Selective Peroxisome Proliferator-activated Receptor Research Articles

Selective activation of PPARα by pemafibrate mitigates peritoneal inflammation and fibrosis through suppression of NLRP3 inflammasome and modulation of inflammation

Peritoneal inflammation and fibrosis remain major challenges to the long-term maintenance of peritoneal dialysis. Pemafibrate, a selective peroxisome proliferator-activated receptor α (PPARα) modulator, has been implicated in the management of fibrosis-related disorders. We investigated whether pemafibrate ameliorates peritoneal inflammation and fibrosis and explored the underlying mechanisms in mice with methylglyoxal (MGO)-induced peritoneal fibrosis (MGO mice). MGO mice exhibited peritoneal fibrosis with increased expression of mesenchymal markers, transforming growth factor-β1 (TGF-β1), and substantial deposition of extracellular matrix (ECM) proteins. Additionally, MGO mice exhibited peritoneal inflammation as indicated by elevated tumor necrosis factor-α expression and macrophage infiltration in peritoneal tissue. These effects were mitigated by pemafibrate treatment, which also restored peritoneal membrane function. Furthermore, pemafibrate promoted anti-inflammatory macrophage polarization in both mice and THP-1 cells. In human peritoneal mesothelial cells (HPMCs), pemafibrate effectively inhibited interferon-γ-induced production of TGF-β1 and ECM while suppressing the proinflammatory cytokines nuclear factor-κB (NF-κB) and activator protein 1. The NF-κB inhibitory effect of pemafibrate involved stabilization of the NF-κB inhibitory protein IkBα. Notably, pemafibrate hindered activation of the NLR family pyrin domain containing 3/caspase-1 axis in interferon-γ-stimulated THP-1 cells. These findings suggest that pemafibrate ameliorates peritoneal inflammation and fibrosis, making it a promising candidate for peritoneal fibrosis therapy.

A Comparison of Alanine Aminotransferase Normalization between Pemafibrate and Bezafibrate in Patients with Nonalcoholic Fatty Liver Disease.

Objective Pemafibrate is a recently developed selective peroxisome proliferator-activated receptor alpha modulator that can improve alanine aminotransferase (ALT) levels in patients with nonalcoholic fatty liver disease (NAFLD). However, the effectiveness of ALT normalization with pemafibrate and bezafibrate, a traditional fibrate, has not been compared. Methods In this retrospective study, we compared the effects of pemafibrate and bezafibrate on ALT normalization in patients with NAFLD. The primary endpoint was the ALT normalization rate at 12 months after administration. Patients Twenty and 14 patients with NAFLD receiving pemafibrate and bezafibrate, respectively, were included in this retrospective analysis. All patients had elevated ALT levels and dyslipidemia at entry. Results The ALT normalization rates at 3, 6, and 12 months were 40%, 55%, and 60% for pemafibrate and 14.3%, 28.6%, and 14.3% for bezafibrate, respectively. The ALT normalization rate at 12 months was significantly higher in patients treated with pemafibrate than in those treated with bezafibrate (p=0.01). Pemafibrate, when compared with bezafibrate, was shown to be a significant factor for ALT normalization in a multivariable analysis with an adjusted odds ratio (95% confidence interval) of 13.8 (1.6-115, p=0.01). Conclusion Pemafibrate is effective in ALT normalization in patients with NAFLD and may be used as a treatment for NAFLD.

Mavodelpar, a selective peroxisome proliferator-activated receptor delta (PPARδ) agonist, improves cellular bioenergetics in fibroblasts from patients with primary mitochondrial myopathy and complex I defiency

Mavodelpar, a selective peroxisome proliferator-activated receptor delta (PPARδ) agonist, improves cellular bioenergetics in fibroblasts from patients with primary mitochondrial myopathy and complex I defiency

Effectiveness of 1-year pemafibrate treatment on steatotic liver disease: the influence of alcohol consumption.

