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

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

Aug 26, 2022 272 likes •611 views

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

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Clinical trials in T2DM & CVD: Review of key outcomes with GLP-1 RA and SGLT2i Eduard Montanya, MD

Barcelona, Spain

Session: Game changing clinical trials in T2DM & CVD: Novel insights & implications

Cardio Diabetes Master Class

February 22-23, 2019 - Barcelona, Spain

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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

Shifting gears in the management of diabetes and CVD

22-23 February 2019, Barcelona

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  • Speaker, Advisory Panel or Research Support:

AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Menarini, Janssen Pharmaceutical, Laboratoires Servier, Merck Sharp & Dohme, Novo Nordisk, and Novartis.

Speaker disclosures

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CVOTs in Diabetes: CV risk with new therapies

FDA, U.S. Food and Drug Administration FDA, 2008 www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf

Requirement to demonstrate that new antidiabetic therapies to treat type 2 diabetes are not associated with an unacceptable increase in cardiovascular risk

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SLIDE 5

Contemporary CVOTs in diabetes

ClinicalTrials.gov. Accessed 08 October 2018

2019 2015 2020 2013 2014 2016 2017 2018 2021

Insulin

DEVOTE (Insulin degludec, insulin) n=7637; duration ~2 yrs Q2 2017 – RESULTS

SGLT-2i

EMPA-REG OUTCOME (Empagliflozin, SGLT-2i) n=7000; duration up to 5 yrs Q3 2015 – RESULTS CANVAS (Canagliflozin, SGLT-2i) n=4418; duration 4+ yrs Q2 2017 – RESULTS DECLARE-TIMI 58 (Dapagliflozin, SGLT-2i) n=17,276; duration ~6 yrs Q3 2018 - RESULTS CANVAS-R (Canagliflozin, SGLT-2i) n=5826; duration ~3 yrs Q2 2017 – RESULTS CREDENCE (cardio-renal) (Canagliflozin, SGLT-2i) n=4464; duration ~5.5 yrs Q3 2018 – CANCELLED (+ve efficacy) VERTIS CV (Ertugliflozin, SGLT-2i) n=8000; duration ~6 yrs Completion Q3 2019

GLP-1RA

ELIXA (Lixisenatide, GLP-1RA) n=6068; follow-up ~2 yrs Q1 2015 – RESULTS REWIND (Dulaglutide, OW GLP-1RA) n=9622; duration ~6.5 yrs Q3 2018 TOPLINE RESULTS FREEDOM (ITCA 650, GLP-1RA in DUROS) n=4000; duration ~2 yrs Q2 2016 – TOPLINE RESULTS EXSCEL (Exenatide ER, OW GLP-1RA) n=14,752; follow-up ~3 yrs Q3 2017 – RESULTS LEADER (Liraglutide, GLP-1RA) n=9340; duration 3.5–5 yrs Q2 2016 – RESULTS HARMONY OUTCOMES (Albiglutide, OW GLP-1RA) n=9574; duration ~4 yrs Q3 2018 - RESULTS PIONEER 6 (Oral semaglutide, GLP-1RA) n=3176; duration ~1.5 yrs Q4 2018 COMPLETED

DPP-4i

EXAMINE (Alogliptin, DPP-4i) n=5380; follow-up ~1.5 yrs Q3 2013 – RESULTS SAVOR-TIMI 53 (Saxagliptin, DPP-4i) n=16,492; follow-up ~2 yrs Q2 2013 – RESULTS TECOS (Sitagliptin, DPP-4i) n=14,671; duration ~3 yrs Q4 2014 – RESULTS CARMELINA (Linagliptin, DPP-4i) n=7003; duration ~4 yrs Q3 2018 – RESULTS ALECARDIO (Aleglitazar, PPAR-αγ) n=7226; follow-up 2 yrs

  • Termin. Q3 2013 – RESULTS

PPAR-αγ

2022

SCORED (Sotagliflozin, SGLT-1i & SGLT-2i) n=10,500*; duration ~4.5 yrs Completion Q1 2022 SUSTAIN 6 (Semaglutide, OW GLP-1RA) n=3297; duration ~2.8 yrs Q3 2016 – RESULTS CAROLINA (Linagliptin, DPP-4i vs SU) n=6103; duration ~8 yrs Completion Q1 2019

