Takeda Development Center Americas Research Articles

110-OR: Type 2 Diabetes (T2D)–Associated TCF7L2 Genetic Variants and Indices of Insulin Secretion and Sensitivity in Individuals at Risk for Type 1 Diabetes (T1D)

In individuals with new onset T1D, T2D-associated TCF7L2 genetic variants are associated with lower area-under-the curve (AUC) glucose and higher AUC C-peptide responses to a mixed meal. We aimed to test whether TCF7L2 variants affect glucose metabolism in nondiabetic islet autoantibody-positive (AbPos) individuals. We studied 1065 TrialNet Pathway to Prevention Study participants (AbPos relatives of persons with T1D) with TCF7L2 SNPs who underwent oral glucose tolerance tests (OGTT) (mean age 16.3 yrs, 63% <18 years old, 91.1% non-Hispanic, 47.7% male; T2D-associated TCF7L2 SNP: 48.1% 0 alleles, 43.9% 1 allele, 8% 2 alleles). We assessed the contribution of TCF7L2 SNP variants on Fasting (FIIS) and OGTT Index of Insulin Sensitivity (OIIS), Insulin Secretion (OIISec), and Disposition Index (ODI) with univariate and multivariate analyses. Then we studied the interaction between TCF7L2 SNP and BMI. With Bonferroni correction for multiple comparisons, p-values <0.0086 were considered statistically significant. Insulin sensitivity and secretion indices were significantly associated with age (FIIS, OIIS, OIISec), BMI Z-score (FIIS, OIIS, OIISec, ODI) and Hispanic ethnicity (FIIS, OIIS) but not sex in univariate analyses. TCF7L2 SNP was not significantly associated with these indices in univariate or multivariate analyses adjusting for BMI, age, sex and race-ethnicity. There was a significant interaction between BMI and presence of 2 (vs. 0) TCF7L2 SNP alleles on insulin sensitivity (OIIS) in children (p=0.0079) but not adults (p=0.94). After adjusting for age, ethnicity and sex, the difference did not reach statistical significance (p=0.0135). Restricting to non-obese participants, the results were similar. In sum, in nondiabetic AbPos individuals, the TCF7L2 variant does not appear to impact insulin sensitivity or secretion indices after accounting for BMI, age, sex and race-ethnicity. Disclosure M.J. Redondo: None. M.V. Warnock: None. L.E. Bocchino: None. S. Geyer: None. A. Pugliese: None. A. Steck: None. I. Libman: Consultant; Self; Novo Nordisk A/S. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. D.J. Becker: None. J. Sosenko: None. F. Bacha: Research Support; Self; AstraZeneca, Takeda Development Center Americas, Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases

59-OR: Lipoprotein Particle Distribution by NMR in Youth with Type 2 Diabetes (T2D) in the TODAY Study

T2D in adolescents is associated with an unfavorable lipid profile, but data on lipoprotein particle size and distribution in this population have yet to be published. The TODAY Study, a randomized treatment trial of T2D in youth, provided the opportunity to evaluate lipoprotein particle distribution and relate lipoprotein particle number and size to HbA1C, need for insulin treatment, gender, race/ethnicity, BMI, and blood pressure (BP). TODAY participants (n=348) with yearly samples available for NMR Lipoprofile assessments (baseline, 12, 24, 36 mos) were included. Baseline participant characteristics (mean±SD) were: age 13.7±2.0 yrs; BMI 34.3±7.6 kg/m2; 62.4% female; 20.7% White, 32.2% Non-Hispanic Black (NHB), 43.7% Hispanic. Analysis demonstrated increasing numbers of LDL, HDL, and VLDL particles over the three yrs (all ps<0.0001) with somewhat weaker trends for decreasing particle size (LDL p=0.0009, HDL p=0.02). HbA1c showed a strong positive correlation with LDL, VLDL, and HDL particle number (all ps<0.005). HbA1c was negatively associated with LDL (p<0.0001) and HDL size (p=0.001) but positively associated with VLDL size (p<0.0001). Need for insulin treatment did not impact these associations. Female subjects had larger HDL particle size than males at baseline (p=0.0004) and throughout (p<0.0001). NHBs had the largest LDL and HDL particle size and smallest VLDL particle size. BMI% and BP showed positive association with LDL, HDL, and VLDL particle numbers but negative association with LDL and HDL size. The preponderance of lipoprotein parameters were strongly associated with TG/HDL ratio and non-HDL-C after adjusting for baseline age, race, gender, BMI%, BP, and need for insulin treatment (p<0.0001). In conclusion, these data demonstrate an atherogenic lipoprotein phenotype in youth with T2D and strong relationships with glycemic control and other cardiac risk factors. Concern regarding premature development of atherosclerosis in youth with T2D is warranted. Disclosure L.E. Katz: None. J.D. Otvos: Employee; Self; LabCorp. K. Drews: None. B. Tesfaldet: None. F. Bacha: Research Support; Self; AstraZeneca, Takeda Development Center Americas, Inc. S.M. Willi: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Tolerion, Inc. Other Relationship; Self; Caladrius Biosciences, Inc. S.M. Marcovina: None. S. Mckay: None. R.S. Weinstock: Board Member; Self; JDRF. Consultant; Self; Insulogic LLC. Research Support; Self; Boehringer Ingelheim International GmbH, Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Insulet Corporation, Jaeb Center for Health Research, Kowa Research Institute, Inc., Medtronic, Tolerion, Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK61212)

56-OR: Degree of ß-Cell Function (ßCF) Impairment and Glycemic Alterations in Obese Youth (OY) Spanning from Normal Glucose Tolerance (NGT) to Impaired Glucose Tolerance (IGT) to Type 2 Diabetes (T2D): Does Race Matter?

