bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk of Foot Ulcer and Lower Extremity Amputation among Participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC)
Authors: BOYKO EDWARD J. , ZELNICK LEILA , BRAFFETT BARBARA , POP-BUSUI RODICA , COWIE CATHERINE C. , LORENZI GAYLE M. , GUBITOSI-KLUG ROSE , ZINMAN BERNARD , BOER IAN DE 
Published: June 2018

We examined whether prior intensive glycemic control during the DCCT reduced the risk of diabetic foot ulcer (DFU) and lower extremity amputation (LEA) among participants with type 1 diabetes in the EDIC study. DFU and LEA occurrence were determined by physical examination during annual EDIC follow-up visits that began about one year following DCCT completion. We also assessed DFU and LEA risk by neurovascular measurements, diabetes characteristics, and clinical factors. Data were available from 23 years of EDIC follow-up. Recurrent DFU was defined if reported on a different limb in subsequent years or the same limb in non-consecutive years. Multivariable Cox models were used to estimate the association of intensive glycemic control and other time-updated risk factors with incident or total (incident + recurrent) DFU or incident LEA. Incident DFU was observed in 86 of the 699 former intensive and 109 of the 7former conventional treatment participants (HR 0.78, 95% CI 0.59 to 1.03). Total DFU numbered 117 in intensive (7.3/1000 person-years (p-y)) and 153 in conventional treatment participants (9.6/1000 p-y) for a significant risk reduction (HR 0.76, 95% CI 0.60 to 0.97, p=0.03). Incident LEA occurred in 15 intensive (1.0/1000 p-y) compared to 21 conventional treatment participants (1.4/1000 p-y, HR 0.70, 95% CI 0.36 to 1.36, p=0.30). Greater HbA1c, lower eGFR, albuminuria, confirmed clinical neuropathy, lower nerve conduction velocity, abnormal cardiovascular autonomic function, proliferative retinopathy, and macular edema were independently associated (p&lt;0.05) with higher risk of incident DFU and LEA. Current smoking was associated with higher risk of LEA only. Ankle-brachial index measured continuously was not associated with risk of either outcome. We conclude that intensive glycemic control decreases the risk of DFU, the most important antecedent in the causal pathway to LEA.

Disclosure
E.J. Boyko: None. L. Zelnick: None. B. Braffett: None. R. Pop-Busui: Research Support; Self; AstraZeneca. C.C. Cowie: None. G.M. Lorenzi: Advisory Panel; Self; Intarcia Therapeutics, Inc.. R. Gubitosi-Klug: None. B. Zinman: Consultant; Self; Novo Nordisk A/S, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi, Merck & Co., Inc., Abbott. I. de Boer: Research Support; Self; Medtronic, Abbott. Consultant; Self; Boehringer Ingelheim GmbH, Ironwood Pharmaceuticals, Inc..
Gemigliptin in Diabetic Kidney Disease in Asian Indians with Type 2 Diabetes in Real-Life Scenarios—Insights from Gem Study
Authors: SHAH KIRAN , PATANGE SONALI A. , GANDHI ALKA P. 
Published: June 2018

Diabetic Kidney disease is strongly associated with cardiovascular events, premature mortality and ESRD. Gemigliptin can be used without dose adjustment in patients with renal failure. The current study aimed to assess the possible renoprotective effects of gemigliptin, using albuminuria and eGFR as indicators. This was a multi-center real-world retrospective analysis of 146 DPP-4 inhibitor naïve type 2 diabetic patients with established moderate DKD (eGFR between 30 to 45ml/min/1.73m2 over last 3 months) with diabetic retinopathy who received gemigliptin 50 mg once daily for 24 weeks in addition to anti-hyperglycemic, anti-hypertensives and statins. Goodness of fit was examined using SPSS statistics 20 and ANOVA was conducted to interpret the results. Baseline characteristics were: 71(48.6%) males and 75 (51.4%) females, the mean age was 60.81 ± 7.42 years, mean duration was 11.92 ± 3.3 years, mean BMI was 26.54 ± 2.59kg/m2. Gemigliptin showed significant improvements in glycaemia, renal and lipid parameters with no deterioration in retinopathy, liver enzymes and with no hypoglycemic episodes and was weight neutral. In the present study, gemigliptin reduced albuminuria independent of age, gender, duration of diabetes, Hba1c, eGFR and SBP. It could ameliorate diabetic nephropathy by reducing urine albumin excretion and mitigating the reduction of eGFR in diabetic patients.
Mean changes in various efficacy parameters at week 24 of the overall study periodParametersAt Baseline (n=146)At 6 months (n=146)% change from Baseline to 6 monthsP valueFBS192.90 ± 52.64129.99 ± 19.4632.6Significant (&lt;0.001)PPBS248.72 ± 62.75170.55 ± 23.0031.4Significant (&lt;0.001)HbA1c9.22 ± 1.517.68 ± 0.571.5Significant (&lt;0.001)UACR306.61 ± 77.17228.36 ± 45.8525Significant (&lt;0.001)Albuminuria521.2 ± 62.2342.4 ± 51.334.2Significant (&lt;0.001)eGFR37.37 ± 5.8641.76 ± 5.5212Significant (&lt;0.001)Serum Creatinine1.70 ± 0.231.55 ± 0.218.8Significant (&lt;0.001)

