Mundipharma International Research Articles

LBA02-09 EMBARK: A Phase 3 Randomized Study of Enzalutamide or Placebo Plus Leuprolide Acetate and Enzalutamide Monotherapy in High-risk Biochemically Recurrent Prostate Cancer

LBA02-09 EMBARK: A Phase 3 Randomized Study of Enzalutamide or Placebo Plus Leuprolide Acetate and Enzalutamide Monotherapy in High-risk Biochemically Recurrent Prostate Cancer

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

131-LB: The Impact of Canagliflozin on the Risk of Neuropathy Events: Results from the CREDENCE Trial

Background: Sodium-glucose cotransporter 2 inhibitors reduce the risk, and progression, of diabetic kidney disease. We hypothesized that sodium-glucose cotransporter 2 inhibitors could similarly improve the microvascular complication of neuropathy. Methods: The CREDENCE trial randomized participants with type 2 diabetes and albuminuria to canagliflozin or placebo. Neuropathy events were defined as any reported adverse event with a Medical Dictionary for Regulatory Activities (MedDRA) term consistent with peripheral or autonomic neuropathy. The effect of canagliflozin on neuropathy events was calculated by Cox regression. In secondary analyses the endpoint was restricted to sensorimotor polyneuropathy, diabetic neuropathy, or non-autonomic neuropathy events, and subgroups were analysed. P-values adjusted for multiplicity using the Holm-Bonferroni correction were derived for the subgroup analyses. Results: Half (48.8%) of the 4401 participants had a diagnosis of neuropathy at baseline. Over a median of 2.45 years follow up, 657 people experienced a neuropathy event (63.2 per 1000 patient-years). The incidence of neuropathy events was similar in people randomized to canagliflozin and placebo (334/2202 vs. 323/2199; HR 1.04, 95% CI 0.89 to 1.21, p=0.66). Canagliflozin had no impact on sensorimotor polyneuropathy (HR 0.93, 95% CI 0.69 to 1.25, p=0.63), diabetic neuropathy (HR 0.91, 95% CI 0.68 to 1.22, p=0.52), or non-autonomic neuropathy (HR 1.03, 95% CI 0.87 to 1.21, p=0.77). The lack of effect on neuropathy events was consistent in subgroup analyses. Conclusions: Canagliflozin did not affect the risk of neuropathy events in the CREDENCE trial despite clear benefits for nephropathy, cardiovascular disease and glycemic control. Disclosure J. Liao: None. 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. A. Levin: Advisory Panel; Self; AstraZeneca, Johnson & Johnson, Research Support; Self; Boehringer Ingelheim International GmbH. D. De zeeuw: Consultant; Self; Boehringer Ingelheim International GmbH, Fresenius Medical Care, Retrophin, Inc., Other Relationship; Self; Bayer Healthcare Pharmaceuticals Inc. B. Neal: Advisory Panel; Self; Abbott, Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Roche Pharma, Servier Laboratories, Research Support; Self; Janssen Pharmaceuticals, Inc., Merck Schering Plough, Roche Pharma, Servier Laboratories. H. Zhang: None. 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. B. Zinman: Advisory Panel; Self; Abbott Diabetes, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. K. W. Mahaffey: Consultant; Self; Abbott, Amgen Inc., Anthos, AstraZeneca, Baim Institute for Clinical Research, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., CSL Behring, Elsevier, Inova, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundipharma International, MyoKardia, National Institutes of Health, Novartis Pharmaceuticals Corporation, Novo Nordisk, Otsuka America Pharmaceutical, Inc., Portola Pharmaceuticals, Inc., Regeneron Pharmaceuticals Inc., SmartMedics, Theravance Biopharma, Research Support; Self; Afferent, AHA, Amgen Inc., Apple, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Cardiva Medical, Inc, Eidos, Ferring Pharmaceuticals Inc., Gilead Sciences, Inc., Google, Johnson & Johnson, Luitpold Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., National Institutes of Health, Novartis Pharmaceuticals Corporation, Sanifit, Sanofi, St. Jude Medical. V. Perkovic: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Baxter, Bayer AG, Boehringer Ingelheim (Canada) Ltd., Bristol-Myers Squibb Company, Eli Lilly Japan K. K., Gilead Sciences, Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Retrophin, Inc., Roche Pharma, Sanofi, Servier Laboratories. M. J. Jardine: Advisory Panel; Self; AstraZeneca, Bayer Inc., Boehringer Ingelheim Intern

797-P: Predictive Factors of Renal Function Decline in Patients with Type 2 Diabetes Treated with Canagliflozin in the Real-WECAN Study