Pemafibrate is a selective peroxisome proliferator-activated receptor α modulator that improves serum alanine aminotransferase (ALT) in dyslipidemia patients. We previously reported that pemafibrate significantly improves liver function, serum triglyceride (TG) levels and liver stiffness in non-alcoholic fatty liver disease patients, however the influence of alcohol consumption was not considered. Therefore, we explored pemafibrate efficacy in patients with steatotic liver disease (SLD) and alcohol-associated liver disease (ALD). We retrospectively evaluated pemafibrate efficacy on liver enzymes and lipids in metabolic dysfunction-associated SLD (MASLD) (n = 93), MASLD plus increased alcohol intake (MetALD; n = 23) and ALD (n = 22) patients who had taken pemafibrate for at least 48 weeks. Liver shear wave velocity (SWV, n = 75) was also evaluated. In MASLD group, ALT, aspartate aminotransferase (AST), γ-glutamyl transpeptidase (γ-GTP) and TG values were significantly decreased from baseline to week 24 and week 48 (P < 0.0001). ALT and TG values in MetALD group and ALT and AST values in ALD group were also significantly decreased from baseline to week 24 and week 48. Study participant SWV values decreased from baseline to week 48. We observed no significant difference in changes to ALT, AST, γ-GTP and TG (value at week 24 or week 48 minus value at baseline) among the three groups. Pemafibrate improves liver function and liver stiffness thus making it a promising therapeutic agent for SLD, even in patients with excess alcohol consumption (MetALD and ALD groups).

Impact of pemafibrate on lipid profile and insulin resistance in hypertriglyceridemic patients with coronary artery disease and metabolic syndrome.

This study examined the effects of pemafibrate, a selective peroxisome proliferator-activated receptor α agonist, on the serum biochemical parameters of male patients with coronary artery disease and metabolic syndrome (MetS). This was a post hoc analysis of a randomized, crossover study that treated hypertriglyceridemia with pemafibrate or bezafibrate for 24weeks, followed by a crossover of another 24 weeks. Of the 60 patients enrolled in the study, 55 were male. Forty-one of 55 male patients were found to have MetS. In this sub-analysis, male patients with MetS (MetS group, n = 41) and those without MetS (non-MetS group, n = 14) were compared. The primary endpoint was a change in fasting serum triglyceride (TG) levels during pemafibrate therapy, and the secondary endpoints were changes in insulin resistance-related markers and liver function parameters. Serum TG levels significantly decreased (MetS group, from 266.6 to 148.0mg/dL, p < 0.001; non-MetS group, from 203.9 to 97.6mg/dL, p < 0.001); however, a percent change (%Change) was not significantly different between the groups (- 44.1% vs. - 51.6%, p = 0.084). Serum insulin levels and homeostasis model assessment of insulin resistance significantly decreased in the MetS group but not in the non-MetS group. %Change in liver enzyme levels was markedly decreased in the MetS group compared with that in the non-MetS group (alanine aminotransferase, - 25.1% vs. - 11.3%, p = 0.027; gamma-glutamyl transferase, - 45.8% vs. - 36.2%, p = 0.020). In conclusion, pemafibrate can effectively decrease TG levels in patients with MetS, and it may be a more efficient drug for improving insulin resistance and liver function in such patients.

Efficacy and Safety of Pemafibrate Extended-Release Tablet: a Phase 3, Multicenter, Randomized, Double-Blind, Active-Controlled, Parallel-Group Comparison Trial.

Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator that lowers serum triglyceride levels and increases high-density lipoprotein cholesterol levels, is approved for treating dyslipidemia as twice-daily immediate-release (IR) tablets. A once-daily extended-release (XR) tablet has also been developed. We aimed to confirm the non-inferiority of XR (0.2 or 0.4 mg/day; once daily) to IR (0.2 mg/day; twice daily) in lowering triglyceride levels in patients with hypertriglyceridemia. This phase 3, multicenter, randomized, double-blind study included patients with fasting triglycerides ≥ 200 mg/dL who received IR (0.2 mg/day) or XR (0.2 or 0.4 mg/day). The primary efficacy endpoint was the percentage change in fasting triglyceride levels from baseline to 4, 8, and 12 weeks. Common treatment effects at weeks 4 through 12 were compared between groups using repeated analysis of covariance. In 356 randomized patients, fasting triglyceride levels decreased by 48.0%, 43.8%, and 48.0% with IR 0.2, XR 0.2, and XR 0.4 mg/day, respectively, confirming the non-inferiority of both XR regimens to IR. The proportion of patients who achieved fasting triglycerides ＜150 mg/dL was 45.7%, 37.4%, and 51.7%, while the percentage change of triglycerides in the subgroup with baseline triglycerides ≥ 500 mg/dL was -59.3%, -52.2%, and -66.3% with IR 0.2, XR 0.2, and XR 0.4 mg/day, respectively. XR (0.2 and 0.4 mg/day) was non-inferior to IR (0.2 mg/day). XR 0.4 mg/day demonstrated a more potent triglyceride-lowering effect than XR 0.2 mg/day and should be considered for patients with high triglyceride levels.

