Lessons from PROMINENT and prospects for pemafibrate.

The neutral result of the PROMINENT trial has led to questions about the future for pemafibrate. This commentary discusses possible reasons for the lack of benefit observed in the trial. There were, however, indicators suggesting therapeutic potential in microvascular ischaemic complications associated with peripheral artery disease, with subsequent analysis showing reduction in the incidence of lower extremity ischaemic ulceration or gangrene. Reassurance about the safety of pemafibrate, together with emerging data from PROMINENT and experimental studies, also suggest benefit with pemafibrate in non-alcoholic fatty liver disease (alternatively referred to as metabolic dysfunction-associated steatotic liver disease) and microangiopathy associated with diabetes, which merit further study.

Managing hypertriglyceridemia for cardiovascular disease prevention: Lessons from the PROMINENT trial.

BACKGROUND: Numerous epidemiological studies have shown that hypertriglyceridemia is a significant risk factor for cardiovascular diseases (CVD). However, large clinical studies on triglyceride-lowering therapy have yielded inconsistent results. In the current review, we reassess the importance of triglyceride-lowering therapy in preventing CVD based on previous literature and the recently published findings of the PROMINENT trial. METHODS: This narrative review is based on literature and public documents published up to November 2023. RESULTS: Meta-analyses of trials on peroxisome proliferator-activated receptor α agonists and triglyceride-lowering therapy, including the PROMINENT trial, have indicated that triglyceride-lowering therapy can reduce CVD events. Mendelian randomization studies have also indicated that triglyceride is indeed a true risk factor for coronary artery disease, leaving no doubt about its relationship to CVD. Meanwhile, the negative results from the PROMINENT trial were likely due to the insufficient triglyceride-lowering effect, slight increases in low-density lipoprotein cholesterol and apolipoprotein B, and the inclusion of mostly high-intensity statin users as target patients. It is unlikely that adverse events counteracted the effectiveness of pemafibrate on outcomes. Additionally, pemafibrate has shown positive effects on non-alcoholic fatty liver disease and peripheral artery disease. CONCLUSION: Although the PROMINENT trial did not demonstrate the significance of pemafibrate as a triglyceride-lowering therapy in a specific population, it does not necessarily negate the potential benefits of treating hypertriglyceridemia in reducing CVD events. It is necessary to explore appropriate populations that could benefit from this therapy, utilize data from the PROMINENT trial and other databases, and validate findings in real-world settings.

XCR1+ conventional dendritic cell-induced CD4+ T helper 1 cell activation exacerbates cardiac remodeling after ischemic myocardial injury.

Cardiac remodeling has no established therapies targeting inflammation. CD4+ T-cell subsets have been reported to play significant roles in healing process after ischemic myocardial injury, but their detailed mechanisms of activation remain unknown. To explore immune reactions during cardiac remodeling, we applied a non-surgical model of coronary heart disease (CHD) induced by a high-fat diet (HFD-CHD) in SR-BI-/-/ApoeR61h/h mice. Flow cytometry analyses throughout the period of progressive cardiac dysfunction revealed that CD4+ T Helper 1 (Th1) cells were predominantly activated in T-cell subsets. Probucol was reported to attenuate cardiac dysfunction after coronary artery ligation model (ligation-MI) in rats. To determine whether probucol suppress cardiac remodeling after HFD-CHD, we treated SR-BI-/-/ApoeR61h/h mice with probucol. We found treatment with probucol in HFD-CHD mice reduced cardiac dysfunction, with attenuated activation of Th1 cells. RNA-seq analyses revealed that probucol suppressed the expression of CXCR3, a Th1-related chemokine receptor, in the heart. XCR1+ cDC1 cells, which highly expresses the CXCR3 ligands CXCL9 and CXCL10, were predominantly activated after HFD-CHD. XCR1+ cDC1 lineage skewing of pre-DC progenitors was observed in bone marrow, with subsequent systemic expansion of XCR1+ cDC1 cells after HFD-CHD. Activation of CXCR3+ Th1 cell and XCR1+ cDC1 cells was also observed in ligation-MI. Notably, post-MI depletion of XCR1+ cDC1 cells suppressed CXCR3+ Th1 cell activation and prevented cardiac dysfunction. In patient autopsy samples, CXCR3+ Th1 and XCR1+ cDC1 cells infiltrated the infarcted area. In this study, we identified a critical role of XCR1+ cDC1-activated CXCR3+ Th1 cells in ischemic cardiac remodeling.

TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis.

Cellular mechanisms that mediate steatohepatitis, an increasingly prevalent condition in the Western world for which no therapies are available, are poorly understood. Despite the fact that its synthetic agonists induce fatty liver, the liver X receptor (LXR) transcription factor remains a target of interest because of its anti-atherogenic, cholesterol removal, and anti-inflammatory activities. Here we show that tetratricopeptide repeat domain protein 39B (Ttc39b, C9orf52) (T39), a high-density lipoprotein gene discovered in human genome-wide association studies, promotes the ubiquitination and degradation of LXR. Chow-fed mice lacking T39 (T39(-/-)) display increased high-density lipoprotein cholesterol levels associated with increased enterocyte ATP-binding cassette transporter A1 (Abca1) expression and increased LXR protein without change in LXR messenger RNA. When challenged with a high fat/high cholesterol/bile salt diet, T39(-/-) mice or mice with hepatocyte-specific T39 deficiency show increased hepatic LXR protein and target gene expression, and unexpectedly protection from steatohepatitis and death. Mice fed a Western-type diet and lacking low-density lipoprotein receptor (Ldlr(-/-)T39(-/-)) show decreased fatty liver, increased high-density lipoprotein, decreased low-density lipoprotein, and reduced atherosclerosis. In addition to increasing hepatic Abcg5/8 expression and limiting dietary cholesterol absorption, T39 deficiency inhibits hepatic sterol regulatory element-binding protein 1 (SREBP-1, ADD1) processing. This is explained by an increase in microsomal phospholipids containing polyunsaturated fatty acids, linked to an LXRα-dependent increase in expression of enzymes mediating phosphatidylcholine biosynthesis and incorporation of polyunsaturated fatty acids into phospholipids. The preservation of endogenous LXR protein activates a beneficial profile of gene expression that promotes cholesterol removal and inhibits lipogenesis. T39 inhibition could be an effective strategy for reducing both steatohepatitis and atherosclerosis.

A Dietary Oxysterol, 7-Ketocholesterol, Exacerbates Imiquimod-Induced Psoriasis-like Dermatitis in Steatohepatitic Mice.

Patients with psoriasis are at a higher risk of developing nonalcoholic fatty liver disease. We previously identified an oxidized derivative of cholesterol, 7-ketocholesterol (7KC), in diet-induced steatohepatitic mice. Here, we investigated whether 7KC exacerbates psoriasis-like dermatitis by accelerating steatohepatitis in mice. A high-fat/high-cholesterol/high-sucrose/bile salt diet (nonalcoholic steatohepatitis (NASH) diet) with or without 0.0125% 7KC was fed to C57BL/6 mice (7KC or control group) for three weeks to induce steatohepatitis. A 5% imiquimod cream was then applied to the ears and dorsal skin for four days to induce psoriasis-like dermatitis. Hepatic lipid accumulation and inflammatory cell infiltration were exacerbated in the 7KC group compared with the control group after three weeks. Serum tumor necrosis factor-α (TNF-α) levels were also elevated in the 7KC group (108.5 ± 9.8 vs. 83.1 ± 13.1 pg/mL, p < 0.005). Imiquimod cream increased the psoriasis area severity index (PASI) score in mice in the 7KC group (9.14 ± 0.75 vs. 5.17 ± 1.17, p < 0.0001). Additionally, Tnfa, Il23a, Il17a, and Il22 mRNA levels in the dorsal lesion were significantly upregulated. Finally, Th17 cell differentiation and the TNF signaling pathway were enhanced in the dorsal lesions and liver of mice in the 7KC group. These data suggest that steatohepatitis and psoriasis are linked by a potent, diet-related factor.

Effects of pemafibrate on glucose metabolism markers and liver function tests in patients with hypertriglyceridemia: a pooled analysis of six phase 2 and phase 3 randomized double-blind placebo-controlled clinical trials.