TZD

TOSCA IT (Pioglitazone, TZD) n=3028; duration ~10 yrs Q4 2017† – RESULTS

AGI

ACE (Acarbose, AGI) n=6522; duration ~8 yrs Q2 2017 – RESULTS AMPLITUDE-O (Efpeglenatide, OW GLP-1RA) n=4000*; duration ~3 yrs Completion Q2 2021 SOLOIST-WHF (Sotagliflozin , SGLT-1i & SGLT-2i) n=4000; duration ~2.7 yrs Completion Q1 2021

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CVOTs in diabetes: GLP1-RA and SGLT-2i

ClinicalTrials.gov. Accessed 08 October 2018

2019 2015 2020 2013 2014 2016 2017 2018 2021

SGLT-2i

EMPA-REG OUTCOME (Empagliflozin, SGLT-2i) n=7000; duration up to 5 yrs Q3 2015 – RESULTS CANVAS (Canagliflozin, SGLT-2i) n=4418; duration 4+ yrs Q2 2017 – RESULTS DECLARE-TIMI 58 (Dapagliflozin, SGLT-2i) n=17,276; duration ~6 yrs Q3 2018 - RESULTS CANVAS-R (Canagliflozin, SGLT-2i) n=5826; duration ~3 yrs Q2 2017 – RESULTS CREDENCE (cardio-renal) (Canagliflozin, SGLT-2i) n=4464; duration ~5.5 yrs Q3 2018 – CANCELLED (+ve efficacy) VERTIS CV (Ertugliflozin, SGLT-2i) n=8000; duration ~6 yrs Completion Q3 2019

GLP-1RA

ELIXA (Lixisenatide, GLP-1RA) n=6068; follow-up ~2 yrs Q1 2015 – RESULTS REWIND (Dulaglutide, OW GLP-1RA) n=9622; duration ~6.5 yrs Q3 2018 TOPLINE RESULTS FREEDOM (ITCA 650, GLP-1RA in DUROS) n=4000; duration ~2 yrs Q2 2016 – TOPLINE RESULTS EXSCEL (Exenatide ER, OW GLP-1RA) n=14,752; follow-up ~3 yrs Q3 2017 – RESULTS LEADER (Liraglutide, GLP-1RA) n=9340; duration 3.5–5 yrs Q2 2016 – RESULTS HARMONY OUTCOMES (Albiglutide, OW GLP-1RA) n=9574; duration ~4 yrs Q3 2018 - RESULTS PIONEER 6 (Oral semaglutide, GLP-1RA) n=3176; duration ~1.5 yrs Q4 2018 COMPLETED

2022

SCORED (Sotagliflozin, SGLT-1i & SGLT-2i) n=10,500*; duration ~4.5 yrs Completion Q1 2022 SUSTAIN 6 (Semaglutide, OW GLP-1RA) n=3297; duration ~2.8 yrs Q3 2016 – RESULTS AMPLITUDE-O (Efpeglenatide, OW GLP-1RA) n=4000*; duration ~3 yrs Completion Q2 2021 SOLOIST-WHF (Sotagliflozin , SGLT-1i & SGLT-2i) n=4000; duration ~2.7 yrs Completion Q1 2021

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SGLT2i CVOTs

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CVOTs in diabetes: SGLT-2i

2019 2015 2020 2013 2014 2016 2017 2018 2021

SGLT-2i

EMPA-REG OUTCOME (Empagliflozin, SGLT-2i) n=7000; duration up to 5 yrs Q3 2015 – RESULTS CANVAS (Canagliflozin, SGLT-2i) n=4418; duration 4+ yrs Q2 2017 – RESULTS DECLARE-TIMI 58 (Dapagliflozin, SGLT-2i) n=17,276; duration ~6 yrs Q342018 - RESULTS CANVAS-R (Canagliflozin, SGLT-2i) n=5826; duration ~3 yrs Q2 2017 – RESULTS CREDENCE (cardio-renal) (Canagliflozin, SGLT-2i) n=4464; duration ~5.5 yrs Q3 2018 – CANCELLED (+ve efficacy) VERTIS CV (Ertugliflozin, SGLT-2i) n=8000; duration ~6 yrs Completion Q3 2019

2022

SCORED (Sotagliflozin, SGLT-1i & SGLT-2i) n=10,500*; duration ~4.5 yrs Completion Q1 2022 AMPLITUDE-O (Efpeglenatide, OW GLP-1RA) n=4000*; duration ~3 yrs Completion Q2 2021 SOLOIST-WHF (Sotagliflozin , SGLT-1i & SGLT-2i) n=4000; duration ~2.7 yrs Completion Q1 2021