Disclosure
K. Shah: None. S.A. Patange: None. A.P. Gandhi: None.
Combination of SGLT2 Inhibitor and Novel Selective PPARα Modulator, Tofogliflozin (Tofo) and Pemafibrate (Pema), Improves Survival Rate in STAM Mice as a Diabetic NASH Model
Authors: YANO WATARU , TAKIZAWA TOSHIAKI , SASAKI YUSUKE , ASAHIYAMA MASATO , KAMIYA WAKANA , NAKAGAWA TAKASHI , YAMAZAKI HIROYUKI , INOUE KEISUKE , MIZUNO KEN , SAKAI JURO , KODAMA TATSUHIKO , TANAKA TOSHIYA 
Published: June 2018

Patients with type 2 diabetes have a high prevalence of nonalcoholic fatty liver disease (NAFLD) which is emerging as a major public health concern in the world. Nonalcoholic steatohepatits (NASH), a severe form of NAFLD, can progress to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). To establish the effective therapeutic method for NASH, we evaluate the therapeutic potential of the combination of SGLT2 inhibitor, tofogliflozin (Tofo), and a novel selective PPARα modulator (SPPARMα), pemafibrate (Pema), in STAM mice as a diabetic animal model of NASH to HCC. STAM mice were administered Tofo and Pema from 6 weeks of age. After 3 weeks of treatment, plasma triglyceride (TG) level was tended to reduce with 0.1 mg/kg Pema monotherapy, and decreased significantly to normal level in combination with 10 mg/kg Tofo. Blood glucose (BG) level was not altered in Pema-treated group, but lowered significantly with the combination therapy. Histological analysis of the liver revealed a tendency to reduce lipid droplet size and ballooning degeneration in Pema group. The combination of Pema and Tofo exhibited the synergistic effects on lipid droplet size and ballooning significantly. Liver TG content was also decreased in mice with the combination therapy. The survival rate of control group was decreased to 10% at 22 weeks of age. STAM mice with Pema in diet showed a tendency to increase the survival rate (30%) and the combination of Pema and Tofo significantly improved the survival rates (50%) compared to control group. Also, both of treated groups markedly reduced the number of tumors in the liver. These results suggested that, in addition of lipid metabolism, glycemic control might play an important role in the treatment of NASH. Combination therapy of SGLT2 inhibitor and SPPARMα would be a potent therapeutic strategy for the treatment of NAFLD, NASH and HCC.

Disclosure
W. Yano: Employee; Self; Kowa Company, LTD. T. Takizawa: Employee; Self; Kowa Company, LTD. Y. Sasaki: Employee; Self; Kowa Company, Ltd. M. Asahiyama: Employee; Self; Kowa Company, Ltd.. Employee; Spouse/Partner; Kowa Company, Ltd.. W. Kamiya: None. T. Nakagawa: Employee; Self; Kowa Company, LTD. H. Yamazaki: Employee; Self; Kowa Company, LTD. K. Inoue: Employee; Self; Kowa Company, LTD. K. Mizuno: Employee; Self; Kowa Company, LTD.. J. Sakai: None. T. Kodama: Consultant; Self; Kowa Company, Ltd. T. Tanaka: Research Support; Self; Kowa Company, Ltd..
Physiological Responses to Daily Use of Beta-Three Adrenergic Receptor Agonist, Mirabegron
Authors: O'MARA ALANA , CYPESS AARON , CERO CHERYL , JOHNSON JAMES W. , LINDERMAN JOYCE D. , LEITNER BROOKS , FLETCHER LAURA , BRYCHTA ROBERT , KAPURIA DEVIKA , MCGEHEE SUZANNE , ROTMAN YARON 
Published: June 2018