BACKGROUND: Increased risk of cardiovascular events is associated not only with dyslipidemias, but also with abnormalities in glucose metabolism and liver function. This study uses pooled analysis to explore the in-depth effects of pemafibrate, a selective peroxisome proliferator-activated receptor α modulator (SPPARMα) already known to decrease elevated triglycerides, on glucose metabolism and liver function in patients with hypertriglyceridemia. METHODS: We performed a post-hoc analysis of six phase 2 and phase 3 Japanese randomized double-blind placebo-controlled trials that examined the effects of daily pemafibrate 0.1 mg, 0.2 mg, and 0.4 mg on glucose metabolism markers and liver function tests (LFTs). Primary endpoints were changes in glucose metabolism markers and LFTs from baseline after 12 weeks of pemafibrate treatment. All adverse events and adverse drug reactions were recorded as safety endpoints. RESULTS: The study population was 1253 patients randomized to placebo (n = 298) or pemafibrate 0.1 mg/day (n = 127), 0.2 mg/day (n = 584), or 0.4 mg/day (n = 244). Participant mean age was 54.3 years, 65.4 % had BMI ≥ 25 kg/m2, 35.8 % had type 2 diabetes, and 42.6 % had fatty liver. Fasting glucose, fasting insulin, and HOMA-IR decreased significantly in all pemafibrate groups compared to placebo. The greatest decrease was for pemafibrate 0.4 mg/day: least square (LS) mean change from baseline in fasting glucose - 0.25 mmol/L; fasting insulin - 3.31 µU/mL; HOMA-IR - 1.28. ALT, γ-GT, ALP, and total bilirubin decreased significantly at all pemafibrate doses vs. placebo, with the greatest decrease in the pemafibrate 0.4 mg/day group: LS mean change from baseline in ALT - 7.6 U/L; γ-GT - 37.3 U/L; ALP - 84.7 U/L; and total bilirubin - 2.27 µmol/L. Changes in HbA1c and AST did not differ significantly from placebo in any pemafibrate groups in the overall study population. The decreases from baseline in LFTs and glucose metabolism markers except for HbA1c were notable among patients with higher baseline values. FGF21 increased significantly in all pemafibrate groups compared to placebo, with the greatest increase in the pemafibrate 0.4 mg/day group. Adverse event rates were similar in all groups including placebo. CONCLUSIONS: In patients with hypertriglyceridemia, pemafibrate can improve glucose metabolism and liver function, and increase FGF21, without increasing adverse event risk.

Progranulin deficiency leads to enhanced age-related cardiac hypertrophy through complement C1q-induced ß-catenin activation.

AIMS: Age-related cardiac hypertrophy and subsequent heart failure are predicted to become increasingly serious problems in aging populations. Progranulin (PGRN) deficiency is known to be associated with accelerated aging in the brain. We aimed to evaluate the effects of PGRN deficiency on cardiac aging, including left ventricular hypertrophy. METHODS AND RESULTS: Echocardiography was performed on wild-type (WT) and PGRN-knockout (KO) mice every 3 months from 3 to 18 months of age. Compared to that of WT mice, PGRN KO mice exhibited age-dependent cardiac hypertrophy and cardiac dysfunction at 18 months. Morphological analyses showed that the heart weight to tibia length ratio and cross-sectional area of cardiomyocytes at 18 months were significantly increased in PGRN KO mice relative to those in WT mice. Furthermore, accumulation of lipofuscin and increases in senescence markers were observed in the hearts of PGRN KO mice, suggesting that PGRN deficiency led to enhanced aging of the heart. Enhanced complement C1q (C1q) and activated ß-catenin protein expression levels were also observed in the hearts of aged PGRN KO mice. Treatment of PGRN-deficient cardiomyocytes with C1q caused ß-catenin activation and cardiac hypertrophy. Blocking C1q-induced ß-catenin activation in PGRN-depleted cardiomyocytes attenuated hypertrophic changes. Finally, we showed that C1 inhibitor treatment reduced cardiac hypertrophy and dysfunction in old KO mice, possibly by reducing ß-catenin activation. These results suggest that C1q is a crucial regulator of cardiac hypertrophy induced by PGRN ablation. CONCLUSION: The present study demonstrates that PGRN deficiency enhances age-related cardiac hypertrophy via C1q-induced ß-catenin activation. PGRN is a potential therapeutic target to prevent cardiac hypertrophy and dysfunction.

Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized, Controlled Trial.

