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 November 16 - 17, 2018 - Dubai, UAE

Shifting gears in the management of diabetes and CVD 15-16 November 2018, Dubai, UAE 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

Cardiovascular 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 ACE EXSCEL REWIND SOLOIST-WHF (Acarbose, AGI) (Exenatide ER, OW GLP-1RA) (Dulaglutide, OW GLP-1RA) (Sotagliflozin , SGLT-1i & SGLT-2i) n=6522; duration ~8 yrs n=14,752; follow-up ~3 yrs n=9622; duration ~6.5 yrs n=4000; duration ~2.7 yrs Q2 2017 – RESULTS Q3 2017 – RESULTS Q3 2018 COMPLETED Completion Q1 2021 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 Completion Q4 2018 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 EXSCEL REWIND SOLOIST-WHF (Exenatide ER, OW GLP-1RA) (Dulaglutide, OW GLP-1RA) (Sotagliflozin , SGLT-1i & SGLT-2i) n=14,752; follow-up ~3 yrs n=9622; duration ~6.5 yrs n=4000; duration ~2.7 yrs Q3 2017 – RESULTS Q3 2018 COMPLETED Completion Q1 2021 PIONEER 6 AMPLITUDE-O (Oral semaglutide, GLP-1RA) (Efpeglenatide, OW GLP-1RA) n=3176; duration ~1.5 yrs n=4000*; duration ~3 yrs Completion Q4 2018 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

SGLT-2i 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

EMPA-REG, CANVAS and DECLARE population and design Baseline Diabetes duration, Patients BMI, kg/m 2 HbA 1c , % Age, years years CANVAS 63 14 32.0 8.2 EMPA-REG 63 NR 30.6 8.1 DECLARE 64 12 32.1 8.3 Median duration of Trial Event-driven Time-driven N follow-up, years EMPA-REG 3.1 7,028 ✓  CANVAS 2.4 10,142 ✓  DECLARE 4.2 17.160 ✓ 

CVD and Non-CVD proportion in CVOTs of SGLT-2i 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

Empagliflozin: EMPA-REG results p -value 20 Primary p=0.04 for endpoint superiority HR: 0.86 [0.74; 0.99] 95% CI , Placebo <0.001 p <0.001 for non-inferiority, CV death Participants with an 15 p =0.04 for superiority* Non-fatal 0.22 MI † event (%) Non-fatal 0.16 Pooled stroke Empagliflozin 10 0,25 0,5 1 2 ← Favours empagliflozin Favours placebo → 5 Heart failure As compared with placebo, 0 empagliflozin resulted in a significantly lower risk of hospitalisation for heart failure 0 6 12 18 24 30 36 42 48 HR: 0.65 [0.50; 0.85] 95% CI , p =0.002 Months since randomisation The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, 1. Zinman et al. N Engl J Med 2015;373:2117 – 28.

Canagliflozin: CANVAS results 20 Placebo HR: 0.86 [0.75; 0.97] 95% CI , Participants with an event (%) p <0.0001 for non-inferiority, Primary cardiovascular outcome 0.86 (0.75-0.97) p =0.0158 for superiority CV death 0.87 (0.72-1.06) 15 Non-fatal MI 0.85 (0.69-1.05) Canagliflozin Non-fatal stroke 0.90 (0.71-1.15) Hospitalization for HF 0.67 (0.52-0.87) 10 CV death or hospitalization for HF 0.78 (0.67-0.91) All-cause mortality 0.87 (0.74-1.01) 0.5 1.0 2.0 5 ← Favours canagliflozin Favours placebo → 0 0 1 2 3 4 5 6 Years since randomisation The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, Neal et al . N Eng J Med 2017; DOI: 10.1056/NEJMoa1611925.

Dapagliflozin: DECLARE-TIMI 58 Results SD Wiviott et al. N Engl J Med 2018. DOI: 10.1056/NEJMoa1812389

Dapagliflozin: DECLARE-TIMI 58 Results SD Wiviott et al. N Engl J Med 2018. DOI: 10.1056/NEJMoa1812389

GLP-1RA CVOTs