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Tirzepatide (TZP) is a novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist in development for T2D. In a continuous glucose monitoring (CGM) sub-study of SURPASS-3 (NCT03882970) , participants with T2D on metformin with or without SGLT-2 inhibitors spent up to 91% of time in range (71-180 mg/dL) for TZP (5, 10, 15 mg) vs. 75% for insulin degludec (IDeg) (p Disclosure R.M.Bergenstal: Advisory Panel; Hygieia, Medtronic, Roche Diabetes Care, Zealand Pharma A/S, Consultant; Abbott Diabetes, Ascensia Diabetes Care, Bigfoot Biomedical, Inc., CeQur SA, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, Onduo LLC, Sanofi, United HealthCare Services, Inc., Research Support; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk, Sanofi. A.Bartee: None. M.Zeytinoglu: Employee; Eli Lilly and Company. R.Bray: Employee; Eli Lilly and Company. S.Allen: None. K.Brown: Employee; Eli Lilly and Company.

Tirzepatide (TZP) is a novel dual GIP/GLP-1 receptor agonist under development for the treatment of type 2 diabetes (T2D). The efficacy and safety of TZP vs. titrated insulin degludec (IDeg) were assessed in insulin-naive patients with T2D inadequately controlled on metformin with/without SGLT-2i. In this open-label, 52-week, Phase 3 study, 1444 patients with T2D were randomized (1:1:1:1) to once-weekly TZP (5, 10, 15 mg) or once-daily IDeg (mean baseline [BL] age, 57.4 years; T2D duration, 8.4 years; HbA1c, 8.17%; BMI, 33.5 kg/m2; 32% on SGLT-2i). The primary efficacy endpoint was mean change in HbA1c from BL to Week 52. Secondary efficacy endpoints included mean change in fasting serum glucose (FSG) and body weight (BW) and proportion of subjects achieving HbA1c and BW goals. All TZP doses were superior to IDeg in mean change from BL in HbA1c and BW, and in the proportion of patients achieving all HbA1c and BW goals at Week 52 (Table). Among patients taking TZP 15 mg, 48.4% achieved HbA1c Disclosure B. Ludvik: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Research Support; Self; Amgen Inc., Eli Lilly and Company, Novo Nordisk, Speaker’s Bureau; Self; MSD Corporation. F. Giorgino: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk, Roche Diabetes Care, Sanofi, Research Support; Self; Lilly Diabetes, Roche Diabetes Care. E. Jodar: Other Relationship; Self; AstraZeneca, Lilly Diabetes, Mundipharma International, Novo Nordisk, Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH. J. 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. Fernandez lando: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. K. Brown: Employee; Self; Eli Lilly and Company. R. Bray: None. A. Rodriguez: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. Funding Eli Lilly and Company

LY3305677 (LY) is an acylated single chain peptide analog of mammalian oxyntomodulin designed for once weekly dosing. It has dual pharmacology of GLP-1 and glucagon and has therapeutic potential for T2D, obesity and NASH. This randomized, double blind, placebo-controlled phase 1 study assessed safety and tolerability of single ascending doses of LY. Healthy subjects (N=48) were randomized (6:2) and 47 received subcutaneous LY (6 doses: 0.03 mg to 5.0 mg) or placebo. Safety biomarkers, LY pharmacokinetics (PK), and key exploratory pharmacodynamic (PD) biomarkers were assessed including fasting insulin, glucagon, triglyceride levels, and body weight. Most common LY-related AEs were gastrointestinal events. Dose-dependent increase in nausea, decreased appetite, and vomiting were seen. Most of the events were mild and transient. Increase in heart rate was noted, which returned to baseline for most groups at follow-up visit. No injection site reactions were seen. Median time to maximum LY concentration ranged from 18.2 to 72.1 h, and geometric mean half-life ranged from 7.5 to 9.8 days. Generally, mean fasting insulin level increased within 24 h and lasted over 8 days. At Day 8, LY 2.5 mg and 5.0 mg reduced mean fasting glucagon levels by 2.33 pmol/L and 2.67 pmol/L, respectively as compared with placebo. At Day 5, mean fasting triglyceride levels reduced from baseline by 0.5 mmol/L with LY 5.0 mg as compared to 0.1 mmol/L with placebo. Change from baseline in body weight reached a maximum -2.4 kg with the 5 mg dose, versus -0.5 kg for placebo at Day 8 and this effect was sustained through Day 29 at 5 mg. LY3305677 PK properties are suitable for once-weekly dosing with a safety and tolerability profile similar to other incretins in Phase 1 trials, supporting future clinical evaluation. Disclosure L. Tham: Employee; Self; Eli Lilly and Company. M. K. Thomas: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. C. Benson: Employee; Self; Eli Lilly and Company. R. Bray: None. C. Tang: Employee; Self; Eli Lilly and Company, Employee; Spouse/Partner; Novartis AG. C. Loghin: Employee; Self; Eli Lilly and Company. Funding Eli Lilly and Company

