bluuebunny/crossref_metadata_2025 huggingface dataset:
1102-P: High vs. Standard Starting Dose of Insulin Glargine 100 U/ml in Patients with Overweight/Obesity and Type 2 Diabetes Uncontrolled with Oral Antidiabetic Drugs in China: A Multicenter, Open-Label Randomized Controlled Trial
Authors: JI LINONG , WAN HAILONG , WEN BINHONG , WANG XUEYING , WANG JUNFEN , BIAN RONGWEN , PANG WUYAN , FENG WEI , ZHANG XIA , CUI NAN
Published: June 2019

With type 2 diabetes (T2D) progression, patients require insulin, but insufficient titration often leads to poor glycemic control. A higher insulin starting dose may reduce the optimal dose deficit, but whether this procedure increases hypoglycemia risk is unknown. This open-label, multicenter trial (NCT02836704) evaluated safety and efficacy of a high (0.3 U/kg) vs. standard (0.2 U/kg) starting dose of glargine 100 U/ml (Gla-100) followed by titration over 16 weeks to achieve self-monitored FBG 4.4-5.6 mmol/L using the same algorithm in each group. Overall, 892 patients with overweight/obesity (BMI 25-40 kg/m2) and uncontrolled T2D (HbA1c 7.5-11.0%; lab FPG >9.0 mmol/L) on stable doses of 2-3 OADs were randomized to receive a high (n=444) or standard (n=448) starting dose of Gla-100. At week 16, 92% of patients completed the study and 866 were analyzed. The primary endpoint (percentage of patients with ≥1 confirmed hypoglycemia, BG <3.9 mmol/L) met the pre-specified threshold (upper bound 95% CI <10%) for non-inferiority of Gla-100 0.3 U/kg vs. 0.2 U/kg with 11.0% and 8.6% in the respective groups (log-binomial regression estimated difference 2.1%; 95% CI: −1.68%, 5.89%). At week 16, symptomatic (9.8% vs. 7.0%, p=0.13) and nocturnal hypoglycemia (2.7% vs. 1.2%, p=0.10), percentage of patients achieving HbA1c <7.0% without hypoglycemia (37.1% vs. 37.1%), and percentage of patients achieving lab FPG targets <5.6 mmol/L (15.9% vs. 16.3%), <6.1 mmol/L (27.6% vs. 26.1%), or <7.0 mmol/L (48.8% vs. 48.3%) were all similar in both groups. However, time to achieve first self-monitored FBG <5.6, <6.1, or <7 mmol/L was 6, 9, and 7 days shorter in the 0.3 U/kg group (all p<0.01).

In conclusion, among patients with overweight/obesity and T2D, a higher Gla-100 starting dose was as safe as a standard Gla-100 starting dose and achieved FBG targets earlier during the course of therapy.

Disclosure

L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Roche Pharma, Sanofi. H. Wan: None. B. Wen: None. X. Wang: None. J. Wang: Research Support; Self; Sanofi. R. Bian: None. W. Pang: None. W. Feng: Employee; Self; Sanofi. X. Zhang: None. N. Cui: Employee; Self; Sanofi.

Funding

Sanofi China
111-OR: Pancreatic Elastase Regulates Human Beta-Cell Proliferation via the Focal Adhesion and PAR2 Signaling Pathways
Authors: BASILE GIORGIO , VETERE AMEDEO , LIU KA-CHEUK , HU JIANG , ANDERSSON OLOV , WAGNER BRIDGET , KULKARNI ROHIT
Published: June 2019

Pancreatic elastase (PE) is a serine protease produced by pancreatic acinar cells. PE is mainly secreted in the intestine during digestion, and is also detectable in stromal pancreatic tissue, including the ECM of islets. Recently, we identified serpinB1 (SB1), a protease inhibitor, as a promoter of human β-cell proliferation by inhibiting PE activity and demonstrated that the PE inhibitor, sivelestat, also induced β-cell regeneration. Here, we report the identification two novel PE inhibitors: telaprevir, an antiviral drug, and tebipenem, an antibiotic. We observed that telaprevir and tebipenem inhibited human PE (hPE) with greater or similar potency than sivelestat respectively (IC50: telaprevir 15.7nM, tebipenem 3.6µM, sivelestat 2.3 µM; n=3). We then tested the effects of the compounds in in vitro cultures of human islets. Telaprevir and tebipenem each increased proliferating human β-cells (∼4-fold and 1.5-fold increase respectively; n=6) compared to vehicle-treated islets. Furthermore, in an independent study, both compounds (at 10µM), stimulated β-cell regeneration in a zebrafish model resulting in ∼1.5-fold increase in insulin+ cells in treated versus non-treated groups. Finally, to identify pathways modulated by PE we treated human islets with the two compounds for 10 or 30 minutes and performed a phosphoprotein microarray assay (Kinexus, CA). We discovered that inhibition of hPE increased phosphorylation levels of PXN-PAK proteins belonging to the focal adhesion pathway. In addition, phosphorylation on the effectors of Protease-activated receptor 2 (PAR2) signaling (i.e., PKC, PYK2 and Src) were increased, resulting in the activation of ERK1/2 proteins and the mitogenic pathway in β-cells. These findings provide new insights regarding the molecular mechanisms underlying regulation of β-cell proliferation processes by PE, leading to identification of potential molecular targets that can be modulated in the long-term goal of treating diabetes.

Disclosure

G. Basile: None. A. Vetere: None. K. Liu: None. J. Hu: None. O. Andersson: None. B. Wagner: None. R. Kulkarni: None.
1119-P: Efficacy and Safety of Sitagliptin (SITA) Compared with Dapagliflozin (DAPA) in People ≥65 Years Old with T2D
Authors: RAJI ANNASWAMY , XU ZHI JIN , LAM RAYMOND L. , KAUFMAN KEITH D. , ENGEL SAMUEL S.
Published: June 2019

In the U.S., ~45% of patients with T2D are ≥65 years old, of whom ~50% have mild renal insufficiency (eGFR ≥60 and <90 mL/min/1.73 m2). Older people may respond to AHA treatment differently from younger people, and assessments focused on the older population are desirable. We conducted a post hoc analysis of the cohort of patients ≥65 years who participated in a 24-week randomized, double-blind clinical trial (NCT02532855) of the efficacy and safety of SITA 100 mg qd vs. DAPA 10 mg qd in people with mild renal insufficiency while on MET ± SU; the primary efficacy endpoint was change in A1C at Week 24, analyzed with an LDA model.