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Comparison of SGLT-2 inhibitors: HbA1c

  • 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

–0.7 –0.8

–0.3

  • 1,0
  • 0,5

0,0 Dapa 5 mg Dapa 10 mg Placebo 0.0

–0.7 –0.9 –0.7

Cana 100 mg Cana 300 mg Sita 100 mg

–0.7 –0.8 –0.1

Empa 10 mg Empa 25 mg Placebo

Change in HbA1c from baseline (%) Study Dapagliflozin (Dapa)1 52-week data Canagliflozin (Cana)2 52-week data Empagliflozin (Empa)3 24-week data Study arm Dapa (5 mg) n=137 Dapa 10 mg n=135 Placebo n=137 Cana 100 mg n=368 Cana 300 mg n=367 Sita 100 mg n=366 Empa 10 mg n=217 Empa 25 mg n=213 Placebo n=207 Baseline HbA1c (%) 8.2 7.9 8.1 7.9 7.9 7.9 7.9 7.9 7.9

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Comparison of SGLT-2 inhibitors: Body weight

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

–3.0 –2.9 –0.3

  • 4,0
  • 3,5
  • 3,0
  • 2,5
  • 2,0
  • 1,5
  • 1,0
  • 0,5

0,0 Dapa 5 mg Dapa 10 mg Placebo 0.0

–3.3 –3.7 –1.2

Cana 100 mg Cana 300 mg Sita 100 mg

–2.1 –2.5 –0.5

Empa 10 mg Empa 25 mg Placebo

Change in body weight from baseline (kg) Study Dapagliflozin (Dapa)1 52-week data Canagliflozin (Cana)2 52-week data Empagliflozin (Empa)3 24-week data Study arm Dapa (5 mg) n=137 Dapa 10 mg n=135 Placebo n=137 Cana 100 mg n=368 Cana 300 mg n=367 Sita 100 mg n=366 Empa 10 mg n=217 Empa 25 mg n=213 Placebo n=207 Baseline body weight (kg) 84.7 86.3 87.7 88.8 85.4 87.7 79.7 81.6 82.2

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EMPA-REG OUTCOME CANVAS Programme DECLARE-TIMI 58 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 m2 1,819 (25.9%) 2,039 (20.1%) 1,256 (7.4%)

Patient populations in SGLT2i CVOTs

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

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66 40 34 60 100 80 60 40 20 EMPA-REG DECLARE

%

CANVAS CVD non-CVD

CVD 7,020 pt’s CVD 6,971 pt’s Non-CVD 10,189 pt‘s Total 17,160 pt‘s CVD 6,656 pt’s Non-CVD 3,486 pt‘s Total 10,142 pt‘s

Patients with CVD and Non-CVD in CVOTs of SGLT2i

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SGLT2i CVOTs: primary outcomes

CI, confidence interval; CVOT, cardiovascular outcomes trial; HR, hazard ratio; MACE, major adverse cardiovascular event; SGLT2, sodium-glucose co-transporter 2

  • 1. Zinman B et al. N Engl J Med 2015;373:2117–2128; 2. Neal B et al. N Engl J Med 2017;377:644–657; 3. Wiviott SD et al. N Engl J Med 2018.

doi: 10.1056/NEJMoa1812389. [Epub ahead of print]

CV death, non-fatal MI or non-fatal ischaemic stroke

10 9 8 7 6 5 4 3 2 1 180 360 540 720 900 1080 1260 1440

HR: 0.93 95% CI: 0.84; 1.03 p=0.17 for superiority

Time from randomisation (days) Cumulative incidence (%)

DECLARE-TIMI 583

6 12 18 30 24 42 36 48 20 10 5 15 Time from randomisation (months) Patients with an event (%)

HR: 0.86 95% CI: 0.74; 0.99 p=0.04 for superiority

EMPA-REG1

Empagliflozin Placebo

Time from randomisation (weeks) 52 260 312 104 156 208

2 6

7 8

13 182

234

286 33 8

20 15 10 5

HR: 0.86 95% CI: 0.75; 0.97 p=0.02 for superiority

CANVAS2

Canagliflozin Placebo Dapagliflozin Placebo

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0,25 0,5 1 2

p-value Primary endpoint p=0.04 for superiority CV death <0.001 Non-fatal MI† 0.22 Non-fatal stroke 0.16

Empagliflozin: EMPA-REG results

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.

