Abstract: Tirzepatide (TZP), a once-weekly GIP/GLP-1 receptor agonist, achieved significantly greater HbA1c and body weight (BW) reductions with all doses (5, 10, 15 mg) vs placebo (SURPASS-1 [S-1]) and semaglutide (SEMA) 1 mg (SURPASS-2 [S-2] ) in randomized Phase 3 trials in people with type 2 diabetes controlled by diet and exercise (S-1) or metformin (S-2). Exploratory post hoc analyses examined changes from baseline in HbA1c and BW in these studies at 40 weeks across HOMA2-B (C-peptide) and HOMA2-IR (insulin) quartiles (Q) from low (lower beta-cell function/insulin resistance) (Q1) to high (Q4) as assessed by mixed model repeated measures (MMRM). HbA1c reductions were greater with all TZP doses than placebo or SEMA within each HOMA2-B and HOMA2-IR baseline Q. HbA1c reductions were largest in people within HOMA-2B Q1, yet similar across all HOMA2-IR Qs (Fig). BW reductions were greater across Qs with all TZP doses (ranging from 6%-14%) than placebo (up to 2%) or SEMA (up to 7%). TZP was more efficacious than placebo or SEMA in reducing HbA1c and BW across a spectrum of pancreatic beta-cell function, notably achieving greater glycemic improvement in people with markers of diminished pancreatic beta cell function at baseline. Disclosure J.M.Maldonado: Employee; Eli Lilly and Company. C.De block: Advisory Panel; Abbott Diagnostics, Indigo Diabetes, Insulet Corporation, Eli Lilly and Company, Novo Nordisk, Research Support; Boehringer-Ingelheim, AstraZeneca, Indigo Diabetes, Eli Lilly and Company, Speaker's Bureau; Novo Nordisk. J.P.Frias: Advisory Panel; Becton, Dickinson and Company, Pfizer Inc., Sanofi, Consultant; Akero Therapeutics, Inc., 89bio, Inc., Aimmune, Boehringer Ingelheim Inc., Eli Lilly and Company, Carmot Therapeutics, Inc., Echosens, Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Employee; Ionis Pharmaceuticals, Research Support; Akero Therapeutics, Inc., 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Carmot Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Oramed Pharmaceuticals, Novartis, Pfizer Inc., Sanofi, Speaker's Bureau; Eli Lilly and Company, Sanofi. C.Lee: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. K.Brown: Employee; Eli Lilly and Company. H.Wang: None. M.K.Thomas: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company

Abstract: In patients with T2D uncontrolled on metformin alone, ExQW + DAPA significantly reduced glycemia, body weight and systolic blood pressure compared to ExQW + placebo (PBO) or DAPA + PBO at 28 weeks (NCT02229396). Here, we examined efficacy and safety after 104 weeks of double-blind therapy. Of 695 patients randomized, 431 (62%) completed 104 weeks; 4.3% withdrew due to adverse events (AEs). Absolute reductions and between-group differences in A1C were maintained over 104 weeks (Figure). Clinically relevant changes vs. baseline in other efficacy end points were also observed (Table). AEs and serious AEs were balanced across treatment groups. Hypoglycemia incidence was low (Table). In conclusion, ExQW + DAPA maintained efficacy over 104 weeks with no unexpected safety concerns.Changes in efficacy end points and hypoglycemia incidence from baseline through week 104ExQW+DAPA N=228 n=147ExQW+PBO N=227 n=132DAPA+PBO N=230 n=152ExQW+DAPA vs ExQW+PBOExQW+DAPA vs DAPA+PBOA1C, % BL mean (SD) 28 wk LSM change from BL (SE) 52 wk LSM change from BL (SE) 104 wk LSM change from BL (SE)□ 9.29 (1.06) −1.98 (0.09) −1.75 (0.10) −1.70 (0.11)□ 