In OY it is not clear what degree of βCF impairment translates to increases in OGTT glucose area under the curve (G-AUC) commensurate with transition from NGT to IGT to T2D, and whether there are racial differences. Given the high rates of T2D in Black (BY) vs. White youth (WY), we hypothesized that βCF decline in BY is more detrimental and results in larger increases in G-AUC than in WY. Here we report the quantitative relationship between differences in clamp disposition index (DI=insulin sensitivity [IS] by a 3-hr hyperinsulinemic (80 mu/m2/min)-euglycemic clamp x 1st-phase insulin by a 2-hr hyperglycemic (225 mg/dL) clamp) and OGTT G-AUC in 152 OY. Two-way ANOVA (race x glycemic status) showed that in BY vs. WY larger decrements in DI from NGT to IGT and from NGT to T2D (all p<0.05) correspond to comparable increments in G-AUC (p=NS, Table), with no significant race interaction from IGT to T2D. Contrary to our hypothesis, loss of βCF in IGT and T2D is less detrimental in BY because a ∼2-3 fold greater impairment in βCF corresponds to a similar increase in G-AUC to that of WY. Such observations of preserved glucose regulation in BY compared with WY in the face of larger declines in βCF suggest an adaptive glucose-stimulated glucoregulatory mechanism protecting against dysglycemia consequent to insulin deficiency. Disclosure J. Kim: None. H.M. Tfayli: None. F. Bacha: Research Support; Self; AstraZeneca, Takeda Development Center Americas, Inc. N. Gebara: None. S.A. Arslanian: Research Support; Self; National Institutes of Health. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development (K24-HD01357, R01HD27503); National Center for Advancing Translational Sciences (UL1TR000005); National Center for Research Resources (UL1RR024153)

53-OR: Efficacy of Efpeglenatide in Patients with Obesity and Prediabetes: A Subanalysis of the BALANCE 205 Study

Once-weekly (QW), subcutaneous efpeglenatide (efpeg) is a long-acting GLP-1 RA being developed to improve glycemic control in T2D. In the 20-week BALANCE 205 study (NCT02075281), all doses of efpeg led to significant reductions in body weight (BW) vs. placebo (PBO) in patients with obesity without diabetes (p<0.0001; primary endpoint). This exploratory analysis investigated the effects of efpeg on glycemic, BW, BMI, waist circumference (WC) and cholesterol parameters in patients from BALANCE with prediabetes (HbA1c 5.7−6.4% or FPG 100−125 mg/dL) at baseline (n=140/295). At study end, percentages of patients with normoglycemia (i.e., no longer prediabetic) were higher with efpeg (4 mg QW, 64.3%; 6 mg QW, 46.2%; 6 mg once every 2 weeks [Q2W], 40.6%; 8 mg Q2W, 41.7%; pooled efpeg, 48.2%) than with PBO (10.0%; Table). All efpeg doses led to significant reductions vs. PBO in BW and HbA1c (p<0.0001 for all comparisons; −6.6 kg and −0.4%, respectively for pooled group), BMI, total cholesterol, FPG and WC (p<0.05 for all), except the 4 mg QW dose for WC. Adverse events (AEs) mirrored those known for GLP-1 RAs, with higher rates of gastrointestinal AEs vs. PBO, with no incidences of severe hypoglycemia. In conclusion, treatment with efpeg led to significant improvements vs. PBO in HbA1c, BW, BMI, FPG, WC and cholesterol, and greater proportions of patients achieving normoglycemia, in patients with obesity and prediabetes. Disclosure R.E. Pratley: Consultant; Self; Sanofi US. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Janssen Global Services, LLC., Janssen Research & Development, Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk Inc., Pfizer Inc., Sanofi, Takeda Development Center Americas, Inc. S. Jacob: Advisory Panel; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novartis AG, Novo Nordisk A/S, Roche Diabetes Care, Sanofi. J. Kang: Employee; Self; Hanmi Pharm. Co., Ltd. M.E. Trautmann: Consultant; Self; CeQur Corporation, Hanmi Pharm. Co., Ltd., Intarcia Therapeutics, Inc., Oramed Pharmaceuticals, ProSciento, Servier. Stock/Shareholder; Self; Lilly Diabetes. M. Hompesch: Stock/Shareholder; Self; ProSciento. O. Han: None. J.A. Stewart: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. I. Ogbaa: Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc. Other Relationship; Self; Sanofi. C.H. Sorli: Employee; Self; Sanofi. K. Yoon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc. Speaker's Bureau; Self; Takeda Pharmaceutical Company Limited. Funding Hanmi Pharmaceutical, Co., Ltd.; Sanofi

1004-P: Oral Semaglutide vs. Placebo in Patients with Type 2 Diabetes and Moderate Renal Impairment: PIONEER 5

Patients (pts) with T2D and renal impairment have limited glucose-lowering treatment options. Oral semaglutide (sema) 14 mg once daily (N=163) was compared with placebo (pbo, N=161) in a 26-week, randomized, phase 3a trial (NCT02827708) in pts with T2D and moderate renal impairment (eGFR 30-59 mL/min/1.73 m2), receiving 1-2 glucose-lowering agents (could include basal insulin). Endpoints: change in HbA1c (primary) and body weight (BW, secondary) to week 26. Two estimands were defined: treatment policy (regardless of trial product discontinuation or rescue medication) and trial product (on trial product without rescue medication) in all randomized pts. Oral sema was superior to (treatment policy) and significantly better than (trial product) pbo in reducing HbA1c and BW (Table). More pts reached HbA1c, BW loss, and composite targets with oral sema. At follow-up, eGFR was unchanged. Fewer pts on oral sema required rescue medication (4 vs. 10%). Adverse events were more frequent with oral sema (74 vs. 65%), most often mild/moderate nausea (19 vs. 7%). More patients on oral sema prematurely discontinued trial product (15 vs. 5%), mainly due to nausea and vomiting. In conclusion, in pts with T2D and moderate renal impairment, oral sema provided superior glycemic control and BW loss compared to pbo at 26 weeks, did not appear to affect renal function, and was well tolerated in line with the population and GLP-1RA class. Disclosure O. Mosenzon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. S. Rosenlund: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. J.W. Eriksson: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. S.R. Heller: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Zealand Pharma A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. R.E. Pratley: Consultant; Self; Sanofi US. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Janssen Global Services, LLC., Janssen Research & Development, Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk Inc., Pfizer Inc., Sanofi, Takeda Development Center Americas, Inc. T. Sathyapalan: Speaker's Bureau; Self; Novo Nordisk Foundation. Other Relationship; Self; Bristol-Myers Squibb Company, Eli Lilly and Company, Sanofi-Aventis. T.M. Blicher: Employee; Self; Novo Nordisk A/S. O.H. Hels: Employee; Self; Novo Nordisk A/S. C. Desouza: Consultant; Self; Novo Nordisk A/S, Sanofi US. Funding Novo Nordisk A/S

