bluuebunny/crossref_metadata_2025 huggingface dataset:
Linagliptin Reduced Renal Injury and Proteinuria in a Rat Model of Crescentic Nephritis
Authors: MAYER ANNA-LENA , AMANN KERSTIN U. , KLEIN THOMAS , DANIEL CHRISTOPH
Published: June 2018

Dipeptidyl peptidase 4 (DPP-4) inhibitors are used in the treatment of type 2 diabetes. In human kidney biopsies we observed high DPP-4 expression in early crescent formation. This glomerular lesion occurs in different kidney diseases and is a hallmark in the pathogenesis of renal dysfunction. Thus, we investigated the potential involvement of DPP-4 in the pathogenesis of anti-GBM (glomerular basement membrane antibody) induced nephritis in Wistar rats. Linagliptin (3 mg/kg, n=11) and vehicle (n=11) were used to treat anti-GBM nephritis in an 8 weeks preventional and therapeutical (treatment started 4 weeks after model induction) regimen. Kidney function, morphologic changes, inflammation and fibrosis was monitored. Disease prevention with linagliptin in anti-GBM nephritic rats significantly (p<0.01) reduced the number of crescents (51±3% vs. 65±3%), glomerulosclerosis (score 1.2±0.07 vs. 1.6±0.1), tubule-interstitial injury (score 1.2±0.1 vs. 1.8±0.2), renal fibrosis (score 1.3±0.13 vs. 1.9±0.14) and proteinuria (265±29 vs. 363±22 mg/24h) compared to untreated nephritic rats. Also, preventional linagliptin therapy significantly reduced the number of Pax8+ cells on the glomerular tuft by 17±5% on day 14 (p<0.05) and 60±5% on week 8 (p<0.001), indicating accelerated resolution of the cellular crescents. Disease intervention with linagliptin resulted in weaker amelioration of renal disease on week 8 but also significantly (p<0.05) reduced renal fibrosis (score 1.4±0.13 vs. 1.9±0.14), crescent formation (52±4% vs. 65±3%) and Pax8-positive cells on glomerular tuft (65±5.2% reduction) compared to vehicle. Proteinuria was also reduced but did not reach significance.

In conclusion, DPP-4 inhibition by linagliptin ameliorates renal injury in a severe rat model with anti-GBM induced nephritis as shown by reduced crescents, proteinuria and fibrosis, and resolution of crescents. Therapeutic intervention with linagliptin showed weaker effects compared to a preventional mode.

Disclosure

A. Mayer: Research Support; Spouse/Partner; Boehringer Ingelheim Pharmaceuticals, Inc.. K.U. Amann: None. T. Klein: Employee; Self; Boehringer Ingelheim GmbH. C. Daniel: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc..
(R)-ND-336 as a Therapeutic Agent for Diabetic Wound Healing
Authors: CHANG MAYLAND
Published: June 2018

Approximately 25% of diabetics develop diabetic foot ulcers (DFUs), resulting in 73,000 lower-limb amputations annually in the United States, with one-year prognosis of 50% mortality. While the involvement of matrix metalloproteinases (MMPs) in wound healing has been known, the challenge remained as to which MMP(s) among the 24 known human variants plays a role in the ailment, compounded by the fact that MMPs exist in three forms, the latent, the activated in complex with protein inhibitors TIMPs, and the activated uninhibited form. The first two are catalytically incompetent. With the use of an affinity resin that fishes out only the catalytically competent MMPs from the complex proteome, we identified active MMP-8 and MMP-9 in wounds of db/db mice and determined that MMP-9 is detrimental and that MMP-8 plays a beneficial role in wound healing. To demonstrate parallels in expression profiles in humans, we studied the debridement tissue from diabetic patients using the affinity resin coupled with proteomics. We identified the very same active MMP-8 and -9 in diabetic human wounds, indicating that the mechanisms of pathology and repair are similar in humans and in mice. Twenty-fold higher levels of the detrimental active MMP-9 were found in Wagner grade 1-4 wounds compared to control. These increased levels for MMP-9 are indeed significant, considering that active MMP-9 is a catalyst that contributes to the recalcitrance of wounds to heal. This observation makes MMP-9 an important target for inhibition with translational potential. We report herein that (R)-ND-336, a novel potent and selective inhibitor of MMP-9, accelerates healing of diabetic wounds and holds promise as recourse in treatment of DFUs. We note that NF-κB levels correlate with that of active MMP-9, hence it is a useful biomarker in identification of candidates for the treatment option.

Disclosure

M. Chang: None.
Combined Treatment with Exendin-4 and Metformin Attenuates Breast Cancer Growth
Authors: IWAYA CHIKAYO , NOMIYAMA TAKASHI , KAWANAMI TAKAKO , HAMAGUCHI YURIKO , TANAKA TOMOKO , YANASE TOSHIHIKO
Published: June 2018

Cancer is a major cause of death in patients with diabetes. Incretin therapy has received much attention, because of its tissue protective effects beyond glycemic control. We have previously reported anti-prostate cancer effect of Ex-4 and metformin (Diabetes 2014, PLOS ONE 2015). In addition, we have recently reported that Ex-4 attenuates breast cancer growth (Endocrinology 2017). Then, we next examined the effect of combined treatment of Ex-4 with Metformin in breast cancer cells. In human breast cancer cell lines, MCF-7, MDA-MB-231 and KPL-1 cell, Ex-4 or metformin reduced cell number in a dose-dependent manner. Further, combined treatment of 0.1mM Metformin and 10nM Ex-4 additively attenuated the growth curve progression of breast cancer cells. In BrdU assay, Ex-4 or Metformin significantly decreased breast cancer cell proliferation, and further reduction of BrdU incorporation was observed by combined treatment of Ex-4 and Metformin, suggesting that Ex-4 and Metformin additively decreased DNA synthesis in breast cancer cells. Although apoptotic cells were not observed in Ex-4 treated breast cancer cells similar to our previous study, apoptotic cells were clearly detected in metformin treated breast cancer cells using TUNEL assay. These data suggest that Ex-4 and metformin attenuates breast cancer cell proliferation and metformin induces apoptosis in breast cancer cells. Combined treatment of Ex-4 and Metformin could be an optional therapy to inhibit breast cancer progression.