Favours placebo → ← Favours empagliflozin

Months since randomisation 20 10 5 15 48 30 42 6 18 24 36 12

Pooled Empagliflozin Placebo

HR: 0.86 [0.74; 0.99]95% CI, p<0.001 for non-inferiority, p=0.04 for superiority*

Participants with an event (%)

Heart failure

As compared with placebo, empagliflozin resulted in a significantly lower risk of hospitalisation for heart failure HR: 0.65 [0.50; 0.85]95% CI, p=0.002

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SLIDE 15

Canagliflozin: CANVAS results

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.

Years since randomisation 20 10 5 15 6 4 1 3 5 2

Canagliflozin Placebo

HR: 0.86 [0.75; 0.97]95% CI,

p<0.0001 for non-inferiority, p=0.0158 for superiority

Participants with an event (%)

Hospitalization for HF 0.67 (0.52-0.87) CV death or hospitalization for HF 0.78 (0.67-0.91) All-cause mortality 0.87 (0.74-1.01) Primary cardiovascular outcome 0.86 (0.75-0.97) CV death 0.87 (0.72-1.06) Non-fatal MI 0.85 (0.69-1.05) Non-fatal stroke 0.90 (0.71-1.15) 0.5 1.0 2.0

Favours placebo → ← Favours canagliflozin

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Dapagliflozin: DECLARE-TIMI 58 Results

SD Wiviott et al. N Engl J Med 2018. DOI: 10.1056/NEJMoa1812389

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SLIDE 17

Dapagliflozin: DECLARE-TIMI 58 Results

SD Wiviott et al. N Engl J Med 2018. DOI: 10.1056/NEJMoa1812389

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SLIDE 18
  • SGLT2i have similar effects on glycemic control and body weight
  • SGLT2i have shown CV safety
  • SGLT2i (empa and cana) have shown reduction in risk of MACE in patients

with stablished ACVD (secondary prevention).

  • SGLT2i have not shown reduction in MACE or CV death in patients with no

stablished ACVD (primary prevention)

  • SGLT2i prevent hospitalization for heart failure, both in patients with and

without established ACVD SGLT2i have shown a more robust and consistent effect on prevention of heart failure (and renal outcomes) than on atherosclerotic cardiovascular events

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SLIDE 19

GLP-1RA CVOTs

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SLIDE 20

CVOTs in diabetes: GLP1-RA

ClinicalTrials.gov. Accessed 08 October 2018

2019 2015 2020 2013 2014 2016 2017 2018 2021

GLP-1RA

ELIXA (Lixisenatide, GLP-1RA) n=6068; follow-up ~2 yrs Q1 2015 – RESULTS REWIND (Dulaglutide, OW GLP-1RA) n=9622; duration ~6.5 yrs Q4 2018 TOPLINE RESULTS FREEDOM (ITCA 650, GLP-1RA in DUROS) n=4000; duration ~2 yrs Q2 2016 – TOPLINE RESULTS EXSCEL (Exenatide ER, OW GLP-1RA) n=14,752; follow-up ~3 yrs Q3 2017 – RESULTS LEADER (Liraglutide, GLP-1RA) n=9340; duration 3.5–5 yrs Q2 2016 – RESULTS HARMONY OUTCOMES (Albiglutide, OW GLP-1RA) n=9574; duration ~4 yrs Q3 2018 - RESULTS PIONEER 6 (Oral semaglutide, GLP-1RA) n=3176; duration ~1.5 yrs Q4 2018 COMPLETED

2022

SUSTAIN 6 (Semaglutide, OW GLP-1RA) n=3297; duration ~2.8 yrs Q3 2016 – RESULTS AMPLITUDE-O (Efpeglenatide, OW GLP-1RA) n=4000*; duration ~3 yrs Completion Q2 2021

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GLP-1RA are not all the same

Long-acting vs short-acting Large vs small molecules GLP-1-based vs exendin-based

Molecular mass (kDa)

10 20 30 40 50 60 70 80 90 100

Native human GLP-1

His Ala Thr Thr Ser Phe Glu Gly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Phe Glu Ile Ala Trp Leu Gly Val Gly Arg Lys
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SLIDE 22

Time (days)

