years and the vast majority (7,664) of participants had no signs or symptoms of CVD at enrolment. After initial 16-week observation (4 weeks of diet, 6 weeks of placebo and 6 weeks of fenofibrate), the patients were randomised either to micronised fenofibrate 200 mg/day (n = 4,895) or placebo (n = 4,900). Median follow-up was 5 years [31]. The results were unconvincing – in the fenofibrate group, the rates of CHD deaths and non-fatal MI were reduced by 11 % (95 % confidence interval [CI]: −24 to 5; p = 0.16), but the reduction was not significant, which was related to a significant drop in the non-fatal MI rate by 24 % (95 %CI: 6–37) and non-significant increase in the CHD death rate by 19 % (95 %CI: −10 to 56) [31]. The lack of significant reduction in the primary end point (apart from non-fatal MI) was widely discussed. It was especially pointed out that the lack of benefits from fenofibrate therapy might have been caused by more frequent use of statins in the placebo group (17 vs 8 %; adjusted analysis which allowed to withdraw all patients with statin therapy showed significant changes of primary end point in fenofibrate group) [31, 33]. It was due to the fact that the Heart Protection Study (HPS) was meanwhile published, and according to the recommendations based on its results, the FIELD investigators were forced to use statins in patients with diabetes [33]. Another possible explanation of these negative results was an unfavourable fibrate selection of subjects with relatively high baseline HDL-C levels (mean 42 mg/dL) in whom only slight increase in HDL-C was seen at the end of the study (by 1.2 %). It is known that the lower the baseline HDL-C, the greater the effect of fenofibrate, which was also seen in the FIELD study – in the subgroup of patients with the lowest baseline HDL levels (<40 mg/dL), a statistically significant reduction in CV events was seen in those receiving fenofibrate (p = 0.02). However, it is worth remembering that the slight increase in HDL levels in diabetic patients may have been caused by decreased affinity of fibrates for PPARα, which is seen in this group of patients [34]. On the other hand, it needs to be also taken into account that in the patients of diabetes we might expect the impaired HDL functionality, therefore this explanation seems to be also questionable [35].

Were there any benefits of fenofibrate therapy in the FIELD study? Of the secondary end points, a statistically significant 10 % reduction in all CV events was seen – CV deaths, MIs, strokes and coronary and carotid revascularisation (95 %CI: 1–19; absolute risk reduction by 1.4 %) [31, 33]. The inhibition of the progression of micro-angiopathic complications was also seen – fenofibrate reduced the risk of peripheral amputations (p = 0.011), the progression of albuminuria (p = 0.002) and diabetic retinopathy [33, 36]. In patients diagnosed with diabetic retinopathy prior to enrolment, retinopathy progression by at least two grades occurred considerably less frequently during therapy with fenofibrate (3 subjects [3.1 %] in the fenofibrate group vs 14 subjects [14.6 %] in the placebo group; p = 0.004) [36]. Also, the need for laser therapy occurred less frequently (164 subjects [3.4 %] vs 238 subjects [4.9 %]; p = 0.0002), which was reflected in a significant reduction in the composite end point of progression of retinopathy by two grades, progression of macular oedema and increase in the need for laser therapy [36].

Despite negative results of FIELD trial (mainly due to methodological limitations), ineffectiveness of statin monotherapy with persistent low levels of HDL-C and especially high levels of TG should prompt physicians to consider treatment with fenofibrate [33]. It is also of interest in the FIELD study, in a small subgroup of patients undergoing combination therapy, there was a significant reduction in coronary events’ risk by 49 % (p <0.001) and all CV events by 26 % (p <0.001) [33, 36].