The Real-WECAN study assessed in a real-world setting the efectiveness and safety of canagliflozin 100 mg (add-on therapy in SGLT-2i naive individuals) and canagliflozin 300 mg (switching from canagliflozin 100 mg or other SGLT-2i) in patients with T2DM. The aim of this analysis is to determine baseline predictors of renal function decline over the follow-up. A multiple linear regression analysis estimated the best predictive model of eGFR reduction using the Mallows criterion. 583 patients were included, mean age 60.4 years, A1C 7.76%, BMI 34.7 kg/m2, eGFR 85.6 ml/min, eGFR 30 mg/g 22.8%, median follow-up 13 months. There was a modest mean decrease in eGFR (-1.9 ml/min, p In summary, in the Real-WECAN study, patients with older age, combined hyperlipidemia, heart failure, higher baseline eGFR and macroalbuminuria showed greater reductions in eGFR after canagliflozin therapy. Disclosure J. J. Gorgojo-martinez: Research Support; Self; AstraZeneca, Novo Nordisk, Speaker’s Bureau; Self; Abbott, AstraZeneca, Lilly Diabetes, Mundipharma International, Novartis Pharmaceuticals Corporation, Novo Nordisk. J. E. M. Wong-cruz: None. M. Brito: Advisory Panel; Self; MSD Corporation, Novo Nordisk, Sanofi, Speaker’s Bureau; Self; Abbott Diabetes, Almirall, S. A., Amgen Inc., AstraZeneca, Eli Lilly and Company, Esteve, MSD Corporation, Mundipharma International, Novo Nordisk, Sanofi-Aventis. T. Anton-bravo: None. A. Galdon-sanzpastor: Speaker’s Bureau; Self; AstraZeneca, Mundipharma International, Novo Nordisk Inc., Sanofi. M. A. Gargallo-fernandez: None.

129-LB: Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex in the CREDENCE Trial

Background: Canagliflozin reduces the incidence of kidney and cardiovascular events in people with type 2 diabetes and chronic kidney disease (CKD). We assessed the effects of canagliflozin according to age and sex in a randomized, placebo-controlled trial. Methods: The CREDENCE study randomized participants with type 2 diabetes and albuminuric CKD. The effects of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of the serum creatinine level, or death from kidney or cardiovascular causes), and secondary outcomes were evaluated by age at baseline ( Results: Of the 4401 participants, 33.5%, 42.1%, and 24.4% were Conclusion: Canagliflozin reduces the risk of kidney and cardiovascular events in people with type 2 diabetes and CKD with consistent effects and no differences in safety outcomes across subgroups defined by age and sex. Disclosure T. Yi: None. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc. D. De zeeuw: Consultant; Self; Boehringer Ingelheim International GmbH, Fresenius Medical Care, Retrophin, Inc., Other Relationship; Self; Bayer Healthcare Pharmaceuticals Inc. 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. A. Levin: Advisory Panel; Self; AstraZeneca, Johnson & Johnson, Research Support; Self; Boehringer Ingelheim International GmbH. B. Neal: Advisory Panel; Self; Abbott, Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Roche Pharma, Servier Laboratories, Research Support; Self; Janssen Pharmaceuticals, Inc., Merck Schering Plough, Roche Pharma, Servier Laboratories. 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. Zhang: None. B. Zinman: Advisory Panel; Self; Abbott Diabetes, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. K. W. Mahaffey: Consultant; Self; Abbott, Amgen Inc., Anthos, AstraZeneca, Baim Institute for Clinical Research, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., CSL Behring, Elsevier, Inova, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundipharma International, MyoKardia, National Institutes of Health, Novartis Pharmaceuticals Corporation, Novo Nordisk, Otsuka America Pharmaceutical, Inc., Portola Pharmaceuticals, Inc., Regeneron Pharmaceuticals Inc., SmartMedics, Theravance Biopharma, Research Support; Self; Afferent, AHA, Amgen Inc., Apple, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Cardiva Medical, Inc, Eidos, Ferring Pharmaceuticals Inc., Gilead Sciences, Inc., Google, Johnson & Johnson, Luitpold Pharmaceuticals, Inc., Medtronic, Merck & C

185-OR: Longitudinal Changes in KidneyIntelX and Association with Progressive Decline in Kidney Function in the CANVAS Trial