Background: Brown Adipose Tissue (BAT) in adult humans has become increasingly recognized to contribute to energy consumption and modulate metabolism. To date, BAT stimulation has predominately relied on cold exposure. However, long-term cold exposure is impractical as a treatment option for obesity and diabetes. Thus, we investigated if a chronic pharmacotherapeutic approach could stimulate BAT and contribute to metabolic health.
Methods: In an ongoing study, 6 healthy female volunteers received 4 weeks of daily mirabegron (Myrbetriq, Astellas Pharma) 100 mg, a β3 adrenergic receptor (AR) agonist. Acute responses were determined by comparing effects before and then five hours after dosing. Chronic changes were assessed after 4 weeks of treatment. The primary endpoint was the change in BAT metabolic activity measured by 18F-FDG PET/CT. Secondary endpoints included resting energy expenditure (REE), insulin and glucose sensitivity, liver steatosis, and cardiovascular stimulation.
Results: Acute effects of mirabegron included consistent increases in rate pressure product (RPP), REE, and serum non-esterified fatty acids (NEFA) (p&lt;0.05, p=0.06, p&lt;.05). After 4 weeks, there was a wide range of changes in BAT volume (41 ± 223 mL, p=0.86). Body weight was unchanged (0.3 ± 0.62 kg). Several physiological responses after chronic treatment were blunted, including smaller mirabegron-induced increases in RPP, NEFA, and REE. Yet, there were significant increases in sleeping EE (72 ± 23 kcal/d, p=0.03), insulin sensitivity (1.5 ± .6 (mU/L*min, p=0.05), and liver steatosis (30 ± 10 dB/m, p = 0.04) after 4 weeks.
Conclusions: Acute treatment with mirabegron in women successfully activates BAT thermogenesis. Preliminary data show chronic treatment resulted in a blunting of several responses, consistent with physiological attenuation of β-AR signaling. The increases in sleeping EE and improved insulin sensitivity suggest chronic mirabegron treatment may help alleviate metabolic disease.

Disclosure
A. O'Mara: None. A. Cypess: None. C. Cero: None. J.W. Johnson: None. J.D. Linderman: None. B. Leitner: None. L. Fletcher: None. R. Brychta: None. D. Kapuria: None. S. McGehee: None. Y. Rotman: None.
The SGLT2 Inhibitor Tofogliflozin Reduces Weight in People with Type 2 Diabetes due to Fluid Loss Initially and to Lipolysis in Late
Authors: YOSHIDA AKIHIRO , KUSAKABE HIROMI , TAKAMURA TOSHINARI , KAKU KOHEI , SUGANAMI HIDEKI 
Published: June 2018

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 loss-related factors, carefully focusing on the clinical process during the long-term intervention with a SGLT2i, tofogliflozin in people with type 2 diabetes. We analyzed data from 775 people with type 2 diabetes that participated in tofogliflozin phase 3 trials. Participants received tofogliflozin (20, or 40 mg; n = 235, and 540, respectively) orally once daily for 52 weeks. The correlation analysis was performed at week 4, 24 and 52. Baseline characteristics showed men (66 %), age (mean: 58 years), HbA1c (8.0 %), BMI (26 kg/m2) and eGFR (84 mL/min/1.73m2). Tofogliflozin significantly reduced body weight at week 4, 24 and 52 (mean: -1.4, -3.0 and -3.0 kg, respectively). At week 4, weight loss was negatively correlated with both the change in body fluid measures (hematocrit, RBC count, serum creatinine level, and uric acid level) and beta-hydroxybutyrate (BHB). At week 24, weight loss was positively correlated with anthropometric measurements (waist and hip circumferences) and hepatic enzymes levels, and negatively correlated with adiponectin, HDL-C, and BHB levels, but not with body fluid measures. Although the values at week 52 were in concert with the results at week 24, there was a modest but significant correlation between weight loss and BHB level. Our results clarified that tofogliflozin reduces weight, especially that of visceral fat in people with type 2 diabetes, at least due to fluid loss initially and to lipolysis in late. Weight loss might contribute to decrease in the hepatic enzymes, whereas it also accompanies an increase in beta-hydroxybutyrate, the safety issue of which to be investigated in future.

