bluuebunny/crossref_metadata_2025_split huggingface dataset:
Eldecalcitol, a Vitamin D Analog, for Diabetes Prevention in Impaired Glucose Tolerance (DPVD Study)
Authors: KAWAHARA TETSUYA 
Published: June 2018

Background: In cohort and observational studies, it was clear that vitamin D deficiency is associated with insulin resistance and risk of future diabetes. However, randomized controlled trials with vitamin D supplementation for improving glucose tolerance or prevention of type 2 diabetes is still controversial.
Methods: We conducted the Diabetes Prevention on Vitamin D (DPVD) study which was a large, randomized, double-blind, placebo-controlled study to examine whether eldecalcitol, an active form of vitamin D analog, can reduce the risk of type 2 diabetes in patients with impaired glucose tolerance. Participants were randomly assigned to receive eldecalcitol or placebo. The primary endpoint was the incidence of type 2 diabetes and the secondary endpoint was the conversion to normal glucose tolerance. The study duration was 3 years.
Results: The mean follow-up was 2.6 years. A total of 1256 participants were enrolled in the study. 57 of 630 (9.0%) participants in the eldecalcitol and 64 of 626 (10.2%) in the placebo group developed type 2 diabetes (hazard ratio, 0.87; 95% confidence interval, 0.68 to 1.09; p=0.37). In the subgroup participants with vitamin D deficiency (serum 25-hydroxyvitamin D&lt;20 ng/ml), the difference of the incidence of type 2 diabetes between the two groups was greater; however, there was no statistical significance. Two hundred ninety-five of 630 (46.8%) participants in the eldecalcitol and 267 of 626 (42.7%) in the placebo group achieved normal glucose tolerance (hazard ratio, 1.10; 95% confidence interval, 0.93 to 1.31; p=0.45). No serious adverse events related to the intervention were recorded.
Conclusion: Our study showed that treatment with eldecalcitol was not associated with a reduction in the incidence of type 2 diabetes or an increase in the conversion to normal glucose tolerance among patients with impaired glucose tolerance.

Disclosure
T. Kawahara: None.
Canagliflozin Ameliorates Arterial Stiffness by Reducing Serum Uric Acid in Type 2 Diabetic Patients
Authors: SANCHEZ RAMIRO A. , SANCHEZ MARIA J. , RAMIREZ AGUSTIN J. 
Published: June 2018

We have previously shown a strong relation between high serum uric acid and pulse wave velocity (PWV) as expression of arterial stiffness. This relation was even stronger than with blood pressure. In addition to its hypoglycemic effect, sodium-glucose transport protein 2 inhibitors (SGLT2i) may reduce serum uric acid (SUA) by a uricosuric effect.
Aims: to evaluate in type 2 diabetic patients with hypertension and normal renal function the effect of canagliflozin on SUA and carotid femoral PWV.
Methods: 20 patients with type 2 diabetes mellitus (DM) 10 females, 59±4y received metformin 2000mg, canagliflozin 100-300mg and amlodipine 10mg daily during 6 months. Laboratory parameters including HbA1C, fasting blood glucose level, glomerular filtration rate, SUA, 24h ambulatory blood pressure monitoring (ABPM) and PWV were determined at baseline and after a 6-month treatment course with canagliflozin 100-300mg.
Results: After 6 months of treatment, PWV dropped from 12±3 to 8.5±4 m/sec, p&lt;0.05, HbA1C decreased from 8.1% to 7.0%, p&lt;0.05, SUA decreased from 7.9mg%±1 to 6.7±2%, p&lt;0.and 24h ABPM decreased from 154±6/96±5mmHg to 141±3/86±4mmHg, p&lt;0.05.
Conclusions: Canagliflozin ameliorates arterial stiffness in patients with type 2 DM and hypertension. This effect seems to be related, among other mechanisms, such as blood pressure drop and plasma volume contraction to the reduction in serum uric acid level. Since SUA has been shown to predict the risk of cardiovascular morbidity and mortality in hypertension and DM, lowering serum uric acid by SGLT2i might be contributing to cardiovascular protection.