Treatment groups were well-balanced at baseline (mean A1C [%] = 7.7/7.7, mean eGFR [mL/min/1.73 m2] = 79/76 for SITA/DAPA). At Week 24, LS mean reduction from baseline A1C was greater with SITA compared with DAPA (Table). With SITA treatment, 41% of participants were at A1C goal of <7.0% compared to 28% with DAPA (Table). The SITA group had greater reductions in post-prandial glucose endpoints, and the DAPA group had greater reductions in FPG (Table). Treatments were generally well tolerated; there were significantly fewer drug-related AEs with SITA than with DAPA, but AE profiles were otherwise similar.

Disclosure

A. Raji: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. Z. Xu: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. R.L. Lam: Employee; Self; Merck & Co., Inc. K.D. Kaufman: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. S.S. Engel: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc.

Funding

Merck & Co., Inc.
112-OR: Critical Role of Tyrosine Kinase 2 (TYK2) in Human Pancreatic Differentiation
Authors: CHANDRA VIKASH , IBRAHIM HAZEM , BALBOA DIEGO , OTONKOSKI TIMO
Published: June 2019

Type 1 diabetes (T1D) is caused by the autoimmune destruction of pancreatic beta cells. Genome wide association and fine mapping studies to identify causal variants predicted several loci in the human genome that are associated with T1D risk. One such candidate gene is a member of the JAK (Janus Kinase) family of tyrosine kinases, TYK2, which plays a critical role in intracellular signaling stimulated by cytokines through STATs. Loss-of-function variants of TYK2 are associated with protection against T1D. In line with this, silencing of TYK2 in beta cells attenuated inflammatory signaling pathways and apoptosis. To study the role of TYK2 in human beta-cell development, we now generated TYK2- knockout (KO) human iPSC lines using CRISPR-Cas9 genome editing and induced them to differentiate to pancreatic endocrine lineage. Our results suggest that absence of TYK2 does not compromise the pluripotency or the early pancreatic endoderm differentiation potential of iPSC. However, in the later stages of differentiation, the mRNA levels of key pancreatic TFs (PDX1(55±17%, p=0.03), NGN3(65±13%, p=0.008)), RFX6(58±14%, p=0.014), NKX6.1(39±19%, p=0.114) and NKX2.2(68±7%, p=0.0008)) were significantly reduced in the TYK2-KO cells. In the final stages of controlled induction to endocrine lineage TYK2-KO lines expressed lower levels of INS(53±9%, p=0.004), GCG(70±10.5%, p=0.002) and SST(62±8.6%, p=0.002) compared to control lines (mean ± SEM of 3 independent experiments). Furthermore immunostaining for INS, GCG and SST confirmed a lower number of endocrine hormone positive cells in TYK2-KO lines. In contrast to the wild type controls, the TYK2-KO iPSC-derived pancreatic cells displayed no activation of STAT1 and STAT2 and showed impaired STAT3 activation in response to IFNαor stimulation by polyinosinic-polycitidilic acid treatment, a viral infection mimetic. The present study suggests that TYK2 plays an important early role in pancreatic endocrine differentiation.

Disclosure

V. Chandra: None. H. Ibrahim: None. D. Balboa: None. T. Otonkoski: None.
1124-P: Beneficial Changes in Glycemic Control in Patients with Hypogonadism and Type 2 Diabetes (T2DM) Receiving Long-Term Treatment with Injectable Testosterone Undecanoate (TU): Ten-Year Data from a Registry
Authors: SAAD FARID , HAIDER KARIM S. , HAIDER AHMAD
Published: June 2019

Background: Men with T2DM have a high prevalence of hypogonadism.

Methods: In a registry of 823 men with hypogonadism, 324 men (39%) had T2DM. 152 received TU 1000 mg/12 weeks (T-group), 172 opted against treatment (CTRL). Changes over time between groups were compared by mixed effects model for repeated measures with random effect for intercept and fixed effects for time, group and their interaction. Changes were adjusted for age, weight, waist circumference, fasting glucose, blood pressure, lipids and quality of life to account for baseline differences between the two groups.

Results: Mean follow-up 7.9±2.4, age: 62.8±5.1 years. T-group: baseline HbA1c: 9.1±1.2%. HbA1c progressively decreased by 2.7±0.3% at 10 years. CTRL: baseline HbA1c: 7.8±0.7%. HbA1c increased by 2.9±0.3%. Estimated adjusted difference between groups: 5.6% (p<0.0001 for all). Fasting glucose (mmol/L) decreased in T-group by 1.7±0.2 and increased in CTRL by 1.6±0.2, difference between groups: 3.2 (p<0.0001 for all). Fasting insulin (µU/mL) decreased in T-group by 17.4±0.4 and increased in CTRL by 10.7±1.1, difference between groups: 28.1 (p<0.0001 for all). In the T-group, baseline HOMA-IR was 10.2±2.1. HOMA-IR progressively decreased by 6.9±0.2 at 10 years. CTRL: baseline HOMA-IR: 7.5±1.3. HOMA-IR increased by 7.6±0.5. Difference between groups: 14.5 (p<0.0001 for all). In the T-group, 92 men (60.5%) received insulin at baseline at a mean dose of 36.5±12.2 U/d and 66 in CTRL at a mean dose of 30.8±6.0 U/d. The dose requirement in the T-group declined by 17.7±1.0 U/d and increased in CTRL by 17.7±1.0 U/d. Difference between groups: 35.3 U/d (p<0.0001 for all). In CTRL, 20 patients were started on insulin during the observation time.

Conclusions: Long-term testosterone therapy with TU in men with hypogonadism and T2DM progressively improved glycemic control which worsened in untreated hypogonadal controls.

