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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 | 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.


Osonoi T.,Naka Memorial Clinic | Saito M.,Naka Memorial Clinic | Mochizuki K.,University of Shizuoka | Fukaya N.,University of Shizuoka | And 4 more authors.
Metabolism: Clinical and Experimental | Year: 2010

In this study, we examined the effects of switching from acarbose or voglibose to miglitol in type 2 diabetes mellitus patients for 3 months on gene expression of inflammatory cytokines/cytokine-like factors in peripheral leukocytes and on glucose fluctuations. We enrolled 47 Japanese patients with type 2 diabetes mellitus, aged 26 to 81 years, with hemoglobin A1c levels ranging from 6.5% to 7.9% and who were treated with the highest approved dose of acarbose (100 mg per meal) or voglibose (0.3 mg per meal) in combination with insulin or sulfonylurea. Their prior α-glucosidase inhibitors were switched to a medium dose of miglitol (50 mg per meal), and the new treatments were maintained for 3 months. Forty-three patients completed the 3-month study and were analyzed. The switch to miglitol for 3 months did not affect hemoglobin A1c, fasting glucose, triglycerides, total cholesterol, or C-reactive protein levels, or adverse events other than hypoglycemia symptoms. Hypoglycemia symptoms and glucose fluctuations were significantly improved by the switch. The expression of interleukin-1β, tumor necrosis factor-α, and S100a4/6/9/10/11/12 genes in peripheral leukocytes, and the serum tumor necrosis factor-α protein levels were suppressed by switching to miglitol. Miglitol reduces glucose fluctuations and gene expression of inflammatory cytokines/cytokine-like factors in peripheral leukocytes of type 2 diabetes mellitus patients more than other α-glucosidase inhibitors and with fewer adverse effects. © 2010 Elsevier Inc. All rights reserved.


Miyachi A.,Sanwa Kagaku Kenkyusho Co. | Murase T.,Sanwa Kagaku Kenkyusho Co. | Yamada Y.,Akita University | Osonoi T.,Naka Memorial Clinic | Harada K.-I.,Meijo University
Journal of Proteome Research | Year: 2013

Gastric inhibitory polypeptide (GIP), an incretin, is an important subject in endocrinology. Some LC-MS assays have been proposed; however, their sensitivities are insufficient for the study of endogenous human incretin. Here, we describe a nanoflow LC hybrid triple quadrupole/linear ion trap MS assay for the simultaneous quantification of GIP1-42 and GIP3-42 from human plasma. We selected the surrogate peptide to avoid oxidative modification, and the endoproteinase Asp-N was selected for the proteolysis of GIP1-42 and GIP3-42. The phenylalanine residue at position 6 in both GIP1-42 and GIP3-42 was substituted with 13C9,15N-labeled phenylalanine, and these substituted GIPs were used as the internal standards. This facilitated accurate and precise quantification because large corrections are possible at all steps of sample pretreatment and ionization efficiency. The lower limit of quantification was 1 pM for GIP1-42 and 10 pM for GIP3-42 by using 200 μL of plasma. Quantification of GIP1-42 and GIP 3-42 in plasma from patients with type 2 diabetes was possible using this method, which included protein precipitation, Asp-N proteolysis, solid-phase extraction, nanoflow LC, and positive-ion multiple reaction monitoring cubed (MRM3) for GIP1-8, and MRM for GIP 3-8 to achieve accurate, precise, and quantitative analysis that can be validated to support large clinical trials. © 2013 American Chemical Society.


Katakami N.,Osaka University | Osonoi T.,Naka Memorial Clinic | Takahara M.,Osaka University | Saitou M.,Naka Memorial Clinic | And 3 more authors.
Cardiovascular Diabetology | Year: 2014

Background: Brachial-ankle pulse wave velocity (baPWV) is a method to estimate arterial stiffness, which reflects the stiffness of both the aorta and peripheral artery; it would be applicable to general practice, since its measurementis automated. The aim of this study was to evaluate whether baPWV can be predictors of future cardiovascular events (CVE) in diabetic patients.Methods: We prospectively evaluated the association between baPWV or carotid intima-media thickness (carotid IMT) at baseline and new onset of CVE in 1040 type 2 diabetic patients without CVE. The predictability of baPWV and/or carotid IMT for identifying patients at high risk for CVE was evaluated by time-dependent receiver-operating-characteristic (ROC) curve analysis.Results: During a median follow-up of 7.5 years, 113 had new CVD events. The cumulative incidence rates of CVE were significantly higher in patients with high baPWV values (≥1550 cm/s) as compared to those with low baPWV values (<1550 cm/s) (p < 0.001, log-rank test). Similarly, the cumulative incidence rate of CVE was significantly higher in patients with higher maximum carotid IMT (maxIMT) values (≥1.0 mm) as compared to those with lower maxIMT values (<1.0 mm) (p < 0.001, log-rank test). Subjects with both " high PWV" and " high IMT" had a significantly higher risk of developing CVE as compared to those with either " high PWV" or " high IMT," as well as those with neither. A multivariate Cox proportional hazards regression model revealed that both baPWV (HR = 1.30, [95%CI: 1.07-1.57]; p = 0.009) and maxIMT (HR = 1.20, [95%CI: 1.01-1.41]; p = 0.033) were independent predictors for CVE, even after adjustment for the conventional risk factors. Time-dependent ROC curve analyses revealed that the addition of maxIMT to the Framingham risk score resulted in significant increase in AUC (from 0.60 [95%CI: 0.54-0.67] to 0.63 [95%CI: 0.60-0.82]; p = 0.01). Notably, the addition of baPWV to the Framingham risk score and maxIMT resulted in further and significant (p = 0.02) increase in AUC (0.72 [95%CI: 0.67-0.78]).Conclusions: Evaluation of baPWV, in addition to carotid IMT and conventional risk factors, improved the ability to identify the diabetic individuals with high risk for CVE. © 2014 Katakami et al.; licensee BioMed Central Ltd.


Osonoi Y.,Juntendo University | Mita T.,Juntendo University | Osonoi T.,Naka Memorial Clinic | Saito M.,Naka Memorial Clinic | And 8 more authors.
Chronobiology International | Year: 2014

"Morningness" and "Eveningness" represent lifestyle patterns including sleep-wake patterns. Although previous studies described a relationship between the morningness-eveningness trait and glycemic control in patients with type 2 diabetes mellitus (T2DM), the mechanism underlying this association remains unknown. The study participants comprised 725 Japanese T2DM outpatients free of history of cardiovascular diseases. Various lifestyles were analyzed using self-reported questionnaires, including morningness-eveningness questionnaire (MEQ). The relationships between morningness-eveningness trait and various biochemical parameters were investigated by linear regression analysis and logistic regression analysis. We classified the study patients into three groups, morning type (n=117), neither type (n=424) and evening type (n=184). Subjects of the evening type had high levels of alanine aminotransferase, triglyceride, fasting blood glucose and HbA1c and low high-density lipoprotein-cholesterol level in a model adjusted for age and gender. Furthermore, multivariate analysis showed that the evening type was associated with high HbA1c and estimated glomerular filtration rate even after adjustment for other lifestyle factors known to affect metabolic control. The results suggest that T2DM patients with eveningness trait are under inadequate metabolic control independent of other lifestyle factors. Thus, the evening trait of T2DM patients represents an important target for intervention to ensure appropriate metabolic function. © 2014 Informa Healthcare USA, Inc. All rights reserved.

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