Bristol-Myers Research Articles

648-P: Glucose-Dependent Insulinotropic Polypeptide (GIP) Induces Lipolysis during Stable Basal Insulin Substitution and Hyperglycemia in Men with Type 1 Diabetes

Glucose-dependent insulinotropic polypeptide (GIP) contributes importantly to postprandial insulin secretion, and - perhaps primarily due to this insulinotropic effect - affects glucose and lipid metabolism. We investigated the effects of exogenous GIP on lipid metabolism during hyperglycemia and stable insulin levels. Ten male patients with type 1 diabetes without endogenous insulin secretion (C-peptide negative), aged [mean±SD: 26±4 years; BMI: 24±2 kg/m2; HbA1c 7.3±0.8%) were studied in a randomized, double-blind, crossover study with continuous intravenous infusions of GIP (4 pmol/kg/min) or placebo (saline), during two separate 90-minute hyperglycemic (12 mmol/L) clamps with basal insulin substitution (0.1-0.2 mU/kg/min). Plasma glycerol concentrations increased from baseline during GIP infusions and decreased during placebo infusions (baseline-subtracted area under the curve (bsAUC): 703±407 vs. -262±240 µmol/L × min, respectively, P<0.001). Free fatty acids increased only during GIP infusions (bsAUC: 5,431±6,393 during GIP vs. -74±2,363 µmol/l × min during placebo infusion, P<0.05). Plasma concentrations of glucose, insulin, and glucagon were similar during GIP and placebo infusions (P=NS). Compared to placebo, GIP increased plasma glycerol and free fatty acids in patients with type 1 diabetes during hyperglycemia and stable basal insulin levels. With this experimental design it was possible to clearly identify an important effect of GIP on lipolysis in humans. Disclosure C. N. Nielsen: None. S. M. Nguyen heimbürger: Speaker’s Bureau; Self; AstraZeneca. S. Calanna: Employee; Self; Novo Nordisk A/S. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S. M. B. Christensen: None.

317-OR: Efficacy and Safety of Dapagliflozin by Glycemic Status in the DAPA-CKD Trial

There is robust evidence that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of adverse cardiovascular and kidney outcomes. The DAPA-CKD trial (NCT03036150) demonstrated a significant risk reduction in participants with chronic kidney disease (CKD), with and without type 2 diabetes, treated with dapagliflozin 10 mg once daily compared with placebo, as an adjunct to standard care. In this prespecified analysis, we compared the efficacy and safety of dapagliflozin according to baseline glycemic status. The trial included individuals with CKD with an estimated glomerular filtration rate (eGFR) of 25 to 75 mL/min/1.73 m2 and a urinary albumin-to-creatinine ratio of 200 to 5000 mg/g. The primary outcome was a composite of sustained decline in eGFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. We analyzed results by baseline glycemic status based on the American Diabetes Association criteria for HbA1c level <5.7% (normoglycemia) vs. ≥5.7 to <6.5% (prediabetes) vs. ≥6.5% or a history of type 2 diabetes. Of the 4304 participants in the trial, 738 had normoglycemia at baseline; 660, prediabetes; and 2906, type 2 diabetes. The relative risk reduction for the primary composite outcome with dapagliflozin (hazard ratio [HR], 0.61; 95% CI, 0.51−0.72) was consistent in participants with normoglycemia (HR, 0.62; 95% CI, 0.39−1.01), prediabetes (HR, 0.37; 95% CI, 0.21−0.66) and type 2 diabetes (HR, 0.64; 95% CI, 0.52−0.79; p-interaction = 0.19). Similarly, we found no evidence of effect modification by glycemic status on secondary or exploratory outcomes. The safety profile of dapagliflozin was similar across glycemic groups, with no events of major hypoglycemia or ketoacidosis in participants with normoglycemia or prediabetes, and no ketoacidosis in any participant treated with dapagliflozin. In conclusion, dapagliflozin reduced the risk of kidney and cardiovascular events independent of baseline glycemic status. Disclosure F. Persson: Advisory Panel; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Mundipharma International, Novo Nordisk, Advisory Panel; Spouse/Partner; AstraZeneca, Bristol-Myers Squibb Company, Research Support; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Mundipharma International, Novo Nordisk. R. D. Toto: Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Medscape Education, Otsuka America Pharmaceutical, Inc., Quest Diagnostics, Reata Pharmaceuticals, Inc., Relypsa Inc. A. Langkilde: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. D. C. Wheeler: Advisory Panel; Self; Merck Sharp & Dohme Corp., Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, GlaxoSmithKline plc., Janssen Global Services, LLC., Mundipharma International, Tricida, Inc., Speaker’s Bureau; Self; Amgen Astellas BioPharma, Astellas Pharma Inc., Napp Pharmaceuticals, Vifor Pharma Management Ltd. H. L. Heerspink: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook, CSL Behring, Fresenius Medical Care, Gilead Sciences, Inc., Janssen Research & Development, LLC, Merck & Co., Inc., Mitsubishi Corporation Life Sciences Limited, Mundipharma International, Novo Nordisk, Retrophin, Inc., Research Support; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC. Dapa-ckd study group: n/a. P. Rossing: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Merck KGaA, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Vifor Pharma Management Ltd. P. Vart: None. G. M. Chertow: Advisory Panel; Self; Ardelyx, Baxter, Cricket Health, DURECT Corporation, Gilead Sciences, Inc., Reata Pharmaceuticals, Inc., Other Relationship; Self; Akebia Therapeutics, Inc., AstraZeneca, Vertex Pharmaceuticals Incorporated. F. Hou: Consultant; Self; AstraZeneca. J. J. Mcmurray: Other Relationship; Self; AbbVie Inc., Amgen Inc., AstraZeneca, Bayer AG, Cytokinetics Inc., DalCor Pharmaceuticals, Merck & Co., Inc., Novartis AG, Servier Laboratories, Theracos, Inc. R. Correa-rotter: Consultant; Self; GlaxoSmithKline plc., Other Relationship; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Novo Nordisk Inc., Speaker’s Bureau; Self; AbbVie Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceutical Co. H. S. Bajaj: Other Relationship; Self; Eli Lilly and Company, Novo Nordisk, Research Support; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Kowa Pharmaceuticals America, Inc., Merck & Co., Inc., Sanofi, Tricida, Inc. B. Stefansson: Employee; Self; AstraZeneca. Funding AstraZeneca

