Ōsaka, Japan
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Katakami N.,Osaka University | Mita T.,Juntendo University | Yoshii H.,Juntendo University | Onuma T.,Juntendo University | And 12 more authors.
Journal of Atherosclerosis and Thrombosis | Year: 2013

Aim: Alogliptin, an efficacious inhibitor of DPP-4 that improves glycemic control, as well as the pancreatic beta-cell function, is now increasingly used to accomplish glycemic targets in type 2 diabetic patients. Interestingly, recent experimental studies have shown that alogliptin exerts anti-atherosclerotic effects in GLP-1-dependent and -independent manners. The aim of the present ongoing study is to investigate the preventive effects of alogliptin on the progression of atherosclerosis in type 2 diabetic subjects using the carotid intima-media thickness (IMT), an established marker of cardiovascular disease. Methods and Results: The Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A) is a prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group, comparative study. Between March 2011 and March 2012, 341 participants were recruited at 11 clinical sites, and were randomly allocated either to an alogliptin treatment group (172 patients) or a conventional treatment group (169 patients). The primary outcomes are the changes in the maximum and mean IMT of the common carotid artery during a 24-month treatment period, as measured by carotid arterial echography. The secondary outcomes include the changes in glycemic control, parameters related to beta-cell function and diabetic nephropathy, the occurrence of cardiovascular events and adverse events and biochemical measurements reflecting vascular function. Conclusions: This is the first study to address the effects of DPP-4 inhibitors on the progression of changes in the carotid IMT, with the patients without DPP-4 inhibitor treatment serving as a control group. The results will be available soon, and these findings are expected to provide clinical data that will be helpful in the prevention of diabetic atherosclerosis and subsequent cardiovascular disease.


Mita T.,Juntendo University | Katakami N.,Osaka University | Shiraiwa T.,Shiraiwa Medical Clinic | Yoshii H.,Juntendo Tokyo Koto Geriatric Medical Center | And 13 more authors.
Diabetes Care | Year: 2016

Objective The effect of additional treatment with oral hypoglycemic agents on the progression of atherosclerosis remains unknown in insulin-treated patients with type 2 diabetes mellitus (T2DM). We assessed the effects of sitagliptin, a dipeptidyl peptidase 4 inhibitor, on carotid intima-media thickness (IMT) in T2DM. Research Design and Methods This prospective, randomized, open-label, blinded end point, multicenter, parallelgroup, comparative study included 282 insulin-treated patients with T2DM free of a history of apparent cardiovascular diseases who were recruited at 12 clinical units and randomly allocated to either the sitagliptin group (n = 142) or the control group (n = 140). The primary outcomes were changes in mean and maximum IMT of the common carotid artery measured by echography at the end of a 104-week treatment period. Results Sitagliptin had a more potent glucose-lowering effect compared with the conventional treatment (20.5 ± 1.0% vs. 20.2 ± 0.9%; P = 0.004), without increasing hypoglycemic episodes or body weight. Changes in the mean and left maximum IMT, but not right maximum IMT, of the common carotid arteries were significantly greater after sitagliptin treatment compared with conventional treatment (20.029 [SE 0.013] vs. 0.024 [0.013] mm [P = 0.005]; 20.065 [0.027] vs. 0.022 [0.026] mm [P = 0.021]; 20.007 [0.031] vs. 0.027 [0.031] mm [P = 0.45], respectively). Over 104 weeks, sitagliptin, but not conventional treatment, significantly reduced the mean IMT and left maximumIMT of common carotid arteries relative to the baseline. Conclusions Sitagliptin attenuated the progression of carotid IMT in insulin-treated patients with T2DM free of apparent cardiovascular disease compared with conventional treatment. © 2016 by the American Diabetes Association.


