Hideki Suganami's research while affiliated with Kowa company and other places
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Publications (79)
Aim: Ezetimibe administration with ongoing statin therapy is an effective option for further lowering low-density lipoprotein cholesterol (LDL-C) levels. Thus, we investigated the long-term efficacy and safety of fixed-dose combination of pitavastatin/ezetimibe (K-924 LD: 2 mg/10 mg; K-924 HD: 4 mg/10 mg).
Methods: We conducted a phase III, multice...
Introduction:
Multidrug regimens for glaucoma treatment often result in adherence issues due to inconvenience; these issues may be improved with fixed-dose combination drugs. The ophthalmic solution of ripasudil-brimonidine fixed-dose combination (RBFC; K-232) is the first treatment combining a Rho kinase inhibitor and an α2-adrenoceptor agonist,...
Aim:
We compared the efficacy and safety of pitavastatin/ezetimibe fixed-dose combination with those of pitavastatin monotherapy in patients with hypercholesterolemia.
Methods:
This trial was a multicenter, randomized, double-blind, active-controlled, parallel-group trial. A total of 293 patients were randomly assigned into four groups receiving...
Purpose
To confirm the superiority of the intraocular pressure (IOP)-lowering effect of the ripasudil-brimonidine fixed-dose combination (RBFC, K-232) to ripasudil 0.4% or brimonidine 0.1% ophthalmic solution.
Design
Two multicenter, randomized, double- or single-masked, active-controlled, phase 3 trials.
Methods
Patients with primary open angle...
OBJECTIVE
High plasma triglyceride (TG) is an independent risk factor for cardiovascular disease. Fibrates lower TG levels through peroxisome proliferator–activated receptor α (PPARα) agonism. Currently available fibrates, however, have relatively low selectivity for PPARα. The aim of this trial was to assess the safety, tolerability, and efficacy...
In this article, we summarize 1) the history of clinical data management (CDM), 2) how different sectors function,3) educational activities for CDM professionals, and 4) the role of data management in biomedical research in Japan. Here, we explain the differences inroles of clinical data managers among those practicing in academic research organiza...
Background
Pemafibrate is a novel, selective peroxisome proliferator-activated receptor α modulator (SPPARMα). In mice, Pemafibrate improved the histological features of non-alcoholic steatohepatitis (NASH). In patients with dyslipidaemia, it improved serum alanine aminotransferase (ALT).
Aims
To evaluate the efficacy and safety of Pemafibrate in...
SGLT2 inhibitors (SGLT2is) increase hematocrit (Ht) and Hb, which may contribute to correcting anemia but also might cause secondary polycythemia. We investigated predictors of Hb after short- and long-term therapy with tofogliflozin (TOFO), a SGLT2i, and explored its impact on Hb in relation to anemia and polycythemia in type 2 diabetes mellitus (...
Aims/Introduction
This study investigated the impact of the DPP‐4 inhibitor, anagliptin, on hepatic insulin clearance (HIC) in Japanese type 2 diabetes patients and explored its relation to glycemic status.
Materials and Methods
Data on 765 participants in anagliptin phase 2 and 3 studies were analyzed. Adjusted changes in variables during 12 week...
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 ele...
Background
Risk-based monitoring (RBM) is a slow uptake in some trial sponsors. There are three main reasons for this. First, there is the fear of making large investments into advanced RBM technology solutions. Second, it is considered that RBM is most suitable for large, complex trials. Third, there is the fear of errors in both critical and non-...
Sodium/glucose‐cotransporter 2 inhibitors (SGLT2is) are drugs that have been reported to have several effects through the regulation of plasma volume such as antihypertensive effects, etc. This study aimed to clarify the impact of long‐term administration and subsequent discontinuation of the SGLT2i tofogliflozin on estimated plasma volume (ePV), b...
SGLT2 inhibitors (SGLT2is) promote diuresis and reduce plasma volume (PV). However, the impact of long-term administration and subsequent withdrawal of SGLT2is on PV is little known. This study investigated the effect of long-term administration and then withdrawal of the SGLT2i, tofogliflozin (TOFO), on PV and explored correlations with variables...
Reduced plasma volume (PV) to decrease ventricular filling pressure and increased beta-hydroxybutyrate (BHB) as a substitute for the energy source by SGLT2 inhibitors (SGLT2is) might contribute to preserving the heart in type 2 diabetes mellitus (T2DM). However, the impact of SGLT2is on PV and BHB is little known according to cardiac workload. We i...
