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Atherosclerosis Journal highlights June 2016

Monday 20 June 2016   (0 Comments)
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Volume 249 Issue June 2016

By Simona Negrini and Arnold von Eckardstein (Editor–in-Chief)

Issue highlights

K-877 (pemafibrate) is a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα) with unique PPARα activity and selectivity. Activation of peroxisome proliferator-activated receptor-α (PPARα), a ligand-activated transcription factor, controls lipid metabolism, cellular cholesterol trafficking in macrophages and influences inflammation. This issue contains two articles (see below) on the clinical efficacy of K-877 (pemafibrate) on dyslipidemia and its effects on reverse cholesterol transport and atherosclerosis in a mouse model, which are also commented by an editorial.

Highlighted articles

Effects of K-877, a novel selective PPARα modulator (SPPARMα), in dyslipidaemic patients: A randomized, double blind, active- and placebo-controlled, phase 2 trial

Ishibashi and colleagues assessed pemafibrate (K-877) efficacy and safety in dyslipidaemic patients with high triglyceride and low high-density lipoprotein cholesterol (HDL-C) levels, in a double-blind, placebo-controlled, parallel-group 12-week clinical trial.
224 patients were randomized to K-877 (0.025, 0.05, 0.1, 0.2 mg BID), fenofibrate (100 mg QD), or placebo (1:1:1:1:1:1) groups.

The authors showed that least squares mean percent changes from baseline triglyceride levels were higher in the K-877 groups compared to the fenofibrate group. In addition, the K-877 groups had a statistically significant improvement from baseline HDL-C, very-low-density lipoprotein cholesterol, chylomicron cholesterol, remnant lipoprotein cholesterol, apolipoprotein B (apoB), and apoC-III levels. The incidence of adverse events in the K-877 groups was comparable to that in the placebo and fenofibrate groups; adverse drug reactions in the K-877 groups were less than those in the placebo (8.3%) and fenofibrate groups.

In conclusion, in dyslipidaemic patients with high triglyceride and low HDL-C levels, K-877 improved triglyceride, HDL-C, and other lipid parameters without increasing adverse events or adverse drug reactions, compared to placebo and fenofibrate.

The novel selective PPARα modulator (SPPARMα) pemafibrate improves dyslipidemia, enhances reverse cholesterol transport and decreases inflammation and atherosclerosis

Hennuyer and colleagues investigated whether pharmacological activation of PPARα with a novel highly potent and selective PPARα modulator, pemafibrate (K-877), improves lipid metabolism, macrophage cholesterol efflux, inflammation and consequently atherosclerosis development, in vitro and in vivo, using human apolipoprotein E2 knock-in (apoE2KI) and human apoA-I transgenic (hapoA-I tg) mice.

They showed that pemafibrate treatment decreased apoB secretion in chylomicrons by polarized Caco-2/TC7 intestinal epithelium cells and reduced triglyceride levels in apoE2KI mice. Pemafibrate treatment of hapoA-I tg mice increased plasma HDL cholesterol, apoA-I and stimulated RCT to feces. In primary human macrophages, pemafibrate promoted macrophage cholesterol efflux to HDL and exerted anti-inflammatory activities. Pemafibrate also reduced markers of inflammation and macrophages in the aortic crosses as well as aortic atherosclerotic lesion burden in western diet-fed apoE2KI mice.

These results demonstrate that the novel selective PPARα modulator pemafibrate exerts beneficial effects on lipid metabolism, RCT and inflammation resulting in anti-atherogenic properties.

In the accompanying commentary, Dr Camejo emphasizes how the results obtained by Hennuyer et al. provide additional insights into some of the beneficial effects of pemafibrate, as reported in the human clinical trial by Ishibashi and colleagues, on patients with high triglycerides and low HDL, supporting the need for further development of this compound.

Overall, the results of the two clinical and basic research studies make pemafibrate an interesting drug to be tested in phase III trials for its efficacy in reducing cardiovascular events in patients with the low HDL-cholesterol/hypertriglyceridemia syndrome, notably in patients with insulin resistance and type 2 diabetes.