55-OR: Oral Semaglutide vs. Liraglutide and Placebo in T2D: PIONEER 4

Patients (pts) with T2D uncontrolled on metformin ± SGLT2i were randomized to oral semaglutide (sema) 14 mg once daily (N=285), liraglutide (lira) 1.8 mg (N=284) or placebo (pbo, N=142) in a phase 3a, 52-week, double-blind, double-dummy trial (NCT02863419). Endpoints: Change (baseline to week 26) in HbA1c (primary) and body weight (BW, confirmatory secondary). Two estimands addressed two efficacy-related questions: Treatment policy (regardless of trial product discontinuation or rescue medication) and trial product (on trial product without rescue medication) in all randomized pts. Treatment policy estimand: Oral sema was non-inferior (margin 0.4%) to lira and superior to pbo in reducing HbA1c, and superior to both in reducing BW at week 26 (Table). Differences in both HbA1c and BW were significant at week 52. Trial product estimand: Oral sema gave significant reductions in HbA1c and BW vs. lira and pbo at weeks 26 and 52. Oral sema had comparable tolerability to lira; 11% (oral sema) vs. 9% (lira) and 4% (pbo) prematurely discontinued trial product due to adverse events (primarily gastrointestinal; 5% [oral sema] vs. 3% [lira] discontinued due to nausea). In conclusion, oral sema was well tolerated in pts with T2D on metformin ± SGLT2i, was non-inferior vs. lira and superior vs. pbo in reducing HbA1c, and was superior in reducing BW vs. both lira and pbo. The reduction in HbA1c was significantly better vs. lira when evaluated by the trial product estimand. Disclosure R.E. Pratley: Consultant; Self; Sanofi US. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Janssen Global Services, LLC., Janssen Research & Development, Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk Inc., Pfizer Inc., Sanofi, Takeda Development Center Americas, Inc. A. Amod: Advisory Panel; Self; Aspen Pharmacare, AstraZeneca, Novartis AG, Novo Nordisk A/S, Sanofi-Aventis. Consultant; Self; Servier. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Sanofi-Aventis, Servier. S.T. Hoff: Employee; Self; Novo Nordisk A/S. T. Kadowaki: Research Support; Self; Astellas Pharma Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kowa Pharmaceutical, Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD, Nippon Boehringer Ingelheim, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Mitsubishi Tanabe Pharma Corporation, MSD, Nippon Boehringer Ingelheim, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. I. Lingvay: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., MannKind Corporation. Consultant; Self; AstraZeneca, Novo Nordisk Inc., Sanofi, TARGET PharmaSolutions, Valeritas, Inc. Research Support; Self; Merck & Co., Inc., Mylan, Novo Nordisk Inc., Pfizer Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. M.A. Nauck: Advisory Panel; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sun Pharma. K. Pedersen: Employee; Self; Novo Nordisk A/S. T. Saugstrup: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Zealand Pharma A/S. J.J. Meier: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Funding Novo Nordisk A/S

2398-PUB: The Interplay of Type 1 Diabetes and Weight: A Qualitative Study of Thematic Progression with Age

The impact of weight management in persons with type 1 diabetes (T1D) from childhood into adulthood is not well described. The purpose of the study is to explore qualitative themes presented by young adults on both weight and T1D management. We analyzed focus group data from 17 young adults with T1D via inductive qualitative analysis. Major themes were compared to published themes presented by youth with T1D to categorize thematic progression from youth to adulthood. Themes from young adults with T1D, when compared to youth, are categorized as: unchanged, evolving, and newly reported. Hypoglycemia and a sense of futility around exercise was an unchanged theme. Importance of insulin usage and a need for a healthy personal relationship with T1D evolved to gather greater conviction. Newly reported themes are unique to integration of adulthood into T1D, such as family planning and work-diabetes balance. Young adults also newly reported negative experiences with providers in their younger years and desire for more supportive provider relationships. Issues identified by youth regarding the dual management of T1D and weight rarely resolve, but rather, persist unchanged or integrate other aspects of young adulthood via evolving or newly emerged themes. Individualized and age-appropriate clinical support and practice guidelines are warranted to facilitate the dual management of weight and T1D in persons with T1D Disclosure A. Addala: None. D. Igudesman: None. A.R. Kahkoska: None. F.R. Muntis: None. K.J. Souris: None. K.J. Whitaker: None. R.E. Pratley: Consultant; Self; Sanofi US. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Janssen Global Services, LLC., Janssen Research & Development, Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk Inc., Pfizer Inc., Sanofi, Takeda Development Center Americas, Inc. E. Mayer-Davis: None.

1000-P: Efficacy and Safety of Semaglutide 0.5 mg vs. Dulaglutide 1.5 mg Once Weekly in Type 2 Diabetes: A Post Hoc Analysis of SUSTAIN 7

Semaglutide and dulaglutide are glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes (T2D). In SUSTAIN 7, an international, open-label, parallel group trial, adults with inadequately controlled T2D were randomized (1:1:1:1) to once-weekly subcutaneous semaglutide or dulaglutide at low (0.5 vs. 0.75 mg) or high (1.0 vs. 1.5 mg) doses. Semaglutide provided superior glycemic control and reductions in body weight at both low and high doses. To study doses available in clinical practice, we performed a post hoc analysis of the effects of semaglutide low (0.5 mg) vs. dulaglutide high (1.5 mg) dose at week 40, using statistical methods in published prespecified analyses. Subjects mean age was 56 years, HbA1c 8.2%, diabetes duration 7.4 years; 77% were white. Efficacy data (Table) show similar glycemic control and blood pressure, and greater weight loss, for semaglutide 0.5 mg vs. dulaglutide 1.5 mg. Frequency and severity of adverse events (AEs) were similar for semaglutide and dulaglutide, including gastrointestinal (GI) AEs (nausea: 23% vs. 20%, respectively; vomiting: 10%, each treatment). Premature discontinuation due to GI AEs occurred in 5% of subjects in each arm. In summary, semaglutide 0.5 mg showed similar improvements in glycemic control and greater weight loss vs. dulaglutide 1.5 mg at week 40, while showing similar tolerability in subjects with T2D. Disclosure R.E. Pratley: Consultant; Self; Sanofi US. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Janssen Global Services, LLC., Janssen Research & Development, Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk Inc., Pfizer Inc., Sanofi, Takeda Development Center Americas, Inc. V.R. Aroda: Consultant; Self; ADOCIA, AstraZeneca, Becton, Dickinson and Company, Novo Nordisk Inc., Sanofi, Zafgen, Inc. Employee; Spouse/Partner; Merck & Co., Inc. Research Support; Self; AstraZeneca, Calibra Medical, Eisai Inc., Janssen Research & Development, Novo Nordisk Inc., Sanofi, Theracos, Inc. T. Gondolf: Employee; Spouse/Partner; Chr. Hansen Holding A/S. Employee; Self; Novo Nordisk A/S. T. Hansen: None. I. Lingvay: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., MannKind Corporation. Consultant; Self; AstraZeneca, Novo Nordisk Inc., Sanofi, TARGET PharmaSolutions, Valeritas, Inc. Research Support; Self; Merck & Co., Inc., Mylan, Novo Nordisk Inc., Pfizer Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. J. Luedemann: None. T.V. Skjoeth: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. A. Viljoen: Advisory Panel; Self; NAPP Pharmaceuticals Limited. Research Support; Self; Eli Lilly and Company, Sanofi-Aventis. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S. Funding Novo Nordisk A/S