Seladelpar combined with complementary therapies improves fibrosis, inflammation, and liver injury in a mouse model of nonalcoholic steatohepatitis.

Seladelpar, a selective peroxisome proliferator-activated receptor δ (PPARδ) agonist, improves markers of hepatic injury in human liver diseases, but histological improvement of nonalcoholic steatohepatitis (NASH) and liver fibrosis has been challenging with any single agent. To discover how complementary agents could work with seladelpar to achieve optimal outcomes, this study evaluated a variety of therapeutics (alone and in combination) in a mouse model of NASH. Mice on a high-fat amylin liver NASH (AMLN) diet were treated for 12 wk with seladelpar, GLP-1-R (glucagon-like peptide-1 receptor) agonist liraglutide, apoptosis signal-regulating kinase 1 (ASK1) inhibitor selonsertib, farnesoid X receptor (FXR) agonist obeticholic acid, and with seladelpar in combination with liraglutide or selonsertib. Seladelpar treatment markedly improved plasma markers of liver function. Seladelpar alone or in combination resulted in stark reductions in liver fibrosis (hydroxyproline, new collagen synthesis rate, mRNA indices of fibrosis, and fibrosis staining) compared with vehicle and the other single agents. Robust reductions in liver steatosis were also observed. Seladelpar produced a reorganization of metabolic gene expression, particularly for those genes promoting peroxisomal and mitochondrial lipid oxidation. In summary, substantial improvements in NASH and NASH-induced fibrosis were observed with seladelpar alone and in combination with liraglutide in this model. Broad gene expression analysis suggests seladelpar should be effective in concert with diverse mechanisms of action.NEW & NOTEWORTHY NASH is a chronic, progressive, and increasingly problematic liver disease that has been resistant to treatment with individual therapeutics. In this study using a diet-induced mouse model of NASH, we found that the PPARδ agonist seladelpar reduced fibrosis and NASH pathology alone and in combinations with a GLP-1-R agonist (liraglutide) or an ASK1 inhibitor (selonsertib). Liver transcriptome analysis comparing each agent and coadministration suggests seladelpar should be effective in combination with a variety of therapeutics.

A Significant Effect of Pemafibrate on Hepatic Steatosis and Fibrosis Indexes in Patients With Hypertriglyceridemia.

We previously reported that the selective peroxisome proliferator-activated receptor alpha modulator, pemafibrate, significantly reduced serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) and significantly increased serum albumin levels at 3, 6 and 12 months after the start of pemafibrate, with an improvement of atherogenic dyslipidemia, in patients with hypertriglyceridemia. We performed a post hoc analysis of our previous data obtained from patients with hypertriglyceridemia who had been prescribed pemafibrate continuously for 1 year or longer. We compared the indexes for hepatic steatosis (hepatic steatosis index (HSI)) and fibrosis (nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS), AST to platelet ratio index (APRI) and FIB-4 index) at baseline with the data at 1 year after the start of pemafibrate. Pemafibrate significantly reduced HSI at 1 year after the start of pemafibrate. NFS did not show a significant change after 1 year. However, APRI was significantly reduced by pemafibrate after 1 year. FIB-4 index significantly decreased in patients with baseline FIB-4 index ≥ 1.45 at 1 year after the start of pemafibrate. HSI at baseline tended to be negatively correlated with change in HSI after 1 year. There was no significant correlation between NFS at baseline and change in this score after 1 year. APRI and FIB-4 index at baseline were significantly and negatively correlated with changes in APRI and FIB-4 index at 1 year after the start of pemafibrate. The 1-year pemafibrate treatment improved hepatic steatosis and fibrosis indexes in patients with hypertriglyceridemia.