BACKGROUND: Evidence regarding the primary prevention of coronary artery disease events by low-density lipoprotein cholesterol (LDL-C) lowering therapy in older individuals, aged ≥75 years, is insufficient. This trial tested whether LDL-C-lowering therapy with ezetimibe is useful for the primary prevention of cardiovascular events in older patients. METHODS: This multicenter, prospective, randomized, open-label, blinded end-point evaluation conducted at 363 medical institutions in Japan examined the preventive efficacy of ezetimibe for patients aged ≥75 years, with elevated LDL-C without history of coronary artery disease. Patients, who all received dietary counseling, were randomly assigned (1:1) to receive ezetimibe (10 mg once daily) versus usual care with randomization stratified by site, age, sex, and baseline LDL-C. The primary outcome was a composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke. RESULTS: Overall, 3796 patients were enrolled between May 2009 and December 2014, and 1898 each were randomly assigned to ezetimibe versus control. Median follow-up was 4.1 years. After exclusion of 182 ezetimibe patients and 203 control patients because of lack of appropriate informed consent and other protocol violations, 1716 (90.4%) and 1695 (89.3%) patients were included in the primary analysis, respectively. Ezetimibe reduced the incidence of the primary outcome (hazard ratio [HR], 0.66; 95% CI, 0.50-0.86; P=0.002). Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; 95% CI, 0.37-0.98; P=0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18-0.79; P=0.007) were lower in the ezetimibe group than in the control group; however, there was no difference in the incidence of stroke, all-cause mortality, or adverse events between trial groups. CONCLUSIONS: LDL-C-lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals aged ≥75 years with elevated LDL-C. Given the open-label nature of the trial, its premature termination and issues with follow-up, the magnitude of benefit observed should be interpreted with caution. Clinical Registration: URL: https://www.umin.ac.jp. Unique identifier: UMIN000001988.

Marked effects of novel selective peroxisome proliferator-activated receptor α modulator, pemafibrate in severe hypertriglyceridemia: preliminary report.

BACKGROUND: Currently available treatments have only been partly successful in patients with severe hypertriglyceridemia, including those with high serum triglycerides above 1,000 mg/dL (11.3 mmol/L), who often suffer from acute pancreatitis. Pemafibrate is a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα) which has been developed as an affordable oral tablet in Japan. We herein report the first three patients with severe hypertriglyceridemia who were successfully treated with pemafibrate. METHODS: Three patients with fasting serum triglyceride (TG) levels above 1,000 mg/dL (11.3 mmol/L) were treated with pemafibrate (0.2-0.4 mg/day, 0.1-0.2 mg BID). RESULTS: Serum TGs decreased from 2,000-3,000 mg/dL (22.6-33.9 mmol/L) to < 250 mg/dL (2.8 mmol/L) without adverse effects in all three patients. Serum TGs in Patient 1 and 2 decreased from 1,326 mg/dL (15.0 mmol/L) to 164 mg/dL (1.9 mmol/L) and from 2,040 mg/dL (23.1 mmol/L) to 234 mg/dL (2.6 mmol/L), respectively. Patient 3 with type 2 diabetes and 12.1% (109 mmol/mol) hemoglobin A1c had a TG level of 2,300 mg/dL (26.0 mmol/L). Even after glycemic control improved, TG remained high. After pemafibrate administration, TG decreased to 200 mg/dL (2.3 mmol/L). All patients showed no serious adverse events. CONCLUSIONS: Pemafibrate demonstrated potential efficacy and safety for severe hypertriglyceridemia which may contribute to the prevention of acute pancreatitis, in a manner that can be easily prescribed and used as an oral tablet.

Pemafibrate, a New Selective PPARα Modulator: Drug Concept and Its Clinical Applications for Dyslipidemia and Metabolic Diseases.