Disclosure

C. Iwaya: None. T. Nomiyama: Research Support; Self; MSD K.K., Sanofi-Aventis, Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceuticals, Japan. T. Kawanami: None. Y. Hamaguchi: None. T. Tanaka: None. T. Yanase: Research Support; Self; MSD K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceuticals, Japan.
Identification of Glucosepane Cross-Link Breaking Enzymes
Authors: STREETER MATTHEW , GODDARD TYLER N. , CRAWFORD JASON M. , SPIEGEL DAVID A.
Published: June 2018

Glucosepane is a member of the class of advanced glycation end-products (AGEs), which form non-enzymatically in the human body. Glucosepane, is the most abundant AGE found in human collagen and has been implicated in the pathophysiology of various conditions ranging from diabetes to normal human aging. Glucosepane crosslinks impact the structural and mechanical properties of collagen and contribute to stiffening of collagenous tissues and vascular dysfunction. We have previously demonstrated the total synthesis of glucosepane, enabling methods for detecting and targeting glucosepane. The present study seeks to identify enzymes that are capable of catalyzing the decomposition of synthetic glucosepane crosslinks. To identify glucosepane crosslink breaking enzymes, we developed a novel screening technology based on metagenomics. Using this strategy, four enzymes were identified for in vitro validation of glucosepane degradation activity. Thus far, our efforts have focused on identifying metabolites of one class I-like enzyme in particular, since it is heterologously expressed at high levels and does not require any unusual cofactors. In vitro enzymatic assays showed that incubation of glucosepane with the class I-like enzyme led to a product consistent with citrulline. We are currently in the process of evaluating the enzyme’s mechanisms of action and identifying other metabolites generated. This is the first demonstration that glucosepane can be broken down enzymatically. Our findings may provide new insight into the role of glucosepane in aging and disease and aid in the development of novel therapeutic strategies for targeting glucosepane.

Disclosure

M. Streeter: None. T.N. Goddard: None. J.M. Crawford: None. D.A. Spiegel: None.
Embryonic Cell Extracts Ameliorate Wound Healing in Diabetic Mice
Authors: LORETELLI CRISTIAN , NASR MOUFIDA BEN , HAJ GHINA AL , ROCCHIO FRANCESCA , FARAVELLI SILVIA , MALVANDI AMIR MOHAMMAD , D'ADDIO FRANCESCA , MAESTRONI ANNA , LETIZIA TERESA , ASSI EMMA , USUELLI VERA , LEON EDUARDO CASTILLO , MERONI ROBERTA , ZUCCOTTI GIANVINCENZO , FIORINA PAOLO
Published: June 2018

Wound healing (WH) is a physiological function in which a balanced inflammatory response is required for tissue regeneration and successful wound closure. In diabetic patients WH is impaired and negatively impacts diabetic individuals in terms of morbidity, mortality and social disability, while the lack of an effective wound care highlights the need for novel therapeutic strategies. Extracts obtained from embryonic stem cells (EXTs) exhibited immunomodulatory properties and we hypothesize that EXTs may improve WH in diabetes. Here we explored the in vitro and in vivo effect of EXTs on WH using the diabetic db/db mouse model. Our data show that in vivo EXT topical administration ameliorates wound closure, contraction and re-epithelization by significantly reducing local inflammation and enhancing angiogenesis as compared to acellular protein extracts from 3T3 fibroblast cells (3T3xt) or no treatment. EXTs increased the percentage of regulatory T cells in the wound in vivo and inhibited T cell activation and IFNγ production in vitro. Db/db-derived dendritic cells exposed to EXTs showed decreased maturation, with downregulation of the costimulatory molecules CD80, CD86 and CD40. On the other hand, in vivo 3T3xt administration caused poorer wound closure with enhanced leucocyte infiltration of wounds and CD80, CD86 and CD40 upregulation on activated dendritic cells both in vivo and in vitro. Finally, proteomic analysis revealed 82 molecular entities differentially segregating in the EXT and 3T3xt group. Following unbiased selection, 10 proteins were filtered and assayed for their immune activity. Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APEX1) revealed strong immunomodulatory properties at ELISpot analysis by inhibiting IFNγ secretion of human PBMCs. APEX1 may result as the key factor mediating the beneficial effect of EXT on WH. EXTs or acellular extracts with upregulated APEX1 is a tool of remarkable translational potential for a safe, innovative and cost-effective application in the clinic.

Disclosure

C. Loretelli: None. M. Ben Nasr: None. G. Al Haj: None. F. Rocchio: None. S. Faravelli: None. A. Malvandi: None. F. D'Addio: None. A. Maestroni: None. T. Letizia: None. E. Assi: None. V. Usuelli: None. E. Castillo Leon: None. R. Meroni: None. G. Zuccotti: None. P. Fiorina: None.
Glucokinase-MODY Frequently Misdiagnosed and Inappropriately Treated
Authors: BOYD SEAN , BYRNE MARIA M.
Published: June 2018

Background: GCK-MODY is an autosomal dominant form of diabetes. Heterozygous inactivating mutations in GCK result in mild, persistent asymptomatic hyperglycemia due to a glucose sensing defect. It is reported that GCK-MODY is not associated with significant diabetic complications and that pharmacological therapy does not alter glycemia.

Aim: We aimed to establish the percentage of GCK-MODY patients on pharmacological therapy and its impact on their glycemic control, along with the incidence of diabetic complications.

Methods: 32 patients were identified. Glycemic tolerance was established using an OGTT. Treatment details were recorded. Diabetic complications were identified. Following genetic diagnosis of GCK-MODY pharmacological therapy with Metformin was discontinued in 7 of 11 patients. HbA1c before and 6 months after discontinuing therapy was compared. Data was analysed in Microsoft Excel and Stata 4.2.

Results: Treatment at diagnosis included, insulin (4), sulfonylurea (2), DPP-4 (5), Metformin only (11), and diet alone (15). Mean HbA1c at MODY diagnosis in all patients was 45.7+/-4.4 mmol/mol. 7/11 patients discontinued metformin only and had no change in glycemic control HbA1c(46.8+/-3.5mmol/mol pre vs. 47.9+/-3.0 mmol/mol post; p=0.38). 40.6% of those screened had background diabetic retinopathy not requiring treatment; 0.03% had Microalbuminuria and 0.125% had CAD.

