Selective Peroxisome Proliferator-activated Receptor Alpha Research Articles

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.

Clinical Efficacy and Safety of Low-Dose Pemafibrate in Patients With Severe Renal Impairment: A Retrospective Study.

The management of hypertriglyceridemia in patients with chronic kidney disease (CKD) is important. Pemafibrate, a novel selective peroxisome proliferator-activated receptor-alpha modulator with less toxic effects on liver and kidney function than those of other fibrates, has recently been approved for the treatment of patients with an estimated glomerular filtration rate (eGFR) lower than 30mL/min/1.73 m2. However, the efficacy and safety of pemafibrate in patients with severe renal impairment have not yet been established. This single-center, retrospective observational study included 12 outpatients with CKD and hypertriglyceridemia, who were newly started on low-dose pemafibrate (0.1 mg/day) treatment between December 2021 and May 2023 and whose eGFRs were less than 30 mL/min/1.73 m2 at baseline. Blood samples were collected before and at 12 weeks after pemafibrate treatment. After 12 weeks of treatment, the serum triglyceride level was significantly decreased, whereas the high-density lipoprotein cholesterol level was significantly increased. The serum alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, and uric acid levels were also significantly decreased, without worsening of the eGFR and serum creatinine levels. In the subgroup analysis, there were no significant differences in the changes in clinical parameters regardless of statin use and CKD stage at baseline. Low-dose pemafibrate administration in patients with severe renal impairment resulted in significant improvements in triglyceride, high-density lipoprotein cholesterol, and serum uric acid levels, and liver function, without adverse events.

Metabolic-Dysfunction-Associated Steatotic Liver Disease-Its Pathophysiology, Association with Atherosclerosis and Cardiovascular Disease, and Treatments.

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease that affects more than a quarter of the global population and whose prevalence is increasing worldwide due to the pandemic of obesity. Obesity, impaired glucose metabolism, high blood pressure and atherogenic dyslipidemia are risk factors for MASLD. Therefore, insulin resistance may be closely associated with the development and progression of MASLD. Hepatic entry of increased fatty acids released from adipose tissue, increase in fatty acid synthesis and reduced fatty acid oxidation in the liver and hepatic overproduction of triglyceride-rich lipoproteins may induce the development of MASLD. Since insulin resistance also induces atherosclerosis, the leading cause for death in MASLD patients is cardiovascular disease. Considering that the development of cardiovascular diseases determines the prognosis of MASLD patients, the therapeutic interventions for MASLD should reduce body weight and improve coronary risk factors, in addition to an improving in liver function. Lifestyle modifications, such as improved diet and increased exercise, and surgical interventions, such as bariatric surgery and intragastric balloons, have shown to improve MASLD by reducing body weight. Sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to improve coronary risk factors and to suppress the occurrence of cardiovascular diseases. Both SGLT2i and GLP-1 have been reported to improve liver enzymes, hepatic steatosis and fibrosis. We recently reported that the selective peroxisome proliferator-activated receptor-alpha (PPARα) modulator pemafibrate improved liver function. PPARα agonists have multiple anti-atherogenic properties. Here, we consider the pathophysiology of MASLD and the mechanisms of action of such drugs and whether such drugs and the combination therapy of such drugs could be the treatments for MASLD.

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.

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.

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).

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.

Higher Responsiveness for Women, High Transaminase Levels, and Fat Percentage to Pemafibrate Treatment for NAFLD.

Pemafibrate (PEM) is a novel selective peroxisome proliferator-activated receptor alpha modulator that is effective for hypertriglyceridemia accompanying non-alcoholic fatty liver disease (HTG-NAFLD). This study aimed to identify the predictors of PEM efficacy for HTG-NAFLD in clinical practice. We retrospectively enrolled 88 HTG-NAFLD patients treated with PEM for 6 months for the analysis of routine blood and body composition testing. A PEM response was defined as a decrease in serum alanine aminotransferase (ALT) of &gt;30% compared with pre-treatment level. The clinical features related to PEM responsiveness were statistically tested between responders and non-responders. All 88 patients completed the 6 month drug regimen without any adverse effects. PEM treatment significantly decreased liver enzymes, triglycerides, and total cholesterol levels, without any detectable impact on body weight or body composition. Comparisons of baseline clinical features revealed female and greater aspartate aminotransferase (AST), ALT, and fat mass % levels to be significantly associated with a PEM response. The optimal cut-off values to predict responders as determined by receiver operating characteristic analysis were AST 45 U/L, ALT 60 U/L, and fat mass 37%. Female HTG-NAFLD patients with higher transaminase and fat mass % levels may be preferentially indicated for PEM treatment. Additional large-scale prospective studies are warranted to verify our results.