Disclosure
R.A. Sanchez: None. M.J. Sanchez: None. A.J. Ramirez: None.
Suppressive Effect of Angiotensin II Receptor Blockers on Progression of Atherosclerosis as Assessed by 3-Dimensional Carotid Ultrasound
Authors: TAKI KENTARO , NISHIMURA RIMEI , NISHIOKA MAKIKO , MIYASHITA YUMI , YOKOTA TAMOTSU , DAISUKE TSUJINO , MORIMOTO AYA , TAJIMA NAOKO , UTSUNOMIYA KAZUNORI 
Published: June 2018

The effect of antihypertensive therapy with ARB on carotid endothelium in diabetic patients with hypertension by using 2- and 3-dimensional ultrasonography has received little attention.
We investigated whether significant differences exist between telmisartan and valsartan or not in carotid intima-media thickness and plaque volume. Eighty-six type 2 diabetic, hypertensive patients received nateglinide and Telmisartan 40 mg or Valsartan 80 mg for 6 months and were evaluated for bilateral maximum IMT and plaque volume by 2-/3-dimensional ultrasonography.
Baseline characteristics in groups telmisartan and valsartan(n=43 each) were: age, 62.0 and 65.0 years; Body Mass Index, 24.6 and 24.4kg/m2; duration of diabetes, 7.0 and 9.0 years; and HbA1c, 7.0 and 6.9%, respectively. Systolic/diastolic blood pressures in group telmisartan vs. valsartan were 143.0/84.0 vs. 144.0/83.0 at baseline and 127.0/76.0 vs. 130.0/74.0 mmHg after antihypertensive therapy, with all later values significantly lower than those at baseline(all P&lt;0.001).
Bilateral maximum IMT in group telmisartan vs. valsartan, as assessed by 2-dimensional ultrasonography, were 1.54 vs. 1.72 at baseline and 1.51 mm vs. 1.62 mm after antihypertensive therapy, without significant differences between groups.
Plaque volume in group telmisartan vs. valsartan, as assessed by 3-dimensional ultrasonography, at baseline and post-antihypertensive therapy, based on 15 measurements, were 57.3 and 42.6 mm3(P&lt;0.001) vs. 70.8 and 47.9 mm3(P&lt;0.001), respectively, with significant reductions revealed after antihypertensive therapy in both groups, but without significant differences between groups.
Significant reductions in plaque volume demonstrated that ARB-based antihypertensive therapy with telmisartan or valsartan was efficacious in suppressing the progression of carotid atherosclerosis as assessed by 3-dimensional ultrasonography.

Disclosure
K. Taki: None. R. Nishimura: Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Astellas Pharma US, Inc., Eli Lilly and Company, Abbott, Medtronic, MSD K.K., Novo Nordisk A/S, Sanofi, Takeda Development Center Asia, Pte. Ltd., Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.. M. Nishioka: None. Y. Miyashita: None. T. Yokota: None. T. Daisuke: None. A. Morimoto: None. N. Tajima: None. K. Utsunomiya: None.
Metformin Activates AMPK Signaling but Inhibits Mitophagy in the Mouse Heart
Authors: ZHANG YAWEN , CHANG MICHAEL M. , PINKHASOVA POLINA R. , ZHAO FENGYI , KOBAYASHI TAMAYO , HUANG YUAN , KOBAYASHI SATORU , LIANG QIANGRONG 
Published: June 2018