9.26 (1.08) −1.60 (0.10) −1.38 (0.10) −1.29 (0.12)□ 9.25 (1.02) −1.39 (0.09) −1.23 (0.10) −1.06 (0.12)□ □ −0.38 (0.13)** −0.37 (0.14)** −0.42 (0.15)**□ □ −0.59 (0.13)*** −0.52 (0.13)*** −0.64 (0.15)***FPG, mg/dL BL mean (SD) 28 wk LSM change from BL (SE) 52 wk LSM change from BL (SE) 104 wk LSM change from BL (SE)□ 195.0 (53.5) −65.8 (2.9) −63.0 (2.9) −49.0 (4.1)□ 189.3 (49.8) −45.8 (3.0) −45.4 (3.1) −29.8 (4.5)□ 188.5 (44.2) −49.2 (2.9) −39.8 (3.0) −21.9 (4.6)□ □ −20.1 (4.0)*** −17.6 (4.1)*** −19.2 (5.9)***□ □ −16.6 (3.9)*** −23.3 (4.0)*** −27.1 (6.0)***2h-PPG, mg/dL BL mean (SD) 28 wk LSM change from BL (SE) 52 wk LSM change from BL (SE) 104 wk LSM change from BL (SE)□ 268.5 (67.5) −87.8 (4.1) −82.4 (4.8) −86.2 (5.9)□ 266.1 (67.2) −60.1 (4.3) −64.0 (5.1) −79.0 (7.0)□ 261.5 (60.2) −61.1 (4.1) −59.6 (5.0) −64.0 (6.6)□ □ −27.7 (5.2)*** −18.4 (6.3)** −7.2 (7.9)□ □ −26.8 (5.1)*** −22.8 (6.2)*** −22.2 (7.9)**Body weight, kg BL mean (SD) 28 wk LSM change from BL (SE) 52 wk LSM change from BL (SE) 104 wk LSM change from BL (SE)□ 92.1 (21.8) −3.6 (0.3) −3.3 (0.4) −2.5 (0.4)□ 89.1 (18.7) −1.6 (0.3) −1.5 (0.4) −0.8 (0.5)□ 90.9 (19.6) −2.2 (0.3) −2.3 (0.4) −3.0 (0.5)□ □ −2.0 (0.4)*** −1.8 (0.5)*** −1.7 (0.6)**□ □ −1.3 (0.4)*** −1.0 (0.5) +0.5 (0.6)Systolic BP, mmHg BL mean (SD) 28 wk LSM change from BL (SE) 52 wk LSM change from BL (SE) 104 wk LSM change from BL (SE)□ 130.7 (12.1) −4.3 (0.8) −4.5 (0.8) −3.1 (1.0)□ 129.3 (12.5) −1.2 (0.8) −0.7 (0.9) −0.1 (1.1)□ 129.6 (12.8) −1.8 (0.8) −2.7 (0.8) −1.1 (1.0)□ □ −3.0 (1.1)** −3.9 (1.1)*** −3.0 (1.4)*□ □ −2.4 (1.1)* −1.8 (1.1) −2.0 (1.4)Hypoglycemia† through 104 wks Major, % pts Minor, % pts Other, % ptsN=231 0 1.7 6.9N=230 0 0 3.5N=233 0 0.4 3.4*P & lt;0.05, **P & lt;0.01, ***P≤0.001 (P-values at wk 52 and wk 104 are nominal). BL, baseline, BP, blood pressure; FPG, fasting plasma glucose; LSM, least-squares mean; N, number comprising the intention-to-treat analysis set; n, number completing 104 weeks of treatment; 2h-PPG, 2-hour post-prandial glucose; pts, patients; SD, standard deviation; SE, standard error; wk, week. †Major hypoglycemia: loss of consciousness, seizure or coma resolving after glucagon or glucose administration or events requiring third-party assistance due to severe impairment of consciousness or behavior with blood glucose concentration & lt;54 mg/dL. Minor hypoglycemia: non-major event with symptoms consistent with hypoglycemia and blood glucose concentration & lt;54 mg/dL. Other hypoglycemia: events not meeting major or minor hypoglycemia criteria. Disclosure S. Jabbour: None. C. Guja: Consultant; Self; AstraZeneca, Bayer AG, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Boehringer Ingelheim GmbH. E. Hardy: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. S. Bhattacharya: None. P.K. Ohman: Employee; Self; AstraZeneca. J.P. Frias: Research Support; Self; AbbVie Inc., Allergan, Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company. Consultant; Self; CeQur Corporation. Research Support; Self; Cirius Therapeutics, AstraZeneca, Calibra Medical, Elcelyx Therapeutics, Inc.. Consultant; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Genentech, Inc., Ionis Pharmaceuticals, Inc., ICON plc., Janssen Pharmaceuticals, Inc.. Consultant; Self; Johnson & Johnson Diabetes Institute, LLC.. Research Support; Self; Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Sanofi. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; Theracos, Inc..