1001-P: Effects of Efpeglenatide on Body Weight, BMI, and Waist Circumference in Patients With Obesity Without Diabetes Stratified by Baseline Characteristics: A Subanalysis of BALANCE 205

Once-weekly (QW) subcutaneous efpeglenatide (efpeg) is a long-acting GLP-1 RA being developed to improve glycemic control in patients with T2D. In the BALANCE 205 study (NCT02075281) in patients with obesity (median BMI 34.9 [28.1−57.7] kg/m2) without diabetes, all doses of efpeg (4 or 6 mg QW; 6 or 8 mg once every 2 weeks [Q2W]) significantly reduced body weight (BW) from baseline (BL) to Week 21 vs. placebo (PBO, p<0.0001; primary endpoint). In this exploratory subgroup analysis, the effects of efpeg (in each treatment arm or pooled data) on BW, BMI, and waist circumference (WC) from BL to Week 21 vs. PBO were investigated in patients stratified by BMI, WC, and age (< or ≥ median BL values). All efpeg groups were associated with significant reductions in BW and BMI from BL vs. PBO across all subgroups (Table). Efpeg also led to significant reductions in WC vs. PBO across subgroups apart from lower doses of efpeg in subgroups with BMI and WC ≥ median (4 mg QW and 6 mg Q2W), and age ≥ median (4 mg QW). The observed adverse events mirrored those known for GLP-1 RAs. In conclusion, all doses of efpeg led to consistent, significant reductions in BW and BMI in patients with obesity without diabetes in all subpopulations tested; results were consistent with those of the overall BALANCE population. Disclosure R.E. Pratley: Consultant; Self; Sanofi US. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Janssen Global Services, LLC., Janssen Research & Development, Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk Inc., Pfizer Inc., Sanofi, Takeda Development Center Americas, Inc. S. Jacob: Advisory Panel; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novartis AG, Novo Nordisk A/S, Roche Diabetes Care, Sanofi. J. Kang: Employee; Self; Hanmi Pharm. Co., Ltd. M.E. Trautmann: Consultant; Self; CeQur Corporation, Hanmi Pharm. Co., Ltd., Intarcia Therapeutics, Inc., Oramed Pharmaceuticals, ProSciento, Servier. Stock/Shareholder; Self; Lilly Diabetes. M. Hompesch: Stock/Shareholder; Self; ProSciento. O. Han: None. J.A. Stewart: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. I. Ogbaa: Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc. Other Relationship; Self; Sanofi. C.H. Sorli: Employee; Self; Sanofi. K. Yoon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc. Speaker's Bureau; Self; Takeda Pharmaceutical Company Limited. Funding Hanmi Pharmaceutical, Co., Ltd.; Sanofi

1210-P: Pooled Analysis of the Safety and Efficacy of Ertugliflozin in the Elderly

Ertugliflozin (ERTU), an SGLT2 inhibitor, improves glycemic control in adult patients (pts) with T2DM. Elderly pts with T2DM are underrepresented in clinical studies, often present with multiple co-morbidities and are more susceptible to adverse events (AEs). Pooled analyses based on 7 phase 3 studies from the VERTIS program evaluated the safety and efficacy of ERTU in subgroups of pts aged <65 and ≥65 years. Pts with T2DM received ERTU (5 or 15 mg ± sitagliptin [SITA] 100 mg) or control (placebo [PBO], glimepiride or SITA). Safety data were evaluated up to 104 weeks. Efficacy was assessed in a subset of 3 PBO-controlled studies at 26 weeks. Baseline (BL) characteristics were similar between pts aged <65 (n=3605) and ≥65 years (n=1254), with the exception of mean BL estimated glomerular filtration rates (90.2 mL/min/1.73 m2 in pts <65 and 71.4 mL/min/1.73 m2 in pts ≥65). The safety profile of ERTU was similar in both age groups, except for a higher incidence of volume depletion AEs with ERTU relative to control (2.4% vs. 1.1%) in pts ≥65. Excluding pts with BL moderate renal impairment, incidence of renal-related AEs was similar across groups in pts ≥65 (ERTU [0.6%] vs. control [0.8%]), suggesting age alone does not increase risk of renal-related AEs. In the 3 PBO-controlled studies, documented hypoglycemia (4.4% vs.6.0%) and severe hypoglycemia rates (0.4% vs. 0.4%) with ERTU were comparable in pts <65 and ≥65. Efficacy of ERTU by age group is shown in the Figure. Disclosure R.E. Pratley: Consultant; Self; Sanofi US. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Janssen Global Services, LLC., Janssen Research & Development, Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk Inc., Pfizer Inc., Sanofi, Takeda Development Center Americas, Inc. S. Dagogo-Jack: Board Member; Self; Jana Care Inc. Consultant; Self; Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi-Aventis. Research Support; Self; AstraZeneca, Novo Nordisk Inc. Stock/Shareholder; Self; Dance Biopharm Holdings Inc. B. Charbonnel: Consultant; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Servier. Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Takeda Pharmaceutical Company Limited. S.M. Patel: Stock/Shareholder; Spouse/Partner; Janssen Pharmaceuticals, Inc. Stock/Shareholder; Self; Merck & Co., Inc. M.A. Hickman: Employee; Self; Pfizer Inc. J. Liu: Employee; Self; Merck & Co., Inc. L. Tarasenko: Employee; Self; Pfizer Inc. M.C. Ellison: Employee; Self; Merck & Co., Inc. I. Gantz: Employee; Self; Merck & Co., Inc. S.G. Terra: Employee; Self; Pfizer Inc. Funding Merck Sharp & Dohme Corp; Pfizer Inc.

