bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and Safety of Sitagliptin (SITA)-Based Dual and Triple Combination Therapy in Older Chinese People with T2D
Authors: LIU XIANGYANG , WANG LI , XING YING , ENGEL SAMUEL S. , CHEN GUOJUAN , ZHANG YE , ZHANG RUYA , LIU SHU , WENG JIANPING , JI QIUHE
Published: June 2018

Despite increasing prevalence of T2D in older Chinese people, no studies have evaluated the efficacy and safety of DPP-4 inhibitor-based combination therapy in this population. In the STRATEGY Study (a multicenter, randomized, active-controlled, open-label clinical trial in Chinese people with T2D), patients were treated for 20 weeks with a combination of SITA and metformin (MET) (Phase 1). Those with A1C ≥7.0% and ≤10.0% at Week 16 were randomly assigned at Week 20 to 1 of 4 additional AHAs and continued treatment for another 24 weeks (Phase 2). Here we report efficacy and safety in the 681 patients aged ≥65 year.

At baseline, the mean age, duration of diabetes, BMI and A1C of the analysis population were 68.4 year, 7.5 year, 25 kg/m2 and 7.7%, respectively; ≈half were male. Changes in A1C are shown in the Table. Achievement of A1C goal of <7% was observed in 44.9% (305/680) during Phase 1, and 65.4% (445/680) during Phases 1 + 2.

Through Week 20/n=681 and Week 44/n=269, the incidences of any adverse events (AEs) were 30% and 31%, of drug-related AEs were 4% and 5%, and of serious AEs were 2% and 3%, respectively. Hypoglycemia incidences were highest with glimepiride and gliclazide (Table); no severe hypoglycemia was reported.

In older Chinese people, dual and triple combination therapy based on SITA and MET provided clinically meaningful improvement in glycemic control and was generally well tolerated.Phase 1 (Baseline through Week 20)Baseline A1C, mean ± SD, %Change from baseline A1C at Week 16, %Hypoglycemia, % (n/N) (APaT Population)SITA + MET, N = 6267.94 ± 0.78-0.81 ± 0.824.3% (29/681)Phase 2 (Weeks 20 through 44)Week 20 A1C, mean ± SD, %Change from Week 20 A1C at Week 44, %Hypoglycemia, % (n/n) (APaT Population)SITA + MET + glimepiride, n = 637.62 ± 0.82-0.73 ± 0.879.6% (7/73)SITA + MET + gliclazide, n = 697.68 ± 0.76-0.65 ± 0.7710.5% (8/76)SITA + MET + repaglinide, n = 477.69 ± 0.70-0.54 ± 0.785.9% (3/51)SITA + MET + acarbose, n = 647.59 ± 0.69-0.46 ± 0.731.5% (1/69)

Disclosure

X. Liu: None. L. Wang: None. Y. Xing: None. S.S. Engel: Employee; Self; Merck & Co., Inc.. Stock/Shareholder; Self; Merck & Co., Inc. G. Chen: Employee; Self; Merck Sharp & Dohme Corp.. Y. Zhang: None. R. Zhang: Employee; Self; Merck Sharp & Dohme Corp.. S. Liu: None. J. Weng: None. Q. Ji: Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Sanofi-Aventis. Speaker's Bureau; Self; Sanofi-Aventis. Research Support; Self; Novo Nordisk A/S. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company, Medtronic. Research Support; Self; Merck & Co., Inc., Merck & Co., Inc..
Development of an Innovative Screening Tool and Identification of Novel ß-Cell Protective Drugs
Authors: SITHARA SMITHAMOL , PATEL BHAVISHA , ELLIS MEGAN K. , CROWLEY TAMSYN , WALDER KEN , ASTON-MOURNEY KATHRYN
Published: June 2018

Type 2 diabetes (T2D) is characterised by progressive β-cell failure. While many drugs assist in the management of diabetes, current treatments cannot stop or slow the progression of this failure. In fact, over 50% of people with T2D have poor glycaemic control despite best practice management. Thus a key tool in T2D management would be the development of new drugs that restore adequate insulin secretion, but also protect against the continual deterioration of the β-cells. Previous drug discovery techniques have focused on single targets or pathways, however because β-cell dysfunction is extremely complex, targeting one pathway has proven to be ineffective. One approach that encompasses the intricacy of complex disease is that of gene expression signatures (GES) which have proved to be a valuable tool in other complex diseases.In this study, we developed a β -cell model consisting of three different conditions: 1) normal function/viability (“healthy”), 2) dysfunction/reduced viability (“diabetic”) and 3) successful treatment of dysfunction/reduced viability with a cocktail of known drugs (selected based on their ability to treat different aspects of β-cell dysfunction, “successfully treated”). We then used a comprehensive screening approach using gene expression profiles under these three conditions to generate a β-cell GES consisting of a gene set that robustly and accurately reflects the overall state of the cell. This GES was then used to screen a library of off-patent compounds, with known safety profiles, and the 12 top candidate compounds identified. In vitro testing of these drugs identified that nine significantly improved beta-cell function and survival. Therefore, we have developed a novel platform for T2D β-cell drug discovery and identified several candidate compounds that could prevent the progressive failure of β-cells. These drugs have the potential to be powerful T2D treatments and thereby reduce the burden of T2D and improve quality of life for millions world-wide.

Disclosure

S. Sithara: None. B. Patel: None. M.K. Ellis: None. T. Crowley: None. K. Walder: None. K. Aston-Mourney: None.
Development of Oral Bioavailable Nicotinamide N-Methyltransferase Inhibitors to Reduce Adiposity, Insulin Resistance, and Hyperglycemia
Authors: NEELAKANTAN HARSHINI , WATOWICH STAN
Published: June 2018

There is a critical need for new mechanism-of-action drugs that reduce adiposity, a prime driver of type 2 diabetes. A novel target to treat adiposity and reverse type 2 diabetes is nicotinamide-N-methyltransferase (NNMT), a cytosolic enzyme with newly identified roles in regulating adipose tissue metabolism and energy homeostasis. We have recently developed first-in-class small molecule NNMT inhibitors and characterized physicochemical, pharmacological, pharmacokinetic (PK), and off-target safety profiles of these inhibitors to identify a drug-like efficacious, orally bioavailable, and safe lead candidate for IND-enabling studies. Our first generation of highly selective, stable, and soluble compounds demonstrated excellent PK properties, including high oral bioavailability (>90%) and half-life of 3 hours in rats. Finally, the efficacy of promising NNMT inhibitors at modulating adiposity and type 2 diabetes endpoints (e.g., fat mass, oral glucose tolerance, adipokine levels, circulating lipids) were assessed using diet-induced obese (DIO) mice maintained on a high-fat diet. Systemic treatment of DIO mice with a potent NNMT inhibitor significantly reduced body weight and white adipose tissue mass, decreased adipocyte cell size, and lowered plasma cholesterol levels (p<0.05). Notably, administration of NNMT inhibitors did not alter total food intake nor produce any observable adverse effects. These results support continued development of small molecule NNMT inhibitors as therapeutics to lessen adiposity and lower the burden of adiposity-associated type 2 diabetes.

