Clinical trials in T2DM & CVD: Review of key outcomes with GLP-1 - PowerPoint PPT Presentation

Session: Game changing clinical trials in T2DM & CVD: Novel insights & implications Clinical trials in T2DM & CVD: Review of key outcomes with GLP-1 RA and SGLT2i Eduard Montanya, MD Barcelona, Spain Cardio Diabetes Master Class February 22-23, 2019 - Barcelona, Spain

Shifting gears in the management of diabetes and CVD 22-23 February 2019, Barcelona Clinical trials in T2DM & CVD. Review of key outcomes with GLP-1 RA and SGLT2i Eduard Montanya, MD, PhD Hospital Universitari Bellvitge IDIBELL CIBERDEM University of Barcelona

Speaker disclosures • Speaker, Advisory Panel or Research Support: AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Menarini, Janssen Pharmaceutical, Laboratoires Servier, Merck Sharp & Dohme, Novo Nordisk, and Novartis.

CVOTs in Diabetes: CV risk with new therapies Requirement to demonstrate that new antidiabetic therapies to treat type 2 diabetes are not associated with an unacceptable increase in cardiovascular risk FDA, U.S. Food and Drug Administration FDA, 2008 www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf

Contemporary CVOTs in diabetes REWIND ACE EXSCEL SOLOIST-WHF (Dulaglutide, OW GLP-1RA) (Acarbose, AGI) (Exenatide ER, OW GLP-1RA) (Sotagliflozin , SGLT-1i & SGLT-2i) n=9622; duration ~6.5 yrs n=6522; duration ~8 yrs n=14,752; follow-up ~3 yrs n=4000; duration ~2.7 yrs Q3 2018 TOPLINE Q2 2017 – RESULTS Q3 2017 – RESULTS Completion Q1 2021 RESULTS ALECARDIO TECOS DEVOTE CARMELINA PIONEER 6 AMPLITUDE-O (Aleglitazar, PPAR- αγ) n=7226; (Sitagliptin, DPP-4i) (Insulin degludec, insulin) (Linagliptin, DPP-4i) (Oral semaglutide, GLP-1RA) (Efpeglenatide, OW GLP-1RA) follow-up 2 yrs n=14,671; duration ~3 yrs n=7637; duration ~2 yrs n=7003; duration ~4 yrs n=3176; duration ~1.5 yrs n=4000*; duration ~3 yrs Termin. Q3 2013 – RESULTS Q4 2014 – RESULTS Q2 2017 – RESULTS Q3 2018 – RESULTS Q4 2018 COMPLETED Completion Q2 2021 ELIXA SUSTAIN 6 CANVAS-R HARMONY OUTCOMES VERTIS CV SCORED (Lixisenatide, GLP-1RA) (Semaglutide, OW GLP-1RA) (Canagliflozin, SGLT-2i) (Albiglutide, OW GLP-1RA) (Ertugliflozin, SGLT-2i) (Sotagliflozin, SGLT-1i & SGLT-2i) n=6068; follow-up ~2 yrs n=3297; duration ~2.8 yrs n=5826; duration ~3 yrs n=9574; duration ~4 yrs n=8000; duration ~6 yrs n=10,500*; duration ~4.5 yrs Q1 2015 – RESULTS Q3 2016 – RESULTS Q2 2017 – RESULTS Q3 2018 - RESULTS Completion Q3 2019 Completion Q1 2022 CREDENCE (cardio-renal) SAVOR-TIMI 53 FREEDOM CANVAS CAROLINA (Canagliflozin, SGLT-2i) (Saxagliptin, DPP-4i) (ITCA 650, GLP-1RA in DUROS) (Canagliflozin, SGLT-2i) (Linagliptin, DPP-4i vs SU) n=4464; duration ~5.5 yrs n=16,492; follow-up ~2 yrs n=4000; duration ~2 yrs n=4418; duration 4+ yrs n=6103; duration ~8 yrs Q3 2018 – CANCELLED Q2 2013 – RESULTS Q2 2016 – TOPLINE RESULTS Q2 2017 – RESULTS Completion Q1 2019 (+ve efficacy) SGLT-2i PPAR- αγ TOSCA IT EXAMINE EMPA-REG OUTCOME LEADER DECLARE-TIMI 58 Insulin (Pioglitazone, TZD) (Alogliptin, DPP-4i) (Empagliflozin, SGLT-2i) (Liraglutide, GLP-1RA) (Dapagliflozin, SGLT-2i) DPP-4i n=3028; duration ~10 yrs n=5380; follow-up ~1.5 yrs n=7000; duration up to 5 yrs n=9340; duration 3.5 – 5 yrs n=17,276; duration ~6 yrs TZD Q4 2017 † – RESULTS Q3 2013 – RESULTS Q3 2015 – RESULTS Q2 2016 – RESULTS Q3 2018 - RESULTS GLP-1RA AGI 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 ClinicalTrials.gov. Accessed 08 October 2018