Aims:
To examine the effects of a sodium-glucose co-transporter 2 (SGLT2) inhibitor, tofogliflozin, on resting heart rate by exploring baseline factors that independently influenced changes in the resting heart rate.
Methods:
Data on 419 participants in tofogliflozin phase 2/3 trials were analysed. Changes in resting heart rate from baseline to...
Many clinical research studies evaluate a time‐to‐event outcome, illustrate survival functions, and conventionally report estimated hazard ratios to express the magnitude of the treatment effect when comparing between groups. However, it may not be straightforward to interpret the hazard ratio clinically and statistically when the proportional haza...
Background
Two issues in clinical trials with multiple endpoints were surveyed: (1) the terminology of multiple endpoints, the relationship between rare events and endpoints, and the differences in multiplicity adjustment between regions, and (2) the current practice on multiplicity adjustment and sample size calculation. This article summarizes th...
Aims:
Obesity and hepatic fat accumulation diminish hepatic insulin clearance, which can cause hyperinsulinemia. Sodium/glucose-cotransporter 2 inhibitors (SGLT2-is) improve insulin resistance and hyperinsulinemia by weight loss via increased urinary glucose excretion in type 2 diabetes. However, there are few reports of the influence of an SGLT2-...
Background:
Two issues on clinical trials with multiple endpoints were surveyed: (1) the terminology of multiple endpoints, relationship between rare events and endpoints, and differences in multiplicity adjustment between regions; and (2) the current practice on multiplicity adjustment and sample size calculation. This article provides a summary...
Aims:
We investigated predictors of the initial response of beta-hydroxybutyrate (BHB) and maximum BHB (max-BHB) values during long-term therapy with the SGLT2 inhibitor, tofogliflozin, and explored the association of the initial elevation of BHB with subsequent clinical effects in those with type 2 diabetes mellitus.
Methods:
Analyzed were 774...
Background:
Two issues on clinical trials with multiple endpoints were surveyed: (1) the terminology of multiple endpoints, relationship between rare events and endpoints, and differences in multiplicity adjustment between regions; and (2) the current practice on multiplicity adjustment and sample size calculation. This article provides a summary...
SGLT2 inhibitors (SGLT2is) reduce hyperglycemia and insulin levels via increased urinary glucose excretion (UGE). Reduced insulin triggers decreased tissue glucose disposal and increased lipid use followed by ketone production. The metabolic response to starvation, the production of beta-hydroxybutyrate (BHB), was reported to be influenced by sex a...
SGLT2 inhibitors (SGLT2is) reduce body weight. They also reduce insulin levels, which trigger lipolysis leading to subsequent fat-mass loss. Lactate (LAC) was reported to inhibit lipolysis in adipocytes and to mediate insulin-dependent inhibition of lipolysis. However, little is known of the effect of SGLT2is on LAC and its relation to weight loss....
Diabetic ketoacidosis characterized by lipolysis due to insulin deficiency is a side effect reported for SGLT2 inhibitors (SGLT2is). However, little is known about predictors of ketosis via SGLT2i. The antilipolytic effect of insulin in adipose tissue can be evaluated as adipose tissue insulin resistance (Adipo-IR). This study investigated predicto...
Aims/Introduction
Tofogliflozin is a potent and highly selective sodium glucose cotransporter 2 inhibitor and is currently used to treat patients with type 2 diabetes mellitus (T2DM). The aim of this study was to evaluate the safety and efficacy of tofogliflozin add‐on to glucagon‐like peptide‐1 (GLP‐1) receptor agonist monotherapy.
Materials and...
Aims
Little is known about whether sodium intake is associated with the clinical effects of SGLT2 inhibitors (SGLT2is); however SGLT2is may increase urinary sodium excretion. Thus, we investigated the impact of daily sodium intake on the estimated glomerular filtration rate (eGFR) via an SGLT2i, tofogliflozin (TOFO), in patients with type 2 diabete...
This study aimed to evaluate the efficacy and safety of pemafibrate in patients with type 2 diabetes and hypertriglyceridemia over a 52‐week period. Patients were randomly assigned to receive treatment with placebo or pemafibrate at a dose of 0.2 or 0.4 mg/day for 24 weeks (treatment period 1). The main results from treatment period 1 have been rep...