Disclosure

H. Neelakantan: None. S. Watowich: None.
Changes in Blood Glucose Levels and Body Weight in Patients Administered Sodium-Glucose Cotransporter 2 Inhibitors
Authors: KIM HUN-SUNG , LEE EUN YOUNG , YOON KUN-HO
Published: June 2018

A few patients who are administered sodium-glucose co-transporter 2 inhibitors (SGLT2i) for the first time often show an increase in their body weight and/or blood glucose levels. In this study, we used an electronic medical record database to identify the factors that affect blood glucose levels and body weight after the administration of SGLT2i. We investigated 1,663 patients who had been prescribed SGLT2i for the first time in a Korean hospital between December 2014 and December 2016. Based on the HbA1c levels measured 3 months following administration of SGLT2i, we observed that the blood glucose levels were significantly lowered in women or in elderly patients (all p < 0.05). In patients who showed an estimated glomerular filtration rate (eGFR) ≥ 90 mg/dL (from 8.3% to 7.4%, p<0.001) and those with an eGFR of 60-90 mg/dL (from 7.9% to 7.2%, p<0.001), the HbA1c was observed to demonstrate a significant drop. However, in patients with an eGFR ≤ 60 mg/dL, the HbA1c tended to demonstrate a marginal rise slightly (from 8.1% to 8.5%, p<0.001). A similar pattern of changes was observed with regard to patients’ weight. Significant weight loss and improvement in blood glucose levels were observed in those with a baseline HbA1c level ≥ 9.0%. However, the weight loss observed was relatively less significant in those with a baseline HbA1c level of 7.0-8.0% and 8.0-9.0%. We conclude that the reduction in blood glucose levels and the weight loss induced by SGLT2i appear to be strongly influenced by/associated with gender, age, and eGFR. While large-scale clinical studies are needed in the future, it seems worthwhile to check the clinical condition of SGLT2i-prescribed patients in advance and expect changes in weight and blood sugar reduction. Although large-scale clinical studies are needed in the future to conclusively corroborate our results, it is recommended that patients administered SGLT2i be monitored closely for weight changes and improvements in blood sugar levels.

Disclosure

H. Kim: None. E. Lee: None. K. Yoon: None.
Maternal Type 1 Diabetes and Risk of Autism in Offspring
Authors: XIANG ANNY , WANG XINHUI , MARTINEZ MAYRA P. , PAGE KATHLEEN A. , BUCHANAN THOMAS A.
Published: June 2018

Children exposed in utero to maternal type 2 diabetes (T2D) or gestational diabetes (GDM) diagnosed by 26 weeks gestation are at increased risk of autism spectrum disorders (ASD). Here we assessed the association between ASD and in utero exposure to maternal type 1 diabetes (T1D). Data were from 419,425 singleton children born at 28-44 weeks’ gestation from 1995-2012 at Kaiser Permanente Southern California (KPSC) hospitals. Children were tracked from birth until the first of the following: date of clinical diagnosis of ASD, last date of continuous KPSC membership, death due to any cause, or December 31, 2016. Relative risks of ASD were estimated by hazard ratio (HR) using Cox regression models adjusted for birth year, maternal age, parity, education, household income, race/ethnicity, history of comorbidity, and sex of the child. A total of 621 children were exposed to T1D, 9,453 to T2D, 11,922 to GDM diagnosed by 26 weeks gestation, and 24,5to GDM diagnosed after 26 weeks gestation. During a median of 6.3 (interquartile range of 3.4-11.2) years after birth, 5,624 children were diagnosed with ASD (19 exposed to T1D, 221 to T2D, 250 to GDM by 26 weeks, 360 to GDM after 26 weeks, and 4,774 not exposed to maternal diabetes). Unadjusted annual ASD incidence rates per 1000 children were 4.7 (T1D), 3.7 (T2D), 3.1 GDM by 26 weeks, 2.2 (GDM after 26 weeks) and 1.9 (unexposed). Relative to no diabetes exposure, the adjusted HRs for exposure to maternal diabetes were 2.5 (95% CI, 1.4-4.4) for T1D, 1.5 (95% CI, 1.3-1.7) for T2D, 1.4 (95% CI, 1.2-1.6) for GDM by 26 weeks, and 1.0 (95% CI, 0.9-1.1) for GDM after 26 weeks gestation respectively. Thus, exposures to T1D, T2D and GDM diagnosed by 26 weeks gestation were all associated with an increased risk of autism spectrum disorders in offspring. Exposure to T1D imparted the highest risk, followed by exposure to T2D and GDM diagnosed by 26 weeks. Rising rates of maternal diabetes may be one factor contributing to rising rates of ASD.