Disclosure
A. Yoshida: Employee; Self; Kowa Pharmaceutical Co. Ltd. H. Kusakabe: Employee; Self; Kowa Pharmaceutical Co.Ltd. T. Takamura: None. K. Kaku: Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation, MSD K.K.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Ono Pharmaceutical Co., Ltd.. Advisory Panel; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Speaker's Bureau; Self; Taisho Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceuticals, Japan Inc., Kowa Pharmaceuticals, Japan Inc.. Advisory Panel; Self; Astellas, Japan Inc. H. Suganami: Employee; Self; Kowa Company, Ltd..
Initial Beta-Hydroxybutyrate Elevation in Relation to Subsequent Weight Loss in Type 2 Diabetes via the SGLT2 Inhibitor Tofogliflozin
Authors: SATO YUICHI , NUNOI KIYOHIDE , KAKU KOHEI , YOSHIDA AKIHIRO , SUGANAMI HIDEKI 
Published: June 2018

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 diabetes participants. Analyzed were 774 type 2 diabetes participants who received tofogliflozin in two phase 3 studies. The participants were divided into four groups according to the quartiles for their change in BHB after 4 weeks of tofogliflozin therapy. The adjusted assessments of variables were analyzed using an analysis of covariance model with the quartiles, their baseline values, age, sex, and eGFR as covariates. BHB levels significantly increased (mean: +107.1 µmol/L) from baseline to week 4. Those changes in the first (Q1), second (Q2), third (Q3), and fourth (Q4) quartiles, respectively, were -33.7, +31.4, +98.0, and +331.1 µmol/L. Glycemic control at baseline was poorer, while CPI was lower within the higher quartiles. The difference of BHB changes among the quartiles was maintained during tofogliflozin therapy. At week 52, the increase of BHB levels from baseline was significant (+142.7 µmol/L) in Q4, but not changed in Q1. The weight loss at week 52 in Q4 (least square mean: -3.6 kg) was greater than in Q1 (-2.4 kg) although the improvement of hyperglycemia was identical. Furthermore, the reduction in waist circumference and increase in adiponectin were greater in Q4. And the increase in fasting free fatty acid was also greater in Q4, but not changed in Q1. The distinct response of BHB elevation was observed early after the SGLT2i, tofogliflozin therapy. The higher initial BHB elevation resulted in the greater reduction in body weight, especially fat mass via lipolysis. The progressive weight loss might be clinically associated with one of the signs of the higher ketone elevation.

Disclosure
Y. Sato: None. K. Nunoi: None. K. Kaku: Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation, MSD K.K.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Ono Pharmaceutical Co., Ltd.. Advisory Panel; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Speaker's Bureau; Self; Taisho Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceuticals, Japan Inc., Kowa Pharmaceuticals, Japan Inc.. Advisory Panel; Self; Astellas, Japan Inc. A. Yoshida: Employee; Self; Kowa Pharmaceutical Co. Ltd. H. Suganami: Employee; Self; Kowa Company, Ltd..
SGLT2 Inhibitors Increase Bone Strength by Increasing Procollagen Type 1 Amino-Terminal Propeptide in Patients with Type 2 Diabetes
Authors: KUSUNOKI MASATAKA , NATSUME YUKIE , MIYATA TETSURO , OSHIDA YOSHIHARU 
Published: June 2018

With regard to osteoporosis in diabetic patients due to SGLT2 inhibitors (SGLT2is), there is no consensus on its onset as yet. At the meeting of the European Association for the Study of Diabetes in 2015, we reported improvement of bone strength after 6-month treatment with three SGLT2is as revealed by quantitative ultrasound analysis of 115 Japanese type 2 diabetic patients. In this study, we investigated the influence of SGLT2is on the bone strength, density and quality in Japanese patients with type 2 diabetes through both quantitative ultrasound analysis and D dual-energy X-ray absorptiometry (DEXA) before and after 6-month of SGLT2i treatment. The study was conducted in 19 Japanese patients with type 2 diabetes mellitus. Treatment with luseogliflozin 2.5 mg qd or dapagliflozin 5 mg qd for 6 months resulted in significant elevation of the ultrasound-measured bone density (ratio to young adults) of the heel from 88 ± 16% to 91 ± 15% (P&lt;0.05). On the other hand, the lumbar spine bone density and femoral bone density measured by DEXA showed no significant difference before and after the treatment. Since the bone density measured by ultrasound is regarded to be equal to the bone quality + bone density, these results suggest that the bone density, reported to account for 70% of the bone strength, was not altered by the treatment with SGLT2is. In other words, the improvement of the bone strength revealed by ultrasound analysis appears to reflect improved bone quality rather than improved bone density. The serum level of TRACP-5b (a marker of bone destruction) did not differ significantly between before and after treatment, while the serum level of total procollagen type 1 amino-terminal propeptide (P1NP) increased significantly after the treatment (from 35.2 ± 10.3 μg/L to 39.0 ± 12.8 μg/L, P&lt;0.05). The improvement of the bone quality and elevation of bone strength following treatment with SGLT2i appears to be correlated with elevation of the serum P1NP level.