Context
Although calorie loss from increased urinary glucose excretion continues after long-term treatment with SGLT2 inhibitors, the mechanisms of the attenuated weight loss due to SGLT2 inhibitors are not well known.
Objective
To examine the mechanism of the attenuated weight loss during long-term treatment with an SGLT2 inhibitor, tofogliflozin...
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...
Figure S2 ¦ Correlation between changes in bodyweight and fasting serum insulin levels. The correlation between the percent change in bodyweight and fasting serum insulin levels was investigated in all patients (left upper panel), the low‐insulin group (L group; insulin ≤5.6 μU/mL, right upper panel), the medium‐insulin group (M group; 5.6< insulin...
Figure S1 ¦ Correlation between changes in body weight and the C‐peptide immunoreactivity index (CPI) area under the curve (AUC). Correlation between percent change of bodyweight and the CPI AUC was investigated in all patients (left upper panel), the low‐insulin group (L group; insulin ≤5.6 μU/mL, right upper panel), the medium‐insulin group (M gr...
Table S1 ¦ Multiple regression of parameters associated with change of glucose area under the curve. Multivariate analysis was followed by stepwise model selection with P‐values <0.05 to determine the baseline factors in Table 1 influencing reduction of glucose area under the curve (AUC) during the meal tolerance test.
Table S2 ¦ Multiple regressi...
Background:
Cardiovascular risk is negatively correlated with cholesterol efflux capacity (CEC) from macrophages to high-density lipoproteins (HDLs) and positively correlated with fasting and nonfasting triglyceride-rich lipoproteins (TRLs). Pemafibrate, a novel selective peroxisome proliferator-activated receptor α modulator, robustly decreases t...
We thank Dr. Chanaka N. Kahathuduwa and colleagues for their thoughtful comments on our recent article [1] appearing in Diabetes, Obesity and Metabolism. We completely understand Dr. Chanaka N. Kahathuduwa et al.’s points [2]. Certainly, leading to the conclusion based only on the impact of regression to the mean, RTM might generally be insufficien...
An elevated resting heart rate (RHR) is a risk factor for vascular complications in patients with and without type 2 diabetes mellitus (T2DM). Recently, the beneficial effects of SGLT2 inhibitors (SGLT2i) on cardiovascular and renal events were reported in large-scale clinical trials. However, their mechanisms are not fully clarified. This study ai...
It is well recognized that sodium/glucose cotransporter 2 inhibitors (SGLT2i) are associated with weight loss in people with type 2 diabetes. However, the time-dependent associations of weight loss with the anthropometric and body fluid measurements and serum parameters during SGLT2i intervention remain unclear. Thus, we aimed to clarify weight los...
The elevation of ketones is clinically concerned in the use of SGLT2 inhibitor (SGLT2i), however little is known about the association between that elevation and subsequent clinical process. We aimed to clarify the association of the initial beta-hydroxybutyrate (BHB) elevation via the SGLT2i, tofogliflozin with subsequent weight loss in type 2 dia...
Recent studies suggested that reduced hepatic insulin clearance (HIC) after mixed meal ingestion was associated with amelioration of postprandial hyperglycemia by supplying sufficient insulin throughout the body and that HIC might be regulated by increases in serum incretins. Despite broad use in practice, the effects of DPP-4i on HIC are little kn...
Aim:
To verify the superiority of pemafibrate over placebo and the non-inferiority of pemafibrate to the maximum dose of fenofibrate for determining the percent change in fasting serum triglyceride (TG) levels and to investigate safety by assessing the incidence of adverse events (AEs) and adverse drug reactions (ADRs).
Methods:
This phase III,...
Figure S1. Correlation between changes in uric acid and glycosylated haemoglobin (HbA1c) at Week 24. A, Men. B, Women. Pearson's product–moment correlation coefficient.
Figure S2. Change in uric acid. (■, Tofogliflozin; □, Placebo). Least squares mean (standard error) (last observation carried forward [LOCF]). One sample‐t vs baseline. **P < .001...
Aims/Introduction
Pemafibrate (K‐877) is a novel selective peroxisome proliferator‐activated receptor α modulator (SPPARMα) with potent triglyceride (TG)‐lowering and high‐density lipoprotein cholesterol‐raising effects. We showed that pemafibrate decreased the homeostasis model assessment for insulin resistance (HOMA‐IR) in patients with dyslipide...