The Efficacy of Camelina sativa Defatted Seed Meal against Colitis-Induced Persistent Visceral Hypersensitivity: The Relevance of PPAR α Receptor Activation in Pain Relief.

Brassicaceae are natural sources of bioactive compounds able to promote gut health. Belonging to this plant family, Camelina sativa is an ancient oil crop rich in glucosinolates, polyunsaturated fatty acids, and antioxidants that is attracting renewed attention for its nutraceutical potential. This work aimed at investigating the therapeutic effects of a defatted seed meal (DSM) of Camelina sativa on the colon damage and the persistent visceral hypersensitivity associated with colitis in rats. Inflammation was induced by the intrarectal injection of 2,4-dinitrobenzenesulfonic acid (DNBS). The acute administration of Camelina sativa DSM (0.1–1 g kg−1) showed a dose-dependent pain-relieving effect in DNBS-treated rats. The efficacy of the meal was slightly enhanced after bioactivation with myrosinase, which increased isothiocyanate availability, and drastically decreased by pre-treating the animals with the selective peroxisome proliferator-activated receptor alpha (PPAR α) receptor antagonist GW6471. Repeated treatments with Camelina sativa DSM (1 g kg−1) meal counteracted the development, as well as the persistence, of visceral hyperalgesia in DNBS-treated animals by reducing the intestinal inflammatory damage and preventing enteric neuron damage. In conclusion, Camelina sativa meal might be employed as a nutraceutical tool to manage persistent abdominal pain in patients and to promote gut healing.

New, Novel Lipid-Lowering Agents for Reducing Cardiovascular Risk: Beyond Statins.

Statins are the cornerstone of the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD). However, even under optimal statin therapy, a significant residual ASCVD risk remains. Therefore, there has been an unmet clinical need for novel lipid-lowering agents that can target low-density lipoprotein cholesterol (LDL-C) and other atherogenic particles. During the past decade, several drugs have been developed for the treatment of dyslipidemia. Inclisiran, a small interfering RNA that targets proprotein convertase subtilisin/kexin type 9 (PCSK9), shows comparable effects to that of PCSK9 monoclonal antibodies. Bempedoic acid, an ATP citrate lyase inhibitor, is a valuable treatment option for the patients with statin intolerance. Pemafibrate, the first selective peroxisome proliferator-activated receptor alpha modulator, showed a favorable benefit-risk balance in phase 2 trial, but the large clinical phase 3 trial (PROMINENT) was recently stopped for futility based on a late interim analysis. High dose icosapent ethyl, a modified eicosapentaenoic acid preparation, shows cardiovascular benefits. Evinacumab, an angiopoietin-like 3 (ANGPTL3) monoclonal antibody, reduces plasma LDL-C levels in patients with refractory hypercholesterolemia. Novel antisense oligonucleotides targeting apolipoprotein C3 (apoC3), ANGPTL3, and lipoprotein(a) have significantly attenuated the levels of their target molecules with beneficial effects on associated dyslipidemias. Apolipoprotein A1 (apoA1) is considered as a potential treatment to exploit the athero-protective effects of high-density lipoprotein cholesterol (HDL-C), but solid clinical evidence is necessary. In this review, we discuss the mode of action and clinical outcomes of these novel lipid-lowering agents beyond statins.

Pemafibrate Prevents Rupture of Angiotensin II-Induced Abdominal Aortic Aneurysms.

BackgroundAbdominal aortic aneurysm (AAA) is a life-threatening disease that lacks effective preventive therapies. This study aimed to evaluate the effect of pemafibrate, a selective peroxisome proliferator-activated receptor alpha (PPARα) agonist, on AAA formation and rupture.MethodsExperimental AAA was induced by subcutaneous angiotensin II (AngII) infusion in ApoE–/– mice for 4 weeks. Pemafibrate (0.1 mg/kg/day) was administered orally. Dihydroethidium staining was used to evaluate the reactive oxygen species (ROS).ResultsThe size of the AngII-induced AAA did not differ between pemafibrate- and vehicle-treated groups. However, a decreased mortality rate due to AAA rupture was observed in pemafibrate-treated mice. Pemafibrate ameliorated AngII-induced ROS and reduced the mRNA expression of interleukin-6 and tumor necrosis factor-α in the aortic wall. Gelatin zymography analysis demonstrated significant inhibition of matrix metalloproteinase-2 activity by pemafibrate. AngII-induced ROS production in human vascular smooth muscle cells was inhibited by pre-treatment with pemafibrate and was accompanied by an increase in catalase activity. Small interfering RNA-mediated knockdown of catalase or PPARα significantly attenuated the anti-oxidative effect of pemafibrate.ConclusionPemafibrate prevented AAA rupture in a murine model, concomitant with reduced ROS, inflammation, and extracellular matrix degradation in the aortic wall. The protective effect against AAA rupture was partly mediated by the anti-oxidative effect of catalase induced by pemafibrate in the smooth muscle cells.