Once daily†3 Once weekly4 Once daily*2

Long-acting and short-acting GLP-1RAs

*Exendin-based; †GLP-1-based GLP-1RA, glucagon-like peptide-1 receptor agonist

  • 1. Reddy S et al. AAPS J 2005;7:M1285; 2. Christensen M et al. IDrugs 2009;12:503–513; 3. Elbrønd B et al. Diabetes Care 2002;25:1398–1404;
  • 4. Fineman M et al. Clin Pharmacokinet 2011;50:65–74

Twice daily1

Plasma GLP-1RA

4 5 3 1 2 6 7 8

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SLIDE 23

Large versus small GLP-1RA molecules

  • 1. Malm-Erjefält M et al. Drug Metab Dispos 2010;38:1944–1953; 2. Dhruva et al. JCD 2016;22:18–25

Molecular mass (kDa)

10 20 30 40 50 60 70 80 90 100

Dulaglutide2 (59.7 kDa) Semaglutide2 (4.1 kDa) Liraglutide1 (3.8 kDa) Exenatide2 (4.2 kDa) Lixisenatide2 (4.9 kDa)

His Ala Thr Thr Ser Phe Glu Gly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Phe Glu Ile Ala Trp Leu Gly Val Gly Arg Glu Arg

C-16

Asp His Gly Thr Thr Ser Phe Glu Gly Asp Leu Ser Lys Gln Met Glu Glu Ala Val Glu Arg Phe Leu Ile Glu Trp Leu Pro Lys Gly Gly Ser Ser Gly Gly Ala Pro Pro Ser Asp His Gly Thr Thr Ser Phe Glu Gly Asp Leu Ser Lys Gln Met Glu Glu Ala Val Glu Arg Phe Leu Ile Glu Trp Leu Pro Lys Gly Gly Ser Ser Gly Gly Ala Pro Pro Lys Lys Lys Lys Lys Lys Lys His Aib Thr Thr Ser Phe Glu Gly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Phe Glu Ile Ala Trp Leu Gly Val Gly Arg Arg Spacer

C-18 fatty di- acid

His Gly Thr Thr Ser Phe Glu Gly Asp Val Ser Ser Tyr Leu Glu Glu Ala Ala Gln Lys Phe Glu Ile Ala Trp Leu Gly Val Gly Gly Lys Phe Ile Ala Trp Leu Gly Val Gly Gly Lys Glu Ser Tyr Leu Glu Glu Ala Ala Gln Lys Ser His Gly Thr Thr Ser Phe Glu Gly Asp Val

IgG

Albiglutide2 (73.0 kDa)

Lys His Gly Thr Thr Ser Phe Glu Gly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Phe Glu Ile Ala Trp Leu Val Gly Arg His Lys Gly Thr Thr Ser Phe Glu Gly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Phe Glu Ile Ala Trp Leu Val Gly Arg

rH-albumin

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SLIDE 24

Dulaglutide5

90% amino-acid homology to human GLP-1

His Gly Thr ThrSer Phe Glu Gly AspVal Ser Ser Tyr Leu Glu Glu Ala Ala Gln Lys Phe Glu Ile Ala TrpLeu Gly Val Gly Gly Lys Linker peptide Modified IgG4 Fc domain Phe Ile Ala TrpLeu Gly Val Gly Gly Lys Glu Ser Tyr Leu Glu Glu Ala Ala Gln Lys Ser His Gly Thr ThrSer Phe Glu Gly AspVal

97% amino-acid homology to human GLP-1

Liraglutide4

His Ala Thr Thr Ser Phe Glu Gly AspVal Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Phe Glu Ile Ala Trp Leu Gly Val GlyArg Glu Arg C-16 Fatty acid

Exenatide1

HisGly Thr ThrSer Phe GluGly Asp Leu Ser Lys Gln Met Glu Glu Ala Val Glu Arg Phe Leu Ile GluTrpLeu Pro Lys GlyGly Asp SerSerGlyAlaProProProSer

~ 50% amino-acid homology to human GLP-1

Lixisenatide6–8

HisGly Thr ThrSer Phe GluGly Asp Leu Ser Lys Gln Met Glu Glu Ala Val Glu Arg IleGluTrpLeu Pro Lys GlyGly Asp SerSerGlyAlaProProProSerLys Lys Lys Lys Lys Lys Phe Leu

~ 50% amino-acid homology to human GLP-1

GLP-1 based versus exendin based GLP-1RAs

Fc, fragment crystallisable; GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor agonist; IgG4, immunoglobulin G4

  • 1. Byetta. Summary of Product Characteristics; 2. DeYoung MB et al. Diab Technol Ther 2011;13:1145–1154; 3. Fineman M et al. Clin Pharmacokinet 2011;50:65–742; 4. Victoza.