Disclosure

A. Xiang: None. X. Wang: None. M.P. Martinez: None. K.A. Page: None. T.A. Buchanan: None.
Dapagliflozin plus Saxagliptin Add-On to Metformin Reduces Liver Fat and Adipose Tissue Volume in Patients with Type 2 Diabetes
Authors: WILDING JOHN P. , HOCKINGS PAUL , JOHNSSON EVA K. , MAASKE JILL , GARCIA-SANCHEZ RICARDO , JOHANSSON LARS
Published: June 2018

Oral administration of a fixed-dose combination of the SGLT2 inhibitor dapagliflozin (DAPA) and the DPP-4 inhibitor saxagliptin (SAXA) is approved for improving glycemic control in adult patients with type 2 diabetes (T2D). A 52-week, multicenter, randomized, double-blind, parallel-group trial (NCT02419612) evaluated the efficacy and safety of DAPA 10 mg/d + SAXA 5 mg/d vs. titrated glimepiride (GLIM) 1-6 mg/d in 443 patients with T2D (A1C 7.5-10.5%) on metformin (MET) ≥1500 mg/d background. In a substudy, we used magnetic resonance imaging (MRI) to assess effects on liver fat (proton density fat fraction [PDFF]) and visceral and subcutaneous adipose tissue volumes over 52 weeks of treatment. MRI was performed on 59 patients; liver fat and adipose tissue volumes were analyzed for 59 and 57 patients, respectively. There was a significant >30% reduction from baseline in liver fat (P=0.007) and a >10% reduction in adipose tissue volumes (P<0.01) with DAPA + SAXA + MET at week 52 vs. GLIM + MET (Table). In the full study population, DAPA + SAXA + MET decreased body weight and serum levels of alanine aminotransferase and aspartate aminotransferase over 52 weeks.

In conclusion, DAPA + SAXA significantly decreased liver fat and adipose tissue volume vs. GLIM, and reduced serum liver enzyme levels, indicating a favorable metabolic profile of DAPA + SAXA in patients with T2D on MET therapy.

Disclosure

J.P. Wilding: Other Relationship; Self; Astellas, AstraZeneca, Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi, Eli Lilly and Company, Orexigen Therapeutics, Inc., Merck & Co., Inc. P. Hockings: Other Relationship; Self; MedImmune, AstraZeneca. E.K. Johnsson: Employee; Self; AstraZeneca. J. Maaske: Employee; Self; AstraZeneca. Employee; Spouse/Partner; AstraZeneca. Stock/Shareholder; Spouse/Partner; AstraZeneca. R. Garcia-Sanchez: Employee; Self; AstraZeneca. L. Johansson: Stock/Shareholder; Self; Antaros Medical.
Canagliflozin Improves a Left Ventricular Diastolic Dysfunction without Affecting Baroreflex Sensitivity in Type 2 Diabetes
Authors: MATSUTANI DAISUKE , SAKAMOTO MASAYA , KAYAMA YOSUKE , UTSUNOMIYA KAZUNORI
Published: June 2018

In type 2 diabetes, there is no effective treatment for gradual progression of left ventricular (LV) diastolic dysfunction and reduced baroreflex sensitivity (BRS), which is a sensitive measure of cardiovascular (CV) autonomic function. Here we prospectively evaluated the effect of Canagliflozin, sodium-glucose cotransporter (SGLT) 2 inhibitor, on LV diastolic dysfunction and BRS at the same time. 37 type 2 diabetic patients with high risks of CV disease were enrolled. All participants were evaluated LV function, BRS, HbA1c, Hb, BNP and t-PA-PAI-1 complex before and after 3 months of the additional treatment with Canagliflozin. Multiple-linear regression was used to assess individual and cumulative effects of δearly diastolic velocity/basal septal diastolic velocity (E/e’) and δLV mass index. UMIN000025964 for Clinical Trials Registry. Characteristics of the subjects are age 64.2 ± 8.1 years (mean±SD), HbA1c 7.9±0.7%, diabetes duration 13.5 ± 8.1 years, complicated CV disease 32.4%. E/e’ ratio (13.7 ± 3.5 to 12.1 ± 2.8, p = 0.001), LV mass index (82.0 ± 15.8 to 77.3 ± 16.4 g/m2, p = 0.003), HbA1c (7.9 ± 0.7 to 7.1 ± 0.6%, p = 0.000), and t-PA-PAI-1 complex (27.0 ± 15.8 to 19.4 ± 7.0 ng/mL, p =0.002) were decreased and Hb (13.9 ± 1.2 to 14.7 ± 1.4 g/dL, p =0.000) was increased. The level of BRS (10.7 ± 8.5 to 10.2 ± 7.3 msec/mmHg, p = 0.721) and BNP (15.1 ± 10.7 to 13.5 ± 10.1 pg/dL, p = 0.062) did not show any differences. Interestingly, δE/e` were negatively correlated with baseline E/e` and δHb (r=-0.618, p=0.000; r=-0.496, p=0.002, respectively). Multiple regression model still revealed that δE/e` were related to baseline E/e` (β=-0.581, p=0.007) and δHb (β=-0.406, p=0.009) independently of age, sex, and baseline SBP (R-squared 0.469). Canagliflozin improved LV diastolic dysfunction without reducing BRS in type 2 diabetic patients with high CV disease risk. Our results suggest that greater increase of Hb is a surrogate marker of improvement of diastolic function.

Disclosure

D. Matsutani: None. M. Sakamoto: None. Y. Kayama: None. K. Utsunomiya: None.
Enteral Insulin Attenuates Fatty Liver Signs and Symptoms in Mice on a High-Fat Diet
Authors: SAFADI RIFAAT , SALHAB AHMAD , AMER JOHNNY , WEISS DANIEL J. , BLUMENFELD DANIELA , MINTZ YOAV , KUNICHER NIKOLAI , KIDRON MIRIAM
Published: June 2018