PURPOSE OF REVIEW: Reduction of serum low-density lipoprotein cholesterol (LDL-C) levels by statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has been shown to significantly reduce cardiovascular events risk. However, fasting and postprandial hypertriglyceridemia as well as reduced high-density lipoprotein cholesterol (HDL-C) remain as residual risk factors of atherosclerotic cardiovascular diseases (ASCVD). To treat patients with hypertriglyceridemia and/or low HDL-C, drugs such as fibrates, nicotinic acids, and n-3 polyunsaturated fatty acids have been used. However, fibrates were demonstrated to cause side effects such as liver dysfunction and increase in creatinine levels, and thus large-scale clinical trials of fibrates have shown negative results for prevention of ASCVD. The failure could be attributed to their low selectivity and potency for binding to peroxisome proliferator-activated receptor (PPAR) α. To resolve these issues, the concept of selective PPARα modulator (SPPARMα) with a superior balance of efficacy and safety has been proposed and pemafibrate (K-877) has been developed. RECENT FINDINGS: Pemafibrate, one of SPPARMsα, was synthesized by Kowa Company, Ltd. for better efficiency and safety. Clinical trials in Japan have established the superiority of pemafibrate on effects on serum triglycerides (TG) reduction and HDL-C elevation as well safety. Although available fibrates showed worsening of liver and kidney function test values, pemafibrate indicated improved liver function test values and was less likely to increase serum creatinine or decrease estimated glomerular filtration rate (eGFR). Very few drug-drug interactions were observed even when used concomitantly with statins. Furthermore, pemafibrate is metabolized in the liver and excreted into the bile, while many of available fibrates are mainly excreted from the kidney. Therefore, pemafibrate can be used safely even in patients with impaired renal function since there is no significant increase in its blood concentration. A large-scale trial of pemafibrate, PROMINENT, for dyslipidemic patients with type 2 diabetes is ongoing. Pemafibrate is one of novel SPPARMsα and has superior benefit-risk balance compared to conventional fibrates and can be applicable for patients for whom the usage of existing fibrates is difficult such as those who are taking statins or patients with renal dysfunction. In the current review, all the recent data on pemafibrate will be summarized.

Gaps in beliefs and practice in dyslipidaemia management in Japan, Germany, Colombia and the Philippines: insights from a web-based physician survey.

BACKGROUND: Implementing evidence-based management of dyslipidaemia is a challenge worldwide. OBJECTIVES: To understand physician beliefs and behaviour and identify uncertainties in dyslipidaemia management across four world regions. METHODS: Web-based survey of 1758 physicians in Japan, Germany, Colombia and the Philippines who were selected randomly from existing databases. Key inclusion criteria were 1) for cardiologists and diabetes/endocrinology specialists: ≥50 dyslipidaemia patients examined in the last month; 2) for specialists in neurology/neurosurgery/stroke medicine: ≥50 dyslipidaemia patients and ≥ 20 patients with a history of ischaemic stroke examined in the last month; and 3) for specialists in nephrology and general medicine: based at centres with ≥20 beds and ≥ 50 dyslipidaemia patients examined in the last month. The self-report survey covered dyslipidaemia management, target low-density lipoprotein cholesterol (LDL-C) levels in different patient groups, and statin safety. All physicians gave voluntary consent and all data were anonymised. Analysis was solely descriptive. RESULTS: The survey highlighted key areas of uncertainty in dyslipidaemia management in the four countries. These related to LDL-C targets in different patient groups, the safety of low LDL-C levels, the safety of statins, especially for effects on cognitive, renal and hepatic function and for haemorrhagic stroke risk, and lipid management strategies in patients with chronic kidney disease, including those with concomitant hypertriglyceridaemia. CONCLUSIONS: This survey of physicians in Japan, Germany, Colombia and the Philippines has identified key gaps in knowledge about dyslipidaemia management. These relate to the safety of low LDL-C levels, the safety of statins, and lipid management of chronic kidney disease. The findings from this survey highlight the need for further education to improve the implementation of guideline recommendations for dyslipidaemia management.

Efficacy and safety of pemafibrate in people with type 2 diabetes and elevated triglyceride levels: 52-week data from the PROVIDE study.

The aim of this study was to evaluate the efficacy and safety of pemafibrate in people with type 2 diabetes and hypertriglyceridaemia over a 52-week period. Participants were randomly assigned to receive treatment with placebo or pemafibrate at a dose of 0.2 or 0.4 mg/d for 24 weeks (treatment period 1). The main results from treatment period 1 have been reported previously. The assigned treatment was continued up to week 52, except that the placebo was changed to pemafibrate 0.2 mg/d after week 24 (treatment period 2). The percentage changes in fasting serum triglyceride (TG) levels at week 52 (last observation carried forward) were -48.2%, -42.3%, and -46.4% in the placebo/pemafibrate 0.2 mg/d (n = 57), pemafibrate 0.2 mg/d (n = 54), and pemafibrate 0.4 mg/d (n = 55) groups, respectively. Levels of TG, non-HDL cholesterol and total cholesterol stably decreased, whereas levels of HDL cholesterol increased with pemafibrate treatments over 52 weeks. Pemafibrate was well tolerated throughout the study period. The present study is the first to show that pemafibrate treatment substantially ameliorated lipid abnormalities and was well tolerated for 52 weeks in people with type 2 diabetes and hypertriglyceridaemia.