Consistent Outcomes with Canagliflozin (CANA) in Patients with Type 2 Diabetes across Geographic Regions—Results from the CANagliflozin CardioVascular Assessment Study (CANVAS) Program

In the global CANVAS Program (n = 10,142), CANA, an SGLT2 inhibitor, demonstrated risk reductions in cardiovascular (CV) and renal outcomes in patients with type 2 diabetes and established CV disease or ≥2 CV risk factors. A pre-specified analysis evaluated outcomes in patients from different geographic regions. Overall, 2,430 (24.0%) were from North America, 1,021 (10.1%) were from Central/South America, 3,609 (35.6%) were from Europe, and 3,082 (30.4%) were from the rest of the world. The primary outcome was comprised of CV death, nonfatal myocardial infarction, or nonfatal stroke; other CV and renal outcomes were also analyzed. The primary outcome occurred in 2.80, 2.99, 3.07, and 2.69 patients per 100 patient-years (unadjusted) in North America, Central/South America, Europe, and the rest of the world, respectively. The effects of CANA on the primary outcome were consistent between patients from different geographic regions (interaction P = 0.89) and with the total population (HR [95% CI]: 0.86 [0.75, 0.97]; Figure). Similar effects between subgroups were observed in the individual components of the primary outcome, all-cause mortality, hospitalization for heart failure, and progression of albuminuria. The risk reduction observed with CANA on CV and renal outcomes was consistent across geographic regions. Disclosure C.H. Wysham: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi. Consultant; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Insulet Corporation, Novo Nordisk Inc., Sanofi. A. Bhattacharyya: None. M. Tsoukas: Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc., Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Eli Lilly and Company. E. Martinez-Abundis: Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Spouse/Partner; AstraZeneca. Advisory Panel; Spouse/Partner; AstraZeneca. Speaker's Bureau; Spouse/Partner; AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. Advisory Panel; Spouse/Partner; Eli Lilly and Company. Speaker's Bureau; Spouse/Partner; Eli Lilly and Company. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Research Support; Self; Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Spouse/Partner; Janssen Pharmaceuticals, Inc.. Research Support; Spouse/Partner; Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Spouse/Partner; Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi. Speaker's Bureau; Spouse/Partner; Sanofi. Advisory Panel; Self; Takeda Development Center Americas, Inc.. Speaker's Bureau; Self; Takeda Development Center Americas, Inc.. Advisory Panel; Spouse/Partner; Takeda Development Center Americas, Inc.. Speaker's Bureau; Spouse/Partner; Takeda Development Center Americas, Inc.. Research Support; Self; Merck Sharp & Dohme Corp.. Research Support; Spouse/Partner; Merck Sharp & Dohme Corp., Pfizer Inc.. Advisory Panel; Self; Laboratorios Silanes. Speaker's Bureau; Self; Laboratorios Silanes. Advisory Panel; Spouse/Partner; Laboratorios Silanes. Research Support; Spouse/Partner; Laboratorios Silanes. Speaker's Bureau; Spouse/Partner; Laboratorios Silanes. A. Slee: Other Relationship; Self; Janssen Scientific Affairs, LLC. W. Shaw: Employee; Self; Janssen Research & Development. K.W. Mahaffey: Research Support; Self; Afferent, Amgen, AstraZeneca, Daiichi, Ferring, Google (Verily), Janssen, Medtronic, Merck, Novartis, Sanofi, and St. Jude. Consultant; Self; Ablynx, AstraZeneca, BAROnova, Bio2 Medical, Boehringer Ingelheim, Bristol-Myers Squibb, Cardiometabolic Health Congress, Cubist, Eli Lilly, Elsevier, Epson, GlaxoSmithKline, Janssen, Merck, Mt. Sinai, Radiometer, Springer Publishing, The Medicines Company, Theravance, Vindico, and WebMD. Stock/Shareholder; Self; BioPrint Fitness. D. de Zeeuw: Other Relationship; Self; AbbVie Inc., Astellas Pharma US, Inc., Eli Lilly and Company, Fresenius SE & Co. KGaA, Janssen Scientific Affairs, LLC., Boehringer Ingelheim GmbH, Bayer AG, Mitsubishi Tanabe Pharma Corporation.

Uncontrolled Glycaemia Is the Strongest Predictive Factor of Liver-Related and Cardiovascular Death in Diabetic Patients with Cirrhosis

Diabetes is a common comorbidity in cirrhotic patients; there are insufficient studies in this context. Aim: to investigate risk factors for liver-related death (LRD) and cardiovascular death (CVD) in a cohort of diabetic patients with cirrhosis. Follow-up 10 years. We included 380 diabetics with cirrhosis, according to Child-Pugh: 141(37.1%) A, 170(44.7%) B, 69(18.2%) C. Thirty three (8.7%) died for LRD, 29(7.6%) died for CVD. Those died for LRD, compared with those alive, had higher glucose 211±80 vs. 143±62 mg/dL p<0.0001; HbA1c 8.0±1.4 vs. 6.8±1.1% p<0.0001. Univariate analysis (UA): hepatic encephalopathy (HE) p=0.02; ascites, spontaneous bacterial peritonitis (SBP), HbA1c >7.0%, and decompensated cirrhosis (Child B/C) were factors associated with LRD p<0.0001. Variceal bleeding (VB) was not significant (NS). Multivariate analysis (MA): only HbA1c >7.0% was associated with liver-related death HR=3.0; 95% CI=1.4-6.6 p<0.006. Those died for CVD had higher glucose 230±92 vs. 143±62 mg/dL p<0.0001; HbA1c 8.8±1.6 vs. 6.8±1.1% p<0.0001. UA: ascites p=0.001; HE, SBP, HbA1c ≥7.0% were associated with CVD p<0.0001. Child B/C and VB were NS. MA: HbA1c ≥7.0% was the strongest factor related to CVD HR=8.4; 95% CI=3.1-22.6 p<0.0001. Uncontrolled glycaemia is the most important risk factor predicting LRD and CVD. A tight glycemic control is need in cirrhotic patients. Disclosure F. Higuera-de la Tijera: Speaker's Bureau; Spouse/Partner; Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Takeda Development Center Americas, Inc., Sanofi-Aventis, Silanes. A.I. Servin-Caamano: Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation, Takeda Development Center Americas, Inc., Eli Lilly and Company, Sanofi-Aventis, silanes. A. Navarro-Estrada: None. R. Rábago-Escoto: None. A. Cruz-Estrada: None. E.G. Alexanderson-Rosas: Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Takeda Development Center Americas, Inc., Sanofi, Silanes, Novo Nordisk Inc., Novartis Pharmaceuticals Corporation, Janssen Pharmaceuticals, Inc..