Nonalcoholic fatty liver disease (NAFLD) is now the most common liver disorder in the USA, affecting 90% of morbidly obese individuals and often clustering with prediabetes or overt type 2 diabetes mellitus. While its exact pathogenesis remains unclear, insulin resistance and obesity are considered contributing and risk factors, suggesting effective blood glucose control as a means of preventing and managing NAFLD. To assess this treatment avenue, C57b1/6J mice maintained on a high-fat diet (HFD) for 13 weeks, were treated daily with insulin (INS; 3.6 mg/kg), delivered via a feeding tube, or sham-saline treatment for three consecutive weeks. Peripheral blood and liver samples were collected to analyze inflammatory and fibrosis markers and to histologically assess NAFLD activity score (NAS). Following the treatment period, INS HFD mice demonstrated lower body weight (8.6±1.8 g vs. 7.5±4.1 g) and significantly lower NAS (0.11 vs. 3.7; p<0.005) as compared to sham HFD mice. Further, the mean baseline alanine aminotransferase (ALT) levels of 212±223.6 U/L dropped to 38.3±34.5 U/L and 88.4±85.3 U/L in sham and INS animals, respectively. However, post-treatment aspartate aminotransferase (AST) levels were unchanged in sham HFD animals (202.8±83.7 U/L), but were two-fold lower in INS mice (123.2±80.4 U/L; p=0.03). Mean AST/ALT ratios, a reliable indicator of liver disease, were significantly lower among INS, as compared to sham mice (2.6±1.3 vs. 4.7±2.9; p=0.04). Change from baseline alpha smooth muscle actin (αSMA) RNA levels, a hallmark of fibrosis, was lowest among INS (0.31±0.23-fold increase) as compared to saline-treated HFD mice (0.58±0.14). In parallel, a consistently higher percentage of active, antifibrotic (NKP46+) CD3+ natural killer cells were observed among INS vs. sham and untreated NFD mice. These preliminary findings provide a proof of concept for the potentially therapeutic effect of enteral insulin on fibrotic and inflammatory processes in the liver.

Disclosure

R. Safadi: None. A. Salhab: None. J. Amer: None. D.J. Weiss: None. D. Blumenfeld: None. Y. Mintz: None. N. Kunicher: None. M. Kidron: Employee; Self; Oramed Pharmaceuticals, Inc..
Pregnancy Glycemia Reflects Life Course Glycemia of the Mother
Authors: MEMANE NILAM S. , BHAT DATTATRAY , RAUT DEEPA A. , BONDARDE SOMNATH J. , LADKAT RASIKA , YAJNIK PALLAVI C. , FALL CAROLINE , YAJNIK CHITTARANJAN S.
Published: June 2018

Background: Current practice of diagnosis and treatment of GDM is largely restricted to late pregnancy, ignoring peri-conceptional window which is crucial for fetal programming of diabetes. A few longitudinal studies reported that metabolic risk factors of GDM are present before pregnancy but there are no reports on a ‘lifecourse’ trajectory of pregnancy glucose insulin metabolism. Pune Maternal Nutrition Study (PMNS) offers a unique opportunity to investigate the association between gestational glycaemia and pre-pregnancy lifecourse glycaemia because of serial measurements from childhood to pregnancy.

Methods: We studied 328 female offspring of PMNS born in 1993-96 for glucose insulin measurements at 6, 12, and 18 year of age. Girls who became pregnant underwent a 75 gm OGTT at 28 weeks gestation. We studied the association between gestational fasting plasma glucose (FPG) with their earlier measurements using multiple linear regression analysis.

Results: Up to October 2017, 110 women had an OGTT at 28 weeks gestation and have delivered. Thirteen (11.8%) were diagnosed GDM (IADPSG criteria 2011) In lifecourse analysis, FPG tracked from 6 years of age to pregnancy through 12 and 18 years. FPG at 28 weeks was directly associated with her own FPG at 18, 12 and 6 years of age (β= ∼0.3, p<0.001), and it was inversely associated with disposition index at 18 and 12 years (p<0.05).

Conclusions: The world’s first description of lifecourse evolution of pregnancy glycaemia suggests that it tracks from early childhood and is associated with impaired beta cell function. The analysis provides an important clue that GDM women have higher pre and peri-conceptional glycaemia which is a risk factor for fetal programming of diabetes. Current clinical approach to GDM ignores this important window. This could be a potential explanation of the failure of current practice of GDM treatment in late pregnancy to reduce long term risks in the offspring.

Disclosure

N.S. Memane: None. D. Bhat: None. D.A. Raut: None. S.J. Bondarde: None. R. Ladkat: None. P.C. Yajnik: None. C. Fall: None. C.S. Yajnik: None.
Efficacy and Safety of Long-Term Administration of Dapagliflozin for Japanese Patients with Type 2 Diabetes Mellitus
Authors: YAMAZAKI MASAHIRO , SAKAI RYOSUKE , OKAMURA TAKURO , FUKUI MICHIAKI
Published: June 2018

Background: There have been few studies yet on the efficacy and safety of SGLT2 inhibitor in Japanese people at 2 years and later. In this study, we administered dapagliflozin to Japanese patients with type 2 diabetes mellitus (DM) and studied its many effects and its safety.

Subjects and Methods: The subjects were 112 patients aged 20 years and older who were administered 5 mg/day of dapagliflozin after outpatient treatment with dapagliflozin between April 2014 and December 2015 at this hospital had been judged as useful by the primary physician. Body weight (BW), systolic blood pressure (sBP), HbA1c, liver enzymes, HDL-cholesterol (HDL-C), and uric acid (UA) were measured during hospital visits, and these values were analyzed by comparing them between before administration and at 104 weeks of administration. Inbody® was used in 44 patients to compare body composition before and after treatment.

Results: Dapagliflozin was administered over a period of 104 weeks, and a significant decrease in HbA1c, from 8.5±1.4% to 7.6±1.4% (week 0 vs. week 104, p<0.001), and a significant decrease in BW, from 82.2±19.3 kg to 78.6±18.9 kg (week 0 vs. week 104, p<0.001), were observed. sBP, UA, and liver enzymes also significantly decreased, and HDL-C significantly increased. When changes in body composition were checked with Inbody®, muscle mass and the amount of fat had both significantly decreased, but because of the large decrease in the amount of fat, the skeletal muscle index significantly increased. Also, the amount of the reduction in fat was significantly correlated with the amount of the decrease in HbA1c. Serious adverse drug reactions were not observed.

Conclusion: Dapagliflozin can be safely administered over a period of 104 weeks to Japanese patients with type 2 DM, and effects such as lower blood sugar, reduced body weight, and improved metabolism can be expected. Also, a reduction in the amount of fat was suggested to be related to a reduction in HbA1c.