Conclusion: Prior to genetic diagnosis of GCK-MODY, patients were frequently misdiagnosed, with 50% on pharmacological therapy. Discontinuation of metformin resulted in no deterioration of glycemic control indicating that metformin therapy had no impact on the glucose sensing defect. Background diabetic retinopathy was the commonest complication, but did not require treatment.

Disclosure

S. Boyd: None. M.M. Byrne: None.
The Effect of Lixisenatide and Dapagliflozin in Nonalcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus Compared with Sitagliptin and Pioglitazone
Authors: KOUTSOVASILIS ANASTASIOS , SOTIROPOULOS ALEXIOS , PAPPA MARIA , PAPADAKI DESPINA , KORDINAS VASILIS , TAMVAKOS CHARALAMPOS , BOURIKOU MARIA , BOUSBOULAS STAVROS , PEPPAS THEODOROS
Published: June 2018

Introduction: Medications currently taken by patients with NAFLD target concomitant metabolic diseases such as hypertension, dyslipidemia and diabetes.

Aim: The aim of the study was to examine the effectiveness of lixisenatide and dapagliflozin in NAFLD patients with type 2 diabetes mellitus (T2DM) compared with sitagliptin and pioglitazone.

Methods: T2DM patients with NAFLD (n=306) were included in the study. Patients were divided in 4 groups according to their treatment with lixisenatide (n=62), dapagliflozin (n=85), pioglitazone (n=67) and sitagliptin (n=92). All patients also received metformin. Mean follow-up period was 76 weeks ± 2 weeks. The evaluation of liver fibrosis depended on calculation of aspartase aminotransferase (AST) to platelet counts ratio (APRI) index. All patients went through an ultrasonography before being included in the study and after the end of the study.

Results: There were no differences between groups in patient age (p=0.256), duration of T2DM (p=0.283), Body Mass Index (BMI) (p=0.337) and HbA1c (p=0.156). There was a greater improvement of APRI index for the lixisenatide group (1.07 (0.46-1.23) vs. 0.74 (0.38-0.90) p<0.001) compared to dapagliflozin (1.12 (0.59-1.22) vs. 0.83 (0.32-1.01) p=0.010) to pioglitazone (1.10 (0.49-1.27) vs. 0.90 (0.41-1.04), p=0.014), and sitagliptin (1.01 (0.39-1.14) vs. 0.99 (0.38-1.15) vs. 0.98 (0.36-1.14) p=0.366). APRI index’s improvement was accompanied by a significant change of fatty liver in ultrasonography. The decrease of body weight in the lixisenatide (p<0.001) and in the dapagliflozin group (p=0.028) was statistically significant.

Conclusions: Administration of lixisenatide and dapagliflozin led not only to good control of T2DM but also improvement of liver inflammation, alteration of liver fibrosis, and reduction of body weight, which are particularly important factors in patients with T2DM.

Disclosure

A. Koutsovasilis: None. A. Sotiropoulos: None. M. Pappa: None. D. Papadaki: None. V. Kordinas: None. C. Tamvakos: None. M. Bourikou: None. S. Bousboulas: None. T. Peppas: None.
Comparing Treatment Strategies for Patients with Very Elevated HbA1c—A Randomized Trial
Authors: ABREU MARCONI , TUMYAN ANNA , ELHASSAN AHMED , PAPACOSTEA OLIVIA , PEICHER KATHERINE , DIMACHKIE PERIHAN , SIDDIQUI MUHAMMAD S. , ADAMS-HUET BEVERLEY , LI XILONG , POP LAURENTIU , LINGVAY ILDIKO
Published: June 2018

Basal-bolus insulin (BBI) is the most established treatment strategy for patients with very elevated HbA1c (>10%), especially if symptomatic. The combination of metformin (Met), GLP-1 receptor agonist (GLP-1RA) and basal insulin (BI) is a very effective glucose lowering strategy, but it has not been evaluated in patients with very elevated HbA1c. This is the first randomized trial comparing a GLP-1RA+BI treatment regimen to a BBI treatment regimen in patients with very uncontrolled (HbA1c>10%) T2D. Basal insulin detemir was either continued at the prior dose or initiated at 0.3 units/kg and self-titrated. GLP-1RA liraglutide was titrated according to label to 1.8 mg/day. Meal-time insulin aspart was initiated at 0.1 units/kg/meal and self-titrated. Metformin was continued or (re)initiated if tolerated, all other hypoglycemic agents were discontinued. The primary outcome was change in HbA1c at 6 months, analyzed using a mixed model repeated measures analysis. We randomized 120 patients with a mean age (SD) 47.4 (9.5) years, Hispanic 48%, diabetes duration of 10.54 (7.19) years, 76% were already treated with insulin, HbA1c 12.1 (1.4) %, BMI 37.2 (10.3) kg/m2, 86% had one or more symptoms of hyperglycemia.

Both treatment strategies lead to dramatic improvements in HbA1c, treatment with GLP-1RA+BI, compared with BBI, resulted in significantly better glycemic control, weight, insulin dosage, and hypoglycemia (Table).Table. Effects of treatment with GLP-1RA + basal insulin (GLP1RA+BI) compared with basal-bolus insulin (BBI) on primary & secondary outcomes.VariableGLP1RA+BI GroupBBI GroupEstimated Treatment DifferenceP value between groupsBaseline6 monthsBaseline6 monthsHbA1c(%)12.2 (11.8 to 12.6)8.1 (7.4 to 8.7)11.8 (11.5 to 12.2)8.8 (6.0 to 9.1)1.1 (0.1 to 2.0)0.03Weight (kg)98.2 (89.7 to 106.6)97.5 (89.1 to 106.0)104.5 (96.2 to 112.8)107.6 (99.3 to 115.9)3.7 (1.53 to 5.9)<0.01TDD Insulin (U/day) (median, 25th to 75th percentile)25.0 (22.0 to 36.0)64.0 (39.5 to 80.0)60.0 (43.0 to 72.0)100.0 (66.0 to 155.0)0.3* (0.1 to 0.5)0.01HbA1c ≤7% N (%)NA20 (44.4)NA9 (20.5)Odds Ratio 0.32 (0.13 to 0.82)0.02Patients with any hypoglycemia (glucose <70 mg/dL) N (%)NA19 (35.2)NA37 (66.1)NA<0.01Data represents Least Squares Means (95% confidence intervals) unless otherwise noted.*ETD for the log transformed value