192-OR: Glycemic Control with Once-Weekly Basal Insulin Fc (BIF) in Persons with Type 2 Diabetes Mellitus (T2DM) Using Continuous Glucose Monitoring (CGM) in a Phase 2 Study

Basal insulin Fc (BIF; LY3209590) is a novel, once-weekly, long-acting IgG Fc-fusion protein assessed for the treatment of diabetes mellitus. A 32-week study evaluating the safety and efficacy of BIF vs. degludec in persons with T2DM previously treated with a basal insulin showed HbA1c non-inferiority of BIF vs. degludec with significantly fewer hypoglycemic events (≤70 mg/dL). Here we present CGM data derived by Dexcom G6, allowing a more detailed assessment of glycemic control of BIF vs. degludec. The study included 2 dosing algorithms for BIF with different fasting glucose (FG) targets: ≤140 mg/dL (BIF-A1) and ≤120 mg/dL (BIF-A2). Degludec was titrated to FG ≤100 mg/dL. Subjects were randomized to 1 of the 3 arms. Subject (N=399) mean age was 60.2 yrs and baseline HbA1c was 8.1%. For the entire 32 weeks, the percent of 24 hrs in range, hyperglycemia and hypoglycemia was similar for the 3 arms (Figure). At Week 32, total duration of hypoglycemia was similar across 7 days post-injection for BIF-A1 and A2, showing that duration of hypoglycemia is independent of day post-injection. CGM data confirm that BIF showed similar glycemic control vs. degludec despite higher FG targets and numerically lower time in hypoglycemia. The flat pharmacokinetic profile enables near peakless insulin concentrations without an increase in hypoglycemia risk at highest exposure. Disclosure C. M. Kazda: Employee; Self; Eli Lilly and Company. J. Chien: Stock/Shareholder; Self; Eli Lilly and Company. Q. Zhang: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. E. Chigutsa: Employee; Self; Eli Lilly and Company. W. Landschulz: Employee; Self; Lilly Diabetes, Employee; Spouse/Partner; Covance Inc., Stock/Shareholder; Self; Lilly Diabetes. P. Wullenweber: None. A. Haupt: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. J. P. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. Funding Eli Lilly and Company

638-P: A Novel, Long-Acting Dual Agonist for GIPR/GLP-1R, HISHS-2001, Demonstrates Effects on HbA1c and Weight Loss in the db/db Mouse Model of Type 2 Diabetes

HISHS-2001 is a novel long-acting, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) dual receptor (R) agonist. In in vitro cAMP assays in human GIP/GLP-1 receptor-expressing cells, HISHS-2001 exerted half-maximal effects at concentrations of 2.3 nM and 4.1 nM on the receptors for GIP (GIPR) and GLP-1 (GLP-1R) respectively. After SC dosing every third day for four weeks, HISHS-2001 at 3, 10 and 21 nmol/kg demonstrated robust effects on HbA1c in db/db mice which were superior to semaglutide and tirzepatide (Table). The effect on body weight was more pronounced with HISHS-2001 than semaglutide and similar to tirzepatide which was associated with a reduction in food intake. Interestingly, HISHS-2001 led to a significant increase in uncoupling protein-1 (UCP-1) levels in intrascapular brown adipose tissue, in inguinal white adipose tissue and serum and liver fibroblast growth factor-21 (FGF-21) levels. A decrease in serum interleukin-6 (IL-6) level was also observed.In conclusion, HISHS-2001 is a potent, long acting GIP/GLP-1R dual agonist, which provides improved control of glucose homeostasis in diabetic mice compared to an existing GLP-1 agonist and a GIP/GLP-1R dual agonist.View largeDownload slideView largeDownload slide DisclosureV. S. Burade: None. A. Garcia-ocana: Consultant; Self; Sun Pharmaceutical Industries Ltd. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. G. A. Rutter: Advisory Panel; Self; Sun Pharmaceutical Industries Ltd. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. B. Thorens: Advisory Panel; Self; Sun Pharmaceutical Industries Ltd. R. Thennati: None.

85-LB: Glucose-Dependent Insulinotropic Polypeptide (GIP) Contributes Substantially to the Improved Beta-Cell Function during Sitagliptin Treatment in Persons with Type 2 Diabetes

In persons with type 2 diabetes (T2D), dipeptidyl peptidase 4 (DPP-4) inhibitor treatment improves glycemic control by raising the active levels of the insulinotropic gut hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide (GIP). Using the GIP receptor antagonist GIP(3-30)NH2, we investigated endogenous GIP’s contribution to the insulinotropic effect of DPP-4 inhibition (assessed by insulin secretion rate (ISR) relative to plasma glucose). In a double-blind, placebo-controlled, cross-over study, 12 persons (eight men and four women) with T2D (mean ± SD; BMI 27.4 ± 2.6 kg/m2, HbA1c 7.1 ± 1.4% (54 ± 15 mmol/mol)) underwent two randomized 12-13-day treatment courses with DPP-4 inhibitor (sitagliptin 100 mg once-daily) and placebo, respectively, with an interposed 1-3-week washout period. In the end of each treatment period, two randomized 5-hour liquid mixed-meal tests with infusion of GIP(3-30)NH2 (1,200 pmol/kg/min) or saline (placebo) were performed. During placebo treatment, GIP(3-30)NH2 lowered postprandial serum C-peptide (determined as difference in baseline-subtracted area under curve (ΔbsAUC%) ± SEM: −31 ± 9%, P = 0.005) and increased postprandial plasma glucose excursions (ΔAUC% ± SEM: 7.3 ± 2.8%, P = 0.017) compared to saline. Sitagliptin increased concentrations of active GIP(1-42) (ΔAUC% ± SEM: 153 ± 21%, P < 0.0001) and lowered fasting plasma glucose (mean: 8.7 vs. 7.6 mmol/L, P < 0.0004), whereas postprandial glucose excursions were unchanged compared to placebo treatment. GIP(3-30)NH2 caused a reduction in AUCISR/AUCglucose ratio equivalent to 37 ± 12% of the increments due to sitagliptin. In conclusion, we demonstrate an insulinotropic and glucose-lowering effect of endogenous GIP in persons with T2D and show that endogenous GIP is responsible for more than one third of the improved beta cell function observed during DPP-4 inhibitor treatment. Disclosure S. Stensen: None. L. S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. M. M. Rosenkilde: Board Member; Self; Bainan Biotech, Synklino ApS, Board Member; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Consultant; Self; Antag Therapeutics, Bainan Biotech, Synklino ApS, Stock/Shareholder; Self; Antag Therapeutics, Bainan Biotech, Synklino ApS, Stock/Shareholder; Spouse/Partner; Antag Therapeutics, Bainan Biotech. B. Hartmann: None. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. M. B. Christensen: None. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S. Funding European Foundation for the Study of Diabetes/Lilly European Diabetes Research Programme (2018); A.P. Møller Foundation