Disclosure

M. Yamazaki: None. R. Sakai: None. T. Okamura: None. M. Fukui: Research Support; Self; Grant-in-Aid for Scientific Research (C), Ono Pharmaceutical Co., Ltd., AstraZeneca, Astellas Pharma US, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kyowa Hakko Kirin Co., Ltd., Kissei Pharmaceutical Co., Ltd., MSD K.K., Novo Nordisk Foundation.
HbA1c, Weight, and Blood Pressure Changes Associated with Early vs. Late Treatment Intensification with Dapagliflozin in U.K. Primary Care Patients with Type 2 Diabetes
Authors: WILDING JOHN P. , RIGNEY UNA , BLAK BETINA T. , NOLAN STEPHEN T. , FENICI PETER , MEDINA JESUS
Published: June 2018

Early treatment intensification in patients with type 2 diabetes (T2D) is often required to achieve glycaemic control. Patients with T2D from the UK Clinical Practice Research Datalink, aged ≥18 years, initiating dapagliflozin between Nov 2012 and Aug 2016 and with prior oral T2D therapy (N=3,774) were included in this study. The relationship between early (2nd line) vs. later (≥3rd line) use of dapagliflozin and changes from baseline in HbA1c (≥1.0% absolute reduction), weight (kg) (≥5.0% relative loss) and systolic BP (≥2 mmHg absolute reduction) after 6-12 months were assessed with logistic regression models. Early use of dapagliflozin occurred in 25.2% patients (951/3774) vs. later use in 74.8% (2823/3774). Patients with later use were older [mean: 60.1 (SD 10.3) vs. 55.7 (SD 10.5) years], more likely to be male (61.6% vs. 55.3%), had T2D for longer [median 8.1 vs. 4.0 years] and higher CVD prevalence (13.9% vs. 11.2%). Patients with early and later use of dapagliflozin had similar baseline mean HbA1c levels [9.3% (SD 1.5) vs. 9.2% (SD 1.7)] and BP [134.2 (SD 14.2) vs. 135.0 (SD 14.6) mmHg]. Late users had lower BMI [mean 33.6 (SD 6.3) vs. 36.5 (SD 6.8) kg/m2] than early users. Early dapagliflozin users experienced mean (S.E) reductions of 1.6 (0.07)%, 3.8 (0.25)% and 3.0 (0.82) mmHg in HbA1c, weight and BP, respectively, vs. 1.0 (0.04)%, 4.6 (0.21)% and 3.1 (0.43) mmHg in later users. Compared to later dapagliflozin use, early initiation was associated with a greater likelihood of adjusted HbA1c reduction ≥1% (OR: 1.68, 95% CI: 1.15-2.45). Weight and BP reductions were observed with similar likelihood among early and late users (weight OR: 0.79, 95% CI: 0.54-1.14; BP OR: 0.87, 95% CI: 0.58-1.30).

In conclusion, glycaemic benefits of dapagliflozin were greater in patients receiving it earlier in their treatment pathway. Weight and BP reductions were achieved with similar likelihood among early and later users.

Disclosure

J.P. Wilding: Other Relationship; Self; Astellas, AstraZeneca, Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi, Eli Lilly and Company, Orexigen Therapeutics, Inc., Merck & Co., Inc. U. Rigney: Employee; Self; AstraZeneca. B.T. Blak: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. S.T. Nolan: Employee; Self; AstraZeneca. P. Fenici: Employee; Self; AstraZeneca. J. Medina: Employee; Self; AstraZeneca.
Dose-Response and Exposure-Response (HbA1c) of Dapagliflozin in T1DM Patients
Authors: PARKINSON JOANNA R. , MELIN JOHANNA , ÅSTRAND MAGNUS , HAMREN BENGT , BOULTON DAVID W. , TANG WEIFENG
Published: June 2018

Dapagliflozin is an inhibitor of the human renal sodium glucose co-transporter type 2 (SGLT2), which lowers plasma glucose by promoting urinary glucose excretion. Dapagliflozin is approved for the treatment of type 2 diabetes mellitus in adults. The effect of dapagliflozin in type 1 diabetes mellitus (T1DM) has been evaluated in 2 clinical trials: DEPICT 1 and DEPICT 2 (NCT02268214 and NCT02460978). The aim of this analysis was to use pooled data from both studies and assess the dose-response (DR) and exposure-response (ER) relationship for dapagliflozin on HbA1c reduction in T1DM patients. In both studies, T1DM patients underwent double-blinded 24-week treatment with either placebo, 5 or 10 mg dapagliflozin doses—plus adjustable insulin. Mixed-Effect Model Repeated Measures including DR/ER functions was used to describe the longitudinal HbA1c data. The DR and ER models described the data from T1DM patients well. DR model predicted HbA1c mean (95% CI) reductions at week 24 (placebo-corrected change from baseline) in T1DM patients to: -0.38% (-0.46, -0.3) and -0.43% (-0.52, -0.35) for 5 mg and 10 mg doses, respectively, which was in good agreement with the actual observations (-0.42% and -0.37% for 5 mg and -0.45% and -0.42% for 10 mg in DEPICT 1 and DEPICT 2 studies, respectively). The estimated ED50 was 1.39 mg and AUC50 (exposure resulting in half maximal effect) was 35.56 ng/ml*h. The effect of several covariates was assessed and the method of insulin administration was found to have an impact on dapagliflozin efficacy in T1DM patients. According to the model, patients who were using insulin pump were predicted to have somewhat larger HbA1c reductions compared to patients who used multiple daily injections. For example, following 10 mg dapagliflozin treatment, patients using pump were predicted to have mean HbA1c reduction of -0.47%, compared to -0.39% in patients without the pump. The difference in the maximum HbA1c reductions was however only approximately 20% and was not deemed to be clinically relevant.