Transforming Pediatric T2D Clinical Research—A Network Model

Background: Treatment options for youth with type 2 diabetes (T2D) are limited compared to those for adults with T2D. As pediatric clinical trials in T2D are difficult to complete, due to lower prevalence and population related recruitment challenges, clinical sites are often reluctant to participate. Protocol design, often not appropriate for pediatrics, administrative and financial burden related to study participation further reduce site interest. Methods: The Pediatric Diabetes Consortium (PDC) is a network of 49 U.S. diabetes centers working together to improve care for children with diabetes. Recognizing challenges associated with pediatric T2D clinical trial participation, the PDC developed a network model to improve efficiency for both sites and sponsors. Innovations: A consulting group was formed to assist with protocol design appropriate for T2D pediatric studies. A PDC master agreement with sites eliminates need for negotiation of standard contract language between sponsor and each site, allowing for a single contract between the PDC and sponsor. A single budget, based upon a clinical trial budget template, reflecting actual site costs, is negotiated by the PDC for all sites. Central archiving of site metrics eliminates need for a feasibility survey before site selection occurs. Monthly site calls led by an investigator oversight committee provide opportunities to discuss enrollment strategies, study challenges and best practices, and provide real-time feedback to sponsor. Conclusion: Efficiencies established by the PDC network model reduce workload for sites and start-up timeline for sponsors. Population-appropriate trial design improves recruitment opportunities. Ongoing site engagement helps to identify and mitigate protocol issues in real-time. The network model improves likelihood of successful trial operations. To date, 26 PDC sites have participated in at least 1 of 3 studies, enrolling 137 across studies so far, contributing to successful recruitment ahead of projected schedule. Disclosure R.L. Gal: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc., Novo Nordisk Inc. L.C. Beaulieu: Research Support; Self; Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc.. K.D. Keelin: None. J.E. Less: None. B.A. Nelson: Speaker's Bureau; Self; Dexcom, Inc.. K.A. Wintergerst: None. G.J. Klingensmith: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Foundation. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceuticals U.S.A., Inc..

Management of Hypertension and Hyperlipidemia in Youth with T2D

Introduction: Youth with T2D are at risk for additional cardiovascular (CVD) diseases such as hypertension (HT) and hyperlipidemia (HLD). We examined healthcare provider (HCP) self-reported practices regarding management and treatment of HT and HLD in youth with T2D. Methods: An electronic survey collected information from prescribing HCPs from Pediatric Diabetes Consortium sites regarding their usual treatment of and barriers related to treatment of HT and HLD in youth with T2D. Results: Respondents (N=70) were predominately female (67%) from urban (77%) academic centers (70%). HT and HLD treatment recommendations focused on lifestyle modifications including healthy eating, weight loss, physical activity, dietitian/nutritionist referral, and improving glycemic control. Medication was recommended initially more than half of time to treat HT and HLD (51% and 62%, respectively). If HT or HLD persisted for an additional 6-12 months, >80% of HCPs would choose to add additional treatment. Less than half of HCPs reported that treatment of HT and HLD is generally effective most/all of the time (42% and 34%, respectively). HCPs reported that obstacles to treatment from the patient’s perspective included lack of support to make lifestyle changes (78%), difficulty following-through with lifestyle changes (80%), lack of motivation to control diseases (68%), socioeconomic challenges (62%), and transportation difficulties (54%). Concerns regarding patient adherence (50%) and inability to focus on both diabetes and HT/HDL due to shortness of visits (42%) were the most commonly cited barriers by HCPs. Conclusion: Given that youth with T2D have high risk of developing CVD complications, HCP approaches to treat both HT and HLD are important. Notably, the majority report their recommendations are ineffective. Patient-related barriers are the biggest challenge to effective treatment; future research should explore ways to mitigate these barriers. Disclosure L.C. Beaulieu: Research Support; Self; Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc.. P. Cheng: None. M. Katz: None. L.M. Laffel: Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi US, MannKind Corporation, Roche Diagnostics Corporation, Dexcom, Inc., Insulet Corporation, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Johnson & Johnson Diabetes Institute, LLC. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. M.A. Van Name: None. N. Bansal: None. C. Kollman: Research Support; Self; JDRF, Bigfoot Biomedical, Dexcom, Inc., Tandem Diabetes Care, Inc., Medtronic MiniMed, Inc., Helmsley Charitable Trust. R.L. Gal: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc., Novo Nordisk Inc..

Clinical Characteristics and Antibody Persistence over Time in Youth in the Pediatric Diabetes Consortium (PDC) Type 2 Diabetes (T2D) Cohort