Long-Term Treatment With Evolocumab Among Japanese Patients　- Final Report of the OSLER Open-Label Extension Studies.

BACKGROUND: Treatment with evolocumab reduces mean low-density lipoprotein cholesterol (LDL-C) up to 75% and cardiovascular events by 16% in the first year and 25% thereafter. Methods and Results: Japanese patients with hypercholesterolemia enrolled in the parent YUKAWA-1-2 studies could enroll, once eligible, in the OSLER studies (n=556). OSLER re-randomized patients 2:1 to evolocumab plus standard of care (SOC; evolocumab+SOC) or SOC alone for 1 year; after year 1, patients could enter the all-evolocumab+SOC open-label extension of OSLER. Patients received evolocumab+SOC from the 2nd year through up to 5 years. Long-term efficacy and safety, including antidrug antibodies, were evaluated. Of 556 patients, 532 continued to the all-evolocumab+SOC extension: mean (standard deviation [SD]) age 61 (10) years, 39% female. A total of 91% of 532 patients completed the studies. Mean (SD) LDL-C change from parent-study baseline with evolocumab from a mean (SD) baseline of 142.3 (21.3) and 105.0 (31.1) mg/dL in OSLER-1 and OSLER-2, respectively, was maintained through the end of the study: -58.0% (19.1%) at year 5 in OSLER-1, -62.7% (25.6%) at year 3 in OSLER-2. The overall safety profile of the evolocumab+SOC periods was similar to that of the year-1 controlled period. Antidrug antibodies were detected transiently in 3 patients. No neutralizing antibodies were detected. CONCLUSIONS: Japanese patients who continued evolocumab+SOC for up to 5 years experienced sustained high LDL-C level reduction. Long-term evolocumab+SOC exposure showed no new safety signals.

Long-Term Efficacy and Safety of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor-α Modulator (SPPARMα), in Dyslipidemic Patients with Renal Impairment.

Pemafibrate (K-877) is a novel selective peroxisome proliferator-activated receptor-α modulator (SPPARMα) with a favorable benefit-risk balance. Previous clinical trials of pemafibrate used stringent exclusion criteria related to renal functions. Therefore, we investigated its safety and efficacy in a broader range of patients, including those with chronic kidney disease (CKD). In this multicenter, single-arm, open-label, phase III trial, 0.2⁻0.4 mg/day pemafibrate was administered for 52 weeks to 189 patients with hypertriglyceridemia and an estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m² on statin or regardless of eGFR when statin was not administered. Post-hoc analyses were performed on subgroups stratified by baseline eGFR. Triglyceride levels decreased by 45.9% at week 52 (last-observation-carried-forward). These reductions were not correlated with baseline eGFR. The eGFR < 30 mL/min/1.73 m² subgroup showed the greatest reduction in chylomicron, very low-density lipoprotein, small low-density lipoprotein cholesterol levels, and an increase in high-density lipoprotein cholesterol levels. The incidences of adverse events and adverse drug reactions were 82.0% and 31.7%, respectively, and these were not associated with baseline eGFR. In CKD patients, pemafibrate blood concentrations were not elevated. Pemafibrate showed a good safety profile and efficacy in correcting lipid abnormalities in a broad range of patients, including those with CKD.

Efficacy and Safety of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα): Pooled Analysis of Phase 2 and 3 Studies in Dyslipidemic Patients with or without Statin Combination.

Hypertriglyceridemia has emerged as an independent risk factor for cardiovascular events, despite low-density lipoprotein-cholesterol (LDL-C) well-controlled with statins. We pooled data from the first 12 weeks of six randomized double-blind placebo-controlled studies of pemafibrate in Japan and investigated its efficacy and safety with and without statins, particularly focusing on patients with renal dysfunction. Subjects were 1253 patients (677 in the "with-statin" group and 576 in the "without-statin" group). At Week 12 (last observation carried forward), triglyceride (TG) was significantly reduced at all pemafibrate doses (0.1, 0.2, and 0.4 mg/day), both with and without statin, compared to placebo (p < 0.001 vs. placebo for all groups). In the "with-statin" group, the estimated percent change from baseline was -2.0% for placebo and -45.1%, -48.5%, and -50.0%, respectively, for the pemafibrate groups. Findings for both groups showed significant decreases in TG-rich lipoproteins and atherogenic lipid parameters compared to placebo. The incidence of adverse events was similar between the pemafibrate and placebo groups and was also similar for patients with and without renal dysfunction in the "with-statin" group. Pemafibrate lowered TG and improved atherogenic dyslipidemia without a significant increase in adverse events in comparison to the placebo, even among "with-statin" patients who had renal dysfunction.