Disclosure

J.R. Parkinson: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. J. Melin: Employee; Self; AstraZeneca. M. Åstrand: Employee; Self; AstraZeneca. B. Hamren: Employee; Self; AstraZeneca. Employee; Spouse/Partner; AstraZeneca. D.W. Boulton: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Bristol-Myers Squibb Company. W. Tang: Employee; Self; AstraZeneca.
ZYDG2, a Potent, Selective, and Safe GPR40 Agonist for Treatment of Type 2 Diabetes
Authors: JAIN MUKUL R. , GIRI SURESH R. , TRIVEDI CHITRANG J. , BHOI BIBHUTI B. , RATH AKSHYAYA CHANDAN. , RATHOD ROHAN MANUBHAI. , SUNDAR RAJESH , BANDYOPADHYAY DEBDUTTA , RAMDHAVE RASHMI , PATEL GAUTAM D. , SRIVASTAVA BRIJESH KUMAR. , DESAI RANJIT C.
Published: June 2018

GPR40 is a G-protein-coupled receptor predominantly expressed in pancreatic β-cells. Agonists of GPR40 are known to stimulate insulin secretion and reduces circulating glucose levels in a glucose-dependent manner. TAK-875, a GPR40 small molecule agonist developed by Takeda Pharmaceuticals showed antidiabetic efficacy in animals and humans, but its development was terminated in phase 3 due to adverse liver effects. ZYDG2 is a safer GPR40 agonist that has shown desirable profile in preclinical studies. ZYDG2 was identified as a potent and selective agonist for GPR40, exhibiting EC50 of 13 nM and 41 nM for hGPR40, in HEK-293 cell-based Ca2+ mobilization assay and IP1 ELISA assays respectively. It increased insulin secretion and showed dose-dependent improvement in glucose tolerance test in n-STZ Wistar rats, DIO mice and db/db mice. It also showed anti-hyperglycemic effects in rats unresponsive to sulfonylureas. No tachyphylaxis was observed after repeated administration for 15 weeks in n-STZ rats. ZYDG2 showed glucose-stimulated insulin secretion as revealed by significant increase in glucose infusion rate in hyperglycemic clamp study using SD rats. ZYDG2 treatment was associated with significant rise in plasma total GLP1 levels in nondiabetic and diabetic animal models which was not observed in case of TAK-875. Since TAK-875 was terminated due to hepatotoxicity associated with bile acid transporter inhibition, this aspect was studied in details. TAK-875 inhibited the hBSEP and hMRP2 at efficacy concentrations whereas ZYDG2 does not show any inhibition (up to 300 µM) for hBSEP and hMRP2. TAK-875 also showed significantly increased cholic acid levels in Sprague Dawley rat which was not shown by ZYDG2. The maximum tolerated dose for ZYDG2 was 2000 mg/kg and 28 days NOAEL was 300 mg/kg. This clearly demonstrates that ZYDG2 has a great potential to become a safe and effective candidate for treatment of type 2 diabetes.

Disclosure

M.R. Jain: None. S.R. Giri: None. C.J. Trivedi: None. B.B. Bhoi: None. A.C. Rath: None. R.M. Rathod: None. R. Sundar: None. D. Bandyopadhyay: None. R. Ramdhave: None. G.D. Patel: None. B.K. Srivastava: None. R.C. Desai: None.
The Impact of Metformin Exposure on Lactate Level in Tibetan Type 2 Diabetes Living at High-Altitude Area
Authors: LUO YINGYING , GENG YANYAN , REN QIAN , ZHOU LINGLI , LV XUEMEI , MENG SHUYOU , YANG LIHUI
Published: June 2018

Objective: To investigate the impact of Metformin exposure on lactate level in Tibetan type 2 diabetics living at high-altitude area.

Methods: Our hospital sits 3600 meters above sea level. We retrospectively reviewed the in-patients’ documents since Nov. 2016 to Dec. 2017 in our department. We selected those who did not receive Metformin previously and initiated Metformin treatment during their stay in the hospital with their lactate level assayed. Firstly, we compared the lactate level before and after Metformin treatment. We then did the subgroup analysis according to the participants’ age, baseline lactate level and baseline oxygen saturation degree. Finally, we analyzed the associated factors which may influence the lactate level after Metformin exposure by logistic regression test.

Results: There were 132 patients recruited into our study, including 98 male patients. The mean age of all the participants were 52±12 years old. There was no significant difference between the lactate level before and after Metformin exposure (3.15±1.82mmol/L vs. 3.29±1.96mmol/L, t=-0.784, P=0.435). For the subgroup analysis, we found that in the normal lactate level (<2.0mmol/L) and hyperlactatemia group (2.0-3.9mmol/L), there was a significant elevation of the lactate level after the exposure of Metformin. Reversely, a significant decrease of the lactate level was seen in the severe hyperlactatemia group (≥4.0mmol/L) after Metformin exposure. There were 73 patients (55.3%) who had an elevated lactate level after the Metformin treatment. We also found that baseline lactate level (P<0.001, OR =0.019, 95% CI 0.002-0.159) and baseline oxygen saturation (P=0.04, OR =1.092, 95% CI 1.004-1.187) were two associated factors leading to the elevation of the lactate level after Metformin treatment.

Conclusion: Metformin treatment does not lead to the elevation of lactate level in Tibetan type 2 diabetics living at high-altitude area. Metformin can be safely used in high-altitude residents.

Disclosure

Y. Luo: None. Y. Geng: None. Q. Ren: None. L. Zhou: None. X. Lv: None. S. Meng: None. L. Yang: None.
Novel Analysis of Bionic Pancreas Trial Data Emphasizing Benefit to Individuals Rather than the Group as a Whole
Authors: SLOANE JASON
Published: June 2018

We previously showed in a multicenter, outpatient, random-order crossover trial (n=39, 11 days each arm) that the bionic pancreas (BP) reduced group mean CGM glucose (141±10 vs. 162±29 mg/dl, p<0.0001) and percent of time spent <60 mg/dl (0.6±0.6% vs. 1.9±1.7%, p<0.0001) relative to usual care (UC) with pump ± CGM (El-Khatib FH, et al. Lancet. 2017; 389:369-80). We applied a new statistical approach to these data to determine how many individuals saw benefit for each outcome. We compared the average CGM glucose and average time <60 mg/dl between the BP and UC arms for each patient using autoregressive time series models to determine significance of differences. We found that 72% of subjects had a statistically significant reduction in mean CGM glucose, 51% had significant reduction in time <60 mg/dl, 44% had a significant reduction in both, and 97% had a significant reduction in at least one outcome. For every subject with mean CGM glucose that was nominally higher in the BP arm, the mean glucose in the BP arm was <154 mg/dl (predicted A1c <7%) and the average time <60 mg/dl was less than in the UC arm (significantly less in 2/6 cases). These analyses provide a new prospective on the efficacy of the BP emphasizing the benefit to individuals rather than the group as a whole. Subjects least likely to benefit were those who had extremely tight glycemic control and minimal hypoglycemia under UC.