CVOTs in diabetes: GLP1-RA and SGLT-2i REWIND EXSCEL SOLOIST-WHF (Dulaglutide, OW GLP-1RA) (Exenatide ER, OW GLP-1RA) (Sotagliflozin , SGLT-1i & SGLT-2i) n=9622; duration ~6.5 yrs n=14,752; follow-up ~3 yrs n=4000; duration ~2.7 yrs Q3 2018 TOPLINE Q3 2017 – RESULTS Completion Q1 2021 RESULTS PIONEER 6 AMPLITUDE-O (Oral semaglutide, GLP-1RA) (Efpeglenatide, OW GLP-1RA) n=3176; duration ~1.5 yrs n=4000*; duration ~3 yrs Q4 2018 COMPLETED Completion Q2 2021 ELIXA SUSTAIN 6 CANVAS-R HARMONY OUTCOMES VERTIS CV SCORED (Lixisenatide, GLP-1RA) (Semaglutide, OW GLP-1RA) (Canagliflozin, SGLT-2i) (Albiglutide, OW GLP-1RA) (Ertugliflozin, SGLT-2i) (Sotagliflozin, SGLT-1i & SGLT-2i) n=6068; follow-up ~2 yrs n=3297; duration ~2.8 yrs n=5826; duration ~3 yrs n=9574; duration ~4 yrs n=8000; duration ~6 yrs n=10,500*; duration ~4.5 yrs Q1 2015 – RESULTS Q3 2016 – RESULTS Q2 2017 – RESULTS Q3 2018 - RESULTS Completion Q3 2019 Completion Q1 2022 CREDENCE (cardio-renal) FREEDOM CANVAS (Canagliflozin, SGLT-2i) (ITCA 650, GLP-1RA in DUROS) (Canagliflozin, SGLT-2i) n=4464; duration ~5.5 yrs n=4000; duration ~2 yrs n=4418; duration 4+ yrs Q3 2018 – CANCELLED Q2 2016 – TOPLINE RESULTS Q2 2017 – RESULTS (+ve efficacy) SGLT-2i EMPA-REG OUTCOME LEADER DECLARE-TIMI 58 (Empagliflozin, SGLT-2i) (Liraglutide, GLP-1RA) (Dapagliflozin, SGLT-2i) n=7000; duration up to 5 yrs n=9340; duration 3.5 – 5 yrs n=17,276; duration ~6 yrs Q3 2015 – RESULTS Q2 2016 – RESULTS Q3 2018 - RESULTS GLP-1RA 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 ClinicalTrials.gov. Accessed 08 October 2018

SGLT2i CVOTs

CVOTs in diabetes: SGLT-2i SOLOIST-WHF (Sotagliflozin , SGLT-1i & SGLT-2i) n=4000; duration ~2.7 yrs Completion Q1 2021 AMPLITUDE-O (Efpeglenatide, OW GLP-1RA) n=4000*; duration ~3 yrs Completion Q2 2021 CANVAS-R VERTIS CV SCORED (Canagliflozin, SGLT-2i) (Ertugliflozin, SGLT-2i) (Sotagliflozin, SGLT-1i & SGLT-2i) n=5826; duration ~3 yrs n=8000; duration ~6 yrs n=10,500*; duration ~4.5 yrs Q2 2017 – RESULTS Completion Q3 2019 Completion Q1 2022 CREDENCE (cardio-renal) CANVAS (Canagliflozin, SGLT-2i) (Canagliflozin, SGLT-2i) n=4464; duration ~5.5 yrs n=4418; duration 4+ yrs Q3 2018 – CANCELLED Q2 2017 – RESULTS (+ve efficacy) SGLT-2i EMPA-REG OUTCOME DECLARE-TIMI 58 (Empagliflozin, SGLT-2i) (Dapagliflozin, SGLT-2i) n=7000; duration up to 5 yrs n=17,276; duration ~6 yrs Q3 2015 – RESULTS Q342018 - RESULTS 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022