Objective: To describe the characteristics of youth diagnosed with T2D who have tested positive for ≥1 islet autoantibody (IA) and to examine the persistence of IA over time. Methods: Youth enrolled in the PDC T2D Registry with ≥2 years follow-up after diagnosis and ≥1 positive IA at any time were identified. T2D was determined using ADA guidelines. IAs were measured at each PDC site according to local practice and included IAA, GADA, IA-2A, ZnT8A, and ICA. Positive IAA tests were excluded if measured after insulin initiation. Clinical characteristics, clinical presentation, and treatment over time were analyzed. Results: Positive IA is an exclusion for enrollment in the PDC T2D Registry; however, on review of the ∼1,300 youth in the PDC, 38 were found to have IA. A single IA was found in 35 and >1 IA in 3 participants. GADA was most common (N=32); 3 were persistently positive, 13 converted to negative, 8 became positive after a negative GADA, and 8 had only 1 IA determination. Positive IAA (N=5), IA-2A (N=4) and ZnT8 (N=1) were uncommon or rare, no positive ICA were found. At diagnosis, those IA positive were more likely to be treated with insulin (95% vs. 73%) but with similar HbA1c (10.4% vs. 10.0%). At last visit, those IA positive had longer diabetes duration (5.7 years. vs. 4.8 years.) and higher insulin use (71% vs. 59%) compared to the IA negative cohort, but HbA1c levels were similar (8.7% vs. 9.0%). Age at diagnosis, race/ethnicity, percent male, and BMI were not different between those with and without IA. Conclusion: Most IA positive youth with a T2D phenotype require insulin at diagnosis and more IA positive than IA negative youth require insulin during follow-up treatment. These findings suggest the importance of IA ascertainment at diagnosis and in those failing oral therapy. In T2D youth GADA is the most common IA; yield from ZnT8 and ICA determinations is low; fluctuations in IA positivity are not uncommon. Additional study of youth with T2D phenotype and IA is needed. Disclosure G.J. Klingensmith: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Foundation. P. Cheng: None. R.L. Gal: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc., Novo Nordisk Inc. L.C. Beaulieu: Research Support; Self; Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceuticals U.S.A., Inc. F. Bacha: Research Support; Self; AstraZeneca, JAEB Center For Health Research, National Institutes of Health, Pediatric Diabetes Consortium. M.M. Kelsey: Other Relationship; Self; Daiichi Sankyo Company, Limited, Merck Sharp & Dohme Corp. C. Kollman: Research Support; Self; JDRF, Bigfoot Biomedical, Dexcom, Inc., Tandem Diabetes Care, Inc., Medtronic MiniMed, Inc., Helmsley Charitable Trust.

Understanding and Addressing Enrollment Challenges in Pediatric T2D Clinical Trials Compared with T1D

Background: While behavior and diet modifications are the first line of defense in treating T2D, pediatric patients requiring additional intervention have few options compared with adults with T2D. The disparity in available treatments can be attributed, in part, to enrollment challenges in pediatric T2D clinical trials that delay FDA approval of new therapies. Methods: Established in 2008, the Pediatric Diabetes Consortium has connected 49 diabetes research institutes and Industry partners to address enrollment challenges at a structural level. Yet, we must also address the social, economic and cultural barriers to participation specific to T2D pediatric patients. Barriers: The overall prevalence in 2009 of T1D vs. T2D in youth was 1.93/1,000 compared to 0.24/1,000, with T1D affecting a wider age span. T2D is rarely diagnosed in children <10 years. While there are racial and ethnic disparities in diabetes prevalence overall, they are more pronounced in T2D. Thus, compared to T1D, potential T2D pediatric study participants are fewer, older and more likely to face barriers to participation that include financial concerns, transportation issues, familial disruptions, distrust of research, health illiteracy, language barriers and parents’ inability to miss work. Conclusion: Addressing barriers is critical to ensure clinical trial success and improved quality of life for these patients. Industry sponsors should make translated materials, such as e-diaries available for non-English speakers, particularly for Spanish speakers and consider quality of life assessments as a secondary outcome. Researchers should partner with community leaders in areas with high T2D prevalence, to establish trust between the patient community and research institution. Additionally, incentives that address families’ social and economic needs should be offered, including direct compensation to offset costs associated with trial participation such as travel and lost income. Disclosure A.M. Terry: None. S. Bollepalli: None. L. Smith: None. A.F. Walker: None. R.L. Gal: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc., Novo Nordisk Inc. L.C. Beaulieu: Research Support; Self; Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc.. R.C. Edelen: None. J.E. Less: None.

Impact of Type 1 Diabetes on 24-Hour Energy Expenditure and Metabolic Flexibility

Type 1 diabetes (T1D) is associated with an increase in resting metabolic rate, but the impact of T1D on other components of 24-hour energy expenditure (EE) and metabolic flexibility (MF) is not known. We measured 24-hour EE, its components and substrate oxidation rates in 11 patients with T1D and 12 nondiabetic, age and BMI matched controls (HC) using whole room calorimetry. MF was defined as the respiratory quotient (RQ) kinetic response after ingesting a standard high CHO breakfast. Briefly, the kinetics between the lowest RQ pre-breakfast and the highest RQ after breakfast were analyzed by a simple linear regression between time (1-minute resolution) and RQ units (RQUnits). Subjects with T1D had marginally higher 24-hour EE and higher 24-hour non-exercise EE, but sleeping EE and basal EE were not significantly different (Table 1). There were no differences in 24-h respiratory quotient (RQ) or sleeping RQ, but MF during the breakfast meal was significantly lower in T1D vs. HC (p=0.042). Among patients with T1D, MF was related to the glycemic response to breakfast. These data suggest that T1D is characterized by alterations in EE and MF. These results have implications for glycemic and weight management among patients with T1D. Disclosure E.A. Carnero: None. K.D. Corbin: None. C.P. Bock: None. S.R. Smith: None. R.E. Pratley: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Pfizer Inc., Sanofi-Aventis, Takeda Development Center Americas, Inc..

T1D and T2D Youth in the Pediatric Diabetes Consortium (PDC) Registries—Comparing Clinical Characteristics and Glycemic Control

Objective: To compare characteristics of youth with T1D (n = 484) vs. T2D (n = 1169) in the PDC. Methods: Participants were 10 to <21 years at diagnosis. Mann-Whitney U and Chi-square tests were used to compare demographics. Linear regression models were used to compare BMI and HbA1c at diagnosis; logistics regression was used to compare DKA at diagnosis. Post-diagnosis HbA1c differences between cohorts were assessed through repeated measures. Results: T2D youth were more likely to be female (62 vs. 45%, p<0.001), overweight/obese (99 vs. 16%, p<0.001) and from low income (75 vs. 30%, p<0.001), minority (82 vs. 29%, p<0.001) families. T1D youth were more likely to present with DKA (32 vs. 11%, p<0.001) and have higher mean HbA1c levels (12.0 vs. 10.0%, p<0.001) at diagnosis. More than 70% in both cohorts achieved target HbA1c levels <7.5% within 6 months but fewer T1D patients were able to maintain HbA1c target after 6 months (Figure). In 410 participants with T2D duration ≥ 24 months at enrollment, 185 (45%) required no insulin therapy; c-peptide was 1.45 mmol/l in the subset of 74 measured at enrollment. Conclusion: While families of youth with T2D face greater socio-economic obstacles and risk factors for poor diabetes outcomes, the greater retention of residual endogenous insulin secretion likely contributes to the increased ability of T2D youth to to maintain target HbA1c levels over time. Disclosure W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. P. Cheng: None. R.L. Gal: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc., Novo Nordisk Inc. C. Kollman: Research Support; Self; JDRF, Bigfoot Biomedical, Dexcom, Inc., Tandem Diabetes Care, Inc., Medtronic MiniMed, Inc., Helmsley Charitable Trust. M.A. Van Name: None. J.L. Lynch: Other Relationship; Self; Novo Nordisk Inc.. Research Support; Self; Daiichi Sankyo Company, Limited. B.A. Nelson: Speaker's Bureau; Self; Dexcom, Inc..