Disclosure

F. Saad: Employee; Self; Bayer AG. Stock/Shareholder; Self; AbbVie Inc., Amgen Inc., Bayer AG. K.S. Haider: Speaker's Bureau; Self; Bayer AG. A. Haider: Research Support; Self; Bayer AG. Speaker's Bureau; Self; Bayer AG.

Funding

Bayer AG
1135-P: Real-World Effectiveness of a Blood Sugar Monitor and Companion Digital Therapeutic Combination in Improving Blood Glucose Levels among People with Diabetes in India
Authors: CHAWLA RAJEEV , KRISHNAKUMAR ARJUN , KHATRY VARSHA , SHAH ABHISHEK , JOSHI SHILPA , SHAIKH SHEHLA SAJID , LATHIA TEJAL , THACKER HEMANT , SAMUDRA KIRTI , MATTOO VINOD
Published: June 2019

Background: The glycaemic control among people with diabetes in India is very poor. This study evaluated the effectiveness an iPDM (integrated personalised self-management) in changing health behavior to improve blood glucose levels.

Methods: We used data from 883 participants (Average = 45.41 years; 72.71% male) who were using Accu-Chek® Active in conjunction with Wellthy Care™ digital therapeutic (WC DTx). The participants had to log the blood sugar values into the app manually. The WC DTx, developed in lines with AADE7 and RSSDI guidelines, includes skill-development through self-management education, and real time feedback and coaching through artificial intelligence (AI).

Results: The users were on the combination of the Accu-Chek® Active blood sugar monitor and its companion WC DTx for an average of 30.87 days. There was a significant difference between the mean first and last logged fasting blood sugar (FBS) (149.33 mg/dl vs. 132.83 mg/dl, p = 0.0013) and random blood sugar (202.20 mg/dl vs. 169.79 mg/dl, p = 0.004) values. The average per-user app interaction was 8.12 instances. A total of 2184 blood glucose measurements were logged with an average of 2.29 measurements per user. There was a step-wise decrease in FBS as the app engagement increased. The lowest tertile of app engagers reduced their FBS by 20.99 mg/dl (p=0.086), the middle tertile of app engagers reduced their FBS 23.98 mg/dl (p=0.038), and those in the highest tertile of app engagers reduced their FBS by 25.36 mg/dl (p=0.016). The reduction in random blood sugar in the highest level of app engagers was significant (p=0.04) than the reduction in the lowest (p=0.144) and middle tertile (0.296) of app engagers.

Conclusion: iPDM using Accu-Chek® Active along with Wellthy Care™ as a companion therapeutic, can help people with diabetes in India to improve self-management skills and overall blood sugar levels.

Disclosure

R. Chawla: None. A. Krishnakumar: Employee; Self; Wellthy Therapeutics. V. Khatry: Employee; Self; Roche Diabetes Care. A. Shah: Stock/Shareholder; Self; Wellthy Therapeutics. S. Joshi: None. S.S. Shaikh: None. T. Lathia: None. H. Thacker: None. K. Samudra: None. V. Mattoo: Consultant; Self; Wellthy Therapeutics.
114-LB: GX-G6, a Novel Long-Acting Glucagon-Like Peptide Receptor Agonist: Result of Phase I Study in Healthy Volunteers
Authors: BYUN MISUN , SEO CHINAM , WOO JUNGWON , SUNG YOUNGCHUL
Published: June 2019

GLP-1 receptor agonists are widely used in T2DM. GX-G6 is a hyFcTM fused long acting GLP-1, and is a proposed alternative to other GLP-1 agents. In this phase I, randomized, double-blind, placebo-controlled, single ascending dose study, 8 subjects randomly received GX-G6 or its matching placebo in a 6:2 ratio, in each of 6 cohorts at 0.01, 0.02, 0.04, 0.08, 0.16 and 0.24 mg/kg. Primary endpoint was safety and tolerability. Pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity were also assessed. GX-G6 was well tolerated, and no subject experienced hypoglycemia. Decreased appetite was the most common treatment-emergent adverse event which resolved spontaneously without treatment. GX-G6 was rapidly absorbed and its average terminal half-life ranged 62-92 hours. AUC0-t and Cmax increased in dose-proportional manner. No dose dependency in plasma glucose level was observed in healthy subject setting. However, in the OGTT, tendency of decrease in glucose concentration compared to placebo was demonstrated at 0.5 hours. No subjects developed antibodies against GX-G6. Single SC doses of GX-G6 were safe and well-tolerated in a dose range of 0.01 to 0.24 mg/kg in healthy subjects. Dose dependent and durable PK profile and OGTT results show potentials of GX-G6 to be both weekly and twice-monthly treatment for T2DM. [Clinicaltrials.gov: NCT03651466].

Disclosure

M. Byun: None. J. Woo: None. Y. Sung: None.
117-OR: Carvedilol Prevents Impairment of the Counterregulatory Response in Recurrently Hypoglycemic Diabetic Rats
Authors: FARHAT RAWAD , CHAN OWEN , SU GONG , VAN VLIET ELIANE DE SANTANA
Published: June 2019

It has been suggested that repeated activation of the adrenergic system during antecedent episodes of hypoglycemia may contribute to the development of counterregulatory failure. We previously showed that treatment with the non-specific β-blocker, carvedilol, can prevent counterregulatory failure in nondiabetic, recurrently hypoglycemic rats. The current study investigated whether carvedilol, can be used to prevent the development of counterregulatory failure in recurrently hypoglycemic diabetic rats. Sprague-Dawley rats were made diabetic with a single injection of streptozotocin (STZ; 60mg/kg; I.P.) One week after the induction of diabetes, carvedilol (4.5mg/kg QID; IP) treatment was started and continued for one week in one subgroup of STZ-diabetic rats. The remaining animals received a saline injection as controls. Three days later, the animals received either 3 bouts of insulin-induced hypoglycemia (RH) over the course of 3 days or they received 3 saline injections. On day 14, the animals underwent a hyperinsulinemic-hypoglycemic clamp to assess the counterregulatory hormone responses. Compared to hypoglycemia-naïve STZ Controls, glucose infusion rates were more than doubled in the STZ+RH animals (P<0.001) and this was associated with an ∼50% reduction in the epinephrine response to hypoglycemia. Treatment of STZ+RH animals with carvedilol improved the epinephrine responses to hypoglycemia. Of note, RH did not further diminish the glucagon response in STZ-diabetic rats. Our data suggests that carvedilol may be useful to prevent impairments in the counterregulatory response during recurring episodes of hypoglycemia in diabetic animals.

