Congrès CardioScopie – 09 mai 2020

Michel P. HERMANSMD (UCL) PhD (UCL & Oxford, UK)

Dip. Natural Sciences (Open University, Milton Keynes, UK)Dip. Earth Sciences (Open University, Milton Keynes, UK)

Dip. Human Geography (Open University, Milton Keynes, UK)Dip. Environment (Open University, Milton Keynes, UK)

PG Certificate in Social Sciences (Open University, Milton Keynes, UK)

Endocrinologie & NutritionCliniques universitaires St-Luc

Université Catholique de Louvain

Updated consensus ADA/EASD for the management of T2D: Key takeaways for best practice in general medicine

Speaker’s Disclosure

• Abbott • Amgen• AstraZeneca • Boehringer Ingelheim • Eurogenerics• Eli Lilly • GSK• Johnson & Johnson

• MSD • Mundipharma• Mylan• Novartis • Novo Nordisk• Sandoz• Sanofi Aventis • Takeda

I have served on advisory panels or received speaker’s honoraria or travel grants from:

(epi) genetic factors environmental cardiometabolic RFs standard RFs

overweight - obesity age

metabolic syndrome gender

gestational diabetes IR / hyperinsulinemia hypertension

pre-diabetes chronic kidney disease smoking

T2DM atherogenic dyslipidemia LDL-C

macrovascular disease (CAD - PAD - CVD)

chronic hyperglycemia (surrogate: HbA1c)

Beta-cell failure

microvascular disease (DRP - PNP - DN)

Pr. Michel P. Hermans 2020

2019 update to: Management of

hyperglycemia in type 2 diabetes, 2018 –

A consensus report by the ADA and EASD

ADA, American Diabetes Association; EASD, European Association for the Study of DiabetesDiabetes Care; 2019:dci190066; Buse JB et al. Diabetologia 2019;doi:10.1007/s00125-019-05039-w

BE20CD00007-17 January 2020

Important updates from 2018

Established ASCVD, such as prior myocardial infarction, ischaemic stroke, unstable angina with ECG changes, myocardial ischaemia on imaging or stress test, or revascularisation of coronary, carotid or peripheral arteries# specifically, patients aged 55 years or older with coronary, carotid or lower extremity artery stenosis >50%, left ventricular hypertrophy, eGFR <60 ml min–1 [1.73 m]–² or albuminuria*eGFR 30 to 60 ml/min/1.73 m2 or urinary albumin-to-creatinine ratio >30 mg/g, particularly >300 mg/gASCVD, atherosclerotic CVD; CVD, cardiovascular disease; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon like peptide-1 receptor agonist; hHF, hospitalization for heart failure; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; MACE, major adverse cardiovascular event; SGLT2is, sodium glucose like cotransporter 2 inhibitors1. Davies MJ et al. Diabetologia. 2018;61:2461-2498; 2. Buse JB et al. Diabetologia 2019;doi:10.1007/s00125-019-05039-w

20181

T2D with established CVD was a compelling indication for treatment with a GLP-1 RA or SGLT2i

20192

In high-risk individuals with established T2D, the decision to treat with a GLP-1 RA or SGLT2i to reduce MACE, hHF, CV death, or CKD progression should be considered independently of baseline HbA1c or individualized HbA1ctarget

SGLT2is are recommended in T2D patients with HF, particularly HFrEF, as well as in T2D patients with CKD* to reduce the progression of CKD, hHF, MACE and CV death

For patients at risk of foot ulcers and amputation should be given proper care while using SGLT2i

GLP-1 RA can be considered in patients with T2D without established CVD but with the presence of specific indicators of high risk#

For patients with T2D and established ASCVD where MACE is the gravest threat, the level of evidence for MACE benefit is greatest for GLP-1 RAs

Buse JB et al. 2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)Diabetologia. 2020;63(2):221-228

Results from GLP-1 RA CVOTs published last year resulted in the ADA/EASD updates Evidence supporting the updates in favor of GLP-1 RA