Mita T.,Juntendo University | Katakami N.,Osaka University | Yoshii H.,Juntendo Tokyo Koto Geriatric Medical Center | Onuma T.,Juntendo Tokyo Koto Geriatric Medical Center | And 12 more authors.
Diabetes Care | Year: 2016

OBJECTIVE Recent experimental studies have shown that dipeptidyl peptidase 4 (DPP-4) inhibitors have antiatherosclerotic benefits in glucagon-like peptide 1-dependent and independentmanners. The current study investigated the effects of alogliptin, a DPP-4 inhibitor, on the progression of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS This prospective, randomized, open-label, blinded-end point, multicenter, parallelgroup, comparative study included 341 patients with T2DM free of a history of apparent cardiovascular diseases recruited at 11 clinical units and randomly allocated to treatment with alogliptin (n = 172) or conventional treatment (n = 169). Primary outcomes were changes in mean common and maximum intima-media thickness (IMT) of the carotid artery measured by carotid arterial echography during a 24-month treatment period. RESULTS Alogliptin treatment had amore potent glucose-lowering effect than the conventional treatment (20.3 ± 0.7% vs. 20.1 ± 0.8%, P = 0.004) without an increase of hypoglycemia. Changes in the mean common and the right and left maximum IMT of the carotid arteries were significantly greater after alogliptin treatment than after conventional treatment (20.026 mm [SE 0.009] vs. 0.005 mm [SE 0.009], P = 0.022; 20.045 mm [SE 0.018] vs. 0.011 mm [SE 0.017], P = 0.025, and 20.079 mm [SE 0.018] vs. 20.015 mm [SE 0.018], P = 0.013, respectively). CONCLUSIONS Alogliptin treatment attenuated the progression of carotid IMT in patients with T2DM free of apparent cardiovascular disease compared with the conventional treatment. © 2016 by the American Diabetes Association.


PubMed | Red Cross, Naka Memorial Clinic, Shiraiwa Medical Clinic, Kawasaki Medical School and 3 more.
Type: Journal Article | Journal: Journal of diabetes investigation | Year: 2016

To assess efficacy and safety of liraglutide in combination with insulin compared with insulin monotherapy in Japanese patients with type 2 diabetes.This was a 36-week, multicenter, double-blind, parallel-group trial, where patients on stable insulin therapy (basal/premixed/basal-bolus) were randomized 1:1 to additional liraglutide 0.9 mg/day (n = 127) or placebo (n = 130). The insulin dose was fixed for 16 weeks, and titrated based on self-measured plasma glucose thereafter. The primary end-point was change in glycosylated hemoglobin after 16 weeks.Superiority of liraglutide plus insulin versus insulin monotherapy was confirmed based on estimated mean difference in glycosylated hemoglobin after 16 weeks of -1.30% (-14 mmol/mol; 95% confidence interval -1.47 to -1.13 [-16, -12]; P < 0.0001). Statistical significance was maintained to week 36. More patients on liraglutide achieved a glycosylated hemoglobin target of <7.0% (<53 mmol/mol) at week 16 (estimated odds ratio 50.57; 95% confidence interval 16.59 to 154.16; P < 0.0001). Improvements in seven-point self-measured plasma glucose and fasting plasma glucose were significantly greater with liraglutide than the placebo at week 16. Insulin dose after 36 weeks was lower with liraglutide than the placebo (estimated treatment ratio: 0.82 [95% confidence interval 0.76-0.90; P < 0.0001]). Occurrence of adverse events was similar in the two groups (85.8 and 81.5%, respectively); most were mild in severity. There were no significant differences in the number of hypoglycemic episodes during the 36 weeks.Adding liraglutide to insulin results in superior glycemic control compared with insulin alone in Japanese patients with type 2 diabetes, and is generally well tolerated.


PubMed | Juntendo University, Naka Memorial Clinic, Osaka General Medical Center, Osaka University and 5 more.
Type: | Journal: Scientific reports | Year: 2017

The effect of hypoglycemia on the progression of atherosclerosis in patients with type 2 diabetes mellitus (T2DM) remains largely unknown. This is a post hoc analysis of a randomized trial to investigate the relationship between hypoglycemic episodes and changes in carotid intima-media thickness (IMT). Among 274 study subjects, 104 patients experienced hypoglycemic episodes. Increases in the mean IMT and left maximum IMT of the common carotid arteries (CCA) were significantly greater in patients with hypoglycemia compared to those without hypoglycemia. Classification of the patients into three groups according to the frequency of hypoglycemic episodes showed that high frequency of hypoglycemic events was associated with increases in mean IMT-CCA, and left max-IMT-CCA and right max-IMT-CCA. In addition, repetitive episodes of hypoglycemia were associated with a reduction in the beneficial effects of sitagliptin on carotid IMT. Our data suggest that frequency of hypoglycemic episodes was associated with changes in carotid atherosclerosis.