752-P: LIVRQNac (AXA1125) Enhances Insulin Sensitivity in Primary Human Hepatocytes and in Subjects with NAFLD and T2D

Background: AXA1125, an investigational composition of 5 amino acids and n-acetyl-cysteine, targets multiple biologies relevant to NAFLD pathogenesis.Methods: Primary human hepatocytes (PHH) from multiple donors were pretreated with AXA1125 components (LIVRQNac), exposed to lipotoxic insult in the presence of LIVRQNac, incubated in high glucose insulin-free medium, followed by glucose-free medium±insulin. Human safety, tolerability, and biologic activity were evaluated in a 16-week, multicenter, randomized, placebo (Pbo)-controlled study (NCT04073368) in subjects with NAFLD±T2D. Results from Pbo and AXA1125 24 g twice daily dosing in subjects with T2D are reported.Results: In PHH, LIVRQNac reduced glucose output by ~50% (p <0.01) and enhanced insulin-dependent Akt phosphorylation by 80% (p<0.001). Clinically, AXA1125 showed greater reductions from BL at W16 vs. Pbo in metabolic and fibroinflammatory biomarkers (Table); both arms had similar baseline characteristics. AEs were mostly mild to moderate.Conclusions: This concordant multifactorial biologic activity, including the effects on glucose homeostasis, suggests a potential enhanced impact of AXA1125 in NAFLD subjects with diabetes that warrants further investigation.View largeDownload slideView largeDownload slide DisclosureS. Baum: Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. J. Zhao: Employee; Self; Axcella Health Inc., Stock/Shareholder; Self; Axcella Health Inc. M. Chakravarthy: None. M. Koziel: None. S. A. Harrison: Consultant; Self; Axcella Health Inc. N. T. Gunn: None. Z. Younes: Research Support; Self; Axcella Health Inc., Novo Nordisk. A. Kohli: Research Support; Self; Axcella Health Inc., Novo Nordisk. R. Patil: Speaker’s Bureau; Self; Intercept Pharmaceuticals, Inc. J. P. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. M. Hamill: Employee; Self; Axcella Health Inc. N. Daou: None.FundingAxcella Health Inc.

101-OR: Efficacy and Safety of Once-Weekly Semaglutide 2.0 vs. 1.0 mg for Type 2 Diabetes: SUSTAIN FORTE Randomized Trial

Once-weekly (OW) subcutaneous semaglutide 0.5 and 1.0 mg are approved maintenance doses for type 2 diabetes (T2D) treatment. We hypothesized that a higher dose of 2.0 mg would provide additional glycemic control with more patients achieving treatment targets vs. 1.0 mg. SUSTAIN FORTE (NCT03989232) was a randomized, double-blind, phase 3b trial investigating the efficacy and safety of OW semaglutide 2.0 vs. 1.0 mg after 40 weeks of treatment in 961 adults with T2D in need of treatment intensification (HbA1c 8.0-10.0%) on stable metformin ± sulfonylurea. All participants initiated semaglutide treatment with the 0.25 mg dose, doubling every 4 weeks until target dose was reached. The primary objective was to establish superiority of semaglutide 2.0 vs. 1.0 mg on glycemic control; secondary objectives included comparison of the effect on body weight (BW) (confirmatory), safety and tolerability. Baseline characteristics and key results are shown in the Table. Superior HbA1c and BW reductions were shown with semaglutide 2.0 vs. 1.0 mg and a greater proportion of participants achieved HbA1c In conclusion, semaglutide 2.0 mg is superior to 1.0 mg in reducing HbA1c and BW, with a comparable safety profile. Disclosure J. P. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. J. B. Buse: Consultant; Self; Cirius Therapeutics, CSL Behring, Fortress Biotch, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego Inc., Stability Health, Zealand Pharma A/S, Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk, vTv Therapeutics, Research Support; Self; NovaTarg Therapeutics, Novo Nordisk, Sanofi, Tolerion, Inc., vTv Therapeutics, Stock/Shareholder; Self; Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Stability Health. P. Auerbach: Employee; Self; Novo Nordisk A/S. H. S. Bajaj: Other Relationship; Self; Eli Lilly and Company, Novo Nordisk, Research Support; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Kowa Pharmaceuticals America, Inc., Merck & Co., Inc., Sanofi, Tricida, Inc. Y. Fukushima: None. I. Lingvay: Advisory Panel; Self; Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Consultant; Self; TARGET PharmaSolutions, Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk, Pfizer Inc., Zealand Pharma A/S, Research Support; Self; Mylan N. V., Sanofi. S. Macura: Employee; Self; Novo Nordisk A/S. A. L. Sondergaard: Stock/Shareholder; Self; Novo Nordisk A/S, Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. T. Tankova: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Medtronic, Novartis AG, Sanofi, Worwag Pharma, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk Pharma Ltd., Sandoz International GmbH, Sanofi, Servier Laboratories. N. Tentolouris: None. Funding Novo Nordisk A/S

102-OR: Efficacy and Safety of Once-Weekly Efpeglenatide vs. Placebo as Monotherapy in Patients with Type 2 Diabetes (AMPLITUDE-M)