Nonalcoholic fatty liver disease (NAFLD) is common in T2D patients and increases the risk of NASH and cirrhosis. In a Phase 2 trial, TZP significantly reduced HbA1c and body weight at 26 weeks (≥ 37% achieved 10% weight loss at 2 highest doses). Patients with T2D were randomly assigned (1:1:1:1:1:1) to receive either once-weekly sc TZP (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo for 26 weeks. Because of the overlap of T2D and NAFLD populations, we measured several NASH related biomarkers to explore whether TZP may have potential efficacy in NASH. These included: ALT, AST, Keratin-18 M30 fragment (K-18, apoptosis marker; Peviva), Pro-C3 (fibrosis marker, a fragment of the NH2-terminal propeptide of type III procollagen; Nordic Bioscience), and adiponectin (adipokine that protects liver from inflammation and fibrosis; Pacific Biomarkers). Results (Table) were analyzed in a modified intent-to-treat population using a mixed model for repeated measures. Significant (p Disclosure M.L. Hartman: Employee; Self; Eli Lilly and Company. A. Sanyal: Consultant; Self; Ardelyx, Boehringer Ingelheim Pharmaceuticals, Inc., Exhalenz, Gilead Sciences, Inc., Hemoshear, Intercept Pharmaceuticals, Inc., Lilly, Mallinckrodt Pharmaceuticals, Nimbus Therapeutics, Nitto Denko, Novartis Pharmaceuticals Corporation, Pfizer Inc. Employee; Self; Sanyal Bio. Research Support; Self; Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Echosens, Galectin Therapeutics Inc., Immuron Ltd, Merck & Co., Inc., Salix Pharmaceuticals, Sequanna. Stock/Shareholder; Self; Akarna Therapeutics, GENFIT, Natural Shield, NewCo LLC, Tiziana. Other Relationship; Self; Elsevier, UpToDate. R. Loomba: Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc. J.M. Wilson: Employee; Self; Eli Lilly and Company. R. Bray: Employee; Self; Eli Lilly and Company. A. Nikooienejad: Research Support; Self; Eli Lilly and Company. K.L. Duffin: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Pfizer Inc. D.A. Robins: Employee; Self; Eli Lilly and Company. A. Haupt: Employee; Self; Lilly Diabetes. Stock/Shareholder; Self; Lilly Diabetes. Funding Eli Lilly and Company

Initiating incretin hormone receptor agonist therapy at a low dose with gradual dose escalation may improve gastrointestinal (GI) tolerability. This randomized, double-blind, placebo-controlled study assessed the efficacy and tolerability of tirzepatide, using 3 different dose escalation algorithms in patients with type 2 diabetes compared with placebo after 12 weeks. The dose-escalations included 1 algorithm to achieve 12 mg top dose by the scheme of 4 mg and 8 mg, each for 4 weeks. The scheme for the first 15 mg top dose group (15 mg-1) was 2.5 mg for 2 weeks, followed by 5 mg for 2 weeks, and then 10 mg for 4 weeks. The scheme for the second 15 mg top dose group (15 mg-2) was 2.5 mg followed by 7.5 mg, each for 4 weeks. A total of 111 subjects were randomized. Mean age was 57.4 years, HbA1c was 8.4%, and BMI was 31.9 kg/m2. At Week 12, LS mean HbA1c% (SE) was 8.6 (0.21), 6.7 (0.19), 6.3 (0.20), 6.6 (0.19) in the placebo, 12 mg, 15 mg-1 and 15 mg-2 groups, respectively. Change from baseline (SE) in HbA1c was greater in tirzepatide groups compared with placebo (placebo, +0.2% [0.21]; 12 mg, -1.7% [0.19]; 15 mg-1, -2.0% [0.20]; 15 mg-2, -1.8% [0.19]). Weight loss was greater in tirzepatide groups compared with placebo (placebo, -0.5 kg [0.86]; 12 mg, -5.3 kg [0.78]; 15 mg-1, -5.5 kg [0.80] and 15 mg-2, -5.7 kg [0.79]). The total incidence of nausea, vomiting and/or diarrhea was 11.5% with placebo, and 48.3%, 57.1% and 46.4% with tirzepatide 12 mg, 15 mg-1, and 15 mg-2 groups, respectively. GI AEs were mild to moderate in intensity. Tirzepatide resulted in clinically meaningful improvements in glycemic control and weight loss. A lower starting dose and a longer dose-escalation period resulted in lower incidence of GI AEs than in a previously published Phase 2 study. Disclosure J.P. Frias: Advisory Panel; Self; Becton, Dickinson and Company, Eli Lilly and Company, Gilead Sciences, Inc., Sanofi. Consultant; Self; Echosens, Genentech, Inc., Johnson & Johnson Diabetes Institute, Novo Nordisk Inc., Zafgen, Inc. Research Support; Self; AbbVie Inc., Akcea Therapeutics, Allergan, Amgen Inc., AstraZeneca, Bayer US, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Cirius Therapeutics, Elcelyx Therapeutics, Inc., Eli Lilly and Company, Enanta Pharmaceuticals, Inc., GENFIT, Intarcia Therapeutics, Inc., Intercept Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., NGM Biopharmaceuticals, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Oramed Pharmaceuticals, Pfizer Inc., Sanofi, TaiwanJ Pharmaceuticals Co., Ltd., Theracos, Inc. Speaker's Bureau; Self; Merck & Co., Inc., Sanofi. M.A. Nauck: Advisory Panel; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sun Pharma. J. Van: Research Support; Self; Eli Lilly and Company, Genentech, Inc., Melior, Merck & Co., Inc., Mylan, Oramed Pharmaceuticals, Sanofi. C. Benson: Employee; Self; Eli Lilly and Company. R. Bray: Employee; Self; Eli Lilly and Company. Z. Milicevic: Employee; Self; Eli Lilly and Company. A. Haupt: Employee; Self; Lilly Diabetes. Stock/Shareholder; Self; Lilly Diabetes. D.A. Robins: Employee; Self; Eli Lilly and Company. Funding Eli Lilly and Company