Effects of Switching from Fenofibrate to Pemafibrate for Asymptomatic Primary Biliary Cholangitis.

The addition of a fibrate to ursodeoxycholic acid (UDCA) is the standard treatment for asymptomatic primary biliary cholangitis (aPBC) with an incomplete response to UDCA. Among the fibrates, bezafibrate and fenofibrate increase the serum creatinine level and reduce the estimated glomerular filtration rate (eGFR). Pemafibrate is an selective peroxisome proliferator-activated receptor alpha modulator (SPPARM-α) mainly metabolized by the liver that was recently approved to treat dyslipidemia. This study confirmed the changes in the biochemical markers after switching from fenofibrate to pemafibrate in aPBC patients. This study examined the effects of switching treatment from fenofibrate to pemafibrate in 16 aPBC patients. The biological parameters of these patients were examined at the initiation of fenofibrate and after switching to pemafibrate, then at 24 and 48 weeks later, respectively. Among patients with aPBC treated with UDCA and fenofibrate, the ALP, GGT, and serum IgM levels decreased significantly (p<0.0001) over 48 weeks. On the other hand, serum creatinine levels increased significantly, and eGFR decreased significantly (p<0.0001). After switching to pemafibrate plus UDCA, patients with aPBC exhibited significantly lower serum creatinine levels (p=0.007) and significantly higher eGFR levels (p=0.014). Pemafibrate has therapeutic efficacy for aPBC patients with an inadequate response to UDCA. Pemafibrate might be another option for aPBC patients given its beneficial effects on renal function, but larger, multicenter studies with a longer follow-up are needed.

Pemafibrate Prevents Retinal Dysfunction in a Mouse Model of Unilateral Common Carotid Artery Occlusion.

Cardiovascular diseases lead to retinal ischemia, one of the leading causes of blindness. Retinal ischemia triggers pathological retinal glial responses and functional deficits. Therefore, maintaining retinal neuronal activities and modulating pathological gliosis may prevent loss of vision. Previously, pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, was nominated as a promising drug in retinal ischemia. However, a protective role of pemafibrate remains untouched in cardiovascular diseases-mediated retinal ischemia. Therefore, we aimed to unravel systemic and retinal alterations by treating pemafibrate in a new murine model of retinal ischemia caused by cardiovascular diseases. Adult C57BL/6 mice were orally administered pemafibrate (0.5 mg/kg) for 4 days, followed by unilateral common carotid artery occlusion (UCCAO). After UCCAO, pemafibrate was continuously supplied to mice until the end of experiments. Retinal function (a-and b-waves and the oscillatory potentials) was measured using electroretinography on day 5 and 12 after UCCAO. Moreover, the retina, liver, and serum were subjected to qPCR, immunohistochemistry, or ELISA analysis. We found that pemafibrate enhanced liver function, elevated serum levels of fibroblast growth factor 21 (FGF21), one of the neuroprotective molecules in the eye, and protected against UCCAO-induced retinal dysfunction, observed with modulation of retinal gliosis and preservation of oscillatory potentials. Our current data suggest a promising pemafibrate therapy for the suppression of retinal dysfunction in cardiovascular diseases.

Effects of Pemafibrate in Patients with Stroke and Hypertriglyceridemia: Baseline Cerebral Artery Diseases and 3-Month Laboratory Outcomes.