Because of the negative results obtained in the FIELD trial and new guidelines how to treat patients with DMt2 (=statins as a first line), there was a need for another trial investigating the effect of fenofibrate as an add-on to statin therapy in diabetic patients. In 2010, the results of another multi-centre, prospective, double-blind study with fenofibrate were announced – ACCORD LIPID, the lipid arm of the ACCORD study [32]. The fundamental question to consider was whether or not combination therapy with statin (simvastatin) and fibrate reduced CV risk compared with statin monotherapy in patients with DMt2. The study finally involved 5,518 subjects – patients with clinical CVD aged 40–79 years and, in the case of subclinical CVD or at least two risk factors for the disease, older patients aged 55–79 years [32]. Prior to the study, LDL-C levels were 60–180 mg/dL (1.55–4.65 mmol/L), HDL-C <55 mg/dL (1.42 mmol/L) in females and in blacks and <50 mg/dL (1.29 mmol/L) in all other subjects, TG levels were <750 mg/dL (8.5 mmol/L) without hypolipidemic therapy or <400 mg/dL (4.5 mmol/L) during therapy [32]. Subjects were randomised to two groups – 2,753 patients were treated with simvastatin (20 mg for primary prevention or 40 mg for secondary prevention), and 2,765 patients were treated with statin in combination with fenofibrate (160 mg if estimated glomerular filtration rate (eGFR) >50 mL/min/1.73 m² or one third of the dose if renal function was moderately impaired: eGFR 30–50 mL/min/1.73 m²). The primary end point was the occurrence of death from CV causes, non-fatal MI and non-fatal stroke. Secondary end points were the combination of primary end point and revascularisation or hospitalisation for congestive heart failure; combination of fatal cardiac event, MI or unstable angina pectoris; MI; fatal or non-fatal stroke; non-fatal stroke; death from any cause; death from CV causes and hospitalisation or death due to heart failure [32]. In the study, end points related to microvascular disorders were also assessed: progression of retinopathy by at least three grades on the Early Treatment Diabetic Retinopathy Study (EDTRS) scale, the need for photocoagulation or vitrectomy and progression of renal function impairment [32, 33].

After nearly 5 years, significant beneficial changes in lipid profile were seen in both groups: reduction in LDL-C levels (from 100 to 81.1 mg/dL in the fenofibrate group and from 101.1 to 80 mg/dL in the placebo group), reduction in TG levels (from 189 to 147 mg/day and from 186.2 to 170, respectively) and increase in HDL-C levels (from 38 to 41.2 mg/dL in the fenofibrate group and from 38.2 to 40.5 mg/dL in the placebo group) [32]. However, no reduction in the primary end point was observed in the group of subjects undergoing combination therapy compared with statin monotherapy – a 10.1 % risk reduction in both groups (p = 0.32) or in secondary end points. One of the reasons of these negative results, which were highly discussed after the study completion, was the fact that patients included to the study were very effectively treated with statins and in fact there were no indications to fenofibrate therapy taking into account their baseline lipid profile [32, 33]. However, in the subgroup of subjects with the lowest levels of HDL-C and, at the same time, the highest levels of TG (≤34 and ≥204 mg/dL, respectively), even 31 % reduction in the primary end point was seen in those undergoing combination therapy (12.37 vs 17.32 % of subjects with a vascular episode; p = 0.057). What is important, the benefits from this approach were seen also in subjects who achieved low LDL-C levels (<70 mg/dL) [32]. In addition, as was anticipated, slowing of the progression of micro-angiopathy was confirmed, reduction in albuminuria was observed and the progression of retinopathy was slower – in 6.5 % of subjects treated with fenofibrate vs 10.2 % of subjects receiving placebo (odds ratio [OR] 0.60; 95 %CI 0.42–0.87; p = 0.006); however, subjects without retinopathy at the moment of the enrolment as well as subjects with severe initial lesions did not benefit from additional therapy with fenofibrate [37, 38].

The results of the FIELD and ACCORD studies were deemed disappointing, and many lipidologists announced the start of the twilight of fibrate therapy. Yet, a question should be asked if such a statement was warranted, since both of those large studies were limited by their design, and on the other hand, they have shown that there is a specific subgroup of diabetic patients in whom CV risk may be reduced by combination therapy with a statin and fibrate – patients with low levels of HDL cholesterol and high levels of TG (atherogenic dyslipidaemia); and in clinical practice, predominantly patients with abdominal obesity or metabolic syndrome; moreover, in all diabetic patients’ therapy with fenofibrate, the progression of microvascular complications can be slowed down. No doubt, patients would not rashly give up the benefits, which might be obtained from such treatment, and before rejecting it, every physician should seriously consider if such a decision is not too hasty [33].