ADA, American diabetes association; ASCVD, atherosclerotic cardiovascular disease; CI, confidence interval; CV, cardiovascular; EASD, European association for the study of diabetes; HR, hazard ratio; MACE, major adverse cardiovascular events; GLP-1 RA, glucagon-like peptide-1 receptor agonist; MI, myocardial infarction1. Gerstein HC et al. Lancet 2019;394:121–130; 2. Husain M et al. N Engl J Med 2019; 381:841-851

REWIND1

Cu

mu

lati

ve r

isk

(%)

Years since randomisation

HR: 0.88(95% CI: 0.79; 0.99)p=0.026

18

0 1 2 3 4 5 6

15

12

9

6

3

0

Dulaglutide Placebo

3-point MACE: CV death, non-fatal MI or non-fatal stroke

PIONEER 62

8

6

4

2

0

10

830 9 18 27 36 45 54 63 72

HR: 0.49 (95% Cl, 0.27; 0.92)

9

7

5

3

1

Oral semaglutidePlacebo

Pat

ien

ts w

ith

eve

nt

(%)

Months since randomisation

CV death

For patients with high risk or established ASCVD

8

6

4

2

0

10

830 9 18 27 36 45 54 63 72

HR: 0.79(95% Cl, 0.57; 1.11)P<0.001 for noninferiorityP=0.17 for superiority

9

7

5

3

1

Oral semaglutidePlacebo

Months since randomisation

Pat

ien

ts w

ith

eve

nt

(%)

Results from SGLT2i CVOTs published last year resulted in the ADA/EASD updatesEvidence supporting the updates in favor of SGLT2i

CI, confidence interval; HR, hazard ratio; CV, cardiovascular; hHF, hospitalization for heart failure; HF, heart failure; MACE, major adverse cardiovascular events; GLP-1 RA, glucagon-like peptide-1 receptor agonist; MI, myocardial infarction1. Neal B et al. N Engl J Med 2017;377:644–657; 2. Wiviott SD et al. N Engl J Med 2019;380:347–357; 3. McMurray JJV et al. N Engl J Med 2019; 381:1995-2008

For patients with or without established ASCVD and HF

CANVAS Program1 DECLARE-TIMI 582

Weeks since randomisation

Pat

ien

ts w

ith

eve

nt

(%)

0 26 78 130 182 286 338

201816141210

86420

HR: 0.86(95% CI: 0.75; 0.97)p<0.001 for non-inferiorityp=0.02 for superiority

Canagliflozin Placebo

Cu

mu

lati

ve i

nci

den

ce (

%)

HR: 0.93(95% CI: 0.84; 1.03)p=0.17 for superiorityp<0.001 for non-inferiority

Days since randomisation

Dapagliflozin Placebo

3-point MACE: CV death, non-fatal MI or non-fatal stroke

Months since Randomization

Cu

mu

lati

ve i

nci

den

ce (

%) 30

25

20

15

10

5

00 3 6 9 12 15 18 21 24

HR: 0.74 (95% CI, 0.65-0.85)p<0.001

Placebo Dapagliflozin

DAPA-HF3

CV death, hHF, or an urgent visit resulting in intravenous therapy for HF

2340123456789

10

0 180 360 540 720 900 1080 1260 1440

End-stage kidney disease, doubling of serum creatinine, renal or CV death

Results from CREDENCE (T2D with CKD) published last year resulted in the ADA/EASD updatesEvidence supporting the updates in favor of SGLT2i

CI, confidence interval; CKD, chronic kidney diseasePerkovic V et al. 2019, N Engl J Med 2019; 380:2295-2306

For patients with established CKD

Pat

ien

ts w

ith

an

Eve

nt

(%)

0 6 12 18 24 30 36 420

5

10

15

20

25

30 HR: 0.70 (95% CI, 0.59-0.82)p=0.00001

Months since Randomization

Primary composite outcome: End-stage kidney disease, doubling of serum creatinine, renal or CV death

0 6 12 18 24 30 36 420

5

10

15

20 HR: 0.66(95% CI, 0.53-0.81)p<0.001

Months since Randomization

Pat

ien

ts w

ith

an

Eve

nt

(%)

Renal specific outcome: End-stage kidney disease, doubling of serum creatinine, renal death