Abstract: Dulaglutide is approved at two doses (0.75 and 1.5 mg) for treatment of T2D. There has been limited assessment of higher doses. We hypothesized that higher doses of dulaglutide may provide further improvement in glucose and body weight control. In this study, 3 and 4.5 mg doses were evaluated for safety/efficacy after 18 weeks (weeks) of treatment, including a 6 week dose escalation. Patients (N=318) on ≥1500 mg metformin, were randomized (1:1:1:1) to placebo (n=82), dulaglutide 1.5 mg (n=81), dulaglutide 3 mg (n=79), dulaglutide 4.5 mg (n=76). The primary objective was superiority of dulaglutide doses over placebo in HbA1c reduction at 18 weeks. Table 1 presents the primary and selected secondary efficacy data. Reductions in HbA1c and body weight were significant for each dose vs. placebo. Incidence of gastrointestinal events (mostly mild to moderate) were dose-dependent for nausea (placebo, 4.9%; dulaglutide 1.5 mg, 22.2%; dulaglutide 3 mg, 24.1%; dulaglutide 4.5 mg, 30.3%) but not for vomiting (placebo 4.9%; dulaglutide 1.5 mg, 11.1%; dulaglutide 3 mg, 10.1%; dulaglutide 4.5 mg, 13.2%). No patients experienced severe hypoglycemia. The results of this trial show that 3 mg and 4.5 mg doses, compared to the 1.5 mg dose, may provide additional glycemic benefit and weight reduction with an acceptable safety profile in treatment of T2D patients, providing support for further phase 3 development. Disclosure J.P. Frias: Research Support; Self; AbbVie Inc., Allergan, Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company. Consultant; Self; CeQur Corporation. Research Support; Self; Cirius Therapeutics, AstraZeneca, Calibra Medical, Elcelyx Therapeutics, Inc.. Consultant; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Genentech, Inc., Ionis Pharmaceuticals, Inc., ICON plc., Janssen Pharmaceuticals, Inc.. Consultant; Self; Johnson & Johnson Diabetes Institute, LLC.. Research Support; Self; Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Sanofi. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; Theracos, Inc.. A.G. Wynne: None. B. Matyjaszek-Matuszek: None. D. Bartaskova: None. D. Cox: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. B. Woodward: Employee; Self; Eli Lilly and Company. G. Li: Employee; Self; Eli Lilly and Company. Z. Milicevic: Employee; Self; Eli Lilly and Company.

Abstract: This multicenter RCT compared clinical, subject-reported, and safety outcomes in T2D subjects on basal insulin (A1C 7.5-11%) initiating mealtime insulin with a wearable bolus insulin delivery patch (Patch, Calibra Medical) vs. an insulin pen (Pen, NovoLog FlexPen®). The Patch was applied at least every 3 days and delivered subcutaneous bolus insulin in 2-U increments per manual click. T2D adults (N=278, age: 59.2 y, duration: 15 y), were randomized to Patch (n=139) or Pen (n=139). Baseline glargine dose was divided 1:1, basal:bolus. Using a pattern-control logbook, subjects adjusted basal and bolus insulin weekly based on fasting and pre-meal glucose targets. Change in A1C (%) from baseline to Week 24 (primary endpoint) for Patch was noninferior (p & lt;.0001) to Pen (LS mean change ± SE: Patch, −1.69 ± 0.vs. Pen, −1.60 ± 0.08) and this reduction was significant (p & lt;.0001) in both groups. A1C improvement was maintained at 44 weeks (Fig). There were no significant differences in adverse events, including hypoglycemia (3 severe episodes/group). There were significantly greater improvements in subject-reported outcomes for Patch vs. Pen. In conclusion, bolus insulin delivered by Patch or Pen along with an algorithm-based weekly insulin dose titration significantly improved A1C levels in subjects with T2D, with improved patient experience and a preference for Patch. Disclosure R.M. Bergenstal: Research Support; Self; Johnson & Johnson Services, Inc.. Consultant; Self; Johnson & Johnson Services, Inc.. Research Support; Self; Abbott. Advisory Panel; Self; Abbott. Research Support; Self; Becton, Dickinson and Company. Consultant; Self; Becton, Dickinson and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Takeda Pharmaceuticals U.S.A., Inc., Dexcom, Inc.. Stock/Shareholder; Self; Merck & Co., Inc.. Research Support; Self; Eli Lilly and Company, Sanofi. Advisory Panel; Self; Sanofi, Roche Pharma. Research Support; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Medtronic. Consultant; Self; Medtronic. Research Support; Self; Hygieia. Advisory Panel; Self; Hygieia, Glooko, Inc.. Research Support; Self; JAEB Center For Health Research, JDRF, National Institute of Diabetes and Digestive and Kidney