Comparison of SGLT-2 inhibitors: HbA 1c Dapagliflozin (Dapa) 1 Canagliflozin (Cana) 2 Empagliflozin (Empa) 3 Study 52-week data 52-week data 24-week data Dapa Dapa Placebo Cana Cana Sita Empa Empa Placebo Study arm (5 mg) 10 mg 100 mg 300 mg 100 mg 10 mg 25 mg n=137 n=135 n=137 n=368 n=367 n=366 n=217 n=213 n=207 Baseline HbA 1c (%) 8.2 7.9 8.1 7.9 7.9 7.9 7.9 7.9 7.9 Dapa 5 mg Dapa 10 mg Placebo Empa 10 mg Empa 25 mg Placebo Cana 100 mg Cana 300 mg Sita 100 mg 0.0 0,0 Change in HbA 1c from – 0.1 baseline (%) – 0.3 -0,5 – 0.7 – 0.7 – 0.7 – 0.7 – 0.8 – 0.8 – 0.9 -1,0 1. Bailey CJ et al. Lancet 2010;375:2223 – 2233; 2. Lavalle Gonzalez FJ et al. Diabetologica 2013;56:2582 – 2592; 3. Häring HU et al. Diabetes Care 2014;37: 1650 – 1659

Comparison of SGLT-2 inhibitors: Body weight Dapagliflozin (Dapa) 1 Canagliflozin (Cana) 2 Empagliflozin (Empa) 3 Study 52-week data 52-week data 24-week data Dapa Dapa Placebo Cana Cana Sita Empa Empa Placebo Study arm (5 mg) 10 mg 100 mg 300 mg 100 mg 10 mg 25 mg n=137 n=135 n=137 n=368 n=367 n=366 n=217 n=213 n=207 Baseline body 84.7 86.3 87.7 88.8 85.4 87.7 79.7 81.6 82.2 Dapa 5 mg Dapa 10 mg Placebo Empa 10 mg Empa 25 mg Placebo Cana 100 mg Cana 300 mg Sita 100 mg 0.0 weight (kg) 0,0 -0,5 Change in body weight – 0.3 – 0.5 from baseline (kg) -1,0 – 1.2 -1,5 -2,0 – 2.1 -2,5 – 2.5 -3,0 – 2.9 – 3.0 -3,5 – 3.3 – 3.7 -4,0 These are not head-to-head trials SGLT-2, sodium – glucose cotransporter-2; sita, sitagliptin 1. Bailey CJ et al. Lancet 2010;375:2223 – 2233; 2. Lavalle Gonzalez FJ et al. Diabetologica 2013;56:2582 – 2592; 3. Häring HU et al. Diabetes Care 2014;37:1650 – 1659

Patient populations in SGLT2i CVOTs EMPA-REG CANVAS Programme DECLARE-TIMI 58 OUTCOME Drug Empagliflozin Canagliflozin Dapagliflozin Doses analysed 10 mg, 25 mg (OD) 100 mg, 300 mg (OD) 10 mg (OD) Median follow-up time, years 3.1 2.4 4.2 Trial participants 7,020 10,142 17,160 Mean age, years 63.1 63.3 63.9 Women 2,004 (28.5%) 3,633 (35.8%) 6,422 (37.4%) Patients with established ASCVD 7,020 (100%) 6,656 (65.6%) 6,974 (40.6%) Patients with a history of heart failure 706 (10.1%) 1,461 (14.4%) 1,724 (10.0%) Patients with eGFR <60 mL/min per 1.73 m 2 1,819 (25.9%) 2,039 (20.1%) 1,256 (7.4%) Data are n (%) unless otherwise specified. The CANVAS Program consists of two trials, CANVAS and CANVAS-R, but are presented combined ASCVD, atherosclerotic cardiovascular disease; CVOT, cardiovascular outcome trial; eGFR, estimated glomerular filtration rate; OD, once daily; T2D, type 2 diabetes; SGLT2, sodium – glucose co-transporter 2 Zelniker TA et al. Lancet 2018;393:31 – 39

Patients with CVD and Non-CVD in CVOTs of SGLT2i 100 80 66 60 60 40 % 34 40 20 0 EMPA-REG CANVAS DECLARE CVD non-CVD CVD 6,971 pt’s CVD 6,656 pt’s CVD 7,020 pt’s Non-CVD 10,189 pt‘s Non-CVD 3,486 pt‘s Total 17,160 pt‘s Total 10,142 pt‘s