KidneyIntelX is a composite risk score incorporating biomarkers and clinical variables for predicting progression of prevalent diabetic kidney disease (DKD). The change of this score over time in response to SGLT2 inhibitors and how these changes associate with future kidney outcomes is unknown. We measured soluble Tumor Necrosis Factor Receptor 1 (sTNFR-1), soluble Tumor Necrosis Factor Receptor 2 (sTNFR-2), and Kidney Injury Molecule (KIM-1) on banked samples from CANVAS trial participants with baseline DKD (eGFR <60 ml/min/1.73 m2 or UACR ≥30 mg/mg) and determined the KidneyIntelX risk score at baseline and year 1. We assessed the effect of canagliflozin (CANA) on KidneyIntelX scores and how changes from baseline to year 1 were associated with subsequent DKD progression (composite outcome of eGFR decline of ≥5 ml/min/year [using 6-week eGFR as baseline in the CANA group], ≥40% sustained decline in eGFR, or kidney failure). There were 1016 participants with prevalent DKD who had baseline and year 1 plasma samples. Median age was 64 years, 30% were female, median eGFR was 66 ml/min and median UACR was 55 mg/g. After year 1, 68 (6.7%) participants experienced the composite outcome over a median of 4.9 years. CANA reduced KidneyIntelX risk by 5.1% (95% CI -6.6 to -3.6) at year 1 vs. increasing by 5.8% (95% CI 3.4 to 8.1) in placebo (p <0.001). Each percent reduction in KidneyIntelX score at year 1 was associated with a 2% lower risk of the composite outcome (OR per unit 0.98, 95% CI 0.97 to 0.99; p <0.001) after adjusting for baseline score and treatment arm. The associations between the change in KidneyIntelX and outcome were consistent in the treatment arm and placebo arm (pinteraction=0.63). In conclusion, CANA treatment reduced KidneyIntelX risk scores. Changes in the KidneyIntelX score from baseline to 1 year predict future risk of DKD progression whether they resulted from kidney protection afforded by SGLT2i therapy, or decline in kidney function caused by disease progression. Disclosure D. W. Lam: None. G. N. Nadkarni: Advisory Panel; Self; Renalytix AI plc., Consultant; Self; AstraZeneca, Renalytix AI plc., Variant Bio, Research Support; Self; Renalytix AI plc., Stock/Shareholder; Self; Renalytix AI plc. B. Neal: Advisory Panel; Self; Abbott, Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Roche Pharma, Servier Laboratories, Research Support; Self; Janssen Pharmaceuticals, Inc., Merck Schering Plough, Roche Pharma, Servier Laboratories. K. W. Mahaffey: Consultant; Self; Abbott, Amgen Inc., Anthos, AstraZeneca, Baim Institute for Clinical Research, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., CSL Behring, Elsevier, Inova, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundipharma International, MyoKardia, National Institutes of Health, Novartis Pharmaceuticals Corporation, Novo Nordisk, Otsuka America Pharmaceutical, Inc., Portola Pharmaceuticals, Inc., Regeneron Pharmaceuticals Inc., SmartMedics, Theravance Biopharma, Research Support; Self; Afferent, AHA, Amgen Inc., Apple, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Cardiva Medical, Inc, Eidos, Ferring Pharmaceuticals Inc., Gilead Sciences, Inc., Google, Johnson & Johnson, Luitpold Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., National Institutes of Health, Novartis Pharmaceuticals Corporation, Sanifit, Sanofi, St. Jude Medical. N. Rosenthal: Employee; Self; Janssen Research & Development, LLC. M. K. Hansen: Employee; Self; Janssen Pharmaceuticals, Inc. 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. S. Coca: Advisory Panel; Self; Akebia Therapeutics, Inc., Bayer AG, Boehringer Ingelheim International GmbH, Consultant; Self; CHF Solutions, Relypsa Inc., Renalytix AI plc., Takeda Pharmaceutical Co., Research Support; Self; inRegen, XORTX Therapeutics Inc., Stock/Shareholder; Self; Renalytix AI plc.

786-P: Glycemic Efficacy and Safety of Ertugliflozin (ERTU) in Patients with Type 2 Diabetes (T2D) and Chronic Kidney Disease Stage 3 (CKD 3): An Analysis from VERTIS CV

VERTIS CV was a cardiovascular (CV) outcome trial that evaluated the CV safety of ERTU in patients with T2D and atherosclerotic CV disease (ASCVD). This analysis assessed the glycemic efficacy and safety of ERTU in VERTIS CV patients with CKD 3. Among 8246 patients in VERTIS CV, 1776 patients with CKD 3 at baseline (BL) were identified based on an eGFR of 30-<60 mL/min/1.73 m2 (1319 patients with CKD 3A [eGFR 45-<60 mL/min/1.73 m2]), calculated via the MDRD equation. Efficacy endpoints were changes from BL in HbA1c, body weight (BW) and systolic blood pressure (SBP) to Week 18, when doses of background antihyperglycemics were to be held constant. Safety assessments included adverse event (AE) reports. BL characteristics did not differ across randomized groups in patients with CKD 3. At Week 18, significant HbA1c reductions from BL for ERTU 5 mg and 15 mg vs. placebo were observed in patients with CKD 3 and in the CKD 3A subgroup (Table). Significant placebo-subtracted reductions in BW (5 mg: −1.4 kg; 15 mg: −1.5 kg) and SBP (5 mg: −2.9 mm Hg; 15 mg: −3.2 mm Hg) occurred in the CKD 3 patients receiving ERTU. The incidence of overall AEs, symptomatic hypoglycemia, hypovolemia and kidney-related AEs did not differ between ERTU and placebo across CKD 3 subgroups. In patients with T2D, ASCVD and CKD 3, ERTU improved glycemic control, BW and SBP, and was generally well tolerated.View largeDownload slideView largeDownload slide DisclosureS. Dagogo-jack: Consultant; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi US, Stock/Shareholder; Self; Aerami Therapeutics, Jana Care Inc. J. P. Mancuso: Employee; Self; Pfizer Inc., Employee; Spouse/Partner; Pfizer Inc., Stock/Shareholder; Self; Pfizer Inc., Stock/Shareholder; Spouse/Partner; Pfizer Inc. A. Raji: Employee; Self; Merck & Co., Inc. I. Gantz: Employee; Self; Merck & Co., Inc. 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. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. B. Charbonnel: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck & Co., Inc., Mundipharma International, Novo Nordisk, Sanofi, Speaker’s Bureau; Self; Takeda Pharmaceutical Company Limited. D. K. Mcguire: Consultant; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., CSL Behring, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. F. Cosentino: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Pfizer Inc., Speaker’s Bureau; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Mundipharma International, Novo Nordisk. W. J. Shih: None. J. Liu: Employee; Self; Merck Sharp & Dohme Corp. R. Frederich: Employee; Self; Pfizer Inc., Other Relationship; Self; Merck Sharp & Dohme Corp., Stock/Shareholder; Self; Bristol-Myers Squibb Company, Pfizer Inc.