Efpeglenatide (Efpeg) is being developed as a long-acting GLP-1 receptor agonist for once weekly, subcutaneous administration. The efficacy and safety of Efpeg vs. placebo (PBO) was assessed in patients with type 2 diabetes (T2D) inadequately controlled with diet and exercise alone. In this double-blind, PBO-controlled, 30+26-week Phase 3 study, patients with T2D were randomized to Efpeg 2 mg (n=100), 4 mg (n=101), and 6 mg (n=103), or PBO (n=102). Endpoints were change from baseline in HbA1c at week 30 (primary) and other parameters of glycemic control, body weight (BW) and safety at weeks 30 and 56 (secondary). Baseline characteristics and key results are shown in the Table. All doses of Efpeg showed significantly greater reductions in HbA1c vs. PBO at weeks 30 and 56, and a greater proportion of patients achieved HbA1c In conclusion, Efpeg as monotherapy in patients with T2D was well tolerated and demonstrated significant improvements versus PBO in HbA1c and BW after 30 weeks of treatment. These improvements generally remained stable through 56 weeks of therapy. Disclosure S. Baek: Employee; Self; Hanmi Pharmaceutical. J. P. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. L. Popescu: Employee; Self; Sanofi. E. Niemoeller: Employee; Self; Sanofi-Aventis Deutschland GmbH, Stock/Shareholder; Self; Sanofi. I. Muehlen-bartmer: Employee; Self; Sanofi-Aventis Deutschland GmbH. J. Rosenstock: Board Member; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Inc., Sanofi, Consultant; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Inc., Sanofi, Research Support; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Genentech, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Oramed Pharmaceuticals, Inc., Pfizer Inc., REMD Biotherapeutics, Sanofi.

1192-P: Robust Arginine-Stimulated Glucagon Secretion in Patients with Type 1 Diabetes Independent of Diabetes Duration, Age, HbA1c, and Beta-Cell Secretory Capacity

In type 1 diabetes (T1D), the counterregulatory glucagon response to hypoglycemia disappears over time. It remains unknown whether this is due to lack of glucagon production or represents a malfunctioning stimulus-secretion coupling in pancreatic alpha cells. Arginine test (5 g of arginine infused intravenously (iv) over 1 minute after an overnight fast) with frequent measurements of plasma glucagon and serum C-peptide concentrations over 30 minutes was performed in 80 patients with T1D (19/61 females/males, age 49 (22-74) years (median (range)), duration 20 (2-46) years, BMI 28 (22-44) kg/m2, HbA1c 8.2 (7.5-10) %). The interrelationship between the arginine-induced glucagon response and demographic, clinical and biochemical parameters was evaluated using a stepwise approach in two multiple linear regression analysis models with glucagon area under curve (AUC) and Cmax, respectively, as dependent parameter. Mean baseline plasma glucagon concentrations amounted to 10.6±5.5 pmol/L (mean±SD). Overall, robust arginine-induced glucagon responses were observed (AUC: 499±209 pmol/L × min; Cmax: 41.0±17.7 pmol/L) independently of diabetes duration, age, HbA1c and beta cell secretory capacity. Fasting plasma glucagon and waist-to-hip ratio predicted the glucagon response in both models. When leaving out fasting plasma glucagon of the models, fasting low-density lipoprotein cholesterol and alanine aminotransferase as well as eGFR also predicted the glucagon response. In conclusion, glucagon secretory capacity in patients with T1D as assessed by iv arginine test seems preserved independently of diabetes duration, age, HbA1c and beta cell secretory capacity positioning pharmaceutical restoration of the glucagon counterregulatory response to hypoglycemia as an attractive therapeutic strategy for the protection of insulin-induced hypoglycemia. Disclosure J. Warnøe: None. T. F. Dejgaard: Advisory Panel; Self; Novo Nordisk, Consultant; Self; Boehringer Ingelheim International GmbH, Research Support; Self; AstraZeneca, Novo Nordisk, Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker's Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S. N. J. Johansen: Employee; Self; Novo Nordisk. A. Lund: Speaker's Bureau; Self; Novo Nordisk, Sanofi. J. I. Bagger: None. N. J. Wewer albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S, Regeneron Pharmaceuticals Inc., Speaker's Bureau; Self; Merck &amp; Co., Inc., Mercodia. B. Hartmann: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. H. U. Andersen: Stock/Shareholder; Self; Novo Nordisk A/S.

119-LB: Increased Adiponectin following Efruxifermin Treatment Is Associated with Improvements in Dyslipidemia, Glucose Metabolism, and Liver Health in a 16-Week, Randomized, Placebo-Controlled NASH Trial

FGF21, an endocrine hormone that regulates whole-body metabolism during energy imbalance, is a promising therapeutic target. Efruxifermin (EFX), an Fc-FGF21 analog, is a balanced FGFR1c, 2c, and 3c agonist under investigation as a potential treatment for nonalcoholic steatohepatitis (NASH). In a clinical trial in biopsy-confirmed NASH, EFX significantly reduced liver fat content (LFC), ALT, and AST, and increased adiponectin.1 Activating FGFR1c in adipose tissue increases circulating adiponectin; the aim of this analysis was to evaluate correlations between changes in adiponectin and markers of dyslipidemia, glucose metabolism and liver health following EFX treatment. Patients (N=80) were randomized to placebo or 28, 50, or 70mg EFX. Larger increases in adiponectin correlated with greater improvements in lipid profiles, including decreases in triglycerides and increases in HDL-C, as well as decreases in LFC (Table). Increases in adiponectin also correlated strongly with markers of improved glucose metabolism, and greater reductions in markers of liver injury and fibrosis. These data suggest adipose tissue-mediated effects of EFX contribute substantially to restoration of liver health, healthy lipoprotein profiles, insulin sensitivity and glucose tolerance.1 Harrison 2020 Hepatol 72 1S; 6AView largeDownload slideView largeDownload slide DisclosureJ. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. E. J. Tillman: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Akero Therapeutics, Inc. R. Shringarpure: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Akero Therapeutics, Inc. E. Fong: Employee; Self; Akero Therapeutics, Inc. B. De temple: Employee; Self; Akero Therapeutics, Inc. T. Rolph: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Pfizer Inc. A. Cheng: Employee; Self; Akero Therapeutics, Inc. K. Yale: Employee; Self; Akero Therapeutics, Inc. S. A. Harrison: Consultant; Self; Axcella Health Inc.

