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Review
. 2017 Oct 4;16(1):124.
doi: 10.1186/s12933-017-0602-y.

Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor alpha modulator for management of atherogenic dyslipidaemia

Jean-Charles Fruchart  1
Affiliations
Review

Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor alpha modulator for management of atherogenic dyslipidaemia

Jean-Charles Fruchart. Cardiovasc Diabetol. .

Abstract

Despite best evidence-based treatment including statins, residual cardiovascular risk poses a major challenge for clinicians in the twenty first century. Atherogenic dyslipidaemia, in particular elevated triglycerides, a marker for increased triglyceride-rich lipoproteins and their remnants, is an important contributor to lipid-related residual risk, especially in insulin resistant conditions such as type 2 diabetes mellitus. Current therapeutic options include peroxisome proliferator-activated receptor alpha (PPARα) agonists, (fibrates), but these have low potency and limited selectivity for PPARα. Modulating the unique receptor-cofactor binding profile to identify the most potent molecules that induce PPARα-mediated beneficial effects, while at the same time avoiding unwanted side effects, offers a new therapeutic approach and provides the rationale for development of pemafibrate (K-877, Parmodia™), a novel selective PPARα modulator (SPPARMα). In clinical trials, pemafibrate either as monotherapy or as add-on to statin therapy was effective in managing atherogenic dyslipidaemia, with marked reduction of triglycerides, remnant cholesterol and apolipoprotein CIII. Pemafibrate also increased serum fibroblast growth factor 21, implicated in metabolic homeostasis. There were no clinically meaningful adverse effects on hepatic or renal function, including no relevant serum creatinine elevation. A major outcomes study, PROMINENT, will provide definitive evaluation of the role of pemafibrate for management of residual cardiovascular risk in type 2 diabetes patients with atherogenic dyslipidaemia despite statin therapy.

Keywords: Atherogenic dyslipidaemia; Fibrates; K-877; Pemafibrate; Peroxisome proliferator-activated receptor alpha; Residual cardiovascular risk; SPPARM; Triglycerides.

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Figures

Fig. 1
Fig. 1
Schematic representation showing how selective nuclear receptor modulation underpins the SPPARM concept. The binding of different ligands to nuclear receptors induces different conformational changes which influence cofactor affinity. Different ligands may share cofactors, resulting in shared biological responses (a) but may also have distinct differences in the cofactor-receptor binding profile (b). Thus, the unique receptor-cofactor binding profile of the ligand is the key determinant of the specificity and potency of receptor binding and in turn modulates gene- and tissue selective effects
Fig. 2
Fig. 2
Structure of pemafibrate (K-877)
Fig. 3
Fig. 3
Anti-atherogenic effects of pemafibrate (K-877) in apolipoprotein E transgenic mice. ApoE2KI mice were fed a Western diet and treated with pemafibrate (0.1 or 1 mg/kg), fenofibrate (250 mg/kg) or control (carboxy methyl cellulose) daily and were sacrificed after 10 weeks. The left panel shows significant reduction in the atherosclerotic lesion area in mice dosed with pemafibrate 0.1 mg/kg compared with control. This effect was enhanced in the pemafibrate 1 mg/kg group. Each symbol represents the average area staining in the aortic sinus of individual animals and the bar represents the median of the values (n = 10 per group). *p < 0.05, ***p < 0.001 versus control. Representative photomicrographs showing Oil-red-O stained fatty-streaks in the atherosclerotic lesions is shown on the right panel. Reproduced with permission from Hennuyer et al. [55]
Fig. 4
Fig. 4
Least squares mean percent change in triglycerides (TG; top panel) and high-density lipoprotein cholesterol (HDL-C) (bottom panel) after 12 weeks treatment with pemafibrate (0.05, 0.1, 0.2 or 0.4 mg/day), fenofibrate (100 mg/day) or placebo in patients with elevated TG (≥ 200 mg/dL or 2.3 mmol/L) and low HDL-C (Adapted from Ishibashi et al. [56])
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