Summary of Product Characteristics; 5. Lund A et al. Eur J Int Med 2014;25:407–414; 6. Lyxumia. Summary of Product Characteristics; 7. Christensen et al. IDrugs 2009;12:503–513;

  • 8. Ratner et al. Diabet Med 2010;27:1024–1032; 9. Stewart MW et al. ADA 2008, poster presentation 522-p; 10. Rendell MS et al. Expert Opin Biol Ther. 2016;16:1557-1569

Semaglutide9

94% amino-acid homology to human GLP-1

C-18 Fatty di-acid chain spacer His Aib Thr Thr Ser Phe GluGly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Phe Glu Ile Ala TrpLeu Gly Val GlyArg Arg

Exenatide1–3

97% amino-acid homology to human GLP-1

Albiglutide10

Lys HisGly Thr ThrSer Phe GluGly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Phe Glu IleAlaTrpLeuVal GlyArgHis Lys Gly Thr ThrSer Phe GluGly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Phe Glu IleAlaTrpLeuVal GlyArg

ALBUMIN

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SLIDE 25

REWIND1 (N=9901) ELIXA2 (N=6068) EXSCEL3 (N=14,752) SUSTAIN 64 (N=3297) LEADER5 (N=9340) HARMONY6 (N=9463) Drug tested Dulaglutide Lixisenatide Exenatide Semaglutide Liraglutide Albiglutide Dosage 1.5 mg /week 20 μg* /day 2.0 mg /week 0.5 or 1 mg /week 1.2 or 1.8 mg /day 30 mg† /week Mean age, years 66 60 63 65 64 64 Gender, % female 46 31 38 39 36 30 Diabetes duration, years 10.0 9.3 12 13.9 12.8 14 Prior CVD, % 31 100 73 59 72 100 Mean BMI, kg/m2 32 30 32 33 33 32 Mean HbA1c, % 7.3 7.7 8.0 8.7 8.7 8.7

GLP-1RA CVOTs. Patient population

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SLIDE 26

p-value

Primary endpoint p<.001 for non-inferiority CV Death 0.85 MI 0.71 Stroke 0.54 Hospitalisation for unstable angina 0.75

Lixisenatide: ELIXA results

The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, or hospitalisation for unstable angina

  • 1. Pfeffer et al. N Engl J Med 2015;373:2247–57.

0,25 0,5 1 2

Favours placebo → ← Favours lixisenatide

12 24 36 5 10 15 20 Months since randomisation HR: 1.02 [0.89; 1.17]95% CI, p<0.001 for non-inferiority, p=0.81 for superiority Participants with an event (%)

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SLIDE 27

Holman RR et al. N Engl J Med 2017;377:1228–1239

Patients with an event (%)

HR: 0.91 (95% CI: 0.83 ; 1.00) Events: exenatide 839/7356; placebo 905/7396 p<0.001 for non-inferiority p=0.061 for superiority

Time from randomisation (years)

  • No. of patients

Exenatide 7356 7101 6893 6580 5912 4475 3595 3053 2281 1417 727 Placebo 7396 7120 6897 6565 5908 4468 3565 2961 2209 1366 687

18 15 9 6 3 1 2 3 4 5 12

0,5 1 1,5 2

p-value

Primary endpoint p<.001 for non-inferiority CV Death 0.096 Non-fatal MI 0.622 Non-fatal Stroke 0.095

Favours placebo → ← Favours exenatide OW

Exenatide once weekly: EXSCEL results

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SLIDE 28

LEADER1

5 10 15 20 8 16 24 32 40 48 56 64 72 80 88 96 104 10 20 30 40 50 5 10 15 20 HR: 0.87 95% CI: 0.78; 0.97 p<0.001 for non-inferiority p=0.01 for superiority Placebo Liraglutide Time from randomisation (months) Patients with an event (%)