CanagliflozinPlaceboCREDENCE

GLP-1 RAs vary in molecular structure and size

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

Liraglutide (3.75 kDa, 97% homology)

C-16 fatty acid(palmitoyl)

HisAla Thr ThrSerPheGluGly AspValSer

SerTyrLeuGluGlyAlaAla GlnLysGlu

Glu

PheIle AlaTrpLeu GlyVal GlyArgArg

Semaglutide (4.11 kDa, 94% homology)

C-18 fatty di-acid

COOH

HisAib Thr ThrSerPheGluGly AspValSer

SerTyrLeuGluGlyAlaAla Gln

Phe

LysGlu

IleAlaTrpLeu GlyVal GlyArgArg

Spacer

Lixisenatide (4.86 kDa, ~50% homology)

HisGly Thr ThrSerPheGluGly AspLeu

Ser

LysGlnMetGluGluAlaVal GluArg

Phe

Leu

IleGluTrpLeu ProLys GlyGlyAsp SerSerGlyAlaProProProSer

HisGly Thr ThrSerPheGluGly AspLeu

SerLysGlnMetGluGluAlaVal GluArg

IleGluTrpLeu ProLys GlyGlyAsp SerSerGlyAlaProProProSerLysLysLys

LysLysLys

Phe

Leu

Exenatide (4.19 kDa, 53% homology) Dulaglutide (~63 kDa, 90% homology)

HisGly Thr ThrSerPheGluGly AspValSer

SerTyrLeuGluGluAlaAla GlnLys

PheGlu

IleAlaTrpLeu GlyVal GlyGlyLys

PheIleAlaTrpLeu GlyVal GlyGlyLysGlu

SerTyrLeuGluGluAlaAla GlnLysSer

HisGly Thr ThrSerPheGluGly AspValLinker peptide

Modified IgG4 Fc domain

Exendin-based GLP-1RAsHuman GLP-1 analogues

Small Large

Albiglutide*HisGly Thr ThrSerPheGluGly AspValSerSerTyrLeuGluGly Ala

AlaGln

LysPheGluIleAlaTrpLeuGly ValGlyArg LysHisGlyThrThrSer Phe GluGly

AspValSerSerTyrLeuGluGly AlaAlaGln Lys PheGlu IleAlaTrp

Leu

Asp

Val

GlyArg

Lys

ALBUMIN

Semaglutide s.c. once-weekly for the treatment of type 2 diabetes

Ozempic®

BE20OZM00003 – 2020-01-17

Baseline characteristicsSUSTAIN 1–5 AND 7–10

SUSTAIN 11

Monotherapy

SUSTAIN 22

vs sitagliptin

SUSTAIN 33

vs exenatideER

SUSTAIN 44

vsIGlar

SUSTAIN 55

Add-on to basal insulin

SUSTAIN 76

vs dulaglutide

SUSTAIN 87

vs canagliflozin

SUSTAIN 98

Add-on to SGLT-2i

SUSTAIN 109

vsliraglutide

Mean[min.;max.]

Mean[min.;max.]

Mean[min.;max.]

Mean[min.;max.]

Mean[min.;max.]

Mean[min.;max.]

Mean[min.;max.]

Mean[min.;max.]

Mean[min.;max.]

Age, years53.7 55.1 56.6 56.5 58.8 56.0 56.6 57.0 59.5

[18;88] [23;83] [20;83] [22;82] [19;86] [22;84] [24;82] [25;83] [29;86]

HbA1c, %8.1 8.1 8.3 8.2 8.4 8.2 8.3 8.0 8.2

[6.4;10.3] [5.9;11.4] [6.5;11.2] [5.5;11.7] [6.8;11.1] [6.6;11.4] [6.3;12.6] [6.1;10.3] [6.5;11.5]

Diabetes duration, years

4.2 6.6 9.2 8.6 13.3 7.4 7.4 9.7 9.3[0.1;34.5] [0.3;39.2] [0.3;54.0] [0.2;59.9] [0.4;39.6] [0.3;32.4] [0;42] [0;46] [0;33]