Treatment with fenofibrate appears to be safe, and undesirable effects are rare. Systemic symptoms which may be noticed by patients receiving fenofibrate, although it has not been definitely established whether or not they are caused by the drug itself, might include weight loss, fatigue/weakness and flu-like symptoms (about 5 %) [39, 40]. Gastrointestinal undesirable effects are quite common – they include dyspepsia (5 %), nausea/vomiting (4 %), flatulence, abdominal pain, constipation or diarrhoea (3 %) and belching (1 %) [39–43]. In addition, fenofibrate may contribute to increased cholesterol excretion into the bile and the development of cholelithiasis [42]. Also, an increased incidence of acute pancreatitis may be one of the undesirable effects of the drug – in the FIELD study, it was developed by 0.8 % of subjects in the fenofibrate group and 0.5 % subjects in the placebo group; however, it is not clear if this was caused by the drug or by hypertriglyceridaemia, which often coexists in this group of patients [31]. Dermal symptoms are similarly rare – they usually include rash (6 %) or pruritus (3 %). Considerably less common effects are photosensitivity, lupus-like syndrome, ichthyosis, telangiectasia and alopecia [42–45].

Muscle-related complications of fenofibrate therapy are rare. They result from the fact that the risk related to therapy with gemfibrozil in combination with a statin is often applied to fenofibrate [46]. However, the metabolism of fenofibrate is completely different from that of gemfibrozil, and it does not cause a significant increase in plasma concentration of statins or the risk of rhabdomyolysis (which is 15 times lower than with gemfibrozil) [46–49]. For example, in the ACCORD study [32], a significant increase in the concentration of creatine kinase (CK) over the normal level (ten times) was observed only in ten (0.4 %) subjects receiving fenofibrate and in nine (0.3 %) subjects receiving placebo. In the FIELD study [31], the most serious complication – rhabdomyolysis – developed only in three subjects receiving fenofibrate and in one subject receiving placebo. To further minimise the risk of myopathy during combination therapy, it is recommended that fenofibrate be taken in the morning and a statin in the evening, so that peak blood concentrations do not overlap [47–49]. Another type of therapy is an alternate-day therapy – new studies on the use of fenofibrate in combination therapy for hyperlipidaemia indicate that the effectiveness of therapy with atorvastatin and fenofibrate taken either on the same day or on alternate days is comparable [47–49]. It is worth emphasising that the meta-analysis showed that combination therapy with statin and fibrate is comparatively safe as therapy with statin only [49].

An adverse effect of fibrates on kidneys is usually seen in CKD patients. There is some risk related to accumulation of the fenofibrate main metabolite – fenofibric acid and the development of myositis and rhabdomyolysis leading to acute renal failure [50, 51]. In patients without CKD, fenofibrate may lead to a slight increase in blood levels of creatinine – e.g. in the ACCORD study, in the first year of fenofibrate therapy, persistent insignificant elevation of creatinine levels was seen (increase from 0.93 to 1.1 mg/dL), but interestingly a similar increase was seen in the placebo group (from 0.93 to 1.04 mg/dL) [32]. In addition, therapy with fibrate was not associated with an increased need for dialysis (75 subjects in the fenofibrate group and 77 subjects in the placebo group). Taking into consideration all the data, it is recommended that fenofibrate be not used in patients with severe impairment of renal function (eGFR <30 mL/min/1.73 m²); when using fenofibrate in other patients, blood levels of creatinine should be monitored and renal function should be assessed – according to the European guidelines, preferably once a year [51]; according to the American guidelines, prior to therapy initiation, within 3 months of therapy initiation and then periodically every 6 months, bearing in mind that in patients with moderate impairment of renal function (eGFR 30–59 mL/min/1.73 m²), the daily dose of fenofibrate should not exceed 54 mg [52].

During therapy with fenofibrate, a significant increase in aminotransferase level, exceeding three times the upper limit of normal (ULN), is possible (in about 6 % of patients). Liver damage may occur as soon as after several weeks or after many years of therapy with fenofibrate and is dose dependent [39–44].