Disclosure

M. Abreu: None. A. Tumyan: None. A. Elhassan: None. O. Papacostea: None. K. Peicher: None. P. Dimachkie: None. M.S. Siddiqui: None. B. Adams-Huet: None. X. Li: None. L. Pop: None. I. Lingvay: Advisory Panel; Self; Novo Nordisk A/S, Eli Lilly and Company, AstraZeneca, Intarcia Therapeutics, Inc., Sanofi-Aventis. Research Support; Self; Novo Nordisk A/S, Merck Sharp & Dohme Corp., Pfizer Inc., GI Dynamics Inc., Novartis AG. Other Relationship; Self; Sanofi, AstraZeneca, Boehringer Ingelheim GmbH, Novo Nordisk A/S.
Liquid Room Temperature Stable Glucagon—Glucose Response in Pediatric Type 1 Diabetes Patients
Authors: BUCKINGHAM BRUCE , CUMMINS MARTIN J. , PRESTRELSKI STEVEN J. , STRANGE POUL
Published: June 2018

Objective: The International Society for Pediatric and Adolescent Diabetes recommends age-specific dosing of glucagon for the rescue of severe hypoglycemia. A novel ready-to-use stable liquid glucagon auto-injector (GAI; Xeris Pharmaceuticals) was evaluated for the treatment of hypoglycemia in pediatric subjects with two age-specific doses.

Research Design and Methods: A sequential efficacy and safety study was conducted involving 31 children with T1D (ages 2-17 years) to evaluate two subcutaneous doses of GAI (0.5 mg or 1 mg) for treatment of hypoglycemia (PG < 80 mg/dL), induced via IV insulin or insulin pump. The primary efficacy endpoint was increase in mean plasma glucose from baseline at 30 minutes following administration of an age-appropriate glucagon dose. As secondary endpoints, subjects were assessed for time from dosing to achieve a 25 mg/dl increase in plasma glucose and other PD and PK parameters.

Results: Statistically significant increases in mean plasma glucose from baseline to 30 minutes post administration of glucagon were observed across the 3 pediatric age groups (81.4±18.3 mg/dL, 84.2±25.3 mg/dL, and 54.0±27.3 mg/dL in the 2 to < 6 years [n=7, 0.5 mg dose], 6 to < 12 years [n=13, 0.5 mg dose], and 12 to < 18 years [n=11, 1 mg dose] age groups, respectively). All evaluable subjects achieved the target glucose elevation of ≥25 mg/dL from baseline. Across age groups there were no notable differences with regards to mean glucose AUC0-90m, Cmax, and Tmax or median time to achieve a 25 mg/dl glucose increase. Plasma glucagon AUC0-240m, Cmax, and Tmax were similar across the age groups. Nausea (36.4%) and vomiting (18.2%) were the most commonly reported AEs.

Conclusions: To prevent medical complications and their sequalae, prompt management of severe hypoglycemia emergencies is critically important. These results demonstrate that age-appropriate doses of GAI were effective in treating hypoglycemia, safe, and well tolerated in pediatric subjects ages 2 through 17 years old.

Disclosure

B. Buckingham: Advisory Panel; Self; Novo Nordisk Inc., ConvaTec Inc.. Research Support; Self; Medtronic, Insulet Corporation, Dexcom, Inc., Tandem Diabetes Care, Inc.. Consultant; Self; Tandem Diabetes Care, Inc., Becton, Dickinson and Company. M.J. Cummins: Employee; Self; Xeris Pharmaceuticals, Inc. S.J. Prestrelski: Employee; Self; Xeris Pharmaceuticals, Inc. P. Strange: Other Relationship; Self; AstraZeneca. Consultant; Self; Valeritas, Inc.. Stock/Shareholder; Self; Valeritas, Inc..
Effect of Testosterone Therapy on Renal and Endothelial Functions in Men with Type 2 Diabetes Mellitus
Authors: KHRIPUN IRINA A. , BOVA ELENA V. , VOROBYEV SERGEY V.
Published: June 2018

Recently, the attention of researchers is attracted to the problem of testosterone (T) deficiency in men. Its negative effect on the cardiovascular system has been established, but the data about the effect of T deficiency on the renal function in patients with type 2 diabetes mellitus (T2DM) haven’t been studied yet.

Aim: Evaluate the effect of T therapy on glycemic control, the renal function and the biochemical parameters of endothelial function in men with T2DM having an androgen deficiency.

Materials and Methods: The study included 80 men (mean age 51.5±6.3 years), with T2DM and T deficiency. Patients were randomized into 2 groups: the 1st-40 men receiving transdermal T (Androgel 50 mg/day) during 9 months and the 2nd group - 40 men who were not assigned to T. Patients underwent a clinical examination, analysis of biochemical parameters of carbohydrate metabolism (fasting glycemia, HbA1c), renal (creatinin, glomerular filtration rate (GFR)) and endothelial functions (p-, e-selectins, ICAM-1, VCAM-1). Statistical analysis was performed with Mann-Whitney and Wilcoxon tests using the Statistica 10 software package.

Results: T therapy in men with T2DM, along with a decrease in body weight by 5.02±0.99 kg (p=0.003) and waist circumference by 6.5±1.6 sm, led to an improvement in carbohydrate metabolism - fasting glycemia by 22.2% and HbA1c by 1% (p=0.00001). At the same time, a statistically significant decrease in the creatinine concentration and an increase in the GFR by 12.5% ​​(p=0.01), as well as a decrease in the levels of endothelial dysfunction markers (ICAM-1 by 56% and p -selectin by 7.7 times (p=0.01)) were found. No significant changes in the 2nd group were found.

Conclusion: T therapy in men with T2DM and androgen deficiency leads not only to a decrease of visceral obesity and an improvement in carbohydrate metabolism, but also ameliorates the renal and endothelial functions, which could reduce the rate of progression of vascular complications of diabetes.

