1895-LB: Fasting C-Peptide and Type 1 Diabetes Polygenic Score Predict Diabetic Ketoacidosis in People with Type 2 Diabetes in DECLARE-TIMI 58
Authors: MI KANG YU , MELLONI GIORGIO E.M. , CAHN AVIVIT , RAZ ITAMAR , MOURA FILIPE , BHATT DEEPAK L. , INZUCCHI SILVIO E. , LEITER LAWRENCE A. , MCGUIRE DARREN K. , WILDING JOHN , GAUSE-NILSSON INGRID A. , OSCARSSON JAN , MARSTON NICHOLAS , RUFF CHRISTIAN T. , SABATINE MARC S. , WIVIOTT STEPHEN D. 
Published: June 2024

Introduction: We aimed to study the association of T1D polygenic score (PS) & C-peptide (C-pep) with the risk of DKA in DECLARE-TIMI 58.
Methods: DECLARE-TIMI 58 was a CV outcomes trial of dapagliflozin (DAPA) vs. placebo (PBO) in pts clinically diagnosed with T2D. T1D PS consists of scores based on HLA and non-HLA allele composition. High T1D PS was defined as having both HLA and non-HLA PS within the top tertile. Fasting C-pep &lt;0.4 nmol/L was considered low. Pts were divided into 4 groups based on the presence/absence of high T1D PS and low C-pep.
Results: Among 10,956 pts with genetic data, 27 (2.5%; 21 in DAPA and 6 in PBO) had DKA over 4.2 yrs. Of all pts, 1,272 (11.6%) had high T1D PS and their risk of DKA was 4-fold higher vs the rest (HR 3.90, 95% CI 1.75-8.70). 9.3% of all pts had low C-pep, and 1.6% had both high T1D PS and low C-pep. The 4-yr KM rate for DKA in pts with no risk factors was 0.06%, followed by 0.21% in pts with high T1D PS only, 1.38% in pts with low C-pep only, and 4.28% in pts with both (Fig A). Absolute differences in rates between DAPA and PBO tended to be greater in the higher-risk groups (P-trend &lt;0.001: Fig B).
Conclusion: Although rare overall, DKA was more common in DAPA arm, and it was largely confined to high-risk pts defined by T1D PS and C-peptide. These tools can help identify pts at increased risk of DKA associated with SGTL2i. The clinical implications of these findings require further investigation.

Disclosure
Y. Kang: None. A. Cahn: Advisory Panel; Novo Nordisk. Speaker's Bureau; Novo Nordisk, AstraZeneca, Eli Lilly and Company, Bayer Inc. Advisory Panel; Eli Lilly and Company. I. Raz: Consultant; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Johnson & Johnson Medical Devices Companies, Bayer Inc. F. Moura: Consultant; Janssen Pharmaceuticals, Inc. D.L. Bhatt: Advisory Panel; Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed,. Board Member; American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock);. Consultant; Broadview Ventures, GlaxoSmithKline, Hims, SFJ, Youngene. Other Relationship; Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute, Boston Scientific, Cleveland Clinic, Contego Medical, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai, Novartis, Popul, ACC, Arnold and Porter Law Firm, Baim Institute, Belvoir Publications, CSL Behring, Cowen and Company, Duke Clinical Research Institute, HMP Global, Journal of the ACC, K2P, Level Ex, Medtelligence/Re, Population Health Research Institute, Wiley, Clinical Cardiology, Lexicon Pharmaceuticals, Inc. Research Support; Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scienti, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Mode, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio. Other Relationship; Elsevier (Editor, Braunwald’s Heart Disease), Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions, American College of Cardiology, FlowCo. Stock/Shareholder; Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock). S.E. Inzucchi: Consultant; AstraZeneca, Boehringer-Ingelheim, Merck & Co., Inc., Pfizer Inc., Novo Nordisk, Bayer Inc. L.A. Leiter: Advisory Panel; Abbott. Other Relationship; Amarin Corporation, Amgen Inc., Applied Therapeutics Inc. Advisory Panel; AstraZeneca. Other Relationship; Bayer Inc. Advisory Panel; Boehringer-Ingelheim. Other Relationship; CRISPR Therapeutics Other, Eli Lilly and Company. Speaker's Bureau; EOCI Pharmacomm. Research Support; ESPERION Therapeutics, Inc. Other Relationship; HLS Therapeutics Inc. Research Support; Kowa Company, Ltd., Lexicon Pharmaceuticals, Inc. Advisory Panel; Merck & Co., Inc. Speaker's Bureau; Novartis AG. Advisory Panel; Novo Nordisk. Other Relationship; Novo Nordisk Canada Inc. Speaker's Bureau; Pfizer Inc. Advisory Panel; Sanofi. Speaker's Bureau; Toronto Knowledge Translation Working Group. Other Relationship; Up-To-Date. D.K. McGuire: Other Relationship; Merck & Co., Inc., Eli Lilly and Company, Boehringer-Ingelheim, Novo Nordisk, Pfizer Inc., AstraZeneca. Consultant; Bayer Inc., Lexicon Pharmaceuticals, Inc., Altimmune Inc., Intercept Pharmaceuticals, Inc., Applied Therapeutics. J. Wilding: Speaker's Bureau; Boehringer-Ingelheim. Consultant; Eli Lilly and Company, Napp Pharmaceuticals Limited, Novo Nordisk. Advisory Panel; AstraZeneca. Consultant; Alnylam Pharmaceuticals, Inc., Rhythm Pharmaceuticals, Inc. Speaker's Bureau; Sanofi. Consultant; A. Menarini Diagnostics. I.A. Gause-Nilsson: Employee; AstraZeneca. J. Oscarsson: Employee; AstraZeneca. Stock/Shareholder; AstraZeneca. N. Marston: Research Support; Ionis Pharmaceuticals, Amgen Inc., Pfizer Inc. C.T. Ruff: Research Support; Anthos, AstraZeneca, Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Novartis AG. Other Relationship; Altimmune Inc. Advisory Panel; Bayer Inc., Merck & Co., Inc., Anthos, Janssen Pharmaceuticals, Inc. M.S. Sabatine: Research Support; Abbott, Amgen Inc. Consultant; Amgen Inc. Research Support; Anthos. Consultant; Anthos. Research Support; AstraZeneca. Consultant; AstraZeneca, Beren Therapeutics. Research Support; Boehringer-Ingelheim. Consultant; Boehringer-Ingelheim. Research Support; Daiichi Sankyo. Consultant; Dr. Reddy's Laboratories. Research Support; Ionis Pharmaceuticals, Merck & Co., Inc. Consultant; Merck & Co., Inc., Moderna, Inc. Research Support; Novartis AG. Consultant; Novo Nordisk. Research Support; Pfizer Inc. Consultant; Precision Biosciences. Research Support; Saghmos Therapeutics. Consultant; Silence Therapeutics. Research Support; Verve Therapeutics. S.D. Wiviott: Consultant; Novo Nordisk, Varian, Icon. Research Support; Amgen Inc., Merck & Co., Inc., AstraZeneca, Pfizer Inc. Other Relationship; Vertex Pharmaceuticals Incorporated, Flagship Pioneering.

Funding
National Institutes of Health (5T32DK007529)