Pressure Overload Impairs Cardiac Function in Long-Chain Fatty Acid Transporter CD36-Knockout Mice.

CD36 is one of the important transporters of long-chain fatty acids (LCFAs) in the myocardium. We previously reported that CD36-deficient patients demonstrate a marked reduction of myocardial uptake of LCFA, while myocardial glucose uptake shows a compensatory increase, and are often accompanied by cardiomyopathy. However, the molecular mechanisms and functional role of CD36 in the myocardium remain unknown.The current study aimed to explore the pathophysiological role of CD36 in the heart. Methods: Using wild type (WT) and knockout (KO) mice, we generated pressure overload by transverse aortic constriction (TAC) and analyzed cardiac functions by echocardiography. To assess cardiac hypertrophy and fibrosis, histological and molecular analyses and measurement of ATP concentration in mouse hearts were performed.By applying TAC, the survival rate was significantly lower in KO than that in WT mice. After TAC, KO mice showed significantly higher heart weight-to-tibial length ratio and larger cross-sectional area of cardiomyocytes than those of WT. Although left ventricular (LV) wall thickness in the KO mice was similar to that in the WT mice, the KO mice showed a significant enlargement of LV cavity and reduced LV fractional shortening compared to the WT mice with TAC. A tendency for decreased myocardial ATP concentration was observed in the KO mice compared to the WT mice after TAC operation.These data suggest that the LCFA transporter CD36 is required for the maintenance of energy provision, systolic function, and myocardial structure.

Apolipoprotein E plays crucial roles in maintaining bone mass by promoting osteoblast differentiation via ERK1/2 pathway and by suppressing osteoclast differentiation via c-Fos, NFATc1, and NF-κB pathway.

Apolipoprotein E (ApoE) plays crucial roles not only in lipid metabolism but also in bone metabolism. Specifically ApoE4, one of major ApoE isoforms, has been demonstrated to be associated with increased risk of developing osteoporosis compared to another major isoform ApoE3. However, the detailed mechanism of how the different ApoE isoforms affect bone metabolism remains unclear. Micro-CT analyses of distal femora demonstrated severely decreased bone mass in 48-week-old female homozygous ApoE-knockout (ApoE-KO) mice compared to age- and gender-matched wild type C57BL/6 J (WT) mice. Physiological levels of either ApoE3 or ApoE4 protein (1-20 µg/ml) significantly increased the expression of osteoblast-related genes and alkaline phosphatase (ALP) activity of primary calvarial osteoblasts by inhibiting extracellular signal-regulated kinase 1/2 (ERK1/2) pathway in a dose-dependent manner, and ApoE3 showed greater osteoblastic induction compared to ApoE4. Furthermore, both ApoE3 and ApoE4 protein inhibited osteoclastogenesis and the expression of osteoclast-related genes of mouse bone marrow derived macrophages (BMDM) via down regulation of c-Fos, nuclear factor of activated T-cells 1 (NFATc1) and nuclear factor-kappa B (NF-κB) pathway. Moreover, ApoE3 showed greater inhibition of c-Fos, dendritic cell-specific transmembrane protein (DC-STAMP), and Cathepsin K gene expression compared to ApoE4. Collectively, ApoE plays crucial roles in preserving bone mass, suggesting that targeting ApoE and its isoforms as a promising treatment candidate of both osteoporosis and hyperlipidemia.

One-Year Efficacy and Safety of Evolocumab in Japanese Patients　- A Pooled Analysis From the Open-Label Extension OSLER Studies.