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)

785-P: Ertugliflozin (ERTU) Delays Insulin Initiation and Reduces Insulin Dose Requirements in Patients with Type 2 Diabetes (T2D): An Analysis From VERTIS CV

VERTIS CV was a cardiovascular (CV) outcome trial that evaluated the CV safety of ERTU in patients with T2D. In VERTIS CV, 8238 patients received ERTU 5 or 15 mg, or placebo (PBO); doses of background antihyperglycemic medications were to be held constant to Week 18. This analysis assessed the insulin requirements of VERTIS CV patients during the entire study. In 4341 (53%) insulin-naive patients, insulin was initiated in 12.8% (ERTU 5 mg), 11.6% (ERTU 15 mg) and 17.5% (PBO) of patients after the randomization visit. There was a significantly reduced likelihood of insulin initiation with ERTU 5 and 15 mg vs. PBO (ERTU 5 mg: HR 0.70, 95% CI 0.58-0.84; ERTU 15 mg: HR 0.64, 95% CI 0.53-0.78) and a delay in initiating insulin with ERTU 5 and 15 mg vs. PBO was observed (Figure). In 3897 (47%) patients on insulin at baseline (BL), mean (95% CI) change in insulin dose from BL to Month 60 was −2.47 (−9.65, 4.72) IU/d with ERTU 5 mg, −1.77 (−11.95, 8.42) IU/d with ERTU 15 mg and 9.42 (1.46, 17.39) IU/d with PBO. More patients in the ERTU 15 mg arm (4.1%) had discontinued insulin therapy at end of study than in the ERTU 5 mg (2.4%) or PBO (2.2%) arms. In insulin-naive patients with T2D, ERTU significantly reduced the likelihood of insulin initiation and delayed new insulin initiations by up to ~1.8 years vs. PBO. In patients already on insulin at BL, ERTU prevented an increase in mean insulin dose. Disclosure S. Dagogo-jack: Consultant; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi US, Stock/Shareholder; Self; Aerami Therapeutics, Jana Care Inc. W. J. Shih: None. U. Masiukiewicz: Employee; Self; Pfizer Inc. I. Gantz: Employee; Self; Merck & Co., Inc. 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. R. Frederich: Employee; Self; Pfizer Inc., Other Relationship; Self; Merck Sharp & Dohme Corp., Stock/Shareholder; Self; Bristol-Myers Squibb Company, Pfizer Inc. B. Charbonnel: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck & Co., Inc., Mundipharma International, Novo Nordisk, Sanofi, Speaker’s Bureau; Self; Takeda Pharmaceutical Company Limited. J. Liu: Employee; Self; Merck Sharp & Dohme Corp. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc. H. Shi: Employee; Self; Pfizer Inc., Employee; Spouse/Partner; Bristol-Myers Squibb Company. D. K. Mcguire: Consultant; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., CSL Behring, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. F. Cosentino: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Pfizer Inc., Speaker’s Bureau; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Mundipharma International, Novo Nordisk.

130-LB: Dapagliflozin and the Incidence of Type 2 Diabetes in Patients with Chronic Kidney Disease

The DAPA-CKD trial demonstrated a significant reduction in the risk of adverse kidney and cardiovascular outcomes in participants with chronic kidney disease (CKD), with and without type 2 diabetes (T2D), treated with dapagliflozin 10 mg once daily compared to placebo (randomized 1:1). This pre-specified analysis explored the effect of dapagliflozin on incident T2D in the cohort without diabetes enrolled in DAPA-CKD. A subgroup of 1,398 participants with CKD, no prior history of diabetes, and HbA1c &amp;lt;6.5% at baseline were included. In this pre-specified exploratory analysis, surveillance for new-onset T2D (confirmed HbA1c ≥6.5%) was accomplished through periodic HbA1c testing (part of the study protocol) and comparison between treatment groups assessed through Cox proportional hazards model. Over a median follow-up of 2.4 years, T2D developed in 33/701 (4.7%) in the placebo group and 21/697 (3.0%) in the dapagliflozin group. This corresponded to event rates of 2.4/100-patient years and 1.5/100-patient years, respectively. Dapagliflozin led to a 38% reduction in T2D incidence (hazard ratio [95%CI] 0.62 [0.36, 1.08]). There was no heterogeneity in the effect of dapagliflozin on T2D prevention based on most key prespecified subgroups, including age, glycemic status, blood pressure, estimated glomerular filtration rate, albuminuria, race and region, but the effect was more pronounced in females (p interaction 0.03). More than 90% of the participants who developed T2D had prediabetes at baseline (HbA1c 5.7-6.4%). A meta-analysis of DAPA-CKD and DAPA-HF (dapagliflozin in heart failure with reduced ejection fraction) demonstrated that dapagliflozin reduced new-onset diabetes compared to placebo (hazard ratio 0.66 [0.51, 0.87]; p=0.003), without heterogeneity between studies (p interaction 0.78). In this pre-specified explorative analysis of patients with CKD, treatment with dapagliflozin reduced the incidence of new T2D, an effect that was consistent across DAPA-CKD and DAPA-HF. Disclosure 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. A. Langkilde: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. D. C. Wheeler: Advisory Panel; Self; Merck Sharp &amp; 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 &amp; Development, LLC, Merck &amp; 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 &amp; Development, LLC. Dapa-ckd study group: n/a. 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. N. Jongs: None. J. J. Mcmurray: Other Relationship; Self; AbbVie Inc., Amgen Inc., AstraZeneca, Bayer AG, Cytokinetics Inc., DalCor Pharmaceuticals, Merck &amp; 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. B. Stefansson: Employee; Self; AstraZeneca. 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. Funding AstraZeneca