Disclosure

I.A. Khripun: None. E.V. Bova: None. S.V. Vorobyev: None.
Health Economics Analysis of Point-of-Care HbA1c Monitoring in Belgian, German, and Swiss Patients with Diabetes Mellitus Type 2
Authors: BOLTYENKOV ARTEM T. , NAVARRO FELIPE , HREN ROK
Published: June 2018

Objectives: In patients with diabetes mellitus (DM) type 2 monitoring of glycated hemoglobin (HbA1c) level is essential to ensure glycemic control. In this study, we assessed overall financial impact of HbA1c monitoring in the point-of-care setting in Belgium, Germany, and Switzerland.

Methods: We developed a health economics model comparing the strategy of using point-of-care (POC) HbA1c monitoring with the strategy of using conventional laboratory-diagnostics (LD) in patients suffering from DM type 2. We followed cohorts of patients diagnosed with DM type 2 in Belgium, Germany and Switzerland for the period of 15 years and estimated the costs of complications (amputation, cataract extraction, kidney failure, heart failure, stroke, and microvascular disease or myocardial infarction) using the local data. To assess the validity of the assumptions and robustness of the model, a thorough sensitivity analysis was undertaken.

Results: In patients with DM type 2, POC HbA1c monitoring resulted in savings of €59.3 million (on average, €182 per patient in the cohort) in Belgium when compared to conventional LD monitoring; corresponding savings in Germany were €848 million (on average, €233 per patient in the cohort) and in Switzerland savings amounted to €118 million (on average, €422 per patient in the cohort). The sensitivity analysis showed robustness of our findings.

Conclusions: Our health economics analysis suggests that the POC HbA1c monitoring in patients suffering from DM type 2 may reduce overall heath care costs in Belgium, Germany, and Switzerland.

Disclosure

A.T. Boltyenkov: Employee; Self; Siemens. F. Navarro: None. R. Hren: None.
Remission of Type 2 Diabetes in 12% (16 of 133) Hypogonadal Men Receiving Long-Term Testosterone Therapy in a Real-Life Registry Study
Authors: HAIDER AHMAD , HAIDER KARIM S. , SAAD FARID
Published: June 2018

Background: According to 2016 AACE/ACE obesity guidelines, hypogonadism should be assessed and treated in indicated in men with type 2 diabetes mellitus (T2DM).

Methods: In a registry of hypogonadal men (testosterone ≤12.1 nmol/L) conducted since 2004 in a urological setting, 133/400 patients (33.3%) had T2DM diagnosed and treated in a diabetes center. All men received testosterone undecanoate (TU) injections 1000 mg/12 weeks (T-group) following an initial 6-week interval. Anthropometric and metabolic parameters were measured at least twice a year and fasting insulin obtained from the diabetes center to calculate HOMA-IR.

Results: Mean follow-up was 6.9, maximum 11 years. 16 patients (12%) were in remission at the last measurement. Their average baseline age was 60.1 years. HbA1c dropped from 8.3% at baseline to 5.7% at the last measurement, fasting glucose from 7.8 mmol/L to 5.4 mmol/L. Fasting insulin declined from 24.7 to 7.6 µU/mL. HOMA-IR dropped from 8.7 to 1.8. Triglycerides decreased from 3.2 to 2.2 mmol/L. Anthropometric parameters: Body weight declined progressively from 107 to 89 kg, waist circumference from 1to 97 cm. All patients had been on oral antidiabetic medication (metformin) at baseline. Five patients were on insulin at an average dose of 21.6 units per day. The average observation time was 106.3 months (8.9 years). The average time to discontinuation of diabetes medication was 74.8 months (6.2 years). One patient was diagnosed with low-grade prostate cancer and developed new onset T2DM while off TU. He went into remission 48 months after resuming TU therapy. Medication adherence to TU was 100 per cent as all injections were administered in the urology office and documented.

Discussion: The registry was not designed to study the effects of testosterone on T2DM. Remission of T2DM has not been described in the literature and was unexpected.

Conclusions: Long-term testosterone treatment in hypogonadal men may result in remission of T2DM.

Disclosure

A. Haider: Research Support; Self; Bayer AG. K.S. Haider: Other Relationship; Self; Bayer AG. F. Saad: Employee; Self; Bayer AG. Stock/Shareholder; Self; Bayer AG, Novo Nordisk A/S.
A Clinical Training Program for Hybrid Closed-Loop Therapy in a Pediatric Diabetes Clinic
Authors: BERGET CARI , THOMAS SARAH , MESSER LAUREL H. , OWEN SUSAN , THIVENER KATIE , SLOVER ROBERT H. , PAUL WADWA R. , ALONSO GUY T.
Published: June 2018

Background: The first hybrid closed loop (HCL) system became commercially available in the U.S. in 2017, and there is no standard process for training patients. The goal of this quality improvement project was to optimize transition to HCL for pediatric patients at a large diabetes center.

Methods: Our multidisciplinary team developed a novel HCL training program, meeting monthly over 4 months to review data and refine training with a Plan-Do-Study-Act model. The HCL training plan for current insulin pump users included 1) in-person group class to reinforce conventional insulin pump and CGM use on the new system, 2) a live videoconference class to teach HCL use, 3) three follow-up phone calls in the first 6 weeks after HCL training to assess system use, make insulin adjustments, and provide targeted re-education.

Results: Seventy-two patients (age 14 ± 4.3y; 46% female) with type 1 diabetes (HbA1c 8.7 ± 1.4%) were trained over 4 months. Mean sensor wear time was 83% and HCL time was 73%. Sensor time in target range (70-180 mg/dl) increased from 49% to 62% between week 1 and week 4 (p= <.001). Sensor wear and HCL time did not change. All patients completed both classes, and 79% and 48% completed 2 and 3 follow-up calls respectively. Mean phone call time was 16 minutes. Trainers strengthened carbohydrate ratios to increase mealtime insulin doses in 75% of patients, with most changes made at breakfast (68% of patients). The most common reason for HCL exit was high sensor glucose (1.98/week). The most common topics during calls were importance of meal boluses, correction boluses for high blood glucose, and responding to system alerts to prevent HCL exits.