Disclosure

R. Farhat: None. O. Chan: Research Support; Self; Zucara Therapeutics Inc. G. Su: None. E. De Santana Van Vliet: None.

Funding

JDRF; National Institutes of Health
1183-P: A Crossover Randomized Controlled Trial Using Dialbetics: Smartphone-Based Self-Management System for Lifestyle-Related Disease Management
Authors: MIYAKE KANA , WAKI KAYO , OHE KAZUHIKO
Published: June 2019

Objective: We evaluated the clinical effects of mHealth system in self-management among subjects at risk of developing diabetes.

Method: DialBetics comprises three modules. (1) Data transmission: patients’ data—blood glucose, blood pressure, body weight, and pedometer counts—are measured at home and sent by smartphone to the server. (2) Evaluation: data are evaluated following the Japan Diabetes Society guideline’s targeted values; DialBetics determines if each reading satisfies the values, then sends the results back to each smartphone. (3) Communication: (a) the patient’s text messages about meals and exercise are sent to the server; (2) processed advice on lifestyle modification. A crossover randomized controlled trial—for six months—was conducted.

Results: The 122 subjects were classified into two groups: 61 in the group A that used the system in the first three months, and 61 in the group B that used the system the latter three months (age, respectively, 46.5±7.2 vs. 46.7±7.1 years). After three month, BMI, abdominal fat area (AFA), and waist circumference (WC) were significantly improved in the group A compared with the group B. At the end of the study, the data of both groups equally improved (Fig. 1).

Conclusions: DialBetics seems effective in improving self-management of subjects who are at risk of developing diabetes.

Disclosure

K. Miyake: Research Support; Self; NTT DOCOMO, INC. K. Waki: Consultant; Self; Nihon Chouzai Co.,Ltd. Research Support; Spouse/Partner; Boehringer Ingelheim Pharmaceuticals, Inc., MSD K.K., Novo Nordisk Inc. Research Support; Self; NTT DOCOMO, INC. K. Ohe: None.

Funding

Daiwa Securities Group Inc.; NTT Docomo Inc.
1187-P: The Novel Biguanide NT1195 Is an Oral Antidiabetes Drug for Patients with Kidney Disease
Authors: BATCHELOR KENNETH W. , LIVINGSTON JAMES N. , BROWN KATHLEEN K. , KAVANAGH KYLIE , COBB JEFFERY E.
Published: June 2019

Metformin, the most prescribed drug for T2D, has significant deficiencies in potency, pharmacokinetics (PK) and safety, especially in patients with kidney disease. Despite these deficiencies no improvements have been made to the biguanide (BIG) drug class. Novel BIGs with greater efficacy and without the risk of lactic acidosis are needed for T2D in patients with impaired renal function. A library of novel BIGs was screened for functional activity against a panel of organic cation transporters (OCTs). This OCT activity profile has allowed us to select BIGs with increased potency, improved PK properties and reduced elimination in urine. NT1195 was identified from this library and examined in more detail. This BIG is 5-10x more potent in mouse OGTT than metformin and is potent in the db:db mouse model, lowering plasma glucose after 8 days of dosing when metformin did not. NT1195 is more effective at elevating GLP-1 levels and inhibited gastric emptying in mice, where metformin did not. Improved potency alone is not sufficient to create the next generation of BIG therapeutics; it is also important to improve drug safety and to reduce the risk of lactic acidosis. Detailed PK studies in mice show that NT1195 has a 28.5h half-life (metformin = 1.97h), high levels of exposure (6x >metformin) and renal clearance that is 50x less than metformin. This latter finding suggests an increase in the safety of NT1195 in patients with impaired renal function, since we anticipate that NT1195 will be cleared by non-renal processes and that drug levels will not be affected by kidney disease. PK studies in cynomolgus monkeys provide similar findings for NT1195 with good exposure and a long half-life after oral administration. Also, NT1195 was found to increases glucose disposal in an IVGTT in insulin resistant monkeys. Safety studies are underway that will prepare NT1195 for a micro-dose study in T2D patients with and without kidney disease.

Disclosure

K.W. Batchelor: None. J.N. Livingston: Consultant; Self; CohBar, Inc. Employee; Self; NovoTarg Therapeutics. K.K. Brown: None. K. Kavanagh: Research Support; Self; Takeda Development Centre Europe Ltd. J.E. Cobb: Consultant; Self; NovaTarg Therapeutics.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases
1218-P: Amlodipine-Related Pedal Edema Resolved by Adding Sodium-Glucose Cotransporter 2 Inhibitor: A Technical Co-prescription for Type 2 Diabetes Mellitus with Hypertension
Authors: GAUTAM ASHISH , AGRAWAL PRABHAT K. , PURSNANI NIKHIL , JAIN APOORVA
Published: June 2019

Idea for this study was conceived after observation form three cases. Amlodipine, a potent CCB Antihypertensive drug often causes pedal edema secondary to arteriolar dilatation leading to intracapillary hypertension and fluid extravasation. Edema usually do not resolve with diuretics and frequently needed to withdraw amlodipine. Selected subjects were patients having DM2 and hypertension, who developed pedal edema after they were prescribed amlodipine (2.5/5/10mg/d) for hypertension. Total 112 subject (60 study cases and 62 comparators) were enrolled. Patients were randomized one to one between study cases and comparators. Without changing dose of amlodipine cases were given Sodium-glucose co-transporter 2 (SGLT2) inhibitor (Canagliflozin) 100 mg once a day with individualized simultaneous reduction of other OHA’s to avoid hypoglycemia. In comparator group Amlodipine was withdrawn, replacing with other antihypertensive drug not affecting study results. Both groups were followed for 4 weeks with subjective grade of edema and weight recorded before and after study duration. 48 out of 60 study cases, whereas 24 out of 62 comparators showed complete remission of pedal edema. Fisher exact value calculated to be 0.0008 at P< 0.05. Average weight loss in 4 weeks of 60 cases was 3.8 Kg, whereas 1.6 Kg in control (Z-Score is -6.3668. The p-value is 0. The result is significant at p≤ 0.05). Due to development of clinical hypotension, 10 (16.6%) study cases needed dose reduction of amlodipine whereas, 16 (25%) comparators needed another antihypertensive drug for blood pressure control. No major side effects observed during study in both groups except one female who developed polyuria and urogenital infection in study group which resolved with oral antibiotics and antifungal.