796-P: Cardiorenal Outcomes with Ertugliflozin by Baseline Cardiorenal Medications: An Analysis from VERTIS CV

VERTIS CV was a placebo-controlled cardiovascular (CV) outcome trial evaluating the SGLT2 inhibitor ertugliflozin. The aim of current analyses was to examine pre-specified CV and kidney outcomes by Cox proportional hazard assessment according to use of renin-angiotensin-aldosterone system inhibitors (RAASi), diuretics, and mineralocorticoid receptor antagonists (MRA) at baseline. Among 8246 randomized patients, at baseline 6686 (81%) were treated with RAASi, 3542 (43%) with diuretics, including 1252 (15%) with loop diuretics, and 674 (8%) with MRA. No significant interactions were observed for cardiorenal outcomes by baseline use of RAASi or MRA (Pinteraction > 0.05 for all; FIGURE). Nominally significant interactions for first event of hospitalization for heart failure (HHF) and HHF/CV death were observed with baseline use of diuretics, including loop diuretics, with an increased benefit of ertugliflozin vs. placebo. In VERTIS CV, baseline use of diuretics, including loop diuretics, appeared to be associated with greater benefit of ertugliflozin on first HHF and HHF/CV death, with no modification of effect based on baseline use of RAASi or MRA.View largeDownload slideView largeDownload slide DisclosureD. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. I. Gantz: Employee; Self; Merck & Co., Inc. R. Frederich: Employee; Self; Pfizer Inc., Other Relationship; Self; Merck Sharp & Dohme Corp., Stock/Shareholder; Self; Bristol-Myers Squibb Company, Pfizer Inc. J. P. Mancuso: Employee; Self; Pfizer Inc., Employee; Spouse/Partner; Pfizer Inc., Stock/Shareholder; Self; Pfizer Inc., Stock/Shareholder; Spouse/Partner; Pfizer Inc. U. Masiukiewicz: Employee; Self; Pfizer Inc. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc. F. Cosentino: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Pfizer Inc., Speaker’s Bureau; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Mundipharma International, Novo Nordisk. D. K. Mcguire: Consultant; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., CSL Behring, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. B. Charbonnel: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck & Co., Inc., Mundipharma International, Novo Nordisk, Sanofi, Speaker’s Bureau; Self; Takeda Pharmaceutical Company Limited. S. Dagogo-jack: Consultant; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi US, Stock/Shareholder; Self; Aerami Therapeutics, Jana Care Inc. 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. W. J. Shih: None. M. Maldonado: Employee; Self; Merck Sharp & Dohme Corp. A. Pong: None.

783-P: Cardiorenal Outcomes with Ertugliflozin by Baseline (BL) Glucose-Lowering Agent (GLA): An Analysis from VERTIS CV

VERTIS CV was the cardiovascular (CV) outcome trial for the SGLT2 inhibitor ertugliflozin, conducted in patients with type 2 diabetes (T2D) and atherosclerotic CV disease. In the overall population, ertugliflozin was noninferior to placebo for major adverse CV events (MACE). Although superiority for the composite endpoint of CV death or hospitalization for heart failure (HHF) and the renal composite (that included doubling of serum creatinine from BL) were not met, the prespecified secondary objective of HHF showed a 30% risk reduction and a prespecified exploratory renal composite (sustained ≥40% decrease in eGFR from BL, dialysis/transplantation, or renal death) showed improved kidney outcomes. This analysis assessed cardiorenal endpoints of VERTIS CV by BL GLA.Among 8246 patients in VERTIS CV, at BL 6292 (76%) used metformin, 3900 (47%) insulin, 3390 (41%) sulfonylureas (SU), and 911 (11%) dipeptidyl peptidase-4 inhibitors (DPP4i), alone or in combination therapy (67% used >1 GLA at BL). For each of the GLAs, metformin, insulin, SU, and DPP4i, no significant differences were observed for cardiorenal outcomes by BL use (yes, no) of the GLA (FIGURE; all interaction P values >0.05). Cardiorenal outcomes were generally similar across the BL GLA subgroups.In VERTIS CV, the effects of ertugliflozin on cardiorenal outcomes in patients with T2D were generally consistent regardless of BL GLA.View largeDownload slideView largeDownload slide DisclosureB. Charbonnel: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck & Co., Inc., Mundipharma International, Novo Nordisk, Sanofi, Speaker’s Bureau; Self; Takeda Pharmaceutical Company Limited. I. Gantz: Employee; Self; Merck & Co., Inc. R. Frederich: Employee; Self; Pfizer Inc., Other Relationship; Self; Merck Sharp & Dohme Corp., Stock/Shareholder; Self; Bristol-Myers Squibb Company, Pfizer Inc. J. P. Mancuso: Employee; Self; Pfizer Inc., Employee; Spouse/Partner; Pfizer Inc., Stock/Shareholder; Self; Pfizer Inc., Stock/Shareholder; Spouse/Partner; Pfizer Inc. 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. S. Dagogo-jack: Consultant; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi US, Stock/Shareholder; Self; Aerami Therapeutics, Jana Care Inc. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. F. Cosentino: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Pfizer Inc., Speaker’s Bureau; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Mundipharma International, Novo Nordisk. D. K. Mcguire: Consultant; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., CSL Behring, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. W. J. Shih: None. J. Liu: Employee; Self; Merck Sharp & Dohme Corp. A. Pong: None.FundingMerck Sharp & Dohme Corp