665-P: Efficacy and Safety of Once-Weekly Semaglutide 2.0 mg vs. 1.0 mg by Baseline HbA1c and BMI: SUSTAIN FORTE Subgroup Analyses

Once-weekly subcutaneous semaglutide 2.0 mg showed superior efficacy with similar safety vs. 1.0 mg in 961 participants with type 2 diabetes (HbA1c 8.0-10.0%) after 40 weeks in SUSTAIN FORTE. We assessed the effect of semaglutide 2.0 mg vs. 1.0 mg on HbA1c and body weight (BW) in prespecified baseline (BL) HbA1c (<9.0%, ≥9.0%) and BMI (<35, ≥35 kg/m2) subgroups.Mean BL HbA1c was 8.9% and BMI 34.6 kg/m2. For HbA1c and BW, estimated treatment differences favored semaglutide 2.0 mg vs. 1.0 mg across all BL HbA1c and BMI subgroups. Treatment-by-subgroup interactions were nonsignificant (HbA1c, p=0.55 and p=0.41; BW, p=0.40 and p=0.13; Figure A-D). Greater mean HbA1c reductions were observed for both doses in the higher vs. lower BL HbA1c subgroup (Figure A). Conversely, greater mean BW reductions were observed for both doses in the lower vs. higher BL HbA1c subgroup (Figure C). Similar mean HbA1c reductions were observed across BL BMI subgroups (Figure B), while greater mean BW reductions were observed for both doses in the higher vs. lower BL BMI subgroup Figure D). Overall, the incidence of adverse events was similar for both doses and across BL HbA1c and BMI subgroups with no new safety concerns identified.In line with the results in the overall population, semaglutide 2.0 mg provided consistently greater reductions in HbA1c and BW vs. 1.0 mg across BL HbA1c and BMI subgroups.View largeDownload slideView largeDownload slide DisclosureJ. B. Buse: Consultant; Self; Cirius Therapeutics, CSL Behring, Fortress Biotch, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego Inc., Stability Health, Zealand Pharma A/S, Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk, vTv Therapeutics, Research Support; Self; NovaTarg Therapeutics, Novo Nordisk, Sanofi, Tolerion, Inc., vTv Therapeutics, Stock/Shareholder; Self; Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Stability Health. J. P. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. P. Auerbach: Employee; Self; Novo Nordisk A/S. H. S. Bajaj: Other Relationship; Self; Eli Lilly and Company, Novo Nordisk, Research Support; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Kowa Pharmaceuticals America, Inc., Merck & Co., Inc., Sanofi, Tricida, Inc. Y. Fukushima: None. I. Lingvay: Advisory Panel; Self; Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Consultant; Self; TARGET PharmaSolutions, Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk, Pfizer Inc., Zealand Pharma A/S, Research Support; Self; Mylan N. V., Sanofi. S. Macura: Employee; Self; Novo Nordisk A/S. A. L. Søndergaard: Stock/Shareholder; Self; Novo Nordisk A/S, Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. T. Tankova: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Medtronic, Novartis AG, Sanofi, Wörwag Pharma, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk Pharma Ltd., Sandoz International GmbH, Sanofi, Servier Laboratories. N. Tentolouris: None.FundingNovo Nordisk A/S

380-P: Endothelial Glycocalyx Dimensions and Cardiovascular Risk Factors in Type 1 Diabetes

Background: The glycocalyx lines the inner surface of the capillary endothelium. Capillaroscopy enables visualization of the sublingual capillaries and measurement of the perfused boundary region (PBR) as an estimate of the glycocalyx. Novel software enables assessment of the PBR estimated at a fixed high flow level (PBR-hf) and the microvascularity by the MicroVascular Health Score (MVHS). Damaged glycocalyx may represent microvascular damage in diabetes and assessment of its dimension might improve early cardiovascular (CV) risk stratification. Aim: To assess the associations between PBR, PBR-hf and MVHS and CV risk factors in persons with type 1 diabetes (T1D); and to compare PBR, PBR-hf and MVHS in persons with T1D and healthy controls. Methods: Cross-sectional study including 161 persons with T1D stratified by stage of diabetic kidney disease according to level of albuminuria and 50 healthy controls without diabetes. The PBR, PBR-hf and MVHS were assessed by the GlucoCheck device (valid measurements were available in 136 (84.5%) with T1D and in all the controls). Higher PBR and PBR-hf indicate smaller glycocalyx width and lower MVHS represents a worse microvascular health. Results: There were no associations between PBR, PBR-hf or MVHS and the CV risk factors in persons with T1D, except for a higher PBR-hf and a lower MVHS in females (p = 0.01 for both). There was no difference in PBR, PBR-hf or MVHS in persons with normo-, micro- or macroalbuminuria (p ≥ 0.34). PBR was higher and MVHS was lower in persons with T1D as compared to the healthy controls (p ≤ 0.02). After adjustment for CV risk factors the difference in PBR remained significant (p = 0.001). Conclusions: The endothelial glycocalyx dimension was impaired in persons with T1D compared to healthy controls. We found no association between the endothelial glycocalyx dimension and the level of albuminuria or CV risk factors among persons with T1D. The use of the GlucoCheck device in T1D may not contribute to CV risk stratification. Disclosure E. Buur stougaard: Employee; Spouse/Partner; Novo Nordisk, Stock/Shareholder; Spouse/Partner; Novo Nordisk. S. Winther: None. H. Amadid: Stock/Shareholder; Self; Novo Nordisk A/S. M. Frimodt-moeller: None. F. Persson: Advisory Panel; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Mundipharma International, Novo Nordisk, Advisory Panel; Spouse/Partner; AstraZeneca, Bristol-Myers Squibb Company, Research Support; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Mundipharma International, Novo Nordisk. T. W. Hansen: Stock/Shareholder; Self; Novo Nordisk A/S. P. Rossing: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Merck KGaA, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi, Vifor Pharma Management Ltd. Funding Novo Nordisk Foundation (NNF14SA0003)

1179-P: Acute Physiological Effects of Gastric Aspiration for the Treatment of Obesity