A judicious co-prescription of Amlodipine and SGLT2 inhibitor can avoid fluid overload and pedal edema in diabetes mellitus with hypertension.

Disclosure

A. Gautam: None. P.K. Agrawal: None. N. Pursnani: None. A. Jain: None.
1229-P: Dapagliflozin Improves Liver Dysfunction in Parallel with a Decrease in Serum Soluble DPP-4/CD26 Level in Type 2 Diabetic Patients with Nonalcoholic Fatty Liver Disease
Authors: KATO KANAKO , ASO YOSHIMASA , JOJIMA TERUO , IIJIMA TOSHIE , USUI ISAO
Published: June 2019

Objective: Serum levels of soluble DPP-4/CD26 are elevated in patients with type 2 diabetes and nonalcoholic fatty disease (NAFLD). Hepatocyte-secreted sDPP-4 induce directly adipose inflammation and insulin resistance in the liver. SGLT2 inhibitors reduce hepatic steatosis by inhibiting hepatic de novo lipogenesis. We investigated effects of dapagliflozin, an SGLT2 inhibitor, on liver dysfunction, hepatic steatosis, and serum levels of sDPP-4 in patients with type 2 diabetes and NAFLD.

Methods: Fifty-seven patients with type 2 diabetes and NAFLD were randomized into a dapagliflozin (5 mg/day) treatment group (n=33) or an active placebo group (n=24) for 24 weeks. Visceral adipose tissue (VAT) volumes were measured using a dual bioelectrical impedance analysis. Hepatic steatosis was evaluated by controlled attenuated parameter (CAP) using a transient elastography.

Results: At baseline, serum sDPP-4 showed positive correlations with AST, ALT, GGT, and HOMA-IR in a total of 57 patients. VAT significantly decreased in the dapagliflozin group, but not in the placebo group. AST, ALT, and GGT showed a significant decrease at 24 weeks in the dapagliflozin group, while they were unchanged in the control group. CAP also significantly decreased in the dapagliflozin group. Although both groups showed a significant reduction in serum sDPP-4 at 24 weeks after treatment, the magnitude of sDPP-4 reduction was greater in the dapagliflozin group. Changes in liver enzymes after dapagliflozin treatment correlated positively with those in serum sDPP-4 levels, but not those in VAT or HbA1c.

Conclusions: An improvement of liver dysfunction was associated with a decrease in serum sDPP-4, but not that in VAT or HbA1c, after treatment with dapagliflozin in these patients, suggesting that reducing serum sDPP-4 by SGLT2 inhibitors may be a therapeutic strategy for treatment of NAFLD/NASH in people with type 2 diabetes.

Disclosure

K. Kato: None. Y. Aso: Research Support; Self; Ono Pharmaceutical Co., Ltd. T. Jojima: None. T. Iijima: None. I. Usui: None.
1263-P: Diabetes Care Network: A Paradigm Shift in Diabetes Care Delivery Utilizing Collaborative Care Pathway
Authors: BANDI ARCHANA , LARSON MEG J. , LUTZ-MCCAIN STACEY J. , SUMMERVILLE ASHLEY M. , LUMLEY BRANDI K. , BOUDREAUX-KELLY MONIQUE Y.
Published: June 2019

Diabetes Care Network is a telemedicine based collaborative care pathway with team-based approach to improve diabetes care and scale the endocrine expertise. Veterans with poorly controlled type 2 diabetes were identified from electronic database, consultation completed via E-consult, and continuity care collaborated with primary care liaisons. We studied the efficacy and sustainability of our approach in improving diabetes care over 12 months.

Methods: Means (+/-SD), frequencies and percentages were presented, and Spearman correlations were assessed. Statistical significance set at p<0.05. Cohort (n=87) was predominantly white (90.8%) males (97.7%), with a mean age 67.2 (8.9), and had an average of 3.3 co-morbid conditions, 0.7 macro and 1.3 micro-vascular complications. Significant decline in A1C occurred from baseline A1C of 10.2% (1.4), to 8.1% (0.99) at 3 months, 7.6% (0.96) at 6 months, and 7.5 % (0.86) at 12 months (all p<0.0001). Proportion of patients out of 87 who achieved A1C of <8 were 38 (43.6%), 56 (64%), and 56 (64%) and those who achieved A1C <7 were 10 (11.4%), 21(24.1%), and 23 (26.4%) at 3, 6, and 12 months respectively. Non-significant improvements were noted in Weight {229.3 lbs (48.1) to 228.4 lbs (46.9)}, LDL {89.0 mg/dl (36.4) to 79.5 mg/dl (32.5)}, systolic BP {130.5 mmHg (16.1) to 123.9 mmHg (17.5)}, and triglycerides {226.9 mg/dl (195.3) to 159.3 (97.4)}. Compared to 12 months pre-enrollment period, no difference in healthcare utilization (ER visits or admissions) was noted in study period. From baseline to completion, non-significant improvement was noted in the use of anti-platelet agents, ACE/ARB, moderate to high-intensity statins and, in the frequency of Urine micro albumin measurements, annual foot and retinal exams.

Conclusion: A paradigm shift in diabetes care delivery is urgently needed. Use of telehealth technologies based collaborative pathways can scale the endocrine expertise and help attain better care for diabetic patients.