Conclusion: Ongoing educational support is vital in the early weeks of HCL use. Scheduled telephone contact helped address barriers and reinforce behaviors essential for success. Patients benefited from increased meal boluses in HCL compared to traditional pump mode. Future work will clarify the support necessary to optimize long- term outcomes with HCL.

Disclosure

C. Berget: None. S. Thomas: None. L.H. Messer: Other Relationship; Self; Medtronic MiniMed, Inc.. S. Owen: None. K. Thivener: None. R.H. Slover: None. R. Wadwa: Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; MannKind Corporation, Dexcom, Inc., Xeris Pharmaceuticals, Inc., Bigfoot Biomedical. G.T. Alonso: None.
Basal-Bolus Insulin Therapy May Not Be the Optimal Strategy in a "Real-World" Hospital Setting for Inpatient Hyperglycemia Management
Authors: SADHU ARCHANA R. , PATHAM BHARGAVI , VADHARIYA AISHA , JOHNSON MICHAEL L.
Published: June 2018

Basal bolus insulin therapy (BB) is recommended for glucose control in noncritically ill inpatients based on two small RABBIT2 trails. However, BB is complex and has limited data in large scale “real world” settings.

This is a retrospective analysis of 4,558 noncritical, medical-surgical admissions from 1/2013 to 9/2015 in patients ≥18 years who received SC but not IV insulin for ≥ 75% of the stay. Insulin therapy was identified within the first 2 days as BB (long + rapid, n=2319), sliding scale (SS, rapid only, n=1855) or Basal Only (BO, long only, n=384). A propensity score analysis adjusted for clinical, demographic and physician variables affecting choice of therapy. Point of care glucose (mg/dl) was used to define patient days as hypo- (any <70), hyper- (mean >180) or euglycemic (no <70 AND mean ≤180). Negative binomial regression analyzed glucose outcomes (number of hypo-, hyper- and euglycemic days, mean glucose); linear regression modeled log of length of stay (LOS); logistic regression modeled odds of 30 and 60 day readmission. All analyses were conducted overall and by medical or surgical DRG.

BB had worse glucose control but less LOS in medical DRG. BO had better hyper-, euglycemic and mean glucose. BB and BO had more hypo- days. This suggests that BO may be superior and simpler than BB for hyperglycemia but medical patients may benefit from BB for reasons beyond glucose control.

Insulin groupsOVERALL (n= 4,558)MEDICAL DRG (n =3,211)SURGICAL DRG (n= 1,347)Length of stay*BB vs SS0.97 (0.141)0.94 (0.003)1.02 (0.540)BO vs SS1.01 (0.711)0.99 (0.741)1.03 (0.665)Hyperglycemic days*BB vs SS0.99 (0.700)0.97 (0.416)1.00 (0.922)BO vs SS0.69 (<0.001)0.69 (<0.001)0.69 (<0.001)Hypoglycemic days*BB vs SS2.45 (<0.001)2.29 (<0.001)2.78 (<0.001)BO vs SS2.71 (<0.001)2.37 (<0.001)3..40 (<0.001)Euglycemic days*BB vs SS0.91 (0.008)0.85 (<0.001)1.01 (0.823)BO vs SS1.15 (0.012)1.11 (0.151)1.20 (0.063)Mean glucose*BB vs SS1.01 (0.415)1.69 (0.266)-1.18 (0.589)BO vs SS-17.27 (<0.001)-17.95 (<0.001)-15.91 (<0.001)1Results for 30 and 60 day readmission are not significantly different across the groups and are not presented in the table;*Results above shown as: Estimate (p-value)

Disclosure

A.R. Sadhu: None. B. Patham: None. A. Vadhariya: None. M.L. Johnson: None.
Duration of Insulin Supply in Type 1 Diabetes—Is 90 Days Better or Worse than 30 Days?
Authors: ROGERS MARY A.M. , KIM CATHERINE , TIPIRNENI RENUKA , BANERJEE TANIMA , LEE JOYCE
Published: June 2018

We evaluated whether the duration of insulin supply was associated with hemoglobin A1c. Data were obtained through the Clinformatics® Data Mart Database, from 2001-2015. Patients were grouped according to the duration of insulin supply: 30 days, 90 days, and a combination of both 30 day and 90 day prescriptions. Generalized estimating equations which account for repeated measures within patients were used, with robust estimates of variance. Prescription duration was regressed on HbA1c (dependent variable) with alpha=0.(2-tailed). There were 16,725 eligible patients (9362 with 30-day, 1280 with 90-day, and 6083 with both 30- and 90-day prescriptions). The mean number of HbA1c tests/patient was 3.1. Patients who used 30-day prescriptions had HbA1c values that were 0.65 greater than those with 90-day prescriptions (p<0.001). Patients who used a combination of 30-day and 90-day prescriptions had HbA1c values that were 0.37 greater compared to 90-day prescriptions (p<0.001). The predicted HbA1c values were 8.33% (95% CI: 8.31%, 8.36%) for 30-day, 8.05% (95% CI: 8.03%, 8.08%) for the combination, and 7.69% (95% CI: 7.64%, 7.73%) for 90-day prescriptions. Results were similar when stratified by age. For those <20 years of age, the predicted HbA1c values were 8.95% for 30-day, 8.71% for the combination, and 8.33% for 90-day prescriptions. For those ≥20 years of age, the results were 8.26%, 7.96% and 7.64%, respectively. Patterns were similar when stratified by sex. Mailed prescriptions were also associated with lower HbA1c (p<0.001). Predicted HbA1c was 7.58% (95% CI: 7.53%, 7.63%) when all prescriptions were mailed and 8.21% (95% CI: 8.19%, 8.23%) when not. After simultaneous adjustment for age, sex, duration of supply, and mailed status, both 90-day prescriptions and mailed prescriptions were associated with lower HbA1c values (p<0.001 for both). In patients with type 1 diabetes, 90-day insulin prescriptions and mailed prescriptions were both independently associated with lower HbA1c values.