Favorable Effect of Pemafibrate on Insulin Resistance and β-Cell Function in Subjects with Type 2 Diabetes and Hypertriglyceridemia: A Subanalysis of the PARM-T2D Study.

Pemafibrate, a novel selective peroxisome proliferator-activated receptor modulator, has beneficial effects on lipid metabolism. However, its effects on glucose metabolism in individuals with type 2 diabetes (T2DM) remain to be fully clarified. This was a subanalysis of the PARM-T2D study, a multicenter prospective observational study on the use of pemafibrate versus conventional therapy for 52 weeks in subjects with T2DM complicated with hypertriglyceridemia. The subanalysis included participants who did not change their treatment for diabetes and did not receive insulin or insulin secretagogues during the study period. Changes in glucose metabolism markers, including homeostatic model assessment (HOMA2) scores and disposition index, were assessed. A total of 279 participants (141 in the pemafibrate group; 138 in the control group) met the criteria for the subanalysis. There were no significant changes in HbA1c during the 52-week study period in both groups. However, the pemafibrate group showed significant improvements versus the control group for insulin resistance assessed by HOMA2-R (-0.15 versus 0.08; estimated treatment difference -0.23 (95% confidence interval -0.44, -0.02); p = 0.03) and maintenance of β-cell function assessed by disposition index (0.015 versus -0.023; estimated treatment difference 0.037 (95% confidence interval 0.005, 0.069); p = 0.02). Correlation analyses showed that improvements in HOMA2-R and disposition index were significantly associated with improvements in lipid abnormalities and γ-glutamyl transpeptidase. In conclusion, pemafibrate reduced insulin resistance and maintained β-cell function in subjects with T2DM and hypertriglyceridemia, presumably by improving lipid profiles and lipid-related hepatocyte stress.

843-P: Effects of Pemafibrate on Glucose Metabolism in Adults with Type 2 Diabetes and Hypertriglyceridemia—Subanalysis of the PARM-T2D Study

Background and Aims: Pemafibrate, a novel selective peroxisome proliferator-activated receptor modulator, has been demonstrated to have potent effects on abnormalities of lipid metabolism in adults with type 2 diabetes (T2DM) and hypertriglyceridemia in real-world clinical practice (PARM-T2D study). However, the effects of pemafibrate on glucose metabolism have not been fully clarified. Materials and Methods: In this multicenter, open-labeled, prospective, observational study, adults with T2DM were treated with pemafibrate (PEMA group) or continued on their current therapy (CTRL group) for dyslipidemia for 52 weeks. This subanalysis consisted of participants who did not change their treatment for diabetes and who did not receive insulin or insulin secretagogues during the study period. Glycemic control, insulin secretion, and insulin resistance were assessed by HbA1c levels, HOMA2-β, and HOMA2-R, respectively. The changes of these parameters between baseline and the end of the study were compared between the groups. Results: In total, 279 of 650 participants met the criteria for this analysis. There were no statistical differences in baseline characteristics between PEMA (n = 141) and CTRL groups (n = 138). There were no significant changes in HbA1c levels and beta-cell function over 52 weeks between the groups, whereas pemafibrate significantly improved insulin resistance assessed by HOMA2-R versus the CTRL group (−0.20 vs. 0.01; estimated treatment difference, −0.23% [95% confidence interval = −0.44, −0.02]; p&amp;lt;0.05). Pemafibrate also ameliorated lipid profiles and liver dysfunction. Changes in serum triglyceride, HDL-cholesterol, γ-GTP, and ALP levels were significantly correlated with those in HOMA2-R (p = 0.024, p = 0.002, p &amp;lt; 0.001, and p = 0.032, respectively). Conclusions: Pemafibrate reduced insulin resistance and improved lipid profiles and liver dysfunction in individuals with T2DM and hypertriglyceridemia. Disclosure H.Nomoto: Speaker's Bureau; Novo Nordisk, Sumitomo Pharma, Co., Ltd. T.Atsumi: Speaker's Bureau; Eli Lilly Japan K.K., Kowa Company, Ltd. H.Miyoshi: Research Support; Abbott, LifeScan Diabetes Institute, Taisho Pharmaceutical Holdings Co., Ltd., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Kowa Company, Ltd., MSD Life Science Foundation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation. K.Kito: None. A.Nakamura: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim Japan, Inc., Daiichi Sankyo, Taisho Pharmaceutical Holdings Co., Ltd., Teijin Pharma Limited, Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation. H.Kameda: None. K.Omori: None. S.Yanagiya: None. H.Iesaka: None. Y.Oe: None. S.Kawata: None.