Short-Term Aerobic and Interval Training Improves Muscle Mitochondrial Function and Reveals a New Role for an Old Protein

Exercise training has well-documented beneficial effects on skeletal muscle (muscle) mitochondrial function, which can be evaluated from clinical and molecular aspects within the same individual. We evaluated two cohorts at baseline: 1) lean/overweight sedentary (LOS) and 2) lean active (LA), and investigated the effects of three weeks of aerobic training in LOS subjects. All assessments were performed before (PRE) and following (POST) the intervention. In vivo muscle mitochondrial function was assessed by 31P-MRS (ATPmax). Muscle biopsies were performed in the vastus lateralis in the fasted state. Muscle tissue mitochondrial function was quantified via 14C-palmitate oxidation (14C-CO2) assays and high-resolution respirometry (Complex I, Complexes I+II, ETS). Transcriptomic profiles were examined by microarrays combined with in-depth bioinformatics analyses and validated via qRT-PCR. Fiber type and mitochondrial (mt)DNA copy number were quantified via immunohistochemistry and qPCR, respectively. LA subjects had significantly higher VO2peak and muscle mitochondrial function in vivo and in tissue vs. LOS PRE. Three weeks of aerobic training significantly improved muscle mitochondrial function in vivo and in tissue in LOS subjects [to the level of LA subjects] without affecting VO2peak, fiber type nor mitochondrial content. Global transcriptomic analyses revealed downregulation of Tribbles 1 in LOS PRE vs. LA that was confirmed by qRT-PCR in LOS PRE vs. LA. Tribbles 1 mRNA was significantly reduced with training (LOS PRE vs. POST) and inversely related with muscle tissue mitochondrial respiration. Our data identified a novel target related to exercise-induced improvements in muscle mitochondrial function and highlight a potential new role for Tribbles 1 in muscle oxidative capacity. Disclosure S. Parsons: None. M.F. Pino: None. A.P. Hodges: None. F. Yi: None. E.A. Carnero: None. R.E. Pratley: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Pfizer Inc., Sanofi-Aventis, Takeda Development Center Americas, Inc.. S.R. Smith: None. L.M. Sparks: None.

Cardiovascular (CV) Safety and Severe Hypoglycemia Benefit of Insulin Degludec vs. Insulin Glargine U100 in Older Patients (=65 Years) with Type 2 Diabetes (T2D)—Observations from DEVOTE

There is limited comparative evidence for the CV safety and hypoglycemia risk of basal insulins in older patients with T2D. This secondary analysis from DEVOTE investigated the CV safety and severe hypoglycemia risk of insulin degludec (degludec) vs. insulin glargine 100 units/mL (glargine U100) in older patients (65-74 and ?75 years age groups). Data from DEVOTE (a treat-to-target, randomized, double-blind trial evaluating 7637 patients with T2D over a median period of 2 years at high risk of CV events) were stratified by three age groups. At baseline, A1C, fasting plasma glucose and estimated glomerular filtration rates decreased with increasing age. Older patients had a higher risk of major adverse cardiovascular events (MACE), all-cause mortality and severe hypoglycemia, regardless of treatment. Treatment differences for MACE, all-cause mortality and severe hypoglycemia were similar across age groups (Figure), with no significant interactions between treatment and age group. Degludec was associated with a lower risk of severe hypoglycemia vs. glargine U100, regardless of age. This analysis supported the CV safety of degludec and demonstrated a lower risk of severe hypoglycemia vs. glargine U100 in older patients with T2D. Disclosure R.E. Pratley: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Pfizer Inc., Sanofi-Aventis, Takeda Development Center Americas, Inc. S.S. Emerson: Consultant; Self; Bayer AG, CTI BioPharma, Arena Pharmaceuticals, SFJ Pharmaceuticals Group, Genentech, Inc., GlaxoSmithKline plc., Janssen Research & Development, Novartis AG, Novo Nordisk A/S, Pfizer Inc., Roche Pharma, Allergan, AstraZeneca, Coherus Biosciences Inc, Emmaus Life Sciences Inc., Indivior, Sandoz, Seattle Genetics. Research Support; Self; National Heart, Lung, and Blood Institute. E. Franek: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Bristol-Myers Squibb Company, Boehringer Ingelheim GmbH, Eli Lilly and Company, Merck & Co., Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Servier. M.P. Gilbert: Consultant; Self; Sanofi US, Novo Nordisk A/S. S.P. Marso: Consultant; Self; Abbott Vascular, Novo Nordisk A/S, University of Oxford, AstraZeneca, Bristol-Myers Squibb Company. Research Support; Self; Novo Nordisk A/S, The Medicines Company, Terumo Medical Corporation. D.K. McGuire: Consultant; Self; AstraZeneca, Sanofi-Aventis, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Sanofi-Aventis, Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Lexicon Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Esperion Therapeutics. T.R. Pieber: Consultant; Self; Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Employee; Self; CBmed. Research Support; Self; Novo Nordisk A/S, AstraZeneca. N.R. Poulter: Advisory Panel; Self; AstraZeneca, Novo Nordisk A/S, Amgen Inc.. Research Support; Self; Servier. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk A/S, Amgen Inc., Servier. Other Relationship; Self; International Society of Hypertension. C.T. Hansen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. M.V. Hansen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. T. Mark: Employee; Self; Novo Nordisk A/S. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. A.C. Moses: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. B. Zinman: Consultant; Self; Novo Nordisk A/S, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi, Merck & Co., Inc., Abbott.