Diseases. M. Peyrot: Consultant; Self; Calibra Medical, Eli Lilly and Company, Novo Nordisk Inc.. Research Support; Spouse/Partner; Eli Lilly and Company, Novo Nordisk Inc. D.M. Dreon: Employee; Self; Calibra Medical. V. Aroda: Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc., AstraZeneca, Calibra Medical, Eisai Inc., Sanofi. Consultant; Self; Sanofi. Research Support; Self; Theracos, Inc.. Employee; Spouse/Partner; Merck & Co., Inc.. Other Relationship; Self; American Diabetes Association. Consultant; Self; ADOCIA. T.S. Bailey: Research Support; Self; Abbott. Consultant; Self; Abbott. Speaker's Bureau; Self; Abbott. Research Support; Self; Ambra BioScience, Ascensia Diabetes Care, Becton, Dickinson and Company. Consultant; Self; Becton, Dickinson and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Calibra Medical. Consultant; Self; Calibra Medical. Research Support; Self; Companion Medical, Dexcom, Inc., Glooko, Inc., GlySens Incorporated, Lexicon Pharmaceuticals, Inc., Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; Medtronic MiniMed, Inc.. Consultant; Self; Medtronic MiniMed, Inc.. Speaker's Bureau; Self; Medtronic MiniMed, Inc.. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Research Support; Self; Sanofi. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; Senseonics. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Versartis, Inc., Xeris Pharmaceuticals, Inc., MannKind Corporation. R.L. Brazg: Research Support; Self; Abbott, Calibra Medical, Dexcom, Inc., Eli Lilly and Company, GlucoMe, Novo Nordisk Inc., Medtronic. Speaker's Bureau; Self; Medtronic. Research Support; Self; Sanofi-Aventis, Senseonics, Gan & Lee Pharmaceuticals, Gelesis. J.P. Frias: Research Support; Self; AbbVie Inc., Allergan, Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company. Consultant; Self; CeQur Corporation. Research Support; Self; Cirius Therapeutics, AstraZeneca, Calibra Medical, Elcelyx Therapeutics, Inc.. Consultant; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Genentech, Inc., Ionis Pharmaceuticals, Inc., ICON plc., Janssen Pharmaceuticals, Inc.. Consultant; Self; Johnson & Johnson Diabetes Institute, LLC.. Research Support; Self; Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Sanofi. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; Theracos, Inc. M.L. Johnson: Research Support; Self; Calibra Medical, Medtronic, Sanofi, Novo Nordisk Inc., Abbott, POPS! Diabetes Care, National Institute of Diabetes and Digestive and Kidney Diseases, Dexcom, Inc., Hygieia, JDRF. D.C. Klonoff: Consultant; Self; Ascensia Diabetes Care, Lifecare, Intarcia Therapeutics, Inc., Voluntis USA, Novo Nordisk Inc., Onduo, Trividia Health, Inc., American Diabetes Association, The Endocrine Society, American Association of Diabetes Educators. D.F. Kruger: Research Support; Self; Dexcom, Inc.. Speaker's Bureau; Self; Dexcom, Inc.. Stock/Shareholder; Self; Dexcom, Inc.. Consultant; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Intarcia Therapeutics, Inc., Abbott. Research Support; Self; Sanofi. Consultant; Self; Sanofi. Research Support; Self; JAEB Center For Health Research. Consultant; Self; Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Research Support; Self; Hygieia, Lexicon Pharmaceuticals, Inc., National Institute of Diabetes and Digestive and Kidney Diseases. Speaker's Bureau; Self; Valeritas, Inc., Insulet Corporation. Consultant; Self; Insulet Corporation. Research Support; Self; Insulet Corporation. Consultant; Self; Merck & Co., Inc. S. Ramtoola: Other Relationship; Self; Janssen Research & Development. Stock/Shareholder; Self; Novo Nordisk A/S, Johnson & Johnson, Eli Lilly and Company. J. Rosenstock: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Consultant; Self; Sanofi. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Merck & Co., Inc., Pfizer Inc., Sanofi, Novo Nordisk Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Intarcia Therapeutics, Inc., Genentech, Inc. P. Serusclat: Board Member; Self; Novo Nordisk A/S, Medtronic, Abbott. Research Support; Self; Novo Nordisk A/S, Eli Lilly and Company, Sanofi. R.S. Weinstock: Research Support; Self; Medtronic MiniMed, Inc., Mylan, Kowa Pharmaceuticals America, Inc., Diasome Pharmaceuticals, Inc., Calibra Medical, Dexcom, Inc., Ultradian Diagnostics LLC., JAEB Center For Health Research, JDRF, National Institute of Diabetes and Digestive and Kidney Diseases. R.G. Naik: Other Relationship; Self; LifeScan, Inc.. D.M. Shearer: None. V. Zraick: Other Relationship; Self; Calibra Medical. B.L. Levy: Employee; Self; LifeScan, Inc..