Aims: The role of hypertriglyceridemia in stroke is poorly understood. The Pemafibrate for Prevention of Atherosclerotic Diseases in Stroke (PPAR Stroke) study was designed to assess the effects of a novel selective peroxisome proliferator-activated receptor alpha modulator, pemafibrate, on vascular outcomes in stroke patients with hypertriglyceridemia. Methods: This was a prospective single-arm study including 74 patients (mean age, 64.1 years; male 75.7%) with stroke and hypertriglyceridemia (defined as fasting serum triglycerides levels of ≥ 150 mg/dL) who were treated with pemafibrate at 0.2 mg or 0.1 mg/day. The present report assessed the association of hypertriglyceridemia with cerebral large and small vessel diseases at baseline and changes in laboratory parameters after a three-month pemafibrate therapy. Results: Patients with triglycerides levels of ≥ 227 mg/dL (higher than the median) more often presented with intracranial artery atherosclerotic stenosis than those with triglycerides levels of 150–227 mg/dL (44.4% vs. 21.6%,p=0.037). On the other hand, no differences were found in the prevalence of extracranial artery atherosclerosis and cerebral small vessel diseases. Mean triglycerides levels were significantly reduced from 285 mg/dL at baseline to 175 mg/dL at 3 months (p＜0.001). High-density lipoprotein cholesterol levels increased from 48 mg/dL to 53 mg/dL (p＜0.001). In addition, significant reductions in alanine aminotransferase, γ-glutamyl transpeptidase, and interleukin-6 levels were observed (p＜0.001,p=0.002, andp=0.044, respectively). Conclusions: Higher triglycerides levels are associated with intracranial artery atherosclerosis. Pemafibrate showed pleiotropic effects not only in ameliorating atherogenic dyslipidemia but also in the reduction of the levels of inflammatory markers and hepatobiliary enzymes.

Potential Effect of a Selective Peroxisome Proliferator-activated Receptor Alpha Modulator on Metabolic Dysfunction-associated Fatty Liver Disease.

Potential Effect of a Selective Peroxisome Proliferator-activated Receptor Alpha Modulator on Metabolic Dysfunction-associated Fatty Liver Disease.

Pemafibrate, a PPAR alpha agonist, attenuates neointima formation after vascular injury in mice fed normal chow and a high-fat diet

Recently, the prevention of cardiovascular events has become one of the most important aims of diabetes care. Peroxisome proliferator-activated receptor (PPAR) agonists have been reported to have vascular protective effects. Here, we examined whether pemafibrate, a selective PPAR alpha agonist, attenuated neointima formation after vascular injury and vascular smooth muscle cell (VSMC) proliferation. We performed endothelial denudation injury in mice treated with a high-fat diet (HFD) or normal chow. Orally administered pemafibrate significantly attenuated neointima formation after vascular injury in HFD and normal chow mice. Interestingly, pemafibrate increased the serum fibroblast growth factor 21 concentration and decreased serum insulin concentrations in HFD mice. In addition, body weight was slightly but significantly decreased by pemafibrate in HFD mice. Pemafibrate, but not bezafibrate, attenuated VSMC proliferation in vitro. The knockdown of PPAR alpha abolished the anti-VSMC proliferation effect of pemafibrate. BrdU assay results revealed that pemafibrate dose-dependently inhibited DNA synthesis in VSMCs. Flow cytometry analysis demonstrated that G1-to-S phase cell cycle transition was significantly inhibited by pemafibrate. Pemafibrate attenuated serum-induced cyclin D1 expression in VSMCs. However, apoptosis was not induced by pemafibrate as assessed by the TUNEL assay. Similar to the in vitro data, VSMC proliferation was also decreased by pemafibrate in mice. These data suggest that pemafibrate attenuates neointima formation after vascular injury and VSMC proliferation by inhibiting cell cycle progression.

PPARα Agonist Oral Therapy in Diabetic Retinopathy.

Diabetic retinopathy (DR) is an eye condition that develops after chronically poorly-managed diabetes, and is presently the main cause for blindness on a global scale. Current treatments for DR such as laser photocoagulation, topical injection of corticosteroids, intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents and vitreoretinal surgery are only applicable at the late stages of DR and there are possibilities of significant adverse effects. Moreover, the forms of treatment available for DR are highly invasive to the eyes. Safer and more effective pharmacological treatments are required for DR treatment, in particular at an early stage. In this review, we cover recently investigated promising oral pharmacotherapies, the methods of which are safer, easier to use, patient-friendly and pain-free, in clinical studies. We especially focus on peroxisome proliferator-activator receptor alpha (PPARα) agonists in which experimental evidence suggests PPARα activation may be closely related to the attenuation of vascular damages, including lipid-induced toxicity, inflammation, an excess of free radical generation, endothelial dysfunction and angiogenesis. Furthermore, oral administration of selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) agonists may induce hepatic fibroblast growth factor 21 expression, indirectly resulting in retinal protection in animal studies. Our review will enable more comprehensive approaches for understanding protective roles of PPARα for the prevention of DR development.