SUSTAIN 62

HR: 0.74 95% CI: 0.58; 0.95 p<0.001 for non-inferiority p=0.02 for superiority* Placebo Semaglutide Patients with an event (%) Time from randomisation (weeks) HR: 0.78 95% CI: 0.68;0.90 p<0.0001 for non-inferiority p=0.0006 for superiority 15 20 5 10 Placebo Albiglutide Time from randomisation (months) Patients with an event (%) 4 16 20 28 8 12 24

HARMONY3

GLP-1RAs CVOTs: primary outcomes

  • 1. Marso SP et al. N Engl J Med 2016;375:311–322; 2. Marso SP et al. N Engl J Med 2016;375:1834–1844; 3. Hernandez AF et al. Lancet 2018;392:1519–1529

Liraglutide, semaglutide and albiglutide demonstrated CV superiority vs placebo; lixisenatide and exenatide ER demonstrated CV safety

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SLIDE 29

Dulaglutide: REWIND

Press Release Results Nov 5 2018

REWIND1 (N=9901) Dulaglutide Dosage 1.5 mg /week Mean age, years 66 Gender, % female 46 Diabetes duration, years 10.0 Prior CVD, % 31 Mean BMI, kg/m2 32 Mean HbA1c, % 7.3

“Dulaglutide significantly reduced major adverse cardiovascular events (MACE), a composite endpoint of cardiovascular (CV) death, non-fatal myocardial infarction (heart attack) or non-fatal stroke, meeting the primary efficacy objective in the precedent-setting REWIND trial”

https://www.prnewswire.com/news-releases/trulicity-dulaglutide-demonstrates-superiority-in-reduction-of-cardiovascular-events-for-broad- range-of-people-with-type-2,

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LEADER1

MACE Cardiovascular death CV death Fatal and non-fatal stroke

Hazard ratio [95% CI] 0,0 0,5 1,0 1,5

Favours liraglutide Favours placebo p=0.01 for superiority p<0.001 for non-inferiority MACE CV death Non-fatal stroke Non-fatal MI

SUSTAIN 62

Hazard ratio [95% CI]

Favours semaglutide Favours placebo p=0.02 for superiority* p<0.001 for non-inferiority

0,0 0,5 1,0 1,5

MACE CV death Fatal and non-fatal stroke Fatal and non-fatal MI

HARMONY4

Hazard ratio [95% CI]

Favours albiglutide Favours placebo p=0.81 for superiority p<0.001 for non-inferiority

0,0 0,5 1,0 1,5

*Superiority was not prespecified. p values for superiority/noninferiority are for the primary endpoint. Note that direct comparisons cannot be made between different clinical trials CV, cardiovascular; CVOT, cardiovascular outcome trial; GLP-1RA, glucagon-like peptide-1 receptor agonist; MACE, major adverse cardiovascular event; MI, myocardial infarction

  • 1. Marso SP et al. N Engl J Med 2016;375:311–322; 2. Marso SP et al. N Engl J Med 2016;375:1834–1844; 3. Holman RR et al. N Engl J Med 2017;377:1228–1239; 4. Hernandez AF et al. Lancet 2018;392:1519–1529

GLP-1RA CVOTs: primary outcomes and the individual components

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  • GLP-1RAs have different PK/PD and molecular structures, with different

efficacy on glucose control and body weight

  • GLP-1RAs inhibitors have shown CV safety
  • GLP-1RAs liraglutide, semaglutide, albiglutide, and dulaglutide have

shown CV benefit with MACE reduction in patients with ACVD (secondary prevention)

  • Results suggest that GLP-1RA may have also CV benefit in patients with

multiple risk factors (primary prevention). GLP-1RA with proven CV efficacy have a more robust and consistent effect

  • n prevention of atherosclerotic events, with more modest effects on renal
  • utcomes, and safety on heart failure.
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Second-line therapy for T2D in patients with established ASCVD or HF

Diabetes Care 2018. dci180033; Davies MJ et al. Diabetologia 2018. doi: https://doi.org/10.1007/s00125-018-4729-5

ADA-EASD 2018 Consensus Report

ASCVD predominates

GLP-1RA with proven CVD benefit SGLT-2i with proven CVD benefit, if eGFR adequate† EITHER/ OR

HF OR CKD predominates

SGLT-2i with evidence of reducing HF and/or CKD progression in CVOT if eGFR adequate If SGLT-2i not tolerated or contraindicated or if eGFR less than adequate†, add GLP-1RA with proven CV benefit OR PREFERABLY