Safety and effectiveness of empagliflozin according to body mass index in Japanese patients with type 2 diabetes: a subgroup analysis of a 3-year post-marketing surveillance study.

BACKGROUND: Empagliflozin, a glucose-lowering drug licensed for type 2 diabetes (T2D), demonstrated tolerability and effectiveness overall in a post-marketing surveillance (PMS) study in Japan. However, the impact of body mass index (BMI) is unclear. RESEARCH DESIGN AND METHODS: This was a prespecified sub-analysis of the prospective, 3-year, PMS study of empagliflozin in Japan where the primary endpoint was adverse drug reactions (ADRs). We evaluated results according to BMI. RESULTS: We enrolled 7931 T2D patients treated with empagliflozin. Baseline mean age was 58.7 years; 63.01% were male. Baseline BMI was <20 kg/m2 in 2.06% of patients, while 21.28%, 37.35%, and 24.97% had BMI 20-<25, 25-<30 and ≥30 kg/m2, respectively. ADRs occurred in 19 (11.66%), 203 (12.03%), 411 (13.88%), and 295 (14.90%) patients with BMI <20, 20-<25, 25-<30 and ≥30 kg/m2, respectively. Excessive/frequent urination was the most frequent ADR of special interest in all BMI subgroups except 20-<25 kg/m2 (urinary tract infection). Mean change in glycated hemoglobin from baseline was -0.75%, with similar magnitude across BMI subgroups. Body-weight reduction seemed dependent on BMI, with almost no change in the <20 kg/m2 subgroup. CONCLUSIONS: Empagliflozin appeared well tolerated and effective in Japanese T2D patients regardless of BMI, although the number of patients with BMI <20 kg/m2 was small in this study.

Safety and effectiveness of empagliflozin in Japanese patients with type 2 diabetes: final results of a 3-year post-marketing surveillance study.

BACKGROUND: Empagliflozin, a sodium-glucose co-transporter-2 inhibitor, was licensed for treating type 2 diabetes (T2D) in Japan and elsewhere in recent years. We conducted a post-marketing surveillance study of empagliflozin in Japan. RESEARCH DESIGN AND METHODS: This was a 3-year, prospective, multicenter, observational study of the safety and effectiveness of empagliflozin in T2D patients in Japanese clinical practice who had not previously received this medication. The primary endpoint was the incidence of adverse drug reactions (ADRs). RESULTS: Of 8145 patients enrolled from 1103 sites, 7931 received ≥1 dose of empagliflozin. Mean age was 58.7 years (10.5% aged ≥75), glycated hemoglobin (HbA1c) 8.0%, body mass index 28.1 kg/m2 (<20 kg/m2 in 2.1%); 63.0% were male and most had comorbidities (renal impairment in ~62%). Median treatment duration was 36.5 months. ADRs occurred in 1024 (12.91%) patients overall (serious ADRs in 2.09%) and 120 patients aged ≥75 years (14.46%). ADRs of special interest included hypoglycemia (0.44% of patients), urinary tract infections (1.07%), genital infections (0.66%), volume depletion (0.50%), diabetic ketoacidosis (0%), and lower limb amputation (0.04%). Overall mean change in HbA1c from baseline was -0.75%. CONCLUSIONS: Empagliflozin is effective and generally well tolerated in Japanese patients, and ADRs are consistent with its known safety profile.

Novel LCAT (Lecithin:Cholesterol Acyltransferase) Activator DS-8190a Prevents the Progression of Plaque Accumulation in Atherosclerosis Models.

OBJECTIVE: Enhancement of LCAT (lecithin:cholesterol acyltransferase) activity has possibility to be beneficial for atherosclerosis. To evaluate this concept, we characterized our novel, orally administered, small-molecule LCAT activator DS-8190a, which was created from high-throughput screening and subsequent derivatization. We also focused on its mechanism of LCAT activation and the therapeutic activity with improvement of HDL (high-density lipoprotein) functionality. Approach and Results: DS-8190a activated human and cynomolgus monkey but not mouse LCAT enzymes in vitro. DS-8190a was orally administered to cynomolgus monkeys and dose dependently increased LCAT activity (2.0-fold in 3 mg/kg group on day 7), resulting in HDL cholesterol elevation without drastic changes of non-HDL cholesterol. Atheroprotective effects were then evaluated using Ldl-r KO×hLcat Tg mice fed a Western diet for 8 weeks. DS-8190a treatment achieved significant reduction of atherosclerotic lesion area (48.3% reduction in 10 mg/kg treatment group). Furthermore, we conducted reverse cholesterol transport study using Ldl-r KO×hLcat Tg mice intraperitoneally injected with J774A.1 cells loaded with [3H]-cholesterol and confirmed significant increases of [3H] count in plasma (1.4-fold) and feces (1.4-fold on day 2 and 1.5-fold on day3) in the DS-8190a-treated group. With regard to the molecular mechanism involved, direct binding of DS-8190a to human LCAT protein was confirmed by 2 different approaches: affinity purification by DS-8190a-immobilized beads and thermal shift assay. In addition, the candidate binding site of DS-8190a in human LCAT protein was identified by photoaffinity labeling. CONCLUSIONS: This study demonstrates the potential of DS-8190a as a novel therapeutic for atherosclerosis. In addition, this compound proves that a small-molecule direct LCAT activator can achieve HDL-C elevation in monkey and reduction of atherosclerotic lesion area with enhanced HDL function in rodent.

