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............................................................................................................................................................................. TG-lowering effects of fibrates have been reported to be markedly less (5 and 20%, respectively) in long-term intervention trials in people with T2DM but without elevated levels of TGs.306,307

8.7.3 Effect on cardiovascular morbidity and mortality The clinical effects of fibrates have been primarily illustrated by six RCTs: the Helsinki Heart Study (HHS), Veterans Affairs High Density Lipoprotein Intervention Trial (VA-HIT), Bezafibrate Infarction Prevention (BIP), Lower Extremity Arterial Disease Event Reduction (LEADER), Fenofibrate Intervention and Event Lowering in Diabetes (FIELD), and Action to Control Cardiovascular Risk in Diabetes (ACCORD) trials; in the latter trial, fenofibrate was added to statin therapy.306311 In CV outcome trials of fibrates, the risk reduction appeared to be proportional to the degree of non-HDL-C lowering.50 Although the HHS reported a significant reduction in CVD outcomes with gemfibrozil, neither the FIELD nor the ACCORD studies involving fenofibrate showed a reduction in total CVD outcomes. The LEADER trial included male participants with lower-extremity arterial disease and failed to show that bezafibrate could lead to a clinically important reduction in CVD combined endpoints. Decreases in the rates of non-fatal MI were reported, although often as a result of post hoc analyses. The effect was most evident in people with elevated TG/low HDL-C levels. However, the data on other outcome parameters have remained equivocal. Only one study, ACCORD, has analysed the effect of a fibrate as an add-on treatment to a statin. No overall benefit was reported in two recent meta-analyses.312,313 Results from other meta-analyses suggest reduced major CVD events in patients with high TGs and low HDL-C in fibratetreated patients, but no decrease in CVD or total mortality.314316 Thus, the overall efficacy of fibrates on CVD outcomes is much less robust than that of statins. Recently, a new selective PPAR-a modulator (pemafibrate) has been reported to have marked efficacy in reducing TRLs.317 The study, Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN PatiENts With DiabeTes (PROMINENT), is an ongoing CVD outcome trial designed to evaluate the efficacy of pemafibrate in some 10 000 high-risk diabetic patients with high TG and low HDL-C levels.318 Overall, the potential CV benefits of fibrates require further confirmation.

8.7.4 Adverse effects and interactions Fibrates are generally well tolerated with mild adverse effects, GI disturbances being reported in <5% of patients, and skin rashes in 2%.319 In general, myopathy, liver enzyme elevations, and cholelithiasis represent the most well-known adverse effects associated with fibrate therapy.319 The risk of myopathy has been reported to be 5.5fold greater with fibrate monotherapy (mainly with gemfibrozil) compared with a statin, and it varies with different fibrates and statins used in combination. This is explained by the pharmacological interactions between the metabolism of different fibrates and pathways of glucuronidation of statins. Gemfibrozil inhibits the metabolism of statins via the glucuronidation pathway, which leads to marked increases in plasma concentrations of statins.320 As fenofibrate does not share the same pharmacokinetic pathways as gemfibrozil, the risk of myopathy is much less with this combination therapy.319 As a class, fibrates have been reported to raise both serum creatinine and homocysteine levels in both short- and long-term studies. The increase of serum creatinine by fibrate therapy seems to be fully reversible when the drug is stopped. Data from meta-analyses suggest that a reduction of calculated glomerular filtration rate (GFR) does not reflect any adverse effects on kidney function.315 Fibrates are associated with a slightly increased risk of pancreatitis.321 The increase in homocysteine levels caused by fibrates has been considered to be relatively neutral with respect to CVD risk. However, a fibrate-induced increase in homocysteine may blunt elevation of both HDL-C and ApoA1 levels, and this effect may contribute to the smaller than estimated benefits of fenofibrate in CV outcome parameters.322

8.8 n-3 fatty acids

8.8.1 Mechanism of action The n-3 (or omega-3) fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] can be used at pharmacological doses to lower TGs. n-3 fatty acids (24 g/day) affect serum lipids and lipoproteins, in particular VLDL concentrations. The underlying mechanism is poorly understood, although it may be related, at least in part, to their ability to interact with PPARs and to decreased secretion of ApoB.

8.8.2 Effects on lipids n-3 fatty acids reduce TGs, but their effects on other lipoproteins are trivial. More detailed data on clinical outcomes are needed to justify wide use of prescription n-3 fatty acids.323 The recommended doses of total EPA and DHA to lower TGs have varied between 24 g/day. Three recent studies in people with high TGs using EPA reported a significant reduction in serum TG levels of up to 45% in a dosedependent manner.324326 The efficacy of omega-3 fatty acids in lowering serum TGs has also been reported in meta-analyses.157 Recently, the EpanoVa fOr Lowering Very high triglyceridEs II (EVOLVE II) trial confirmed the efficacy of omega-3 fatty acids in lowering serum TGs.327

8.8.3 Effect on cardiovascular morbidity and mortality A Cochrane meta-analysis, including 112 059 people from 79 trials, reported no overall effect of omega-3 PUFAs on total mortality (relative risk 0.98, 95% CI 0.901.03) or CV events (relative risk 0.99, 95% Cl 0.941.04), with only a suggestion that omega-3 fatty acids reduced CHD events (relative risk 0.93, 95% Cl 0.880.97).328 Recently, the A Study of Cardiovascular Events iN Diabetes (ASCEND) trial,329 which randomly assigned 15 480 patients with DM but without atherosclerotic CV disease to n-3 fatty acids or placebo, showed no significant difference in the risk of serious vascular events after a mean follow-up of 7.4 years (relative risk 1.00, 95% Cl 0.911.09). The data remain inconclusive and the clinical efficacy of omega-3 fatty acids appears to be related to non-lipid effects.330,331 Moreover, studies with omega-3 fatty acids have suffered from the dose used (1 g/day), which does not affect plasma lipids to a large extent, as the dose required to decrease plasma TGs is >2 g/day. The Reduction of Cardiovascular Events with EPA-Intervention Trial (REDUCE-IT)195 aimed to evaluate the potential benefits of omega-3 oil (EPA) on Downloaded from academic.oup.com/eurheartj/article/41/1/111/5556353 by guest on 07 October 2026