Disclosure

J. Sloane: None.
HD-6277, a Novel GPR40 Agonist, Improves Glucose Homeostasis and Enhanced Glucose-Dependent Insulin Secretion in Beta Cells and Type 2 Diabetic Rats
Authors: KIM DAEHOON , KIM CHUN HWA , CHOI HYO SUN , YANG GOEUN , KANG SEUNG JUN , LEE SUN HEE , LIM KWAN SOO , PARK MIN AH , KIM DOO YOUNG , RHEE JAE KEOL
Published: June 2018

GPR40 is known as free fatty acid receptor 1. Currently, HD-6277, a novel GPR40 agonist, is being developed by Hyundai Pharm in first in human study. The aim of this study was to determine the effects of the novel GPR40 agonist. HD-6277 is a highly potent, selective and orally available small molecule agonist. The potency was measured in vitro and in vivo studies. In vitro potency was determined by HD-6277, TAK-875 and GW95(EC50, <10 nM, 27 nM and 14 nM) in stably hGPR40 expressed CHO cells. Selective GPR40 activity of HD-6277 was evaluated by GPCR panel assay.In vivo glucose lowering effect was determined by oral glucose tolerance test (OGTT) and HbA1c in Sprague-Dawley (SD) rats and various type 2 diabetes rats, respectively. Oral administration of HD-6277 (0.1∼10 mg/kg) once daily reduced plasma glucose excursion and enhanced insulin secretion in GK, DIO, OLETF and ZDF rats. Antidiabetic efficacy compared with Metformin, Glimepiride, Linagliptin, Empagliflozin, Rosiglitazone and Fasiglifam respectively. HD-6277 treatment showed potent anti-hyperglycemic effects than commercially available antidiabetic drugs. GSIS was assessed in INS-1 cells and rats with sulfonylurea and glinides. HD-6277 enhanced insulin excursion in high glucose condition, whereas in low glucose circumstance was not, thus hypoglycemic risk was low. Repeat dosing for 7day in SD rats, glibenclamide (10 mg/kg) and nateglinide (50 mg/kg) caused hypoglycemia but HD-6277 (100 mg/kg) was not.

In conclusion, HD-6277 shows a promising new drug candidates to treat type 2 diabetes mellitus.

Disclosure

D. Kim: Employee; Self; Hyundai Pharm. Corp. C. Kim: Employee; Self; Hyundai Pharm. corp.. H. Choi: None. G. Yang: Employee; Self; Hyundai Pharm. CORP. S. Kang: Employee; Self; Hyundai Pharm. corp. S. Lee: Employee; Self; Hyundai Pharm. CORP. K. Lim: Employee; Self; Hyundai Pharm. corp. M. Park: Employee; Self; Hyundai Pharm.corp. D. Kim: Employee; Self; Hyundai Pharm. CORP. J. Rhee: Employee; Self; Hyundai Pharm. corp..
Saroglitazar Delays and Prevents Type 2 Diabetes in db/db Mice
Authors: GIRI SURESH R. , BHOI BIBHUTI B. , TRIVEDI CHITRANG J. , RATH AKSHYAYA C. , RATHOD ROHAN M. , JAIN MUKUL R.
Published: June 2018

Saroglitazar is a novel dual PPARα/γ agonist that shows significant triglyceride-lowering and insulin-sensitizing effects in animal models and humans. Saroglitazar causes insulin sensitization and increases flux of lipids in adipocytes thereby preventing the glucotoxicity and lipotoxicity. It also improves mitochondrial bioenergetics potential and increased the ATP production rate and reduces the expression of pro-inflammatory (TNFα, IL1β and IL6) genes. In this study, we have evaluated the potential of saroglitazar to delay the onset or prevent development of T2DM in db/db mice. The db/db mouse is a widely used model for T2DM and shows progressive changes starting with development of obese phenotype at the age of 4 weeks followed by hyperglycemia and hyperinsulimenic condition between 4-8 weeks of age and hypoinsulinemia accompanied by hyperglycemia at 12-16 weeks of age. Group of male db/db mice were treated with saroglitazar (0.8 and 2.5 mg/kg, p.o.) or metformin (250 mg/kg, p.o.) starting at the age of 4 weeks (prediabetes condition) and continued the treatment for 12 weeks (till animals become 16 weeks old and develop frank T2DM). Saroglitazar treatment for 12 weeks completely prevented diabetes onset as reflected by normal fed and fasting blood glucose levels during 6-16th week, whereas metformin treated animals showed elevated fasting blood glucose levels after 8 weeks. Saroglitazar also caused almost 100% improvement in glucose tolerance and insulin sensitivity which was not shown by metformin. Furthermore, as compared to placebo and metformin treated db/db mice, saroglitazar-treated showed HbA1c levels similar to normal C57 mice indicating total protection from development of diabetes. It appears that by unique engagement of PPARα and PPARγ, saroglitazar not only normalizes lipids and glucose, but it also preserves the pancreatic β cell function and prevents development of T2DM by a combination of mechanisms involving anti-inflammatory, anti-oxidant, lipid regulating and glucose regulatory pathways.

Disclosure

S.R. Giri: None. B.B. Bhoi: None. C.J. Trivedi: None. A.C. Rath: None. R.M. Rathod: None. M.R. Jain: None.
Prevalence and Trends in Gestational Diabetes Mellitus among Women in the United States, 2006–2016
Authors: ZHOU TAO , SUN DIANJIANYI , LI XIANG , HEIANZA YORIKO , NISA HOIRUN , HU GANG , PEI XIAOFANG , SHANG XIAOYUN , QI LU
Published: June 2018

Gestational diabetes mellitus (GDM) is a common medical complication in pregnancy, carries adverse health outcomes for both mothers and offspring. However, national data on the prevalence and secular trends of GDM during the past 10 years in the U.S. is lacking. This study included 26,340 ever-pregnant women aged ≥ 18 years from the National Health Interview Survey in 20and 2016. We examined GDM prevalence in 20and 2016. The prevalence of GDM increased from 4.6% in 20to 8.2% in 2016 (P<0.001). non-Hispanic white women showed less increase in the prevalence (2.8%) than non-Hispanic black women (3.8%), Hispanic women (4.1%), and women with other race/ethnicity (8.4%). The prevalence of GDM in non-Hispanic white women was higher than in non-Hispanic black (P=0.01) and women with other race/ethnicity (P=0.01) in 2006; but similar with in non-Hispanic black and lower than in women with other race/ethnicity (p=0.02) in 2016. The prevalence of GDM in non-Hispanic white and Hispanic women was similar in 20and 2016. In addition, the increase of GDM was more evident among women who were overweight, had low income, aged between 45-64 years, and had insufficient physical activity.