AspireAssist® allows aspiration of ~30% of an ingested meal through a percutaneous gastrostomy tube thereby reducing caloric uptake. We evaluated the acute effects of aspiration therapy on postprandial glucose tolerance, responses of gluco-regulatory and appetite-regulating gut hormones, appetite sensations and food intake. Seven AspireAssist®-treated persons without diabetes (median [IQR] age 52 [44;54] years; BMI 35.6 [31.5;40.5] kg/m2) underwent two mixed meal tests on separate days with double-blinded aspiration (aspiration visit) and sham aspiration (sham visit), respectively. Seven age and BMI-matched controls (age 43 [42;54]; BMI 34.1 [31.6;38.7] kg/m2) underwent one meal test (control visit). All mixed meal tests were followed by an ad libitum meal for evaluation of food intake. Compared to sham visits, postprandial glucose tolerance was improved on aspiration visits (median [IQR] baseline-subtracted area under the curve (bsAUC) 170 [88;356] vs. 388 [239;456] mmol/L × min, P = 0.025). Postprandial responses (bsAUCs) of C-peptide, cholecystokinin (CCK) and glucose-dependent insulinotropic polypeptide (GIP) were reduced during aspiration vs. sham visits (113 [28;224] vs. 302 [215;433] nmol/L × min, P = 0.014; 223 [59.4;402] vs. 467 [416;546] pmol/L × min, P = 0.005; and 4,634 [1,488;9,044] vs. 15,382 [9,588;18,850] pmol/L × min, P = 0.025). Glucagon, gastrin, ghrelin and peptide YY, respectively, were similar on aspiration and sham visits. Appetite sensations and ad libitum food intake were similar on aspiration and sham visits. Responses of plasma glucose, gut hormones, appetite sensations and food intake were similar on sham and control visits. In this study, aspiration therapy acutely improved postprandial glucose tolerance without causing a compensatory increase in appetite sensations or food intake at a subsequent ad libitum meal; pointing to acute beneficial metabolic effect of aspiration therapy in addition to the long-term bodyweight-lowering effect of this treatment. Disclosure I. Gether: None. M. M. Jensen: None. T. Jorsal: None. C. Nexøe-larsen: None. L. S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. L. P. S. Naver: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S. Funding Augustinus Fonden

1174-P: Application of NIS4 Technology for Stand-Alone and Sequential Identification of At-Risk NASH or Advanced Fibrosis in Nondiabetic, Prediabetic, and Type 2 Diabetic Patients

Background: Type 2 diabetes (T2D) is an independent risk factor for the development of nonalcoholic steatohepatitis (NASH. However, there is a need for non-invasive tests (NIT) to identify at-risk NASH patients requiring intense lifestyle or clinical intervention. Aim: The aim of this study was to access clinical performance metrics of NIS4™ either alone or in combination with other NITs in patients characterized as nondiabetic, pre-diabetic and T2D and with either at-risk of NASH (NAS≥4 and F≥2) or advanced fibrosis (F≥3). Methods: Patients in the RESOLVE-IT DIAG cohort presented with one or more risk factors for NAFLD and had corresponding NIT data: NIS4™ (miR-34a-5p, α2M, YKL-40, HbA1c), Fibrosis-4 (FIB-4), NAFLD activity score (NFS), and FibroScan™ (FS). NIT data were used to simulate different testing strategies to identify patients with at-risk NASH or advanced fibrosis. Results: The 467 patients were divided into 3 subgroups with 200 (43%) non-T2D, 67 (14%) pre-diabetic and 200 (43%) T2D with a prevalence for at-risk NASH ranging 42-71%, 58-78% and 66-84%, respectively. The corresponding prevalence for advanced fibrosis in the same groups was 18-27%, 34-40%, 42-49%, respectively. Generally, the performance was impacted by variability in sample size and prevalence which mainly affected PPV and NPV. Under these circumstance NIS4™ together with FS or FIB-4 provided a strong overall balanced performance (Acc: 66-82%, Sen: 50-80%, Spe: 58-94%). Conclusion: In this cohort, the sequential use of NIS4™ together with another blood-based test FIB-4 or an imaging-based FibroScan™ test provided an overall more balanced performance for identification of at-risk NASH or advanced fibrosis for nondiabetic and T2D patients. Therefore, NIS4™ has the potential to be a valuable clinical tool for also identifying diabetic patients at higher risk of negative outcomes. Disclosure C. Rosenquist: Employee; Self; GENFIT. Y. Hajji: None. J. Magnanensi: Employee; Self; GENFIT. N. Stankovic-valentin: Employee; Self; GENFIT, Stock/Shareholder; Self; GENFIT. S. Hosmane: Stock/Shareholder; Self; GENFIT, Stock/Shareholder; Spouse/Partner; Vertex Pharmaceuticals Incorporated. A. J. Sanyal: Advisory Panel; Self; Novo Nordisk, Consultant; Self; Akero Therapeutics, Inc., Alnylam Pharmaceuticals, Inc., Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Genentech, Inc., Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Inventiva Pharma, Lilly Diabetes, Lipocine Inc., Merck &amp; Co., Inc., NGM Biopharmaceuticals, Novartis Pharmaceuticals Corporation, Pfizer Inc., Regeneron Genetics Center, Siemens Corporation, Other Relationship; Self; AstraZeneca, UpToDate, Stock/Shareholder; Self; GENFIT, HemoShear Therapeutics, LLC, Indalo Therapeutics, Inc., Tiziana Life Sciences plc.

1191-P: Increased Glucagon Sensitivity in Totally Pancreatectomized Patients

Glucagon secretion and signaling are affected in several metabolic disorders including different types of diabetes. To understand these mechanisms better, we investigated the effect of exogeneous glucagon in participants deprived of endogenous glucagon and/or insulin. We included nine middle-aged, normal-weight patients who had undergone total pancreatectomy (PX), eight patients with type 1 diabetes (T1D) and nine healthy controls in a randomized, double-blinded crossover study (groups were matched by age, gender and BMI). Participants received a 2.5-hour intravenous infusion of glucagon (4 ng/kg/min) and placebo (saline), respectively, under fasting conditions with usual basal insulin administration. Glucagon infusion increased plasma glucagon to similar supraphysiologic levels in all groups and increased glucose levels as assessed by baseline-subtracted area under the curve (bsAUC) by 2.2 and 3.5-fold, respectively, in the PX group compared to the T1D group (P=0.015) and control group (P In conclusion, well-known actions of glucagon are more pronounced in PX patients compared to matched T1D patients and healthy controls indicating an increased sensitivity to glucagon in response to the underlying loss of pancreatic glucagon secretion in PX patients. Disclosure I. Rix: Employee; Self; Zealand Pharma A/S. A. Lund: Speaker9s Bureau; Self; Novo Nordisk, Sanofi. L. F. Garvey: None. K. Owen: Employee; Self; Zealand Pharma A/S. C. Hansen: None. G. Van hall: n/a. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. T. Vilsboll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker9s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S. Funding Innovation Fund Denmark; Novo Nordisk Foundation; A.P. Moller Foundation; Aase and Ejnar Danielsen Foundation; Inge & Per Refhall9s Research Grant; Augustinus Foundation