Bavachinin selectively modulates PPAR γ and maintains bone homeostasis in Type 2 Diabetes.

Full peroxisome proliferator-activated receptor (PPAR) γ agonists, Thiazolidinediones (TZDs), effectively prevent the process of Type 2 Diabetes Mellitus (T2DM), but their side effects have curtailed use in the clinic, including weight gain and bone loss. Here, we identified that a selective PPAR γ modulator, Bavachinin (BVC), isolated from the seeds of Psoralea Corylifolia L., could potently regulate bone homeostasis. MC3T3-E1 pre-osteoblast cells and C3H10T1/2 mesenchymal stem cells were assessed for osteogenic differentiation activities, and receptor activator of NF-κB ligand (RANKL)-induced RAW 264.7 cells were assessed osteoclasts formation. Leptin receptor-deficient mice and diet-induced obesity mice were applied to evaluate the effect of BVC on bone homeostasis in vivo. Compared to full PPAR γ agonist rosiglitazone, BVC significantly increased the osteogenesis differentiation activities under normal and high glucose conditions in MC3T3-E1 cells. Moreover, BVC could alleviate osteoclast differentiation in RANKL-induced RAW 264.7 cells. In vivo, synthesized BVC prodrug (BN) has been applied to improve water solubility, increase the extent of oral absorption of BVC and prolong its residence time in blood circulation. BN could prevent weight gain, ameliorate lipid metabolism disorders, improve insulin sensitivity, and maintain bone mass and bone biomechanical properties. BVC, a unique PPAR γ selective modulator, could maintain bone homeostasis, and its prodrug (BN) exhibits insulin sensitizer activity while circumventing the side effects of the TZDs, including bone loss and undesirable weight gain.

Combination Therapy Using Pemafibrate and Dapagliflozin for Metabolic Dysfunction-associated Fatty Liver Disease.

Metabolic syndrome, including diabetes mellitus, obesity, and dyslipidemia, is associated with the development and progression of metabolic dysfunction-associated fatty liver disease. Therapeutic strategies, particularly optimal medical therapies, for treating metabolic dysfunction-associated fatty liver disease remain unestablished. We encountered a 37-year-old man with obesity (body mass index 39.0), metabolic dysfunction-associated fatty liver disease, and nephrotic syndrome due to obesity-related focal segmental glomerulosclerosis. Combination therapy using pemafibrate and dapagliflozin, together with body weight reduction, ameliorated his hypertriglyceridemia, hyperglycemia, hepatic injury, and proteinuria. Combination therapy using selective peroxisome proliferator-activated receptor α modulator and sodium-glucose cotransporter 2 inhibitor, together with body weight reduction, might be a promising dual-medical strategy for ameliorating metabolic dysfunction-associated fatty liver disease.

Peptide Helix-Y12 as Potential Effector for Peroxisome Proliferator-Activated Receptors.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the regulation of lipids and glucose metabolism, and immune response. Therefore, they have been considered pharmacological targets for treating metabolic diseases, such as dyslipidemia, atherosclerosis, and non-alcoholic fatty liver disease. However, the available synthetic ligands of PPARs have mild to significant side effects, generating the necessity to identify new molecules that are selective PPAR ligands with specific biological responses. This study aimed to evaluate some components of the atheroprotective and hepatoprotective HB-ATV-8 nanoparticles [the amphipathic peptide Helix-Y12, thermozeaxanthin, thermozeaxanthin-13, thermozeaxanthin-15, and a set of glycolipids], as possible ligands of PPARs through blind molecular docking. According to the change in free energy upon protein-ligand binding, ∆G b, thermozeaxanthins show a more favorable interaction with PPARs, followed by Helix-Y12. Moreover, Helix-Y12 interacts with most parts of the Y-shaped ligand-binding domain (LBD), surrounding helix 3 of PPARs, and reaching helix 12 of PPARα and PPARγ. As previously reported for other ligands, Tyr314 and Tyr464 of PPARα interact with Helix-Y12 through hydrogen bonds. Several PPARα's amino acids are involved in the ligand binding by hydrophobic interactions. Furthermore, we identified additional PPARs' amino acids interacting with Helix-Y12 through hydrogen bonds still not reported for known ligands. Our results show that, from the studied ligand set, the Helix-Y12 peptide and Tzeaxs have the most significant probability of binding to the PPARs' LBD, suggesting novel ligands for PPARs.