Metformin, a commonly prescribed first-line drug for the treatment of type 2 diabetes mellitus, has been shown to reduce cardiac injury under diabetic and other pathological conditions. However, the mechanisms that mediate the cardioprotective effects of metformin remain controversial. One prevailing hypothesis suggests that metformin activates AMPK-autophagy pathway which eliminates protein aggregates and damaged mitochondria, thus protecting the heart from injury. In the present study, we tested this hypothesis using both in vivo and in vitro models. FVB/N mice were administered 200 mg/kg of metformin through gavage once a day for two days. As expected, metformin activated AMPK signaling in the heart as shown by the increased phosphorylation of AMPK alpha at Thr172 and its downstream effecter Acetyl-CoA Carboxylase at Ser79. Autophagy and mitophagy were determined by Western blot analysis of LC3-II, a well-established marker of autophagic vesicles. Surprisingly, however, metformin did not affect LC3-II levels in total tissue lysates and significantly reduced LC3-II in mitochondrial fractions, suggesting that metformin actually inhibited rather stimulated mitophagy, contrary to the current belief. This was confirmed by measuring mitophagy flux using lysosomal inhibitors pepstatin A and E64d. The ability of metformin to inhibit mitophagy was also corroborated by a novel dual fluorescent mitophagy reporter showing reduced degradation rate of mitochondria in the lysosomes. All these results were reproduced in H9c2 rat cardiac myoblast cells. Collectively, our results show that metformin is able to activate AMPK signaling but paradoxically inhibits mitophagy in the heart, suggesting that the cardioprotective benefit of metformin observed in many different models may be mediated through mechanisms other than autophagy and mitophagy. Future studies will explore the mechanisms by which metformin inhibits mitophagy and protects the heart.

Disclosure
Y. Zhang: None. M.M. Chang: None. P.R. Pinkhasova: None. F. Zhao: None. T. Kobayashi: None. Y. Huang: None. S. Kobayashi: None. Q. Liang: None.
Simplified Transition Algorithm from Intravenous to Subcutaneous Insulin in Nondiabetic Cardiac Surgery Patients with Stress Hyperglycemia
Authors: CARDONA SAUMETH , GALINDO RODOLFO J. , TSEGKA KATERINA G. , URRUTIA MARIA A. , VELLANKI PRIYATHAMA , FAYFMAN MAYA , SONYA HAW J. , PASQUEL FRANCISCO J. , PENG LIMIN , UMPIERREZ GUILLERMO E. 
Published: June 2018

Intravenous (IV) insulin is recommended to treat stress hyperglycemia (SH) in nondiabetic (non-DM) patients after cardiac surgery. Many patients with SH require transition to subcutaneous (SQ) insulin after stopping IV drip in the ICU. We report a simplified protocol for the transition from IV to SQ insulin in cardiac surgery patients with SH. Patients requiring IV insulin &gt;2 U/hour were transitioned to SQ basal bolus regimen at 70% of calculated daily insulin requirement. Patients requiring ≤ 2 U/hour were treated with sliding scale insulin (SSI), if &gt;2 episodes of BG &gt; 140 mg/dl patients were started on rescue therapy with basal insulin.
Among 150 non-DM patients with SH in the ICU, 30 patients (20%) required &gt;2 U/hour and were transitioned to SQ basal/bolus at a mean SQ dose of 0.34 U/kg/day for a duration of treatment of 5.5±3.6 days. A total of 120 (80%) patients required ≤ 2 U/hour and were transitioned to SSI. Of them, the mean blood glucose (BG) was 129.8±16 mg/dl and only 3 (2.5%) patients required a single dose of basal insulin during the hospital stay. There were no differences in LOS or in a composite of complications between groups.
Our results indicate that cardiac surgery patients with SH requiring continuous IV insulin ≤ 2 U/hour in the ICU can be safely transitioned to SSI; however, patients requiring &gt; 2 U/hour should be transitioned to basal insulin to maintain glycemic targets.
Transition to SSITransition to Basalp-valuePatients, n (%)120 (80)30 (20)BMI, Kg/m228.8 ± 6.530.3 ± 5.40.15HbA1c, %5.6 ± 0.45.8 ± 0.70.047ICUDaily BG during IV insulin drip, mg/dl133.9 ± 17142.9 ± 150.004Total insulin in the ICU, U/day57.4 ± 8973.8 ± 640.005TRANSITIONAverage BG after transition, mg/dl123.4 ± 12129.8 ± 160.022Patients who required SQ SSI99 (83)30 (100)&lt;0.001Patients with BG &lt; 70 mg/dl, n (%)13 (10.8)2 (6.7)0.74Composite of complications53 (44)14 (47)0.81Data are n (%) or mean ± SD. Composite complications: major CV events, infections, respiratory failure and acute kidney injury.