PubMed | Internal Medicine, Juntendo University, Naka Memorial Clinic, Jinnouchi Hospital and 8 more.
Type: Journal Article | Journal: Diabetes care | Year: 2015

Recent experimental studies have shown that dipeptidyl peptidase 4 (DPP-4) inhibitors have antiatherosclerotic benefits in glucagon-like peptide 1-dependent and -independent manners. The current study investigated the effects of alogliptin, a DPP-4 inhibitor, on the progression of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM).This prospective, randomized, open-label, blinded-end point, multicenter, parallel-group, comparative study included 341 patients with T2DM free of a history of apparent cardiovascular diseases recruited at 11 clinical units and randomly allocated to treatment with alogliptin (n = 172) or conventional treatment (n = 169). Primary outcomes were changes in mean common and maximum intima-media thickness (IMT) of the carotid artery measured by carotid arterial echography during a 24-month treatment period.Alogliptin treatment had a more potent glucose-lowering effect than the conventional treatment (-0.3 0.7% vs. -0.1 0.8%, P = 0.004) without an increase of hypoglycemia. Changes in the mean common and the right and left maximum IMT of the carotid arteries were significantly greater after alogliptin treatment than after conventional treatment (-0.026 mm [SE 0.009] vs. 0.005 mm [SE 0.009], P = 0.022; -0.045 mm [SE 0.018] vs. 0.011 mm [SE 0.017], P = 0.025, and -0.079 mm [SE 0.018] vs. -0.015 mm [SE 0.018], P = 0.013, respectively).Alogliptin treatment attenuated the progression of carotid IMT in patients with T2DM free of apparent cardiovascular disease compared with the conventional treatment.


PubMed | Juntendo University, Naka Memorial Clinic, Osaka General Medical Center, Osaka University and 9 more.
Type: Comparative Study | Journal: Diabetes care | Year: 2016

The effect of additional treatment with oral hypoglycemic agents on the progression of atherosclerosis remains unknown in insulin-treated patients with type 2 diabetes mellitus (T2DM). We assessed the effects of sitagliptin, a dipeptidyl peptidase 4 inhibitor, on carotid intima-media thickness (IMT) in T2DM.This prospective, randomized, open-label, blinded end point, multicenter, parallel-group, comparative study included 282 insulin-treated patients with T2DM free of a history of apparent cardiovascular diseases who were recruited at 12 clinical units and randomly allocated to either the sitagliptin group (n = 142) or the control group (n = 140). The primary outcomes were changes in mean and maximum IMT of the common carotid artery measured by echography at the end of a 104-week treatment period.Sitagliptin had a more potent glucose-lowering effect compared with the conventional treatment (-0.5 1.0% vs. -0.2 0.9%; P = 0.004), without increasing hypoglycemic episodes or body weight. Changes in the mean and left maximum IMT, but not right maximum IMT, of the common carotid arteries were significantly greater after sitagliptin treatment compared with conventional treatment (-0.029 [SE 0.013] vs. 0.024 [0.013] mm [P = 0.005]; -0.065 [0.027] vs. 0.022 [0.026] mm [P = 0.021]; -0.007 [0.031] vs. 0.027 [0.031] mm [P = 0.45], respectively). Over 104 weeks, sitagliptin, but not conventional treatment, significantly reduced the mean IMT and left maximum IMT of common carotid arteries relative to the baseline.Sitagliptin attenuated the progression of carotid IMT in insulin-treated patients with T2DM free of apparent cardiovascular disease compared with conventional treatment.


Takahara M.,Osaka University | Shiraiwa T.,Shiraiwa Medical Clinic | Shindo M.,Shiraiwa Medical Clinic | Arai A.,Shiraiwa Medical Clinic | And 5 more authors.
Hypertension Research | Year: 2014