Effect of Pemafibrate on Hemorheology in Patients with Hypertriglyceridemia and Aggravated Blood Fluidity Associated with Type 2 Diabetes or Metabolic Syndrome

Persistent high serum triglyceride (TG) and free fatty acid (FFA) levels, which are common in metabolic syndrome and type 2 diabetes, are risk factors for cardiovascular events because of exacerbated hemorheology. To explore the effects of pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, on hemorheology, we performed a single-center, nonrandomized, controlled study in patients with type 2 diabetes (HbA1c 6-10%) or metabolic syndrome, with fasting TG levels of ≥ 150 mg/dL and a whole blood transit time of > 45 s on a microarray channel flow analyzer (MCFAN). Patients were divided into a study group, receiving 0.2 mg/day of pemafibrate (n = 50) for 16 weeks, and a non-pemafibrate control group (n = 46). Blood samples were drawn 8 and 16 weeks after entry to the study to evaluate whole blood transit time as a hemorheological parameter, leukocyte activity by MCFAN, and serum FFA levels. No serious adverse events were observed in either of the groups. After 16 weeks, the pemafibrate group showed a 38.6% reduction in triglycerides and a 50.7% reduction in remnant lipoproteins. Pemafibrate treatment did not significantly improve whole blood rheology or leukocyte activity in patients with type 2 diabetes mellitus or metabolic syndrome complicated by hypertriglyceridemia and exacerbated hemorheology.

Effect of pemafibrate on liver enzymes and shear wave velocity in non-alcoholic fatty liver disease patients.

Pemafibrate is a selective peroxisome proliferator-activated receptor α modulator that improves serum alanine aminotransferase (ALT) in dyslipidemia patients. Pemafibrate was reported to reduce ALT in non-alcoholic fatty liver disease (NAFLD) patients, but efficacy was not clearly elucidated due to the small size of previous study populations. Therefore, we explored pemafibrate efficacy in NAFLD patients. We retrospectively evaluated pemafibrate efficacy on liver enzymes (n = 132) and liver shear wave velocity (SWV, n = 51) in NAFLD patients who had taken pemafibrate for at least 24 weeks. Patient ALT levels were decreased from 81.0 IU/L at baseline to 48.0 IU/L at week 24 (P < 0.0001). Serum levels of aspartate aminotransferase (AST), γ-glutamyl transpeptidase (γ-GTP) and triglyceride (TG) were significantly decreased, and high-density lipoprotein cholesterol and platelet count were significantly increased, with no change in body weight being observed. Study participant SWV values decreased from 1.45 m/s at baseline to 1.32 m/s at week 48 (P < 0.001). Older age (P = 0.035) and serum TG levels (P = 0.048) were significantly associated with normalized ALT. Changes in AST, ALT, γ-GTP and body weight were significantly correlated with change in SWV. Pemafibrate significantly improves liver function, serum TG and liver stiffness in NAFLD patients. Pemafibrate is a promising therapeutic agent for NAFLD and may be a candidate for NAFLD patients with elevated TG.

Design and methods of an open-label, randomized controlled trial to evaluate the effect of pemafibrate on proteinuria in CKD patients (PROFIT-CKD).