In conclusion, the prevalence of GDM increased by 3.6% from 20to 2016; and the rise was more marked among non-white, overweight, low income, age 45-64 years, and insufficient activity groups.

Disclosure

T. Zhou: None. D. Sun: None. X. Li: None. Y. Heianza: None. H. Nisa: None. G. Hu: None. X. Pei: None. X. Shang: None. L. Qi: None.
Cardiometabolic Management—Success of Online CME at Expanding Diabetes Management Past Glycemic Control
Authors: LARKIN AMY , LACOUTURE MICHAEL , LE ANNE
Published: June 2018

We sought to determine if an online continuing medical education (CME) curriculum could improve the clinical knowledge and competence of primary care physicians (PCPs) and diabetologists/endocrinologists (diabs/endos) regarding cardiometabolic management of T2D incorporating recent cardiovascular outcomes trial (CVOT) data.

The online CME activities consisted of a 2 faculty, 15-minute video consultation and an interactive, case-based text activity. A 4-question repeated pairs pre-/post-assessment study design and McNemar’s chi-squared test were used to determine the efficacy of online education. P values < .are considered statistically significant. Activities were launched online on June 26, 2017 and August 28, 2017, with data collected until July 27, 2017 and September 28, 2017, respectively.PCPs baseline knowledge seen to be significantly lower than that of diabs/endosTopicPCP Baseline Correct ResponsesDiab/endo Baseline Correct ResponsesP valueAvoidance of TZDs in patent with T2D and HF36% (N=344)71% (N=41)P < 0.001Optimizing T2D therapy to meet cardiac-related goals47% (N=344)78% (N-41)P < 0.001T2D treatment intensification in patient with CVD25% (N=344)54% (N=41)P < 0.001Identification of blood pressure lowering as an extraglycemic effect of SGLT2 inhibitors49% (N=200)81% (N=78)P < 0.001Significant overall improvements were seen post educationTopicPCP Change pre-to-postP valueDiab/endo Change pre-to-postP valueSelection of liraglutide to treat a patient with T2D, CVD, and renal disease51% (N=344)P<.000139% (N=41)P<.0001Recognition of TZDs as a bad therapeutic option in a patient with T2D and HF27% (N=344)P<.000114% (N=41)P=.114Identification of antihyperglycemic agents that have been shown to have positive CV effects16% (N=200)P<.00118% (N=78)P=.006Recognized blood pressure lowering as an extraglycemic effect of SGLT2 inhibitors13% (N=200)P<.00114% (N=78)P=.003Persistent knowledge/competence gapsTopicPCP Gap (Percent incorrect)Diab/endo Gap (Percent incorrect)Knowledge of CVOT data40% (N=344)37% (N=41)Therapeutic intensification strategy for T2D and CVD39% (N=344)15% (N=41)Utilization of TZDs in patent with T2D and HF37% (N=344)15% (N=41)Knowledge of CVOT data40% (n=200)37% (N=78)Efficacy of antihyperglycemia therapies24% (n=200)14% (N=78)

This study demonstrates the success of an online curriculum with multiple educational components consisting of both video discussions and interactive text-based cases improving knowledge and competence of PCPs and diab/endos. Additional and persistent gaps were identified for future educational targets.

Disclosure

A. Larkin: None. M. LaCouture: None. A. Le: None.
Consistent Accuracy over 10 Days with a Factory-Calibrated Continuous Glucose Monitoring System in Children and Adults
Authors: ZHANG XIAOHE , JOHNSON TERRI , PRICE DAVID A. , BALO ANDREW
Published: June 2018

The burden of calibrating continuous glucose monitoring (CGM) systems may be addressed by factory calibration (FC). We evaluated the accuracy of the "G6 FC" CGM System (Dexcom, Inc.) in adults ages 18+ and children ages 6-17 with type 1 diabetes. This was a prospective, non-randomized, multi-center, single-arm study that enrolled 76 subjects at 4 U.S. sites. Subjects participated in either 1 or 2 clinic sessions of varying duration, depending on age. System performance was evaluated in terms of percent accuracy with respect to YSI. Accuracy was characterized as the proportion of CGM values that were within ± 15%, ± 20% of their paired YSI values for glucose levels > 100 mg/dL or within ± 15 mg/dL, ± 20 mg/dL of YSI for glucose levels ≤ 100 mg/dL. The two-sided 95% bootstrapped confidence interval (CI) was calculated for its statistical significance. Accuracy was also measured by comparing the difference, absolute difference, relative difference and absolute relative difference of the G6 FC System with respect to YSI. The G6 FC System showed an overall percent % 20/20 accuracy of 93.9% (95% CI: 89.8, 97.1%) based on 3,532 matched pairs from 62 subjects (25 adults and 37 children). Similarly, the overall percent % 15/15 accuracy was 83.3% (95% CI: 76.7, 89.4%). The Day-1 and Day 10 percent % 20/20 accuracies were 92.2% and 92.5%, respectively; Day-1 and Day 10 mean absolute relative difference (MARD) values were 9.3% and 9.0%, respectively. The percent % 20/20 accuracy was 92.5% for adults and 96.2% for children. The MARD was 9.0% overall, 9.8% for adults, and 7.7% for children. Mean bias and mean relative difference were -8.3 mg/dL and -5.0%, respectively for overall; -10.9 mg/dL and -6.9% for adults; and -4.3 mg/dL and -2.1% for children. The G6 FC System showed high accuracy using multiple metrics for pediatric and adult subjects across days of wear, including Day 1. Elimination of the requirement for calibrations should improve the acceptability and utility of this novel CGM system.

Disclosure

X. Zhang: Employee; Self; Dexcom, Inc. T. Johnson: Employee; Self; Dexcom, Inc. D.A. Price: Employee; Self; Dexcom, Inc. A. Balo: Employee; Self; Dexcom, Inc..