Disclosure
S. Cardona: None. R.J. Galindo: None. K.G. Tsegka: None. M.A. Urrutia: None. P. Vellanki: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. M. Fayfman: None. J. Haw: None. F.J. Pasquel: Consultant; Self; Merck Sharp & Dohme Corp., Sanofi, Boehringer Ingelheim Pharmaceuticals, Inc.. L. Peng: None. G.E. Umpierrez: Research Support; Self; Sanofi US, Merck & Co., Inc., Novo Nordisk Inc., AstraZeneca. Advisory Panel; Self; Sanofi, Intarcia Therapeutics, Inc..
A Phase 3 Comparison of a Novel Liquid Glucagon Autoinjector to Glucagon Emergency Kit for the Treatment of Severe Hypoglycemia
Authors: CHRISTIANSEN MARK P. , CUMMINS MARTIN J. , PRESTRELSKI STEVEN J. , STRANGE POUL 
Published: June 2018

Objective: To prevent medical complications and serious sequalae of severe hypoglycemic emergencies, prompt and reliable rescue intervention is critically important. A novel ready-to-use stable liquid glucagon autoinjector (GAI; Xeris Pharmaceuticals) was evaluated for the rescue treatment of severe hypoglycemia.
Research Design and Methods: A randomized, controlled, double-blind, crossover clinical trial was conducted in 80 adults with T1D (mean age 43.6 years) to compare subcutaneous 1 mg doses of GAI vs. Glucagon Emergency Kit (GEK; Eli Lilly) for the treatment of insulin-induced severe hypoglycemia. Efficacy was evaluated as either an increase in plasma glucose to ≥70 mg/dL or an increase in plasma glucose ≥20 mg/dL from a baseline glucose &lt;50 mg/dL, within 30 min of dosing.
Results: On an intent-to-treat basis, efficacy was comparable between the groups (97.4% GAI, 100% GEK, p=NS), and all subjects were rescued from severe hypoglycemia without additional measures. GAI was similar to GEK in terms of glucose Cmax, Tmax, and AUC (0-90 min). The incidence of AEs was low in both groups; the most commonly reported AE was nausea [GAI (20.5%), GEK (12.7%); p=NS], followed by vomiting and headache.
Conclusions: These results demonstrate that GAI is an effective, safe, and well tolerated rescue treatment for severe hypoglycemia and is a viable alternative to GEK.

Disclosure
M.P. Christiansen: Research Support; Self; Dexcom, Inc., Insulet Corporation, Medtronic MiniMed, Inc., Abbott, Novo Nordisk Inc., Senseonics, REMD Biotherapeutics, Xeris Pharmaceuticals, Inc. M.J. Cummins: Employee; Self; Xeris Pharmaceuticals, Inc. S.J. Prestrelski: Employee; Self; Xeris Pharmaceuticals, Inc. P. Strange: Other Relationship; Self; AstraZeneca. Consultant; Self; Valeritas, Inc.. Stock/Shareholder; Self; Valeritas, Inc..
Simplici-T1—First Clinical Trial to Test Activation of Glucokinase as an Adjunctive Treatment for Type 1 Diabetes
Authors: BUSE JOHN B. , VALCARCE CARMEN , FREEMAN JENNIFER L. , DUNN IMOGENE , DVERGSTEN CHRIS , SUE KIRKMAN M. , KASS ALEXANDER , DINER JAMIE , BERGAMO KATHERINE A. 
Published: June 2018

