Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons
Open accessAbstract
There are three peroxisome proliferator-activated receptors (PPARs) subtypes which are commonly designated PPAR alpha, PPAR gamma and PPAR beta/delta. PPAR alpha activation increases high density lipoprotein (HDL) cholesterol synthesis, stimulates "reverse" cholesterol transport and reduces triglycerides. PPAR gamma activation results in insulin sensitization and antidiabetic action. Until recently, the biological role of PPAR beta/delta remained unclear. However, treatment of obese animals by specific PPAR delta agonists results in normalization of metabolic parameters and reduction of adiposity. Combined treatments with PPAR gamma and alpha agonists may potentially improve insulin resistance and alleviate atherogenic dyslipidemia, whereas PPAR delta properties may prevent the development of overweight which typically accompanies "pure" PPAR gamma ligands. The new generation of dual-action PPARs – the glitazars, which target PPAR-gamma and PPAR-alpha (like muraglitazar and tesaglitazar) are on deck in late-stage clinical trials and may be effective in reducing cardiovascular risk, but their long-term clinical effects are still unknown. A number of glitazars have presented problems at a late stage of clinical trials because of serious side-effects (including ragaglitazar and farglitazar). The old and well known lipid-lowering fibric acid derivative bezafibrate is the first clinically tested pan – (alpha, beta/delta, gamma) PPAR activator. It is the only pan-PPAR activator with more than a quarter of a century of therapeutic experience with a good safety profile. Therefore, bezafibrate could be considered (indeed, as a "post hoc" understanding) as an "archetype" of a clinically tested pan-PPAR ligand. Bezafibrate leads to considerable raising of HDL cholesterol and reduces triglycerides, improves insulin sensitivity and reduces blood glucose level, significantly lowering the incidence of cardiovascular events and new diabetes in patients with features of metabolic syndrome. Clinical evidences obtained from bezafibrate-based studies strongly support the concept of pan-PPAR therapeutic approach to conditions which comprise the metabolic syndrome. However, from a biochemical point of view, bezafibrate is a PPAR ligand with a relatively low potency. More powerful new compounds with pan-PPAR activity and proven long-term safety should be highly effective in a clinical setting of patients with coexisting relevant lipid and glucose metabolism disorders.
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Rosiglitazone is a selective agonist of PPARγ, while bezafibrate is a pan-PPAR agonist.
“It is well-known that rosiglitazone is a selective agonist of PPARγ, while bezafibrate is a pan-PPAR agonist [52].”
From Lipoprotein Lipase Regulates Microglial Lipid Droplet Accumulation (2021) · cites this paper as [52]
The bezafibrate lessons section (page unavailable) explicitly calls bezafibrate a pan-PPAR activator. The Clinical studies of PPAR ligands and Dual and pan-PPAR co-agonism sections describe glitazones as PPARγ ligands, including “pure” PPARγ ligands, but our copy does not name rosiglitazone or establish its selectivity specifically. (LLM, conf=0.84)
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- Authors
- Tenenbaum, A., Motro, M., & Fisman, E. Z.
- Affiliations
- Sheba Medical Center (IL)
- Tel Aviv University (IL)
- Corresponding author
- Tenenbaum, Alexander
- Venue
- Cardiovascular Diabetology
- Published
- 2005-09-16
- Volume
- 4
- Issue
- 1
- Pages
- 14-14
- ISSN
- 1475-2840 (ISSN-L)
- PMC
- PMC1236941
- OpenAlex
- W2137116210
- Cited by
- 246
- References
- 44
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 6 · 2023: 9 · 2022: 12 · 2021: 12 · 2020: 12 · 2019: 8 · 2018: 5 · 2017: 7 · 2016: 7 · 2015: 12 · 2014: 9 · 2013: 11 · 2012: 24
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Cardiovascular Diabetology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- bezafibrate, peroxisome proliferator-activated receptors, PPARα, PPARγ, PPARδ, metabolic syndrome, HDL cholesterol, triglycerides, insulin sensitivity, cardiovascular risk, fibrates, drug safety
- MeSH terms
- Hypolipidemic Agents, Bezafibrate, Cardiovascular Diseases, Coronary Disease, Diabetes Mellitus, Type 2, Humans, Hyperlipidemias, Cholesterol, HDL, Male, Middle Aged, Myocardial Infarction, Triglycerides, Peroxisome Proliferator-Activated Receptors, PPAR alpha, PPAR delta, PPAR gamma
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