133-LB: Canagliflozin Improves Cardiovascular and Renal Outcomes across Broad Geographic Regions: Results from CREDENCE

Background: Diabetes is the most common cause of kidney disease in people requiring renal replacement therapy (RRT). RRT is projected to dramatically increase globally, with the greatest increase in Asia. CREDENCE showed canagliflozin reduces kidney and cardiovascular (CV) events in individuals with type 2 diabetes (T2DM) and chronic kidney disease (CKD). Methods: We explored canagliflozin efficacy across geographic regions. A Cox proportional-hazards model was used to analyze the primary outcome (composite of end-stage kidney disease [dialysis, transplantation, or a sustained eGFR of Results: A total of 4401 participants were enrolled across North America (n=1182, 27%), Central and South America (n=941, 21%), Eastern Europe (n=947, 21%), Western Europe (n=421, 10%), Asia (n=749, 17%), and Other (n=161, 4%). Placebo event rates ranged widely, with 32 and 77 events/1000 patient-years in Western Europe and Asia, respectively. Canagliflozin consistently reduced the risk of the primary outcome in all geographic regions (see Figure, previously reported data on race also included). Conclusions: Event rates varied two-fold across regions and needs further study. Canagliflozin reduces the risk of kidney and CV events in all geographic regions. Disclosure K. Cardoza: None. B. Zinman: Advisory Panel; Self; Abbott Diabetes, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. M. J. Jardine: Advisory Panel; Self; AstraZeneca, Bayer Inc., Boehringer Ingelheim International GmbH, Chinook, CSL Behring, Janssen Pharmaceuticals, Inc., Vifor Pharma Management Ltd., Research Support; Self; Amgen Inc., Dimerix, Eli Lilly and Company, Merck & Co., Inc., Speaker’s Bureau; Self; Amgen Inc. C. Arnott: None. A. Levin: Advisory Panel; Self; AstraZeneca, Johnson & Johnson, Research Support; Self; Boehringer Ingelheim International GmbH. K. W. Mahaffey: Consultant; Self; Abbott, Amgen Inc., Anthos, AstraZeneca, Baim Institute for Clinical Research, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., CSL Behring, Elsevier, Inova, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundipharma International, MyoKardia, National Institutes of Health, Novartis Pharmaceuticals Corporation, Novo Nordisk, Otsuka America Pharmaceutical, Inc., Portola Pharmaceuticals, Inc., Regeneron Pharmaceuticals Inc., SmartMedics, Theravance Biopharma, Research Support; Self; Afferent, AHA, Amgen Inc., Apple, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Cardiva Medical, Inc, Eidos, Ferring Pharmaceuticals Inc., Gilead Sciences, Inc., Google, Johnson & Johnson, Luitpold Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., National Institutes of Health, Novartis Pharmaceuticals Corporation, Sanifit, Sanofi, St. Jude Medical. A. Kang: None. B. Smyth: None. T. Yi: None. G. Di tanna: Consultant; Self; Amgen Inc. C. A. Pollock: None. D. De zeeuw: Consultant; Self; Boehringer Ingelheim International GmbH, Fresenius Medical Care, Retrophin, Inc., Other Relationship; Self; Bayer Healthcare Pharmaceuticals Inc. 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. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc.

791-P: Ertugliflozin in Older Patients with Type 2 Diabetes (T2D): An Analysis from VERTIS CV

VERTIS CV was a cardiovascular (CV) outcome trial of ertugliflozin vs. placebo in patients (pts) with T2D and atherosclerotic CV disease. Here we analyzed the cardiorenal outcomes and safety of ertugliflozin in older pts.Among 8238 pts randomized and treated with ertugliflozin 5 mg, 15 mg, or placebo, 4093 (49.7%) were <65 yrs, 4145 (50.3%) were ≥65 yrs, with 903 (11.0%) ≥75 yrs. Baseline characteristics were similar across treatment groups within each age group; mean eGFR was lower in older pts (82.2, 69.9, and 63.6 mL/min/1.73m2 for pts <65, ≥65, and ≥75 yrs, respectively). Cardiorenal outcomes for ertugliflozin vs. placebo did not differ between pts ≥65 and <65 yrs, with interaction P values >0.05 for all outcomes assessed (FIGURE). The incidences of adverse events (AEs), serious AEs (including deaths), and discontinuations due to an AE were higher in older vs. younger pts, but generally similar across treatment groups in pts ≥65 and ≥75 yrs. The incidence of renal-related AEs was similar across treatment groups in younger and older pts. The incidences of genital mycotic infection and urinary tract infection were higher with ertugliflozin vs. placebo in older pts. The incidences of hypovolemia AEs with ertugliflozin vs. placebo in pts ≥65 was 5.3% vs. 4.5% and in pts ≥75 yrs was 6.9% vs. 5.8%.Cardiorenal outcomes were similar in pts ≥65 and <65 yrs. Ertugliflozin was generally well tolerated in pts ≥65 and ≥75 yrs.View largeDownload slideView largeDownload slide DisclosureR. 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. I. A. Adamsons: Employee; Self; Merck Sharp & Dohme Corp. D. Lawrence: Employee; Self; Pfizer Inc., Employee; Spouse/Partner; Becton, Dickinson and Company. W. J. Shih: None. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc. S. Dagogo-jack: Consultant; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi US, Stock/Shareholder; Self; Aerami Therapeutics, Jana Care Inc. B. Charbonnel: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck & Co., Inc., Mundipharma International, Novo Nordisk, Sanofi, Speaker’s Bureau; Self; Takeda Pharmaceutical Company Limited. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. F. Cosentino: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Pfizer Inc., Speaker’s Bureau; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Mundipharma International, Novo Nordisk. D. K. Mcguire: Consultant; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., CSL Behring, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. M. N. Essex: Employee; Self; Pfizer Inc., Stock/Shareholder; Self; Pfizer Inc. P. L. S. Jones: Employee; Self; Pfizer Inc. J. Liu: Employee; Self; Merck Sharp & Dohme Corp.FundingMerck Sharp & Dohme Corp

