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Heinz Drexel, Christoph H Saely, Stefan Agewall, Fibrates: one more lost paradise in lipid treatment, European Heart Journal - Cardiovascular Pharmacotherapy, Volume 9, Issue 2, March 2023, Page 121, https://doi.org/10.1093/ehjcvp/pvac072
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Fibrates are widely used drugs to reduce triglycerides in plasma. Their mode of action is peroxisome proliferator receptor alpha activation. This leads to class-specific pronounced decreases in plasma triglycerides with a marked increase in HDL cholesterol. These effects and particularly reductions in LDL cholesterol—which are only modest—vary between compounds.
The published RCTs on secondary cardiovascular prevention by fibrates are discussed elsewhere.1 In general, the results were disappointing, particularly in comparison with the trials testing the strongly LDL-C lowering drugs, statins and PCSK9 antibodies. However, in subgroup analysis, patients with both elevated triglycerides and low HDL cholesterol appeared to benefit. The value and limitations of subgroup analyses have recently been highlighted in this journal.2
With a new fibrate compound potentially offering more benefit, pemafibrate, new hope arose. Recently, the results of the Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabeTes (PROMINENT) Trial1 were published. The study was stopped prematurely. Rules to prematurely stop trials have been published recently in this journal.3 The main reasons justifying early stop are lack of efficacy, futility, or harm. Futility and potential harm with pemafibrate prompted the decision of the Data Safety Monitoring Board of PROMINENT.
Therefore, the use of fibrates to prevent atherosclerotic events appears no more warranted. However, in the chylomicronemia syndrome with triglycerides readings around 1000 mg/dL, fibrates remain an option.
What other options remain to lower triglycerides and improve cardiovascular outcomes? Omega 3-fatty acids are amongst the most promising drugs. The Reduction of Cardiovascular Events With EPA—Intervention (REDUCE-IT) Trial included 8179 patients with established cardiovascular disease or with diabetes plus other risk factors and plasma triglyceride values between 135 and 499 mg/dL. The trial compared eicosapentaenoic acid 4 g/day to a placebo (mineral oil) on top of statins. The results were very positive: the primary composite endpoint of a 5-point MACE was reduced by 25%, P < 0.001.4
Also in a journal dedicated to pharmacotherapy we should not forget life style. In contrast to LDL, triglycerides strongly respond to both nutritional changes and exercise.
In conclusion, fibrates, by their failure to improve cardiovascular outcomes, share the fate of nicotinic acid and CETP inhibitors. Regrettably, this is another paradise lost in lipid therapy.
Data availability
No original data were used for this work.
Conflict of interest: The author SA is an Editor of The European Heart Journal—Cardiovascular Pharmacotherapy and was not involved in the peer review process or publication decision of this paper.