770-P: The Glucose-Lowering Effect of the Bile Acid Sequestrant Sevelamer Is Not Mediated by Glucagon-Like Peptide-1

Bile acid sequestrants are cholesterol-lowering drugs, which also improve glycemic control in patients with type 2 diabetes (T2D). The mechanism behind the glucose-lowering effect of bile acid sequestrants is unknown but has been proposed to involve glucagon-like peptide 1 (GLP-1) secretion. Using the GLP-1 receptor antagonist exendin(9-39), we investigated the GLP-1-mediated contribution to the glucose-lowering effect of the bile acid sequestrant sevelamer in patients with T2D. In a randomized, double-blind, placebo-controlled, crossover study, patients (9 men/6 women) with T2D (median [interquartile range] age 68 [63-71] years, BMI 30.1 [26.6-33.0] kg/m2, HbA1c 48 [45-61] mmol/mol (6.5 [6.3-7.7]%), on metformin mono-therapy) underwent two 14-day treatment periods with either sevelamer or placebo in a randomized order. After each treatment period, patients participated in two experimental days, each involving a four-hour liquid meal test with concomitant infusion of exendin(9-39) or saline. Compared to placebo, sevelamer lowered both fasting plasma glucose concentrations ((mean ± SEM) 8.7 ± 0.3 vs. 10.2 ± 0.5 mmol/L, P &amp;lt;0.001) and postprandial plasma glucose excursions (baseline-subtracted area under the curve (bsAUC): 456.5 ± 40.3 vs. 620 ± 63.6 mmol/L × min, P &amp;lt;0.001). In both treatment periods, exendin(9-39) increased the glucose bsAUC compared to saline (P &amp;lt;0.001) with no absolute or relative difference between the two treatment periods (∆bsAUC: 365 ± 34.4 mmol/L × min [170 ± 27.6%] (sevelamer) vs. 428 ± 58.2 mmol/L × min [165 ± 40.2%] (placebo treatment), P = 0.17). In conclusion, using the GLP-1 receptor antagonist exendin(9-39), we were not able to detect a GLP-1-mediated glucose-lowering effect of sevelamer; leaving the mechanism behind the glucose-lowering effect of sevelamer unresolved. Disclosure H. H. Nerild: Employee; Spouse/Partner; Novo Nordisk. A. Brønden: None. D. P. Sonne: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S.

89-OR: Cardiovascular and Mortality Risk with Intravitreal Anti-Vascular Endothelial Growth Factor (VEGF) Inhibitors in Patients with Diabetic Retinopathy (DR)

While intravenous anti-VEGF agents are known to contribute to arterial thromboembolic events, the cardiovascular (CV) safety of intravitreal anti-VEGF inhibitors remain unclear. Using Medicare and 2 U.S. commercial claims datasets (1/2009-12/2017), we identified 1:1 propensity score matched patients aged ≥18 years with DR initiating treatment with (1) intravitreal anti-VEGF injections or (2) laser procedure or intravitreal steroid injections (30,681 matched pairs). We assessed a composite CV outcome [myocardial infarction (MI) or stroke], its individual components, and mortality, using an intention-to-treat (ITT) scheme censoring at 180 days and 365 days of follow-up. We estimated pooled HRs and 95% CIs adjusting for 85 baseline covariates. Compared to laser or steroid treatment, intravitreal anti-VEGF injections were associated with a similar risk of the composite CV outcome [HR:0.91 (95% CI:078, 1.06)], MI [0.91 (0.74, 1.11)], stroke [0.92 (0.74, 1.15)], or risk of mortality [1.14 (0.87, 1.51)] at 6 months of follow up. Results were consistent in an ITT analysis censoring at 365 days (Table). Intravitreal anti-VEGF injections, compared to laser or steroid treatment, had similar risk of CV events and mortality in patients with DR. Disclosure M. Roh: None. H. Tesfaye: None. L. P. Aiello: Consultant; Self; KalVista Pharmaceuticals, Novo Nordisk, Regeneron Pharmaceuticals Inc., Stock/Shareholder; Self; KalVista Pharmaceuticals. S. C. Kim: Research Support; Self; AbbVie Inc., Bristol-Myers Squibb Company, Pfizer Inc., Roche Pharma. E. Patorno: Research Support; Self; Boehringer Ingelheim International GmbH, National Institutes of Health.

103-OR: The Glucagon-Like Peptide-1 Analog, Liraglutide Is a Safe and Effective Treatment of Bile Acid Malabsorption: A Proof of Concept Study

Bile acid malabsorption (BAM) is caused by excessive spill-over of bile acids to the colon and is estimated to affect ∼1% of the general population. It is a socially debilitating disease with watery diarrhea and high stool frequency as main symptoms. BAM is diagnosed by the 75selenium homotaurocholic acid test (SeHCAT) measuring the retention of bile acids. Bile acid sequestrant (BAS) treatment, which is the only recommended treatment of BAM, is associated with poor effect and low compliance. Case reports suggest that the glucagon-like peptide 1 receptor analog (GLP-1RA) liraglutide may be an effective treatment of BAM. In this double-blind, double-dummy, non-inferiority study, nondiabetic individuals with SeHCAT-verified BAM, age 18-75 years and BMI 18.5-40 kg/m2 were randomized to receive the GLP-1RA liraglutide (uptitrated to 1.8 mg per day) or the BAS colesevelam (1.875 mg × 2 per day) for 6 weeks prior to a 7-day run-in period without treatment. SeHCAT was made at baseline, week 3 and week 6. The primary outcome was the proportion of patients experiencing a reduction in stool frequency of ≥25% per day. Of 52 randomized subjects (18 males, 34 females, mean age 50.2 years and BMI 29.9 kg/m2), one patient from each group dropped out due to gastrointestinal side effects. At end-of-treatment, 20 (77%) individuals on liraglutide had experienced a reduction in stool frequency of ≥25% per day vs. 13 (50%) on colesevelam treatment, corresponding to a statistically superior risk difference of -0.27 (one-sided 95% CI: -1; -0.06). In contrast to the colesevelam-treated group, the liraglutide-treated group exhibited a significant increase in SeHCAT values resulting in significantly higher values at end-of-treatment (mean (SD) 8.9 (7.3) vs. 0.9 (2.0) %, P&amp;lt;0.0001). In conclusion, we show that liraglutide enhances the reabsorption of bile acids and constitutes a safe and effective treatment of BAM which is superior compared to current standard of care (colesevelam). Disclosure M. L. Kårhus: None. A. Brønden: None. J. Forman: None. A. Haaber: None. E. Langholz: None. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. D. P. Sonne: None. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S. Funding Novo Nordisk Foundation (NNF17OC0029710); A.P. Møller and Chastine Mc-Kinney Møller Foundation (19-L-0002)