107-OR: Six-Day Subcutaneous GIP Infusion Increases Circulating Free Fatty Acids without Altering the Adipose Tissue Transcriptome, Adipocyte GIP Receptor Levels, or Circulating Inflammation Markers in Patients with Type 1 Diabetes

Glucose-dependent insulinotropic polypeptide (GIP) has been proposed to increase adipose tissue lipolysis (at low insulin levels), adipokine secretion and circulating levels of inflammation markers via the GIP receptor (GIPR) in adipose tissue. We investigated the effect of a 6-day subcutaneous (sc) GIP infusion on circulating lipids and inflammation markers, the adipose tissue transcriptome and the presence of GIPR mRNA (ISH) in adipose tissue in patients with type 1 diabetes (T1D). In a randomized, placebo-controlled, double-blind, crossover study, 20 men with T1D (age [mean± SD] 26±8 years, BMI 23.8±1.8 kg/m2, HbA1c 51±10 mmol/mol (6.8±3.1%) underwent 2 × 6 days of continuous sc GIP (6 pmol/kg/min) infusion and placebo (saline) infusion, with an interposed 7-day washout period. Fasting blood samples were drawn frequently within the initial 3 hours and after 1 and 6 days of infusion. Adipose tissue biopsies were collected before and after 6 days of infusion. During the initial 3 hours of infusion, but not at day 1 and 6, GIP increased baseline-subtracted area under the curve of plasma free fatty acids (FFA) compared to placebo (16.8±10.4 vs. 4.4±9.2 min × mmol/L, P &amp;lt;0.001) without affecting plasma glycerol and triglycerides. A panel of 23 circulating inflammation markers were unaffected by the GIP infusion. Adipose tissue transcriptomics did not show differentially expressed genes after 6 days of GIP infusion compared to placebo. In situ hybridization (ISH) localized the GIPR mRNA in the adipocyte and not in connective tissue. ISH verified GIPR mRNA levels were not altered by 6 days of GIP infusion. In patients with T1D, a 6-day sc GIP infusion temporarily increases circulating levels of FFA without altering the adipose tissue transcriptome, GIPR mRNA levels in adipocytes or circulating inflammation markers. Disclosure S. M. Nguyen heimbürger: Speaker’s Bureau; Self; AstraZeneca. 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. C. Pyke: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. 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. B. Hoe: None. C. N. Nielsen: None. 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. F. Dela: None. A. Overgaard: Stock/Shareholder; Self; Novo Nordisk A/S. J. Størling: 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. Funding The Leona M. and Harry B. Helmsley Charitable Trust (2018PG-T1D037)

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&amp;lt;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&amp;lt;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 &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. M. B. Christensen: None.

674-P: Efficacy and Safety of Cotadutide, a Dual GLP-1 and Glucagon Receptor Agonist in Patients with T2DM and DKD