BACKGROUND: Evolocumab, a fully human monoclonal antibody against PCSK9, significantly reduced low-density lipoprotein-cholesterol (LDL-C) levels in Japanese patients by up to 76% when administered with a statin. We evaluated the efficacy and safety of 1 year of evolocumab in a pooled analysis of patients from the 12-week YUKAWA studies who continued into the open-label extension (OLE) OSLER studies.Methods and Results:YUKAWA-1 and YUKAWA-2 were conducted in hypercholesterolemic, high-cardiovascular-risk Japanese patients who were receiving statin therapy. Patients completing these studies were eligible for an OLE study. At OLE entry, patients were re-randomized 2:1 to evolocumab+standard of care (SOC) or SOC alone (OSLER-1: evolocumab 420 mg monthly; OSLER-2: evolocumab 140 mg biweekly or 420 mg monthly). A 1-year analysis was performed on patients enrolled from the YUKAWA studies into OSLER. At parent-study baseline (YUKAWA-1 or YUKAWA-2 patients continuing into OSLER), mean (SD) age was 61 (10) years; 39% were female; mean (SD) baseline LDL-C (on statin) was 119.7 (33.0) mg/dL. Overall rates of adverse events were comparable between evolocumab+SOC and SOC alone. In YUKAWA patients receiving evolocumab+SOC, mean (SE) reductions in LDL-C from parent-study baseline to OLE 1 year were 69.1% (1.2%; OSLER-1) and 65.1% (2.2%; OSLER-2). CONCLUSIONS: In a pooled 1-year analysis of Japanese patients in the ongoing OSLER studies, treatment with evolocumab+SOC was well tolerated and resulted in sustained LDL-C reductions at 1 year.

Re-evaluation of cholesteryl ester transfer protein function in atherosclerosis based upon genetics and pharmacological manipulation.

PURPOSE OF REVIEW: To re-evaluate the functions of plasma cholesteryl ester transfer protein (CETP) in atherosclerosis based upon recent findings from human genetics and pharmacological CETP manipulation. RECENT FINDINGS: CETP is involved in the transfer of cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins, a key step of reverse cholesterol transport (RCT). CETP inhibitors have been developed to raise serum HDL-cholesterol (HDL-C) levels and reduce cardiovascular events. However, outcome studies of three CETP inhibitors (torcetrapib, dalcetrapib and evacetrapib) were prematurely terminated because of increased mortality or futility despite marked increases in HDL-cholesterol and decreases in LDL-cholesterol except for dalcetrapib. Patients with CETP deficiency show remarkable changes in HDL and LDL and are sometimes accompanied by atherosclerotic cardiovascular diseases. Recent prospective epidemiological studies demonstrated atheroprotective roles of CETP. CETP inhibition induces formation of small dense LDL and possibly dysfunctional HDL and downregulates hepatic scavenger receptor class B type I (SR-BI). Therefore, CETP inhibitors may interrupt LDL receptor and SR-BI-mediated cholesterol delivery back to the liver. SUMMARY: For future drug development, the opposite strategy, namely enhancers of RCT via CETP and SR-BI activation as well as the inducers of apolipoprotein A-I or HDL production might be a better approach rather than delaying HDL metabolism by inhibiting a main stream of RCT in vivo.

Detrimental effects of high-fat diet loading on vascular endothelial function and therapeutic efficacy of ezetimibe and statins in patients with type 2 diabetes.

Several recent reports from large clinical trials have described the role of postprandial hyperlipidemia in the onset of atherosclerosis. In this pilot study, the effects of postprandial lipid abnormalities induced by high-fat diet loading on vascular endothelial function in type 2 diabetes were investigated and the effects of ezetimibe and statins on endothelial function were compared. In 20 patients in Study 1, peripheral arterial tonometry tests were performed before and 4h after loading to measure the reactive hyperemia index (RHI). In Study 2, the same patients were randomly allocated to ezetimibe or rosuvastatin. After 1 week of treatment, loading tests were conducted in the same manner. In Study 1, the RHI decreased from 1.86 to 1.60. There were no significant correlations between changes in RHI and the area under the curve (AUC) or coefficient of variation (CV) of each metabolic marker. In Study 2, ezetimibe treatment resulted in a significant improvement in RHI. The two drugs had comparable effects on changes in AUC. There were no significant correlations between changes in RHI and changes in AUC or changes in CV. When age, sex, drug, hemoglobin A1c, and changes in each lipid were evaluated as independent variables with RHI improvement as the dependent variable, drug differences were found to exert the greatest effect on RHI improvement using a stepwise procedure. The results of this study suggest that the progression of atherosclerosis is due to abnormalities in postprandial lipid metabolism and that ezetimibe can potentially inhibit the aggravation of vascular endothelial dysfunction after high-fat diet loading.