Aims
Little is known of the effect of sodium‐glucose cotransporter 2 (SGLT2) inhibitors on the renal tubules. We investigated the effect of the SGLT2 inhibitor, tofogliflozin (TOFO) on renal tubular indices, according to the degree of albuminuria, in type 2 diabetes mellitus (T2DM) patients with preserved renal function.
Materials and methods
A to...
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...
Aim:
Hepatic insulin clearance (HIC) is important in regulating plasma insulin levels. Diminished HIC causes inappropriate hyperinsulinaemia, and both obesity and fatty liver (FL), which are known to decrease HIC, can be found either together in the same patient or on their own. The mechanism by which obesity reduces HIC is presumed to be mediated...
Aim:
Children with Familial Hypercholesterolemia (FH) are widely prescribed statins, and it has been suggested that the effects of statins differ among ethnicities. We compared the efficacy and safety of pitavastatin in children and adolescents with FH in clinical trials conducted in Japan and Europe.
Methods:
Low-density lipoprotein cholesterol...
An integrated analysis was performed with data from four phase 2 and phase 3 studies of tofogliflozin in which patients with type 2 diabetes mellitus received the sodium-glucose cotransporter 2 inhibitor tofogliflozin for up to 24 weeks. Sex differences, baseline haemoglobin A1c (HbA1c) and serum uric acid (UA) levels, and log10-transformed urinary...
Introduction:
Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new class of drugs for the treatment of type 2 diabetes mellitus that improve control of plasma glucose and body weight, giving great hope for the clinical utility of these agents. However, it is unclear for which patients that SGLT2 inhibitors will be useful.
Materials and me...
Background:
To overcome the concerns associated with the use of fibrates, pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor modulator, was developed. In a previous phase 2 trial, we showed excellent efficacy and safety of pemafibrate in patients with dyslipidemia.
Objective:
The objective of the study was to evalu...
Background and aims:
Substantial residual cardiovascular risks remain despite intensive statin treatment. Residual risks with high triglyceride and low high-density lipoprotein cholesterol are not the primary targets of statins. K-877 (pemafibrate) demonstrated robust efficacy on triglycerides and high-density lipoprotein cholesterol and a good sa...
Background:
This study provides the results of a survey on the current practice of multiplicity adjustment and sample size calculation in multi-arm clinical trials.
Methods:
The survey was aimed at members of the Japan Pharmaceutical Manufacturers Association (JPMA) and was conducted in 2015.
Results:
Of the 66 JPMA member companies, effective...
Background and aims:
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 choleste...
Background: Residual cardiovascular risk remains despite intensive treatment with statins. K-877, a Selective PPAR-α Modulator (SPPARMα), has shown significant reductions in atherogenic lipids with fewer adverse effects than existing PPARα agonists. We hypothesized that combination with pitavastatin may provide further reduction in atherosclerotic...
Purpose:
To investigate the effect and safety of a selective Rho kinase inhibitor, ripasudil 0.4% eye drops, on corneal endothelial cells of healthy subjects.
Design:
Prospective, interventional case series.
Methods:
In this study, 6 healthy subjects were administered ripasudil 0.4% in the right eye twice daily for 1 week. Morphological change...
To investigate the intra-ocular pressure (IOP)-lowering effects and safety of 0.4% ripasudil (K-115), a Rho kinase inhibitor, twice daily for 52 weeks, in patients with open-angle glaucoma or ocular hypertension (OHT).
In this multicentre, prospective, open-label study, 388 patients with primary open-angle glaucoma, OHT or exfoliation glaucoma were...
The purpose of this study was to evaluate the efficacy and safety of LIVALO(®) tablets (pitavastatin) in Japanese male children with heterozygous familial hypercholesterolemia (FH).
A multicenter, randomized, double-blind, parallel study was conducted in 14 male children 10-15 years of age with heterozygous FH. Pitavastatin (1 mg/day or 2 mg/day) w...
Ripasudil hydrochloride hydrate (K-115), a novel rho kinase inhibitor, provides statistically significant intraocular pressure (IOP)-lowering effects and has a tolerable safety profile. However, no studies have evaluated ripasudil combined with β-blockers and prostaglandin analogues.
To evaluate the additive IOP-lowering effects and the safety of r...
To investigate the intra-ocular pressure (IOP)-lowering effects of a selective Rho kinase inhibitor, ripasudil (K-115), over 24 hr in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT).