Abstract: Orforglipron [OFG (LY3502970)] is an oral, non-peptide, glucagon-like peptide-1 receptor agonist (GLP-1 RA). The 26-week, randomized, double-blind, double placebo, phase 2 study enrolled 383 patients with type 2 diabetes (T2D) treated with diet, exercise, ± metformin. At baseline, mean age was 58.9 yr, HbA1c was 8.1%, and body weight (BW) was 100.3 kg. Patients were randomly assigned to OFG 3, 12, 24, 36, or 45 mg once daily, placebo (PBO), or dulaglutide 1.5 mg (dula). Protocols guided the initial OFG dose and escalation schemes. Primary endpoint was HbA1c change from baseline (CFB) at wk 26 for OFG vs PBO. Secondary endpoints included CFB at wk 26 in HbA1c for OFG vs dula, and CFB in fasting blood glucose (FBG) and body weight (BW) for OFG vs PBO and dula. OFG resulted in improvements in glycemic control and BW (table). At wk 26, HbA1c reduction with OFG ranged from 1.19 to 2.10% vs PBO 0.43% (P & lt;0.001, all doses vs PBO). Significantly greater reductions in HbA1c were also noted with 12, 24, 36, and 45 mg OFG vs dula (p & lt;0.001). Most adverse events (AE) were gastrointestinal (nausea: PBO 5.5%, OFG 30.6%, dula 18.0%) and mild or moderate in severity. OFG resulted in significant reductions in HbA1c, FBG, and BW with an AE profile consistent with other GLP-1RAs. OFG does not have food or water administration restrictions and may provide a safe, effective, and convenient oral treatment option for patients with T2D. Disclosure J.P.Frias: Advisory Panel; Becton, Dickinson and Company, Pfizer Inc., Sanofi, Consultant; Akero Therapeutics, Inc., 89bio, Inc., Aimmune, Boehringer Ingelheim Inc., Eli Lilly and Company, Carmot Therapeutics, Inc., Echosens, Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Employee; Ionis Pharmaceuticals, Research Support; Akero Therapeutics, Inc., 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Carmot Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Oramed Pharmaceuticals, Novartis, Pfizer Inc., Sanofi, Speaker's Bureau; Eli Lilly and Company, Sanofi. A.Haupt: Employee; Lilly, Stock/Shareholder; Lilly. D.A.Robins: None. S.H.Hsia: Research Support; Eli Lilly and Company. S.Eyde: None. R.Liu: None. X.Ma: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. M.Konig: None. C.M.Kazda: Employee; Eli Lilly and Company. E.J.Pratt: Employee; Eli Lilly and Company. K.J.Mather: Employee; Eli Lilly and Company.