7-LB: Lowering of Blood Pressure and Pulse Rate by Switching from DPP-4 Inhibitor to Luseogliflozin in Patients with Type 2 Diabetes and Hypertension: A Multicenter, Prospective, Randomized, Open-Label, Parallel-Group Comparison Trial

Objective: Sodium-glucose cotransporter-2 inhibitor (SGLT2i) treatment had the effect of reducing blood pressure (BP) and cardiovascular events in recent mega-scale trials, but the effects on BP circadian rhythm remained unclear. The present study aimed to determine the nocturnal antihypertensive effect of SGLT2i compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) in patients with type 2 diabetes and hypertension. Research Design and Methods: In this randomized, open-label, parallel-group trial, patients treated with DPP-4i were either switched to luseogliflozin 2.5 mg/day (Luseo group; n=30) or continued DPP-4i (DPP-4i group; n=26). The patients undertook 24-h ambulatory BP monitoring before and 8 weeks after the group allocation. The primary endpoint was mean change in nighttime systolic BP (SBP). Results: Changes in both nighttime and daytime SBP were significantly reduced in the Luseo group compared with the DPP-4i group (nighttime, −4.0±11.4 vs. 3.6±10.7 mmHg, P=0.01; daytime, −4.4±10.9 vs. 3.7±11.9 mmHg, P=0.01). Similarly, nighttime pulse rate (PR) was significantly reduced in the Luseo group compared with the DPP-4i group (−2.0±4.8 vs. 0.9±4.8 bpm, P=0.03). Abnormal BP circadian rhythms (non-dipper and riser types) were significantly decreased in the Luseo group (56.7% to 36.6%, P&amp;lt;0.05). Conclusions: Switching from DPP-4i to luseogliflozin decreased not only daytime but also nighttime SBP and PR, and improved BP circadian rhythm. These improvements could be some of the factors involved in the cardiovascular event suppression observed with SGLT2i therapy. Disclosure R. Hashimoto-kameda: None. K. Cho: None. H. Nomoto: None. A. Nakamura: Research Support; Self; Boehringer Ingelheim International GmbH, Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Taisho Pharmaceutical Co., Ltd. K. Omori: None. S. Kawata: None. H. Kameda: None. T. Atsumi: Research Support; Self; Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly Japan K. K., Gilead Sciences, Inc., Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., UCB Japan Co. Ltd., Speaker’s Bureau; Self; AbbVie Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K. K., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Takeda Pharmaceutical Co., UCB Japan Co. Ltd. H. Miyoshi: Research Support; Self; Abbott Japan Co., Ltd., Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Speaker’s Bureau; Self; Astellas Pharma Inc., Eli Lilly Japan K. K., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd. Funding Taisho Pharmaceutical Co., Ltd.

1055-P: The Machine Learning Prediction Model NASHmap Identifies Higher Insulin Resistance in Type 2 Diabetes Mellitus (T2DM) Patients at Risk for Nonalcoholic Steatohepatitis (NASH)

Background: Phenotypic methods such as elevated liver tests and/or the presence of obesity or hypertension are often used to identify patients with T2DM at risk for NASH. Machine learning (ML) models allow the prediction of outcomes with many interacting features and may be superior to phenotype in the context of NASH and T2DM. Here we present an intergroup comparison between patients with T2DM predicted as positive or negative for NASH by NASHmap, a ML model showing high prediction performance in real-word datasets. Methods: We evaluated a subgroup of patients from a large T2DM clinical trial database (2002-2012) who had data for 14 NASHmap parameters. These include clinical observations and routine laboratory parameters but not HOMA-IR. We compared the profile of patients predicted by NASHmap (NASH positive or negative) using 17 parameters (14 NASHmap and 3 additional parameters). We compared HOMA-IR values between NASHmap positive and negative patients in the subgroup where the values were available. Results: The clinical database had 23038 metabolically compensated T2DM patients without chronic liver disease of other etiologies. Data for all 14 NASHmap parameters were available in 4336 patients. NASHmap positive patients were younger, had higher HbA1c, liver enzymes, triglycerides, WBC, body mass index, platelets, and a higher rate for hypertension. Data for HOMA-IR were available in 1208 patients. Median HOMA-IR value was 4.2 in NASHmap positive group vs. 2.6 in NASHmap negative group. Patients in both groups had a similar median duration of diabetes. Conclusion: Overall, the patients identified as at risk for NASH by NASHmap showed a metabolically unfavorable phenotype indicated by the higher HOMA-IR values in this group that the ML algorithm is also able to detect. ML models may be an important tool in effectively identifying patients at risk for NASH in electronic health records and clinical care. Disclosure A. Tietz: Employee; Self; Novartis AG, Stock/Shareholder; Self; Novartis AG. G. Bader: Employee; Self; Novartis AG. M. Docherty: Employee; Self; ZS Associates. B. Reinhart: Employee; Self; ZS Associates. M. Balp: Employee; Self; Novartis AG. M. Pedrosa: Employee; Self; Novartis AG. S. K. Acharya: Employee; Self; Novartis Healthcare Pvt. Ltd., Employee; Spouse/Partner; Novartis Healthcare Pvt. Ltd. J. Loeffler: Employee; Self; Novartis AG, Stock/Shareholder; Self; Novartis AG. J. M. Schattenberg: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Consultant; Self; Boehringer Ingelheim, BMS, Echosens, Genfit, Gilead Sciences, Intercept Pharmaceuticals, Madrigal, Novartis, Novo Nordisk, Nordic Bioscience, Pfizer, Roche, Sanofi, Siemens Healthcare GmbH, Zydus, Bristol-Myers Squibb Company.