Disclosure

A. Bandi: None. M.J. Larson: None. S.J. Lutz-McCain: None. A.M. Summerville: None. B.K. Lumley: Employee; Spouse/Partner; Quest Diagnostics. M.Y. Boudreaux-Kelly: None.
1268-P: Evaluation of Inpatient Insulin Dose Requirements and Glycemic Control of Patients Using U-500 Regular Insulin Prior to Admission
Authors: ZADEH PARIA SANATY , LUTZ MARK F. , FELEKE AFOMIA A.
Published: June 2019

Objective: Questions remain regarding the appropriate use of U-500 insulin particularly, in the hospital setting. The objective of this study was to evaluate the inpatient insulin dose requirements and glycemic control of patients using U-500 insulin prior to admission.

Methods: A retrospective chart review of adult patients using U-500 insulin prior to admission to Beaumont Hospitals between March 2012 and July 2017 was conducted. Inpatient insulin dose requirements and glycemic control were compared between those who were continued on U-500 insulin and those transitioned to a U-100 insulin regimen.

Results: A total of 95 patients were included in the study. Seventeen patients were continued on U-500 insulin while the remaining 78 received U-100 insulin during their inpatient stay. U-500 insulin group received significantly more units of insulin per day (181 units versus 99.65 units; p = 0.0048). However, the proportion of insulin administered inpatient relative to the prior to admission dose was similar between the two groups (59% in the U-500 group and 46% in U-100 group; p = 0.1344). Glycemic control was similar between the groups except for significantly more hypoglycemia events in the U-500 group compared to the U-100 group (p < 0.0001). When patients were further stratified by prior to admission dose or HbA1c, significantly more hypoglycemia was observed in the U-500 group with HbA1c < 8% and those with prior to admission dose between 300-600 units.

Conclusions: Our retrospective review demonstrated that only very few patients were continued on a U-500 insulin regimen during their hospitalization. Inpatient use of U-500 insulin posed higher risk of hypoglycemia even when used at much lower doses than the established home regimen. Continued use of U-500 insulin in the hospital requires careful assessment of the risks and further investigation is needed to determine the appropriate dosing.

Disclosure

P. Sanaty Zadeh: None. M.F. Lutz: None. A.A. Feleke: None.
1269-P: Assessing the Performance of the UKPDS 82 Risk Equations to Predict Cardiovascular Events in the DECLARE-TIMI 58 Trial Population
Authors: MCEWAN PHILIP , FOOS VOLKER , BENNETT HAYLEY , KARTMAN BERNT , EDMONDS CHRISTOPHER , GAUSE-NILSSON INGRID ANNA
Published: June 2019

Risk equations (RE) from the UK Prospective Diabetes Study (UKPDS) remain the most commonly used within economic models of type 2 diabetes mellitus (T2DM). However, clinical practice has evolved since UKPDS reported and the applicability of these RE to contemporary T2DM patients is uncertain. The Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 trial assessed cardiovascular (CV) outcomes in a broad T2DM population treated with dapagliflozin (DAPA) versus placebo (PLA). This study aimed to assess the performance of the UKPDS 82 RE in the DECLARE-TIMI 58 population. RE for myocardial infarction (MI), heart failure (HF) and stroke were applied to baseline characteristics and 12-month effects of DAPA versus PLA on HbA1c, weight and blood pressure from DECLARE-TIMI 58. Predicted annual probabilities were converted to event rates per 1,000-person years and associated relative risks (RR) for DAPA versus PLA derived for comparison to trial outcomes. Due to misalignment of the UKPDS and DECLARE-TIMI 58 endpoints, predictions of congestive heart failure were compared to observed incidence of hospitalization for HF and stroke to ischemic stroke, respectively. Predicted (study reported) rates per 1,000 person years for MI, HF and stroke were 8.15 (11.7), 2.47 (6.20) and 3.28 (6.90) for DAPA, and 8.53 (13.2), 2.59 (8.50) and 3.46 (6.80) for PLA. Predicted RR of MI, HF and stroke for DAPA versus PLA were 0.96, 0.95, 0.95, respectively, compared to reported hazard ratios of 0.89 (95% CI: 0.77, 1.01), 0.73 (0.61, 0.88) and 1.01 (0.84, 1.21) in DECLARE-TIMI 58. UKPDS 82 RE did not predict the reduction in CV events demonstrated for DAPA versus PLA based on risk factor improvements observed in DECLARE-TIMI 58. These findings add to a growing body of evidence that suggests the CV effects of sodium-glucose co-transporter inhibitors such as DAPA cannot be fully described via treatment-induced changes in conventional prognostic factors.

Disclosure

P. McEwan: Consultant; Self; AstraZeneca. Employee; Self; Health Economics and Outcomes Research Ltd. V. Foos: Employee; Self; Health Economics and Outcomes Research Ltd., IQVIA. H. Bennett: Consultant; Self; AstraZeneca. Employee; Self; Health Economics and Outcomes Research Ltd. B. Kartman: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. C. Edmonds: Employee; Self; AstraZeneca. I.A. Gause-Nilsson: Employee; Self; AstraZeneca.

Funding

AstraZeneca
1292-P: Projected Long-Term Clinical Benefit and Cost-Effectiveness of Empagliflozin Compared with Glimepiride in Patients with Type 2 Diabetes in China
Authors: LAMOTTE MARK , SALEM AHMED , METTAM SAM R. , USTYUGOVA ANASTASIA V. , ZHANG EDMUND , RAMOS MAFALDA
Published: June 2019

In a 4-year clinical trial in patients with type 2 diabetes (T2D), uncontrolled by metformin alone, limepiride showed a higher occurrence of cardiovascular death, non-fatal myocardial infarction (MI) and stroke compared to empagliflozin. The current modelling study aimed to extrapolate lifelong the results of the 4-year study and to assess the cost-effectiveness of empagliflozin versus glimepiride in China.