Identification of activating enzymes of a novel FBPase inhibitor prodrug, CS-917.

CS-917 (MB06322) is a selective small compound inhibitor of fructose 1,6-bisphosphatase (FBPase), which is expected to be a novel drug for the treatment of type 2 diabetes by inhibiting gluconeogenesis. CS-917 is a bisamidate prodrug and activation of CS-917 requires a two-step enzyme catalyzed reaction. The first-step enzyme, esterase, catalyzes the conversion of CS-917 into the intermediate form (R-134450) and the second-step enzyme, phosphoramidase, catalyzes the conversion of R-134450 into the active form (R-125338). In this study, we biochemically purified the CS-917 esterase activity in monkey small intestine and liver. We identified cathepsin A (CTSA) and elastase 3B (ELA3B) as CS-917 esterases in the small intestine by mass spectrometry, whereas we found CTSA and carboxylesterase 1 (CES1) in monkey liver. We also purified R-134450 phosphoramidase activity in monkey liver and identified sphingomyelin phosphodiesterase, acid-like 3A (SMPADL3A), as an R-134450 phosphoramidase, which has not been reported to have any enzyme activity. Recombinant human CTSA, ELA3B, and CES1 showed CS-917 esterase activity and recombinant human SMPDL3A showed R-134450 phosphoramidase activity, which confirmed the identification of those enzymes. Identification of metabolic enzymes responsible for the activation process is the requisite first step to understanding the activation process, pharmacodynamics and pharmacokinetics of CS-917 at the molecular level. This is the first identification of a phosphoramidase other than histidine triad nucleotide-binding protein (HINT) family enzymes and SMPDL3A might generally contribute to activation of the other bisamidate prodrugs.

Effects of vitamin D receptor gene polymorphisms on low-resistance training using exercise machines: the 'Power Rehabilitation' program.

The enhancement and promotion of health is necessary to maintain the quality of life (QOL) of the aged population in developed nations such as Japan where the number of elderly has been increasing rapidly. For this purpose, low-resistance training using exercise machines ('Power Rehabilitation') has been established as a rehabilitation program. To investigate the individual factors which influence the effects of 'Power Rehabilitation', single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene and the ciliary neurotrophic factor (CNTF) gene were analyzed, and the relationship between SNP patterns and the effects of 'Power Rehabilitation' was evaluated. 'Power Rehabilitation' had an effect on the physiological functions involved in the activities of daily life (ADL) rather than muscle strength and size. In addition, certain SNP patterns showed better improvement of parameters associated with the effects of 'Power Rehabilitation' as analyzed by comparison between SNP patterns and factor analysis. Large scale analyses are required to ensure this tendency and to discover individual factors which may help to promote the health and QOL of the aged population.

Method of evaluation of the bitterness of clarithromycin dry syrup.

The degree of bitterness of clarithromycin (CAM) dry syrup was evaluated using several methods. Using the inversion method, shaking method, and paddle method, a reasonable correlation between the bitter taste and the amount dissolved was not observed. A mini-column with inner diameter of 0.76 cm and height of 5 cm packed with CAM dry syrup was used for the release test. The release rate of CAM in test solution, which passed through the mini-column, was then measured to evaluate bitterness. The release rate of CAM in the release test using the mini-column correlated well with the results of a sensory test for the bitterness of CAM dry syrup. The dissolution rate constant, defined as the percentage of CAM dissolved from the unit void surface multiplied by the void volume, was inversely proportional to the linear velocity of the test solution. The critical factors affecting evaluation of bitterness were the void volume of the column and linear velocity of the test solution. The optimum linear velocity and void volume were 0.048-0.021 cm/min and 0.27-0.12 cm3, respectively. In addition, the threshold of bitterness of CAM dry syrup was defined as the concentration at which half of the volunteers recognized bitterness in the sensory test. This threshold was found to be 135 microg/ml using the mini-column.