TTP399 is an oral liver selective Glucokinase Activator (GKA). Because it exhibits an insulin-independent mechanism of action, it may be suitable as an adjunctive treatment for type 1 diabetes (T1DM).
In clinical trials in type 2 diabetes (T2DM), TTP399 has shown significant reduction in postprandial glucose, increased percentage time in range and decreased percentage time in hypo or hyperglycemia. Moreover, TTP399 significantly reduced HbA1c without significant hypoglycemia, dyslipidemia, or ketoacidosis.
The Simplici-T1 trial (NCT03335371) is an adaptive three-part (sentinel, learning phase and confirming phase) Phase 1b/2 Proof of Concept study designed to explore the effect of TTP399 as adjunctive therapy for the treatment of T1DM. The aims of the study are to: (1) evaluate the safety of TTP399 and (2) evaluate whether TTP399 can replace or reduce mealtime insulin bolus and improve A1c in patients with T1DM.
The sentinel phase, an open label, dose escalation study in 5 adults with T1DM on insulin pump therapy and continuous glucose monitoring (CGM), showed that TTP399 was well tolerated. No incidents of severe hypoglycemia or diabetic ketoacidosis were observed. When compared to baseline, trends toward improved glycemic control while reducing insulin dose (Table) were observed with TTP399 treatment, supporting continuing to the randomized, placebo controlled phase of the study.

Disclosure
J.B. Buse: Other Relationship; Self; ADOCIA, AstraZeneca, Dexcom, Inc., Elcelyx Therapeutics, Inc., Eli Lilly and Company, Fractyl Laboratories, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Metavention, NovaTarg, Novo Nordisk A/S, Sanofi, VTV Therapeutics. Research Support; Self; Boehringer Ingelheim GmbH, Johnson & Johnson Services, Inc., Theracos, Inc.. Other Relationship; Self; Shenzhen Hightide Biopharmaceutical, Ltd.. Research Support; Self; National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences. Other Relationship; Self; National Institute of Diabetes and Digestive and Kidney Diseases, American Diabetes Association. Research Support; Self; Patient-Centered Outcomes Research Institute. Other Relationship; Self; National Institute of Environmental Health Sciences. C. Valcarce: Employee; Self; VTV Therapeutics. J.L. Freeman: Employee; Self; VTV Therapeutics. Stock/Shareholder; Self; VTV Therapeutics. Stock/Shareholder; Spouse/Partner; VTV Therapeutics. I. Dunn: Employee; Self; VTV Therapeutics. C. Dvergsten: Employee; Self; VTV Therapeutics. M. Kirkman: Research Support; Self; Bayer AG, Theracos, Inc.. Consultant; Self; National Institutes of Health. Research Support; Self; National Institutes of Health, Centers for Disease Control and Prevention. A. Kass: None. J. Diner: None. K.A. Bergamo: None.
The Effectiveness of Text Message Support for Weight Loss to Reduce Diabetes Risk
Authors: FISCHER HENRY , RAGHUNATH SILVIA , DURFEE JOSH , RITCHIE NATALIE 
Published: June 2018