Hypertriglyceridemia is increasingly considered a residual risk of cardiovascular disease in patients with chronic kidney disease (CKD). Pemafibrate-a novel selective peroxisome proliferator-activated receptor alpha modulator and a new treatment for hypertriglyceridemia in CKD patients-is reported to have fewer side effects in CKD patients than other fibrates. Appropriate control of hypertriglyceridemia can be expected to improve renal prognosis. However, data on the renal protective effect of pemafibrate are limited. This study aims to evaluate the effectiveness of pemafibrate on urinary protein excretion in CKD patients. The Pemafibrate, open-label, Randomized cOntrolled study to evaluate the renal protective eFfect In hyperTriglyceridemia patients with Chronic Kidney Disease (PROFIT-CKD) study is an investigator-initiated, multi-center, open-label, parallel-group, randomized controlled trial. Participants are outpatients with hypertriglyceridemia aged 20years and over, who have received the care of a nephrologist or a diabetologist for more than 3months. Inclusion criteria include the following: proteinuria (urine protein/creatinine ratio of ≥ 0.15g/gCr) within three months before allocation, and hypertriglyceridemia (triglycerides ≥ 150mg/dL and < 1,000mg/dL) at allocation. In the treatment group, pemafibrate is added to conventional treatment, while conventional treatment is continued with no additional treatment in the control group. Target patient enrollment is 140 patients. The primary endpoint is the change from baseline in the logarithmic urine protein/creatinine ratio at 12months after study start. This study will provide new findings on the renal protective effect of pemafibrate in CKD patients. This clinical trial was registered at the University Hospital Medical Information Network (UMIN) Center (UMIN-CTR: UMIN000042284).

Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2–3 trial

Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy. ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2-3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18-65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 μg·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing. Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: -27·7 [41·4] m; placebo: -30·3 [60·5] m; least-squares mean difference -1·2 m; 95% CI -22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group. The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy. Minoryx Therapeutics.

Pemafibrate, a potent selective peroxisome proliferator-activated receptor α modulator, a promising novel treatment for ischemic retinopathy?

Pemafibrate, a potent selective peroxisome proliferator-activated receptor α modulator, a promising novel treatment for ischemic retinopathy?

Reduction of Cardiovascular Risk with Pemafibrate

It has been established that increased cardiovascular risk is seen in individuals with elevated triglycerides; however, whether reduction of the same alleviates the risk is still unclear. A decrease in triglycerides and improvement in other lipid levels is observed with Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator. Pradhan and researchers conducted a randomized, double-blind clinical trial on an international scale. Patients with type 2 diabetes mellitus were divided into two groups; high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter and or lower and mild to moderate hypertriglyceridemia (200 to 499 mg per deciliter), where one group received a placebo and the other 200µg tablets BD Pemafibrate. A cohort of parameters, namely coronary revascularization, ischemic stroke, myocardial infarction, and death from cardiovascular disease, were factored in as the primary efficacy endpoints. An HDL cholesterol level of 33 mg per deciliter, a median baseline fasting triglyceride level of 271 mg per deciliter, and an LDL cholesterol level of 78 mg per deciliter were observed in a sum-total 10,497 patients, of whom 66.9% had a previous history of cardiovascular disease. After 16 months, a significant reduction of 26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, 25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), 27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B were observed in Pemafibrate group in comparison to the placebo group. In both groups, no significant difference was seen in the incidence of adverse events. However, a lower incidence of non-alcoholic fatty liver disease and a higher incidence of venous thromboembolism and adverse renal events were associated with Pemafibrate. N Engl J Med ( 2022) DOI: 10.1056/NEJMoa2210645.

Effects of Pemafibrate on Reducing Oxidative Stress and Augmenting Angiogenesis in Ischemic Limb Tissue.

Oxidative damage is observed in the ischemic limbs of patients with arteriosclerosis obliterans. We investigated whether pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, reduced oxidative stress in ischemic limbs and consequently rescued limb damage in model mice. We surgically induced hind-limb ischemia in mice and orally administered pemafibrate solution (P-05 group, 0.5 mg/kg/day; P-10 group, 1.0 mg/kg/day) or control solution (control group). Seven days after the surgery, differences in reactive oxygen species (ROS) contents, antioxidative enzyme and transcription factor expression, blood flow, and capillary density in ischemic limbs were assessed. Tissue ROS levels were lower in the P-05 and P-10 groups compared with those in the control group. Although the tissue expression levels of nuclear factor-erythroid 2-related factor 2 increased in the P-10 group compared with that in the control group, no corresponding changes were observed in the tissue expression of four antioxidative enzymes. The limb salvage rates and capillary densities in ischemic limbs were higher in the P-05 and P-10 groups than that in the control group. Pemafibrate treatment reduced oxidative stress and augmented angiogenesis in ischemic limbs, contributing to prevention of limb damage in mice.