The IQVIA Core Diabetes Model, a well-established model, was calibrated to reproduce the 4-year outcomes of the trial for both arms. Baseline characteristics and observed effects on physiological parameters (HbA1c, BMI, blood pressure, lipids) were used as inputs. The effects of the trial were applied up until treatment switch (reaching HbA1c of 8.5%) after which the UKPDS82 risk equations predicted events based on physiological parameters. Insulin-glimepiride was the next line therapy after reaching an HbA1c of 8.5%. The Chinese payer’s perspective was taken. Discounting of 3% was applied.

CDM projected 11.414 and 11.137 quality-adjusted life-years (QALYs) and 42,802 USD and 42,620 USD total lifetime costs for empagliflozin and glimepiride, respectively. The incremental cost-effectiveness ratio of empagliflozin versus glimepiride was 659 USD/QALY. On average 8% of cardiovascular events can be avoided.

In patients with T2D, uncontrolled with metformin, empagliflozin has the potential to reduce the risk of cardiovascular events for a good cost-effectiveness versus glimepiride.

Disclosure

M. Lamotte: Employee; Self; IQVIA. Employee; Spouse/Partner; Janssen Research & Development. A. Salem: None. S.R. Mettam: Employee; Self; Boehringer Ingelheim International GmbH. A.V. Ustyugova: Employee; Self; Boehringer Ingelheim International GmbH. E. Zhang: Employee; Self; Boehringer Ingelheim China. M. Ramos: Employee; Self; IQVIA.

Funding

Boehringer Ingelheim Pharma GmbH
1308-P: Improved Transition in Young Adults with Diabetes: A Pragmatic Clinical Trial
Authors: BUTALIA SONIA , MCGUIRE ASHLEE , CRAWFORD SUSAN , DYJUR DAVE , MERCER JULIA , PACAUD DANIÈLE
Published: June 2019

Background: The transition from pediatric to adult diabetes care is a vulnerable period for youth with diabetes. During transition, youth with diabetes are at high risk for loss to follow-up, worsening glycemic control, and increased hospitalizations.

Objective: Our objective was to assess the effect of a technology enhanced transition coordinator on loss to follow-up in youth with diabetes transitioning from pediatric to adult diabetes care.

Methods: This open label, pre-post pragmatic clinical trial, assessed the effect of a technology enhanced transition coordinator in transitioning young adults with diabetes from pediatric to adult diabetes care. Our primary outcome was the rate of loss to follow-up defined as no outpatient diabetes appointments in the one year following transfer. The usual care (control) cohort were youth with diabetes who received usual care (i.e., transition preparation during pediatric diabetes appointments prior to transfer). The intervention cohort received the usual care and had a transition coordinator who assisted them through the transition period with regular, per protocol contact, by texting, emailing, Twitter®, and/or postings on a private Facebook® page.

Results: Baseline average hemoglobin A1c was not different between the intervention cohort [number (n) = 101, 47.5% females] versus the usual care cohort (n= 209, 49.3% female) [8.9 ± 2.0 standard deviation (SD) versus 9.1 ± 2.4 SD, p=0.28] in the year prior to transfer. In the year following transfer, 49.3% of young adults in the usual care cohort versus 11.8% of young adults in the intervention group did not attend any outpatient diabetes appointments (p< 0.01) in the year following transfer.

Conclusions: Our technology enhanced transition coordinator intervention was successful in reducing loss to follow-up in transitioning young adults with diabetes. Importantly, this program used simple readily accessible technologies which increases the transferability and sustainability of this intervention.

Disclosure

S. Butalia: None. A. McGuire: None. S. Crawford: None. D. Dyjur: None. J. Mercer: None. D. Pacaud: Other Relationship; Self; Novo Nordisk A/S, Sandoz, TOLMAR.

Funding

Lawson Foundation
1342-P: Development of Type 2 Diabetes (T2D) in Obese Adolescent Girls with Polycystic Ovary Syndrome (PCOS)
Authors: HUDNUT-BEUMLER JULIA , KAAR JILL , PYLE LAURA , KELSEY MEGAN M. , NADEAU KRISTEN J. , ZEITLER PHILIP , CREE-GREEN MELANIE
Published: June 2019

PCOS is a common endocrine disorder that starts in adolescence and, when accompanied by obesity, is associated with a 4-fold risk of T2D. Adolescent onset of T2D carries significant morbidity and decreased life expectancy; rates of T2D are 12.5 cases/100,000/year in the general youth population. The incidence and prevalence of T2D in teen girls with PCOS and obesity are unknown. We conducted a retrospective chart review at a large tertiary care center. Using ICD9/10 codes for PCOS, girls aged 11-21 years with clinic visits between 7/1/2013-8/15/2018 and a BMI %ile > 85th were identified. Diagnosis of PCOS and T2D were confirmed using Endocrine Society and ADA guidelines, respectively. Key demographic and diagnostic information, including time of T2D diagnosis relative to PCOS diagnosis, was extracted. Prevalence of T2D in the PCOS cohort was calculated 1) from the entire T2D cohort and 2) only the incident T2D cases, as our site may have excess new T2D diagnosis referrals. We identified 600 cases of PCOS (15.2 ± 1.8 years, BMI %ile 96.2 ± 12.1) and 54 of these also had T2D, of whom 23 were diagnosed with PCOS prior to T2D (incident cohort). The prevalence of T2D in girls with PCOS and overweight/obesity was 4% including only incident cases and 9% with inclusion of all T2D. The incidence of T2D among adolescents with obesity and PCOS is 129 cases/1000/year and T2D presents 26 ± 19 months after PCOS diagnosis. Girls with T2D were more likely to be Hispanic (67% vs. 49%; p<0.0001) have obstructive sleep apnea (32% vs. 17%; p=0.01) and a 1st-degree relative with T2D (56% vs. 22%; p<0.001) than those who didn’t develop T2D. Girls with PCOS and obesity are at high-risk for developing T2D in adolescence, with 1 in 23 developing T2D within 2 years of diagnosis with PCOS. Girls at higher risk include those with a strong family history of T2D and Hispanic ethnicity. Further work is needed to confirm these rates in the overall adolescent population and to develop strategies for prevention of T2D in these high-risk youth.