Disclosure

M.A.M. Rogers: None. C. Kim: None. R. Tipirneni: None. T. Banerjee: None. J. Lee: Consultant; Self; Unitio.
Dulaglutide Has Higher Adherence and Persistence than Liraglutide and Exenatide QW—One-Year Follow-Up from U.S. Real-World Data
Authors: MODY REEMA , HUANG QING , YU MARIA , ZHAO RUIZHI , PATEL HIREN , GRABNER MICHAEL , LANDO LAURA FERNANDEZ
Published: June 2018

The objective of this retrospective real-world observational study was to compare 1-year adherence and persistence among patients initiating GLP-1 receptor agonists (GLP-1RA), dulaglutide (DULA) vs. liraglutide (LIRA) or DULA vs. exenatide QW (EQW) in the U.S., using claims data between November 2014 and May 2016 (index date=earliest GLP-1RA fill date) from the HealthCore Integrated Research Database (HIRD®).

Patients ≥18 years old, with T2DM, no claim for index drug in the 6 months pre-index period, and continuous enrollment 6 months pre- and 1-year post-index were included. DULA users were propensity-matched 1:1 to LIRA (2,427 pairs) or EQW (1,8pairs) users. Matched cohorts were balanced in baseline characteristics and the mean age was 54 years with around 52% males.

The key adherence and persistence outcomes are included in the table. At 1-year, DULA users were more likely to be adherent [Proportion of Days Covered (PDC)≥80%] than LIRA (odds ratio [OR]=1.76, 95% CI=[1.56, 1.99]) or EQW users (OR=2.31, 95% CI=[2.00, 2.66]). Cox regression showed that DULA users were less likely to discontinue therapy than LIRA (hazard ratio [HR]=0.75, 95% CI=[0.69, 0.81]) or EQW users (HR=0.58, 95% CI=[0.53, 0.63]).

At 1-year follow-up, patients initiating DULA had higher medication adherence, and were more persistent to their treatment compared to patients initiating either LIRA or EQW.

Table: 1-Year Follow-up Adherence and Persistence Outcomes Among GLP-1 RA InitiatorsMatched DULA vs. LIRA CohortsMatched DULA vs. EQW1 CohortsDULALIRAp-value2DULAEQW1p-value2N=2,427N=2,427N=1,808N=1,808Proportion of Days Covered (PDC), mean (SD) in %67.3% (32.1)59.5% (32.6)<0.00166.8% (32.2)51.3% (34.6)<0.001Adherence (PDC ≥ 80%), %51.2%38.2%<0.00150.7%31.9%<0.001Patients who discontinued therapy, %51.1%62.0%<0.00151.1%70.9%<0.001Persistence3, mean (SD) days251.9 (135.7)217.3 (143.0)<0.001250.5 (136.8)191.6 (139.3)<0.0011The study included only exenatide QW pen users.2P-values for categorical variables were obtained using Chi-square tests; p-values for continuous variables were obtained using Wilcoxon rank sum tests.3The number of days of continuous index GLP-1 RA therapy since initiation, allowing for a maximum gap (between fills) of 45 days. Patients who were censored at the end of the 1-year follow-up period were included.

Disclosure

R. Mody: Employee; Self; Eli Lilly and Company. Q. Huang: Other Relationship; Self; Eli Lilly and Company. M. Yu: Employee; Self; Eli Lilly and Company. R. Zhao: Other Relationship; Self; Eli Lilly and Company. H. Patel: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. M. Grabner: Employee; Self; HealthCore, Inc. L. Fernandez Lando: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.
Institutional Inpatient Diabetes Management—We're Still Not Doing It Right
Authors: KRAVCHENKO MARIA , WARDIAN JANA L. , GRAYBILL SKY
Published: June 2018

Introduction: Morbidity and mortality increase with substantial glucose excursions during hospitalizations. The American Diabetes Association recommends an optimal glucose target of 140-180mg/dL for most inpatients with diabetes; glucose ranges of 80-180mg/dL are acceptable. They recommend against using correctional insulin alone; however, previous surveys have shown widespread use. The aim of this project was to identify current glycemic management patterns in our institution and find areas for improvement.

Methods: We investigated inpatient admissions to San Antonio Military Medical Center from March to September 2017. Patients included adults on medical or surgical services who received subcutaneous insulin, regardless of diabetes status. Data were collected for insulin orders, administration times, glucose values, and HbA1c levels.

Results: There were 1656 patients; 59% received only correctional insulin; 27% received basal and correctional insulin; 13% received basal/bolus insulin. Most patients (73%) did not reach glycemic targets; rates of hypoglycemia were 4-23%, which was higher than expected. Patients with HbA1c values of 8-9% were more likely to receive basal insulin; despite this, glycemic control remained poor. Troublingly, 13% of patients receiving correctional insulin alone had normoglycemia or normal baseline HbA1c values; 19% of these patients developed hypoglycemia during hospitalization.

Conclusion: Despite national guidelines, the majority of patients in our institution received only correctional insulin and did not achieve glucose targets. Additionally, most patients receiving basal/bolus insulin did not achieve glucose targets, suggesting inadequate titration. This requires systematic interventions to improve inpatient diabetes management.

Disclaimer: The views expressed are those of the authors and do not reflect the official views or policy of the Department of Defense or its Components.

Disclosure

M. Kravchenko: None. J.L. Wardian: None. S. Graybill: None.
Incorporating Cardioprotective Effects of Once-Weekly Semaglutide in Estimates of Health Benefits for Patients with Type 2 Diabetes
Authors: EVANS MARC , JOHANSEN PIERRE , VRAZIC HRVOJE
Published: June 2018