In this multicenter, prospective, randomized, open-label, 3-period, Latin-square crossover clinical study, 28 patients with POAG or OHT w...
This study aims to survey the current practice in Japan for the prevention and treatment of missing data in clinical trials since the publication of regulatory guidelines on missing data issues. A web-based questionnaire was conducted among 65 member companies of the Japan Pharmaceutical Manufacturers Association in 2013. Responses were obtained on...
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 P...
Objective: To evaluate long-term safety and efficacy of tofogliflozin in Japanese patients with type 2 diabetes as monotherapy or in combination with other oral antidiabetic agents, we conducted 52-week, open-label, randomized controlled trials.
Research design and methods: The single-agent trial included patients with inadequate glycemic control o...
Citations
... In our previous phase 3, double-blind, randomized controlled trial, we reported the superiority of K-924, a fixed-dose combination of pitavastatin/ezetimibe (K-924 LD:2 mg/10 mg, K-924 HD:4 mg/10 mg) over pitavastatin monotherapy in reducing LDL-C levels after 12 weeks of treatment 16) . In this study, we investigated the LDL-C-lowering effect and safety of the K-924 fixed-dose combination of pitavastatin/ezetimibe over a period of 52 weeks. ...
![[object Object]](https://i1.rgstatic.net/ii/profile.image/886919047151616-1588469387252_Q64/Kenichi-Tsujita.jpg)
... The ripasudil-brimonidine fixed-dose combination (RBFC; development code K-232) is the first combination topical therapy containing ripasudil hydrochloride hydrate (ripasudil 0.4%), a Rho-associated coiled-coil containing protein kinase (Rho kinase; ROCK) inhibitor, and brimonidine tartrate 0.1% (brimonidine), an a 2 -adrenoceptor agonist. The efficacy and safety of RBFC was previously demonstrated in two multicenter, randomized, phase 3 clinical trials, in which RBFC significantly reduced IOP in patients with primary open-angle glaucoma or ocular hypertension and IOP levels of at least 18 mmHg [18]. Ripasudil reduces IOP by increasing aqueous humor outflow via the conventional outflow pathway through modulation of the trabecular meshwork cell cytoskeleton, production of extracellular matrix, and Schlemm's canal endothelial cell permeability [19][20][21][22]. ...
... To our knowledge, no randomized controlled trial has evaluated the effect of RC reduction on CMD for primary prevention [38]. Observational studies illuminated that high RC levels persist in patients treated with statins, and interventional studies have shown that statins combined with evolocumab or pemafibrate is effective in reducing the RC levels [39][40][41]. However, the PROMINENT study suggested that pemafibrate failed to improved cardiovascular outcomes despite reductions in RC in patients with T2D, hypertriglyceridemia, and below-average HDL-C [42]. ...
... Recent research has shown that pemafibrate helps patients with chronic liver diseases, including NAFLD, by lowering ALT and triglyceride (TG) levels (10)(11)(12)(13)(14)(15)(16). In addition, a phase II study of pemafibrate in patients with NAFLD, regardless of dyslipidemia status, showed improvement in ALT levels and liver stiffness (17). Therefore, pemafibrate can be used to treat NAFLD. ...
![[object Object]](https://i1.rgstatic.net/ii/profile.image/272293406441510-1441931215562_Q64/Yuichiro-Eguchi.jpg)
![[object Object]](https://i1.rgstatic.net/ii/profile.image/279506662248449-1443650989185_Q64/Masato-Yoneda.jpg)
... In this secondary analysis of the prospective observational PARM-T2D trial on the use of pemafibrate in adults with hyperglycemia complicated with T2DM, administration of pemafibrate significantly improved insulin resistance as well as β-cell function assessed by HOMA2-R and the disposition index. A preferable effect of pemafibrate on insulin resistance was found in a previous pooled meta-analysis involving short-term phase 2 and 3 trials investigating the efficacy of pemafibrate compared with a placebo in patients affected by dyslipidemia with or without T2DM [20]. The strengths of the present subanalysis were: (1) targeting the T2DM population only, (2) including participants who were treated with several insulin sensitizers, reflecting real-world clinical settings, (3) excluding subjects who changed their anti-diabetic medications during the study period, and (4) having a relatively long-term study design (52 weeks). ...
![[object Object]](https://i1.rgstatic.net/ii/profile.image/272264033730567-1441924212516_Q64/Hidenori-Arai.jpg)