Objective: To reach the estimated 84.1 million U.S. adults with prediabetes, lower-cost alternatives to the National Diabetes Prevention Program (NDPP) are needed, which is estimated to cost $500 per person. In a previous randomized controlled trial, we demonstrated efficacy of a 12-month text message support program (SMS4PreDM) in individuals with prediabetes. We now explore effectiveness in a pragmatic study in a healthcare system, in addition to calculating per-person costs of SMS4PreDM.
Research Design and Methods: English- and Spanish-speaking patients with diabetes risks (e.g., A1C 5.7-6.4) were referred by their healthcare providers and offered NDPP classes, SMS4PreDM, or both. This analysis focused on comparing weight outcomes among SMS4PreDM-only participants to a usual care control group of patients with diabetes risks who were not referred. As a pragmatic study, weights for both groups were collected from electronic health records at baseline and 12 months. Rates of achieving ≥3% weight loss were compared using logistic regression, including a sub-analysis by language.
Results: Among 183 SMS4PreDM-only participants, 51.4% (N=94) had documented pre- and post-intervention weights and 30.9% (N=29) achieved ≥3% weight loss, compared with 23.4% of 1,871 control patients (p=0.10). English-speakers receiving SMS4PreDM trended toward ≥3% weight loss at a higher rate than English-speaking controls (36.5% vs. 25.6%, p=.07). There was no significant difference among Spanish-speakers. In an intention-to-treat analysis that assumed no weight loss among participants with missing data, there was no significant difference in achieving ≥3% weight loss as compared to controls (20.8% vs. 20.2%, p=.49). Costs of SMS4PreDM were $100.92 per capita.
Conclusions: SMS4PreDM trends toward greater achievement of ≥3% weight loss compared to usual care and at a lower cost than the NDPP. However, results may not be sufficiently robust or generalizable to support long-term implementation.

Disclosure
H. Fischer: None. S. Raghunath: None. J. Durfee: None. N. Ritchie: None.
Real-World Comparative Effectiveness, Treatment Patterns, and Costs in Type 2 Diabetes Mellitus (T2DM) Patients Initiated on Canagliflozin 300 mg (CANA) or a Glucagon-Like Peptide-1 Receptor Agonist (GLP-1)
Authors: SINGHAL MUKUL , TAN HIANGKIAT (JASON) , COLEMAN CRAIG I. , HERMAN WILLIAM H. , CAI JENNIFER , HAN MICHELLE , INGHAM MIKE 
Published: June 2018

This study compared HbA1c control, treatment patterns, and costs in adults with T2DM initiated on CANA or a GLP-1 based on administrative claims data from the HealthCore Integrated Research Database (4/2013-02/2016) augmented with laboratory data. The analysis included adult patients with ≥1 HbA1c result at baseline (BL) and in the 12-month follow-up period; statistical analysis was performed at 3-month intervals. Inverse probability of treatment weighting (IPTW) accounted for differences in BL characteristics. From 12 months pre- to 12 months post-index (Figure), there were no significant differences in HbA1c at each 3-month interval in patients initiated on CANA (n = 750) or GLP-1 (n = 2417); results were consistent regardless of BL HbA1c (≥7%, ≥8%, or ≥9%) (data not shown). A greater proportion of patients were adherent to index medication (proportion of days covered ≥80%) over 12 months with CANA vs. GLP-1 (47.5% vs. 37.5%; P &lt;0.001). The likelihood of discontinuation from index medication was lower with CANA than GLP-1 (49.6% vs. 57.4%; HR [95% CI]: 0.78 [0.70, 0.88]). Continuous 12-month pharmacy costs were $1,421 lower with CANA vs. GLP-1.
In summary, CANA initiation resulted in similar HbA1c values, greater adherence, less discontinuation, and lower treatment cost compared to GLP-1 in T2DM patients.

Disclosure
M. Singhal: Other Relationship; Self; Janssen Scientific Affairs, LLC. H. Tan: Other Relationship; Self; Janssen Scientific Affairs, LLC. C.I. Coleman: Research Support; Self; Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc. W.H. Herman: Other Relationship; Self; Merck Sharp & Dohme Corp., Lexicon Pharmaceuticals, Inc.. Consultant; Self; Janssen Scientific Affairs, LLC.. Research Support; Spouse/Partner; Nestlé. Other Relationship; Self; American Diabetes Association. Advisory Panel; Self; National Committee for Quality Assurance (NCQA). J. Cai: Employee; Self; Janssen Scientific Affairs, LLC. M. Han: Employee; Self; Janssen Scientific Affairs, LLC. M. Ingham: Employee; Self; Janssen Scientific Affairs, LLC..