Disclosure

J. Hudnut-Beumler: None. J. Kaar: None. L. Pyle: None. M.M. Kelsey: None. K.J. Nadeau: None. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc. M. Cree-Green: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (K23DK107871)
135-OR: A Novel Thiazolidinedione (TZD) with Minimal PPAR-γ Activity Maximized for Mitochondrial Pyruvate Carrier (MPC) Modulation: Six-Month Analysis of Glycemia in a 12-Month Nonalcoholic Steatohepatitis (NASH) Study
Authors: CUSI KENNETH , KOLTERMAN ORVILLE G. , HARRISON STEPHEN A. , DITTRICH HOWARD C.
Published: June 2019

The MPC facilitates entry of pyruvate into the Krebs cycle and in the setting of over nutrition, is critical to adverse manifestations including T2D and NASH. MSDC-0602K is a novel insulin sensitizer engineered to modulate pyruvate utilization with minimal ppar-γ activity. The EMMINENCE study is examining its effects on NASH and glycemia. U.S. sites (57) enrolled 402 patients with liver biopsy evidence of NASH and fibrosis; >50% of subjects with T2D (not taking insulin/pioglitazone) with entry HbA1c ≤ 9.5%. Randomization was 1:1:1:1 to daily oral doses of MSDC-0602K (62.5, 125, and 250mg) or placebo. Safety and glycemia were examined when 328 subjects reached 6 mo visit: 59% female, median age 57, 52% diabetic. (See Table) No meaningful changes in lipids, heart rate or BP were noted. The % of subjects reporting 1 or more adverse events was equal across all 4 cohorts. Importantly, the frequency of peripheral edema was 11% at baseline and unchanged across cohorts at 6 months. MSDC-0602K shows potent effects on glycemic control parameters and insulin sensitization with modest expected weight gain and no evidence of peripheral edema at 6 months, a key ppar-γ related side effect of first generation TZDs. This drug shows promise for glycemic control in NASH patients with T2D/insulin resistance.

Disclosure

K. Cusi: Consultant; Self; Allergan, AstraZeneca, Genentech, Inc., Novo Nordisk Inc., Poxel SA, ProSciento. Research Support; Self; Cirius Therapeutics, Echosens, Eli Lilly and Company, Inventiva Pharma, Janssen Research & Development, Novartis AG, Novo Nordisk Inc. O.G. Kolterman: Advisory Panel; Spouse/Partner; Intarcia Therapeutics, Inc. Advisory Panel; Self; Zafgen, Inc. Board Member; Self; American Diabetes Association, GlySens Incorporated, Viacyte, Inc. Consultant; Self; ADOCIA, Cirius Therapeutics Inc, DiaVacs Inc, JDRF, Nanoprecisionmedical, NuSirt Biopharma, Inc., Renova Therapeutics, Sensulin, LLC. Employee; Self; Whole Biome Inc. Stock/Shareholder; Self; Corcept Therapeutics, GI Therapeutics, Xeris Pharmaceuticals, Inc. Other Relationship; Spouse/Partner; American Diabetes Association. S.A. Harrison: Advisory Panel; Self; Gilead Sciences, Inc. H.C. Dittrich: Employee; Self; Cirius Therapeutics.
1353-P: Baseline Assessment of Transition Preparedness in Youth with Type 1 Diabetes
Authors: KRISHNA KANTHI BANGALORE , REALL MACY
Published: June 2019

Background: Transition planning should start early and topics covering healthcare navigation and autonomy be discussed, however, whether this is consistently implemented is unclear. At our center, we are working on implementing transition readiness classes to better prepare our youth (age 16-19) for transitioning care. A standardized questionnaire assessing transition readiness (Table 1) was administered prior to attending this class.

Results: n=21. ∼60% of subjects stated that they were unprepared or neither prepared nor unprepared. Figure 1 shows the subject’s perspective of their transition readiness.

Discussion: There are clear deficits in several key aspects of healthcare navigation and autonomy. These findings support the need for a structured transition program which should include periodic assessments of transition readiness.

Disclosure

K. Bangalore Krishna: None. M. Reall: None.
136-LB: Effective Treatment of T2D Patients Uncontrolled on Multiple Diabetes Medications by Adding Afrezza Mealtime Ultra-Rapid Insulin
Authors: LEVIN PHILIP , BROMBERGER LEE A. , BRUCE SIMON R.
Published: June 2019

Fourteen T2D subjects in a real-world practice setting, uncontrolled on oral/injectable combo therapy (mean A1C 9%), received inhaled human insulin (INH-Afrezza), added to current therapy and titrated weekly for up to 12 weeks. A1C and 2-week continuous glucose monitoring (CGMS) profiles (Libre Pro) were collected at baseline and after 3 months.

All subjects started INH 4 units (u) prior to each meal and titrated rapidly to 12 u/meal over 9 days. Thereafter, INH was adjusted for each meal once weekly, based on PPG at 2-2.5 hours measured on days 1 and 2 of each week, as follows: Add 4 u if PPG > 160 mg/dl, no change if PPG 90-160 mg/dl and decrease by 4 u if PPG < 90 mg/dl. More than 1/2 of subjects were taking basal insulin.

Addition of the only available inhaled ultra-rapid rapid mealtime insulin (Afrezza) lowered glucose safely in patients with T2D inadequately controlled on oral and/or injectable therapy. Initiation and titration, following a simple algorithm, resulted in significant A1c reduction (-1.6%, p<.0001), a decrease in mean daily glucose (∼50 mg/dl), and a 76% increase in time-in-range on CGMS, with no significant increase in hypoglycemia (Time<70 mg/dL). No severe hypoglycemia occurred. Final mealtime Afrezza doses achieved were 18, 16 and 20 u at breakfast, lunch, dinner respectively.

Disclosure

P. Levin: Research Support; Self; MannKind Corporation, Novartis AG, Novo Nordisk Inc. Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Lilly Diabetes, Merck & Co., Inc., Sanofi. L.A. Bromberger: None. S.R. Bruce: Consultant; Self; Dance Biopharm Holdings Inc., MannKind Corporation, Oramed Pharmaceuticals.

Funding

MannKind Corporation