Disclosure
M. Kusunoki: Research Support; Self; Taisho Toyama Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Kaken Pharmaceutical Co., Ltd. Y. Natsume: Research Support; Spouse/Partner; Taisho Toyama Pharmaceutical Co., Ltd., Kaken Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd.. T. Miyata: None. Y. Oshida: None.
Discovery and Development of HGR4113 as a Novel Antidiabetes Oral Agent
Authors: KIM KYUNGIL , YOO SANG-KU , JO IN GEUN , LIM KEUN-WAN 
Published: June 2018

HGR4113 is a novel compound that was discovered by Glaceum Inc. through a Quantitative Structure-Activity Relationship (QSAR) study on Glabridin and its derivatives. HGR4113 showed competitive antihyperglycemic effects in db/db mice without any adverse event of obesity. The test consisted of a vehicle control group (db/db mice), a test group (HGR4113 150mg/kg), and two positive control groups (Metformin 300mg/kg and Pioglitazone 75mg/kg). HGR4113 was given orally once daily for 7 days for 8 consecutive weeks (qd×7×8). During the course of this study, HGR4113 exhibited a level of efficacy highly comparable to Pioglitazone, one of the oral antihyperglycemic agents available. More importantly, however, HGR4113 demonstrated weight maintenance effects similar to Metformin in db/db mice, whereas Pioglitazone caused db/db mice to develop significant signs of obesity as a critical adverse effect.
In conclusion, our test results suggest HGR4113 as a safe and effective drug for T2DM along with further clinical development.

Disclosure
K. Kim: None. S. Yoo: Employee; Self; Glaceum. I. Jo: Employee; Self; Glaceum Incoporation. K. Lim: Employee; Self; Glaceum Inc..
Systematic Literature Review and Network Meta-analysis (NMA) of SGLT2i as Monotherapy for Type 2 Diabetes Mellitus (T2DM)
Authors: DAVIES GLENN M. , MCNEILL ANN MARIE , KRUGER ELIZA , KOWAL STACEY L. , EJZYKOWICZ FLAVIA , HANNACHI HAKIMA , CATER NILO B. , MCLEOD EUAN 
Published: June 2018

Objective: Indirectly compare the efficacy and safety of ertugliflozin (ertu) from the VERTIS MONO trial to other SGLT2i when used as monotherapy.
Methods: Pubmed, EMBASE and Cochrane were searched through to end of 2016 for RCTs of 24-26 weeks duration in T2DM patients with uncontrolled A1C on no anti-hyperglycemic therapy. Comparators to ertu 5mg and 15mg were low and high doses of SGLT2i licensed in Europe and USA: canagliflozin (cana), dapagliflozin (dapa) and empagliflozin (empa). Included outcomes vs. placebo at 24-26 weeks were change in A1C, weight loss (WL), systolic (SBP), A1C &lt;7%, urinary and genital mycotic infections, hypoglycemia and patients with ≥1 adverse event (AE). Evidence was synthesized using both fixed effect (FE) and random effects (RE) Bayesian NMA, with model selection informed by guidelines. Credible intervals (CrI), analogous to 95% confidence intervals, were used to determine significance.
Results: The NMA included 10 RCTs with FE models selected for all analyses except A1C &lt;7% and WL. For change in A1C ertu 15mg was significantly more effective vs. dapa 10mg (mean difference (MD): -0.36%, CrI -0.65, -0.08) and empa 25mg (MD:-0.31%, CrI -0.58, -0.04). There were no other significant differences for efficacy outcomes between ertu and other SGLT2i, except a larger reduction in SBP for cana 300mg vs. ertu 15mg (MD: 3.45 mmHg, CrI 0.15, 6.76). Analyses of safety outcomes did not identify any significant differences or could not be interpreted due to scarcity of events in placebo arms preventing network convergence. The impact of inter-trial heterogeneity was tested, but remains a potential confounder.
Conclusions: In an indirect comparison ertu 5mg was comparable to other low dose SGLT2i at reducing A1C whereas ertu 15mg was more effective vs. dapa 10mg and empa 25mg. With the exception of SBP for ertu 15mg vs. cana 300mg, remaining outcomes were comparable to other SGLT2i for both ertu 5mg and 15mg.

Disclosure
G.M. Davies: Employee; Self; Merck & Co., Inc. A. McNeill: Employee; Self; Merck & Co., Inc.. Stock/Shareholder; Self; Merck & Co., Inc. E. Kruger: Employee; Self; QuintilesIMS. S.L. Kowal: None. F. Ejzykowicz: Employee; Self; Merck Sharp & Dohme Corp. H. Hannachi: Employee; Self; Merck & Co., Inc. N.B. Cater: Employee; Self; Peter Sheehan Diabetes Care Foundation, Inc. E. McLeod: Employee; Self; Pfizer Inc..