We investigated whether 10 mg per day of azilsartan, one-half of the normal dosage, would be non-inferior to 8 mg per day of candesartan cilexetil for controlling blood pressure in Japanese patients with hypertension. In this open-label, randomized, crossover trial, 309 hypertensive Japanese adults treated with 8-mg candesartan cilexetil were randomized into two arms and received either 10-mg azilsartan or 8-mg candesartan cilexetil in a crossover manner. The primary efficacy outcome was systolic blood pressure, and the margin of non-inferiority was set to be 2.5 mm Hg. The participants were 67±11 years old, and 180 (58%) were male. The baseline systolic and diastolic blood pressure levels were 127.1±13.2 and 69.7±11.2 mm Hg, respectively. During the study period, the difference in systolic blood pressure between the treatments with 10-mg azilsartan and 8-mg candesartan cilexetil was -1.7 mm Hg, with the two-sided 95% confidence interval (CI) ranged from -3.2 to -0.2 mm Hg. The upper boundary of the 95% CI was below the margin of 2.5 mm Hg, confirming the non-inferiority of 10-mg azilsartan to 8-mg candesartan cilexetil. The difference also reached significance (P=0.037). The corresponding difference in diastolic blood pressure was -1.4 (95% CI: -2.4 to -0.4) mm Hg (P=0.006). Treatment with 10-mg azilsartan was similar to 8-mg candesartan cilexetil in its association with rare adverse events. In conclusion, 10-mg azilsartan was non-inferior to 8-mg candesartan cilexetil for controlling systolic blood pressure in Japanese hypertensive patients already being treated with 8-mg candesartan cilexetil. copy; 2014 The Japanese Society of Hypertension All rights reserved.


Takahara M.,Osaka University | Shiraiwa T.,Shiraiwa Medical Clinic | Katakami N.,Osaka University | Kaneto H.,Osaka University | And 2 more authors.
Endocrine Journal | Year: 2014

We investigated the efficacy of once-and thrice-daily voglibose, an alpha-glucosidase inhibitor, as an add-on therapy to alogliptin, a dipeptidyl peptidase-4 inhibitor, on glycemic control in Japanese type 2 diabetic patients. In this 12-week, parallel-group, randomized, open-label, three-arm trial, 151 participants treated with alogliptin were randomly allocated to the following three arms; one was the group to initiate once-daily voglibose, another was to initiate thrice daily voglibose, and the other was the control group. The primary endpoint was the change of hemoglobin A1c levels at the end of the study, which was revealed to be significantly different among groups (p < 0.001). The once-and thrice-daily voglibose groups had a significantly greater reduction than the control group; the difference was -0.27% and -0.33% in the once-and thrice-daily voglibose group, respectively (both p < 0.001). No significant difference was observed between the two voglibose groups (p = 0.615). On the other hand, the increase of 1,5-anhydroglucitol levels were 3.3 and 5.5 μg/mL greater in the once-and thrice-daily voglibose groups than the control group (both p < 0.001). The thrice-daily voglibose group had a greater increase of 1,5-anhydroglucitol levels compared to the once-daily voglibose group (p = 0.005). In conclusion, once-and thrice-daily voglibose as an add-on to alogliptin significantly improved glycemic control in Japanese type 2 diabetic patients. © The Japan Endocrine Society.


Takahara M.,Osaka University | Shiraiwa T.,Shiraiwa Medical Clinic | Matsuoka T.-A.,Osaka University | Katakami N.,Osaka University | Shimomura I.,Osaka University
Endocrine Journal | Year: 2015

It remains to be seen whether pancreatic β cell dysfunction in type 2 diabetic patients can be ameliorated just by correcting hyperglycemia. The current pilot study investigated β cell function after a four-week treatment with a sodiumglucose cotransporter 2 (SGLT2) inhibitor ipragliflozin in Japanese patients with type 2 diabetes mellitus. Ten participants (age, 51 ± 13 years; hemoglobin A1c levels, 9.4 ± 1.0%) took 50 mg of ipragliflozinL-proline for four weeks and thereafter discontinued the agent for one week. A 75-g oral glucose tolerance test (OGTT) was performed at 0 (baseline), 4 (end of medication), and 5 weeks (end of washout). The β cell function was evaluated using the disposition index, which was calculated as the product of the ΔIns0–120/ΔGlu0–120 and the Matsuda index, where ΔIns0–120/ΔGlu0–120 represents the ratio of the incremental concentrations of insulin to those of glucose during the 0- to 120-min time period of the OGTT. The fasting glucose level was 182 ± 34 mg/dL at 0 week, 137 ± 20 mg/dL at 4 weeks (p < 0.001), and 154 ± 31 mg/dL at 5 weeks (p = 0.001). Compared to baseline, the disposition index was significantly elevated not only at 4 weeks (p < 0.001) but also at 5 weeks (p = 0.008). In conclusion, the current pilot study showed that the β cell function assessed by the OGTT-derived disposition index was significantly improved after a four-week treatment with ipragliflozin in Japanese patients with type 2 diabetes mellitus. © The Japan Endocrine Society.

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