Cholesterol efflux capacity is an independent predictor of all-cause and cardiovascular mortality in patients with coronary artery disease: A prospective cohort study

Although diminished cholesterol efflux capacity is positively correlated with prevalent coronary artery disease, its prognostic value for incident cardiovascular events remains a topic of debate.
This study aimed at investigating the association between cholesterol efflux capacity and all-cause and cardiovascular mortality in patients with coronary artery disease.

To this purpose, Liu and colleagues measured cholesterol efflux capacity at baseline in 1737 patients with coronary artery disease from the Guangdong Coronary Artery Disease Cohort.

They showed that during 6645 person-years of follow-up, 166 deaths were registered, 122 of which were caused by cardiovascular diseases. After multivariate adjustment for factors related to cardiovascular diseases, the hazard ratios of cholesterol efflux capacity in the fourth quartile compared with those in the bottom quartile were 0.24 for all-cause mortality and 0.17 for cardiovascular mortality. Adding cholesterol efflux capacity to a model containing traditional cardiovascular risk factors significantly increased its discriminatory power and predictive ability for all-cause and cardiovascular death, respectively.

Taking these results into account, it can be suggested that cholesterol efflux capacity may serve as an independent measure for predicting all-cause and cardiovascular mortality in patients with coronary artery disease.

A loss-of-function variant in OSBPL1A predisposes to low plasma HDL cholesterol levels and impaired cholesterol efflux capacity

Motazacker and collaborators identified a genetic variant of OSBPL1A (p.C39X) in heterozygosis, in subjects with high-density-lipoprotein cholesterol (HDL-C) below the 1st percentile. This allele encodes a short truncated protein fragment that co-segregates with low plasma HDL-C.

The composition and function of HDL in carriers and non-carriers of the variant allele and the properties of the mutant protein in cultured hepatocytes were studied.

The authors reported that plasma HDL-C and apolipoprotein (apo) A-I were lower in carriers versus non-carriers, while there was no difference in the other plasma components or HDL parameters analyzed. Sera of the carriers showed a reduced capacity to act as cholesterol efflux acceptors, while the cholesterol acceptor capacity of their isolated HDL was normal.

Fibroblasts from a p.C39X carrier showed reduced cholesterol efflux to lipid-free apoA-I, but not to mature HDL particles, suggesting a specific defect in ABCA1-mediated efflux pathway.

In hepatic cells, GFP-OSBPL1A partially co-localized in endosomes containing fluorescent apoA-I, suggesting that OSBPL1A may regulate the intracellular handling of apoA-I. The GFP-OSBPL1A-39X mutant protein remained in the cytosol and failed to interact with Rab7, which normally recruits OSBPL1A to late endosomes/lysosomes, suggesting that this mutation causes a loss of function.

The present work represents the first characterization of a human OSBPL1A mutation.

The results indicate that a familial loss-of-function mutation in OSBPL1A affects the first step of the reverse cholesterol transport process and is associated with a low HDL-C phenotype, suggesting that rare mutations in OSBPL genes may contribute to dyslipidemias.

The predictive value of the antioxidative function of HDL for cardiovascular disease and graft failure in renal transplant recipients

Protection of low-density lipoproteins (LDL) against oxidative modification is a key anti-atherosclerotic property of high-density lipoproteins (HDL).

This study evaluated the predictive value of the HDL antioxidative function for cardiovascular mortality, all-cause mortality, and chronic graft failure in renal transplant recipients (RTR).

To this purpose, the capacity of HDL to inhibit native LDL oxidation was determined in vitro in a prospective cohort of renal transplant recipients.

Leberkühne and colleagues showed that the HDL antioxidative functionality was significantly higher in patients experiencing graft failure than in those without graft failure, while there were no differences in cardiovascular and all-cause mortality.

Glomerular filtration rate and C-reactive protein levels independently associated with antioxidative functionality in multivariate linear regression analyses. Cox regression analysis showed a significant relationship between antioxidative functionality of HDL and graft failure in age-adjusted analyses, but significance was lost following adjustment for baseline kidney function and inflammatory load. No significant association was found between HDL antioxidative functionality and cardiovascular and all-cause mortality.

This study demonstrates that the antioxidative function of HDL does not predict cardiovascular or all-cause mortality in RTR, but conceivably contributes to the development of graft failure, however, not independent of baseline kidney function and inflammatory load.

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