Economic modeling of type 2 diabetes (T2D) relies on sets of risk equations (e.g., UKPDS 68) to predict cardiovascular (CV) events and mortality as mediated through changes in risk factors (e.g., HbA1c). Recent CV outcomes trials (CVOTs) have shown significant benefits in events over a short time period (between 2-4 years), along with beneficial changes in risk factors such as blood pressure, HbA1c, and weight. The contributions of these changes to the observed outcomes within these CVOTs are unclear. In patients with high CV risk, the SUSTAIN 6 trial of once-weekly semaglutide+standard of care (SoC) reported a statistically significant reduction in stroke (HR=0.61) after 104 weeks vs. placebo+SoC. We sought to establish the contribution of risk factor changes to this observed outcome, by evaluating the performance of traditional risk equations in predicting outcome benefits seen with once-weekly semaglutide. As a secondary objective, the impact of incorporating the stroke benefit on estimated long term health benefits was assessed. The IQVIA Core Diabetes Model was used to assess predictive accuracy of the UKPDS 68 risk equations on the observed stroke benefit. Secondly, the model was calibrated to preserve the ratio of the observed cumulative incidence of stroke between treatment arms. Finally, results were extrapolated over 50 years. The UKPDS 68 equations were able to predict 64% of the observed 2-year stroke risk reduction, suggesting a drug-mechanistic effect other than changes in risk factors. Calibration results indicate that a relative risk of stroke of 0.83 (17% reduction) applied to once-weekly semaglutide was required to preserve the cumulative incidence ratio. Results of extrapolation increased quality-adjusted life-years by 0.18 and life-years by 0.29 vs. placebo+SoC. Results of this analysis may have implications on future approaches assessing the long term economic impact of new therapies in T2D in this era of multiple CVOTs.

Disclosure

M. Evans: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novartis AG, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp. P. Johansen: Consultant; Self; Janssen Global Services, LLC.. Employee; Self; Novo Nordisk A/S. H. Vrazic: Employee; Self; Novo Nordisk A/S.
Electronic Messaging Use via a Patient Portal Is Associated with Primary Care Utilization in Patients with Type 2 Diabetes
Authors: SUN RAN , SEREIKA SUSAN M. , SAUL MELISSA , KORYTKOWSKI MARY T. , LI DAN , BURKE LORA E.
Published: June 2018

Background: Electronic messaging via a patient portal is being used with increasing frequency for patient-provider communication, especially for the ongoing management of type 2 diabetes (T2DM). Providing patients online access to providers may reduce the need for face-to-face contact; yet little is known about the usage pattern and its association with the frequency of office visits to primary care providers (PCP).

Methods: A cross-sectional analysis was conducted using the data from the ambulatory electronic health records of UPMC Physician Services. Adults with T2DM who were seen in UPMC PCP offices between Jan 2015 and Dec 2016 were included. The number of days messaging was used, and the number of PCP visits for each patient were calculated during the study period. Descriptive statistics were applied. Negative binomial regression was performed to examine the association of messaging use with the number of PCP visits, adjusting for age, gender, race, education, income, insurance type, and the number of comorbidities.

Results: The sample (N=42,746) was 85.5% white and 49.9% female with a mean age of 65.2±11.9 years. About a third (36.7%, n=15,698) used the messaging feature at least once during the study period. The median number of days that patients used the messaging feature was 13.0 (range 1-395). Negative binomial regression revealed that greater use of messaging was associated with a greater number of PCP visits (Incidence Rate Ratio 1.0014, 95% CI, 1.0011-1.0018).

Conclusion: In our study, over one-third of the patients used the messaging feature via the portal. More frequent use of messaging was associated with a greater number of PCP visits, suggesting that both measures represent patient engagement in health care services. However, the frequency of PCP visits may not be an accurate indicator of clinical outcomes. Future studies that include patient outcome measures, such as HbA1c, according to portal use are needed as use of this technology increases.

Disclosure

R. Sun: None. S.M. Sereika: None. M. Saul: None. M.T. Korytkowski: Advisory Panel; Self; Novo Nordisk Inc.. Other Relationship; Self; JAEB Center For Health Research. D. Li: None. L.E. Burke: None.
Medical Costs of Diabetic Ketoacidosis Presenting at Diagnosis of Diabetes among Privately Insured Youth, 2016
Authors: SHRESTHA SUNDAR , ZHANG PING , IMPERATORE GIUSEPPINA
Published: June 2018

Diabetes ketoacidosis (DKA) is a potentially preventable acute and severe complication of diabetes (DM). Youth often present with DKA at DM diagnosis and having DKA predicts poor long-term glycemic control. Little is known about the medical costs associated with DKA presenting at DM diagnosis. Using 2010-2016 MarketScan claims data, we estimated the occurrence of DKA at DM diagnosis and compared medical costs 60 days prior and post DM diagnosis in youth (age <20 years) with and without DKA. We identified newly diagnosed DM as having ≥1 inpatient or ≥2 outpatient claims 30 days apart with DM codes, but no DM claim or prescription of DM medications in the two years prior to DM diagnosis, no history of acute/chronic pancreatitis, and no gestational DM. Both DM and DKA were identified using ICD9 or ICD10 claim codes. We estimated medical costs (in U.S. $2016) using regression models (Table). Among 3,301 youth with newly diagnosed DM, 43% presented with DKA. As compared to youth without DKA, those with DKA were younger and more likely to be males (p<0.05). Health services use and total medical costs are presented in Table. The presence of DKA at DM diagnosis was associated with large financial burden to both the health care system (>$6,500) and to patients (>$1,100). These data could be used for planning and evaluating interventions aimed at preventing this life-threating condition.

Table.Heath services use and medical costs among youth, 60 days prior and post diabetes diagnosis by DKA status at diagnosis.Outcomes60 Days Prior DM Diagnosis 60 Days Post DM Diagnosis With DKAWithout DKAExcess With DKAWithout DKAExcessMean Health Services use:No. of outpatient visits2.103.27-1.17***4.594.66-0.07No. of office visits1.061.38-0.32***2.362.080.28***No. of ER visits0.270.270.010.230.210.03No. of inpatient admissions1.000.650.35***1.010.670.34***Length of stay, days2.451.820.63***2.472.0060.47***Estimated Medical costs:Outpatient#$2,075$1,275$801***$2,883$1,792$1,091***Inpatient##$13,706$8,698$5,008***$13,765$9,227$4,538***Prescription drugs#$91$175-$84***$2,417$1,463$954***Total#$15,872$10,147$5,725***$19,065$12,482$6,583***Total copay#$2,099$1,193$907*** $2,588$1,453$1,135***Notes: *=p<0.05, **=p<0.01, ***=p<0.001; ER= Emergency Room; # Estimated using a generalized linear model with log link and gamma distribution; ## Estimated using a two-part model: logistic regression and generalized linear model with log link and gamma distribution controlling for age and sex.

Disclosure

S. Shrestha: None. P. Zhang: None. G. Imperatore: None.