Background: Cotadutide, a dual glucagon-like peptide (GLP-1) and glucagon receptor agonist, is in development for NASH and T2DM with DKD. GLP-1 receptor agonists have been shown to delay the onset of macroalbuminuria in DKD. The glycemic and renal effects of cotadutide were assessed in a phase 2a, randomized, controlled trial (NCT03550378). Methods: The trial enrolled 41 patients with T2DM (HbA1c 6.5-10.5%) and CKD stage 3 (eGFR 30-59 mL/min/1.73 m2), on insulin and/or oral glucose-lowering therapy and BMI 25-45 kg/m2. Patients were randomized to once-daily subcutaneous cotadutide (n = 21) titrated up to 300 µg or placebo (PBO; n = 20) for 32 days. Endpoints included glucose response during a mixed meal tolerance test (MMTT), time spent within a target glucose range over a 7-day period on continuous glucose monitoring (CGM) and body weight. Exploratory measures included eGFR, UACR, C-peptide and NT-proBNP. Results: After 32 days, cotadutide compared with PBO reduced MMTT glucose AUC (-26.7%; 90% CI -34.6% to -18.8%; 7-day mean glucose -47.9 mg/dL vs. PBO) and increased CGM time spent in target range over 32 days by 36.0% vs. PBO to 78.7% (both p ≤ 0.003). Cotadutide was associated with 35.2% reduction in insulin dose, 0.88 µg/L increase in C-peptide and 3.7% reduction in body weight (all p ≤ 0.012). There was no change in eGFR. In patients with baseline micro- or macroalbuminuria (n = 18), UACR was reduced by 50.6% (p = 0.0504 vs. PBO). In addition, NT-proBNP level was reduced with cotadutide vs. PBO (-79.7 ng/L vs. -9.42 ng/L, p = 0.040). Safety and tolerability findings were consistent with the known mechanism of action of GLP-1 receptor agonists. There were no episodes of severe hypoglycemia, and CGM time &amp;lt; 54 mg/dL was 1.65% with cotadutide vs. 0.82% with PBO. Conclusion: In patients with T2DM and DKD, short term treatment with cotadutide had robust effects on glucose lowering. The reduction in albuminuria suggests that cotadutide has renoprotective potential in DKD, but further evaluation is warranted. Disclosure V. E. Parker: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. P. Ambery: Employee; Self; AstraZeneca. 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 &amp; Development, LLC, Merck &amp; 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 &amp; Development, LLC. R. J. Mccrimmon: Advisory Panel; Self; Novo Nordisk Inc., Sanofi-Aventis, Board Member; Self; Novo Nordisk Foundation, Research Support; Self; AstraZeneca. L. Jermutus: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. T. Hoang: None. H. Schlichthaar: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk. F. W. Gibb: Speaker’s Bureau; Self; Abbott Diabetes. B. Wenzel: None. M. G. Posch: None. Y. Chang: None. M. Petrone: None. L. Hansen: Employee; Self; AstraZeneca.

81-OR: Once-Weekly Semaglutide 2.4 mg Improved Glucose Metabolism and Prediabetes in Adults with Overweight/Obesity in the STEP 1 Trial

Semaglutide 2.4 mg demonstrated 14.9% body weight (BW) loss in adults with overweight/obesity in STEP 1. We evaluated effects on glucose metabolism in subjects with prediabetes at baseline (BL). Subjects (N=1961) were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo (PBO), plus lifestyle intervention, for 68 wks. Post-hoc analyses included change from BL to wk 68 in glycemic status (normoglycemia, prediabetes, or type 2 diabetes; all investigator assessed), HbA1c, fasting plasma glucose (FPG), and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Statistical analyses were not adjusted for multiplicity. At BL, 856 (43.7%) subjects had prediabetes (593 semaglutide/263 PBO; mean HbA1c: 5.9/5.9%, FPG: 98.7/97.6 mg/dL, HOMA-IR: 4.2/4.1, BW: 106.9/106.9 kg). By wk 68, 84.1% of those with prediabetes at BL were normoglycemic with semaglutide vs. 47.8% with PBO (p<0.0001) (Figure); of those who reverted from prediabetes to normoglycemia in the semaglutide group, the majority achieved weight loss ≥10%. Treatment with semaglutide vs. PBO lowered HbA1c (difference: -0.35 percentage‑points; p<0.0001), FPG (-8.49 mg/dL; p<0.0001) and HOMA-IR (relative % change: -28%; p<0.0001).In conclusion, once weekly semaglutide 2.4 mg allowed most adults with overweight/obesity and prediabetes to revert to normoglycemia at wk 68.View largeDownload slideView largeDownload slide DisclosureL. Perreault: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk, Consultant; Self; Sanofi, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk. C. Le roux: Advisory Panel; Self; Boehringer Ingelheim International GmbH, GI Dynamics, Herbalife International of America, Inc., Johnson & Johnson, Medtronic, Novo Nordisk A/S. M. J. Davies: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Boehringer Ingelheim Limited (UK), Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi, Other Relationship; Self; AstraZeneca, NIHR Leicester Biomedical Research Centre, Novo Nordisk, Speaker’s Bureau; Self; Astra Zeneca Pharma India Ltd, Boehringer Ingelheim (China), Boehringer Ingelheim (Philippines), Inc., Boehringer Ingelheim International GmbH, Boehringer Ingelheim Limited (UK), Boehringer Ingelheim Saudi Arabia Trading, Boehringer Ingelheim Singapore Pte. Ltd, Boehringer Ingelheim Sp. Z o. o., Eli Lilly and Company, Napp Pharmaceuticals, Novo Nordisk, Novo Nordisk A/S, S. C. Sanofi Romania SRL, Sanofi K. K. 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. N. Laursen: Employee; Self; Novo Nordisk A/S. 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. Machineni: Consultant; Self; Novo Nordisk, Rhythm Pharmaceuticals, Inc., Other Relationship; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk. A. Varbo: Employee; Self; Novo Nordisk A/S. J. Wilding: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Mundipharma International, Napp Pharmaceuticals, Novo Nordisk, Rhythm Pharmaceuticals, Inc., Saniona, Sanofi, Research Support; Self; AstraZeneca, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Napp Pharmaceuticals. S. O. R. Wallenstein: Employee; Self; Novo Nordisk.FundingNovo Nordisk A/S

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 &amp;lt; 0.0001) and lowered fasting plasma glucose (mean: 8.7 vs. 7.6 mmol/L, P &amp;lt; 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 &amp; 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