Abstract: Add-on therapy with a single oral antihyperglycemic agent is often insufficient to provide glycemic control in patients with type 2 diabetes (T2D) uncontrolled on metformin (MET) monotherapy. This randomized, parallel-group, double-blind, 52-week trial (NCT02419612) evaluated the efficacy and safety of dual add-on therapy with dapagliflozin (DAPA) 10 mg/d + saxagliptin (SAXA) 5 mg/d vs. single add-on of titrated glimepiride (GLIM) 1-6 mg/d in patients with T2D (A1C, 7.5-10.5%) receiving stable MET ≥1500 mg/d. The primary end point was change in A1C from baseline to week 52; secondary end points were changes in body weight and systolic blood pressure (SBP) and the proportions of patients achieving A1C & lt;7% or requiring treatment intensification by week 52. Mean±SD baseline data (N=443) were similar in both arms: age, 56.1±9.7 years; A1C, 8.5±0.8%; weight, 89.7±18.5 kg; duration of T2D, 7.8±6.4 years. DAPA + SAXA + MET resulted in significant reductions in A1C, body weight and SBP, a greater proportion of patients achieving A1C & lt;7% and a lower proportion of patients requiring treatment intensification vs. GLIM + MET (Table). All treatments were well tolerated. Hypoglycemia incidence was lower for DAPA + SAXA + MET (18.5%) than GLIM + MET (44.0%). Add-on of DAPA + SAXA provided greater improvement in glycemic control and reduced body weight vs. GLIM in patients with T2D poorly controlled by MET. Disclosure J.P. Frias: Research Support; Self; AbbVie Inc., Allergan, Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company. Consultant; Self; CeQur Corporation. Research Support; Self; Cirius Therapeutics, AstraZeneca, Calibra Medical, Elcelyx Therapeutics, Inc.. Consultant; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Genentech, Inc., Ionis Pharmaceuticals, Inc., ICON plc., Janssen Pharmaceuticals, Inc.. Consultant; Self; Johnson & Johnson Diabetes Institute, LLC.. Research Support; Self; Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Sanofi. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; Theracos, Inc.. G. Gonzalez-Galvez: None. E.K. Johnsson: Employee; Self; AstraZeneca. J. Maaske: Employee; Self; AstraZeneca. Employee; Spouse/Partner; AstraZeneca. Stock/Shareholder; Spouse/Partner; AstraZeneca. A. Peters: Advisory Panel; Self; Abbott, Bigfoot Biomedical. Research Support; Self; Dexcom, Inc.. Advisory Panel; Self; Eli Lilly and Company, Insulin Algorithms, JDRF, Lexicon Pharmaceuticals, Inc., Livongo Health. Research Support; Self; MannKind Corporation. Other Relationship; Self; Medscape. Advisory Panel; Self; Merck & Co., Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Omada Health, Inc., Optum Rx, Inc., Sanofi. Research Support; Self; T1D Exchange. Advisory Panel; Self; The Endocrine Society. Research Support; Self; The Leona M. and Harry B. Helmsley Charitable Trust. Advisory Panel; Spouse/Partner; Johnson & Johnson Diabetes Institute, LLC..

Abstract: Introduction: Exenatide is primarily eliminated through the kidneys. Safety/efficacy of exenatide once weekly (EQW) were characterized in patients (pts) with CKD stage 2 and 3 (mild and moderate renal impairment). Methods: Pts treated with EQW or placebo/non-GLP-1RA comparator drug (sitagliptin, metformin, pioglitazone, dapagliflozin, insulin) from 8 phase 3 double-blind or open-label 26/28-week studies were pooled and stratified by CKD stage. Studies were performed on a broad range of background drugs. Results: Pts with baseline CKD2 (N=772) or CKD3 (N=182) on EQW differed in some baseline characteristics: age & lt;65 y (79% vs. 56%), mean BMI (31.6 vs. 28.3 kg/m2), and T2D duration (7.6 vs. 9.7 y), while BP (131/79 vs. 133/77) and HbA1c (8.5% vs. 8.3%) were similar. CKD3 EQW pts were mostly Asian (61% vs. 20% CKD2) as 59% of these were from a Japanese study. Efficacy was similar in CKD2 vs. CKD3 pts (Figure). Rates of any AE were slightly higher in CKD3 vs. CKD2 pts (EQW: 81% vs. 72%; comparators: 74% vs. 68%) and for AEs leading to study or treatment discontinuation (EQW: 8% vs. 5%; comparators: 4% vs. 2%) but similar for SAEs (EQW: 3% vs. 3%; comparators: 6% vs. 5%). One pt in each arm had a SAE of acute kidney injury: EQW in CKD3 and comparator in CKD2 group. Conclusion: Pooled results of 8 studies show EQW is well tolerated and efficacious in pts with CKD2 and 3. Changes in HbA1c, body weight, and SBP were similar between the 2 CKD groups. Disclosure C. Guja: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. 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. L.J. Suchower: Stock/Shareholder; Self; AstraZeneca, Express Scripts, Merck & Co., Inc. Other Relationship; Self; AstraZeneca. E. Hardy: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. J. Holden: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. C. Sjöström: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. S. Jabbour: Consultant; Self; AstraZeneca, Janssen Pharmaceuticals, Inc. Funding AstraZeneca