To assess the efficacy and safety of K-877 (Pemafibrate), a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that possesses unique PPARα activity and selectivity, compared with placebo and fenofibrate in dyslipidaemic patients with high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels. This study was a double blind, placebo-controlled, parallel-group 12-week clinical trial. The study randomized 224 patients to K-877 0.025, 0.05, 0.1, 0.2 mg BID, fenofibrate 100 mg QD, or placebo (1:1:1:1:1:1) groups. Least squares mean percent changes from the baseline TG levels were -30.9%, -36.4%, -42.6%, -42.7% for the K-877 0.025, 0.05, 0.1, 0.2 mg BID respectively (p < 0.001), which were greater than that of the fenofibrate 100 mg QD (-29.7%, p < 0.001) group. Statistically significant improvements from the baseline HDL-C, very-low-density lipoprotein cholesterol, chylomicron cholesterol, remnant lipoprotein cholesterol, apolipoprotein (apo) B (apoB), and apoC-III were also observed in the K-877 groups. The incidence of adverse events (AEs) in the K-877 groups (32.4-56.8%) was comparable to those in placebo (47.2%) and fenofibrate 100 mg QD (56.8%); adverse drug reactions (ADRs) in the K-877 groups (2.7-5.4%) were less than those in placebo (8.3%) and fenofibrate 100 mg QD (10.8%) groups. In dyslipidaemic patients with high TG and low HDL-C, K-877 improved TG, HDL-C, and other lipid parameters without increasing AEs or ADRs, compared to placebo and fenofibrate. K-877 can be expected to improve atherogenicity and to be a new beneficial treatment for dyslipidaemic patients.

In recent years, several oral antidiabetic drugs with new mechanisms of action have become available, expanding the number of treatment options. Sodium/glucose cotransporter-2 (SGLT2) inhibitors are a new class of oral antidiabetic drugs with an insulin-independent mechanism promoting urinary glucose excretion. We report the results of a combined Phase 2 and 3 clinical study (Japic CTI-101349) of the SGLT2 inhibitor tofogliflozin (CSG452, RG7201) in Japanese patients with type 2 diabetes mellitus. The efficacy and safety of tofogliflozin were assessed in this multicenter, placebo-controlled, randomized, double-blind parallel-group study involving 230 patients with type 2 diabetes mellitus with inadequate glycemic control on diet/exercise therapy. Between 30 October 2010 and 28 February 2012, patients at 33 centers were randomized to either placebo (n = 56) or tofogliflozin (10, 20, or 40 mg; n = 58 each) orally, once daily for 24 weeks. The primary efficacy endpoint was the change from baseline in HbA_1c at week 24. Overall, 229 patients were included in the full analysis set (placebo: n = 56; tofogliflozin 10 mg: n = 57; tofogliflozin 20 and 40 mg: n = 58 each). The least squares (LS) mean change (95% confidence interval) from baseline in HbA_1c at week 24 was −0.028% (−0.192 to 0.137) in the placebo group, compared with −0.797% (−0.960 to −0.634) in the tofogliflozin 10 mg group, −1.017% (−1.178 to −0.856) in the tofogliflozin 20 mg group, and −0.870% (−1.031 to −0.709) in the tofogliflozin 40 mg group (p < 0.0001 for the LS mean differences in all tofogliflozin groups vs placebo). There were also prominent decreases in fasting blood glucose, 2-h postprandial glucose, and body weight in all tofogliflozin groups compared with the placebo group. The main adverse events were hyperketonemia, ketonuria, and pollakiuria. The incidence of hypoglycemia was low. Furthermore, most adverse events were classified as mild or moderate in severity. Tofogliflozin 10, 20, or 40 mg administered once daily as monotherapy significantly decreased HbA_1c and body weight, and was generally well tolerated in Japanese patients with type 2 diabetes mellitus. Phase 3 studies were recently completed and support the findings of this combined Phase 2 and 3 study. This study was registered in the JAPIC clinical trials registry (ID: Japic%CTI-101349 ).

OBJECTIVE Type 2 diabetes is frequently complicated with atherogenic dyslipidemia. This study aimed to evaluate the efficacy and safety of pemafibrate (K-877) in patients with type 2 diabetes comorbid with hypertriglyceridemia. RESEARCH DESIGN AND METHODS Patients were randomly assigned to three groups and received placebo (n = 57), 0.2 mg/day pemafibrate (n = 54), or 0.4 mg/day pemafibrate (n = 55) for 24 weeks (treatment period 1). Subsequently, the patients received follow-up treatment for another 28 weeks (treatment period 2), in which the placebo was switched to 0.2 mg/day pemafibrate. This article presents the results of treatment period 1, which were the primary objectives. RESULTS The pemafibrate groups showed significantly reduced fasting serum triglyceride levels by ∼45% compared with the placebo group (P < 0.001). Additionally, the pemafibrate groups displayed significant decreases in non-HDL and remnant lipoprotein cholesterol, apolipoprotein (Apo) B100, ApoB48, and ApoCIII levels and significant increases in HDL cholesterol and ApoA-I levels. LDL cholesterol levels were not considerably altered in the pemafibrate groups. Furthermore, the 0.2 mg/day pemafibrate group showed a significantly reduced HOMA–insulin resistance score compared with the placebo group; however, no significant changes compared with placebo were found in fasting plasma glucose, fasting insulin, glycoalbumin, or HbA_1c levels. The pemafibrate groups also showed significantly increased fibroblast growth factor 21 levels compared with the placebo group. All groups displayed comparable rates of adverse events and drug reactions. CONCLUSIONS Pemafibrate significantly ameliorated lipid abnormalities and was well tolerated in patients with type 2 diabetes comorbid with hypertriglyceridemia.

Oxidative stress is defined as excessive production of reactive oxygen species (ROS) in the presence of diminished anti‐oxidant substances. Increased oxidative stress could be one of the common pathogenic factors of diabetic complications. However, the mechanisms by which hyperglycemia increases oxidative stress are not fully understood. In this review, we focus on the impact of mitochondrial derived ROS (mtROS) on diabetic complications and suggest potential therapeutic approaches to suppress mtROS. It has been shown that hyperglycemia increases ROS production from mitochondrial electron transport chain and normalizing mitochondrial ROS ameliorates major pathways of hyperglycemic damage, such as activation of polyol pathway, activation of PKC and accumulation of advanced glycation end‐products (AGE). Additionally, in subjects with type 2 diabetes, we found a positive correlation between HbA1c and urinary excretion of 8‐hydroxydeoxyguanosine (8‐OHdG), which reflects mitochondrial oxidative damage, and further reported that 8‐OHdG was elevated in subjects with diabetic micro‐ and macro‐ vascular complications. We recently created vascular endothelial cell‐specific manganese superoxide dismutase (MnSOD) transgenic mice, and clarified that overexpression of MnSOD in endothelium could prevent diabetic retinopathy in vivo. Furthermore, we found that metformin and pioglitazone, both of which have the ability to reduce diabetic vascular complications, could ameliorate hyperglycemia‐induced mtROS production by the induction of PPARγ coactivator‐1α (PGC‐1α) and MnSOD and/or activation of adenosine monophosphate (AMP)‐activated protein kinase (AMPK). We also found that metformin and pioglitazone promote mitochondrial biogenesis through the same AMPK–PGC‐1α pathway. Taking these results, mtROS could be the key initiator of and a therapeutic target for diabetic vascular complications. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00013.x, 2010)

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.