Pemafibrate Protects Against Retinal Dysfunction in a Murine Model of Diabetic Retinopathy.

Diabetic retinopathy (DR) is one of the leading causes of blindness globally. Retinal neuronal abnormalities occur in the early stage in DR. Therefore, maintaining retinal neuronal activity in DR may prevent vision loss. Previously, pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, was suggested as a promising drug in hypertriglyceridemia. However, the role of pemafibrate remains obscure in DR. Therefore, we aimed to unravel systemic and retinal changes by pemafibrate in diabetes. Adult mice were intraperitoneally injected with streptozotocin (STZ) to induce diabetes. After STZ injection, diet supplemented with pemafibrate was given to STZ-induced diabetic mice for 12 weeks. During the experiment period, body weight and blood glucose levels were examined. Electroretinography was performed to check the retinal neural function. After sacrifice, the retina, liver, and blood samples were subjected to molecular analyses. We found pemafibrate mildly improved blood glucose level as well as lipid metabolism, boosted liver function, increased serum fibroblast growth factor21 level, restored retinal functional deficits, and increased retinal synaptophysin protein expression in STZ-induced diabetic mice. Our present data suggest a promising pemafibrate therapy for the prevention of early DR by improving systemic metabolism and protecting retinal function.

SPPARM alpha: the Lazarus effect.

Atherogenic dyslipidaemia, characterized by high plasma triglycerides (a surrogate for triglyceride-rich remnant lipoproteins) and low high-density lipoprotein cholesterol (HDL-C), is prevalent in patients with type 2 diabetes mellitus (T2DM) and contributes to a high modifiable residual cardiovascular risk. Fibrates are effective in managing hypertriglyceridaemia but lack consistent cardiovascular benefit in clinical trials and exhibit pharmacokinetic interaction with statins (gemfibrozil) and renal and hepatic safety issues (fenofibrate). The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm offers potential for improving potency, selectivity and the benefit-risk profile. The present review discusses evidence for the novel SPPARMα agonist, pemafibrate. Clinical trials showed robust lowering of triglyceride-rich lipoproteins, elevation in HDL-C and nonlipid beneficial effects including anti-inflammatory activity. There was a favourable safety profile, with no increase in serum creatinine, evident with fenofibrate, and improved renal and hepatic safety. The cardiovascular outcomes study PROMINENT is critical to confirming the SPPARMα concept by validating reduction in residual cardiovascular risk in patients with T2DM and long-term safety. SPPARMα offers a new paradigm for reducing residual cardiovascular risk in T2DM. PROMINENT will be critical to differentiating the first SPPARMα, pemafibrate, as a novel therapeutic class distinct from current fibrates.

Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study

Observational, genetic, and experimental data indicate that triglyceride rich lipoproteins (TRLs) likely participate causally in atherothrombosis. Yet, robust clinical trial evidence that triglyceride (TG) lowering therapy reduces cardiovascular events remains elusive. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARM-α), pemafibrate, will be used to target residual cardiovascular risk remaining after treatment to reduce low-density lipoprotein cholesterol (LDL-C) in individuals with the dyslipidemia of type 2 diabetes mellitus (T2). The PROMINENT study will randomly allocate approximately 10,000 participants with T2D, mild-to-moderate hypertriglyceridemia (TG: 200-499 mg/dl; 2.26-5.64 mmol/l) and low high-density lipoprotein cholesterol levels (HDL-C: ≤40 mg/dl; 1.03 mmol/l) to either pemafibrate (0.2 mg twice daily) or matching placebo with an average expected follow-up period of 3.75 years (total treatment phase 5 years; 24 countries). At study entry, participants must be receiving either moderate-to-high intensity statin therapy or meet specified LDL-C criteria. The study population will be one-third primary and two-thirds secondary prevention (established cardiovascular disease). The primary endpoint is a composite of nonfatal myocardial infarction, nonfatal ischemic stroke, hospitalization for unstable angina requiring urgent coronary revascularization, and cardiovascular death. This event-driven study will complete when 1092 adjudicated primary endpoints have accrued with at least 200 occurring in women. Statistical power is at least 90% to detect an 18% reduction in the primary endpoint. Pre-specified secondary and tertiary endpoints include all-cause mortality, hospitalization for heart failure, new or worsening peripheral artery disease, new or worsening diabetic retinopathy and nephropathy, and change in biomarkers including select lipid and non-lipid biomarkers, inflammatory and glycemic parameters.