Body weight, kg

91.9 89.5 95.8 93.5 91.7 95.2 90.2 91.7 96.9[39.8;185.3] [43.6;167.0] [49.9;198.3] [43.0;187.8] [47.5;165.6] [46.0;209.6] [39.0;220.0] [44.6;163.0] [50.0;190.7]

min.;max. Novo Nordisk data on file.Exenatide ER, exenatide extended release; IGlar, insulin glargine; max., maximum; min., minimum; SGLT-2i, sodium−glucose cotransporter-2 inhibitor.1. Sorli C et al. Lancet Diabetes Endocrinol 2017;5:251–60; 2. Ahrén B et al. Lancet Diabetes Endocrinol 2017;5:341–54; 3. Ahmann AJ et al. Diabetes Care 2018;41:258–66; 4. Aroda VR et al. Lancet Diabetes Endocrinol 2017;5:355–66; 5. Rodbard HW et al. J Clin Endocrinol Metab 2018;103:2291–301; 6. Pratley RE et al. Lancet Diabetes Endocrinol 2018;6:275–86; 7. Lingvay I et al. Lancet Diabetes Endocrinol2019;7:834–44; 8. Zinman B et al. Lancet Diabetes Endocrinol 2019;7:356–67; 9. Capehorn MS et al. Diabetes Metab 2019. doi: 10.1016/j.diabet.2019.101117 [Epub ahead of print].

-1,5-1,6

-0,02

-1,3

-1,6

-0,5

-1,5

-0,9

-1,5

-1,1

-1,8

-1,4-1,5

-1,0

-1,5

-0,1

-1,7

-1,0

-1,2

-1,6

-0,8

-1,4

-1,8

-0,1

-2,0

-1,5

-1,0

-0,5

0,0

Cha

nge

from

bas

elin

e in

HbA1c

(%-p

oint

)

Change in HbA1c SUSTAIN 1–5 AND 7–10

*p<0.0001 vs comparator. dur, duration; exenatide ER, exenatide extended release; IGlar, insulin glargine; MET, metformin; N/A, not applicable; OAD, oral antidiabetic drug; SGLT-2i, sodium−glucose cotransporter-2inhibitor; SU, sulphonylurea; TZD, thiazolidinedione; w, week. 1. Sorli C et al. Lancet Diabetes Endocrinol 2017;5:251–60; 2. Ahrén B et al. Lancet Diabetes Endocrinol 2017;5:341–54; 3. Ahmann AJ et al. Diabetes Care 2018;41:258–66; 4. Pratley RE et al. Lancet Diabetes Endocrinol 2018;6:275–86; 5. Lingvay I et al. Lancet Diabetes Endocrinol 2019;7:834–44; 6. Zinman B et al. Lancet Diabetes Endocrinol 2019;7:356–67; 7. Capehorn MS et al. Diabetes Metab 2019. doi: 10.1016/j.diabet.2019.101117 [Epub ahead of print]; 8. Aroda VR et al. Lancet Diabetes Endocrinol 2017;5:355–66; 9. Rodbard HW et al. J Clin Endocrinol Metab 2018;103:2291–301.

**

*

* *

*

*

*

*

Placebo1N/A

308.1

Sitagliptin2MET±TZD

568.1

Exenatide ER31–2 OADs

(MET/TZD/SU)568.3

Dulaglutide4MET

408.2

Placebo6SGLT-2i±MET±SU

308.0

Liraglutide71–3 OADs

MET±SU±SGLT-2i308.2

IGlar8MET±SU

308.2

Placebo9Basal

insulin±MET308.4

Comparator:Background:

Treatment dur. (w):Baseline HbA1c (%):

**

*

MONOTHERAPY ADD-ON TO OADVS/ADD-ON TO BASAL INSULIN

*

*

Canagliflozin5MET

528.3

Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo Sitagliptin 100 mg Exenatide ER 2.0 mg

Canagliflozin 300 mgDulaglutide 1.5 mgDulaglutide 0.75 mg Liraglutide 1.2 mg IGlar

SUSTAIN 1 SUSTAIN 2 SUSTAIN 7 SUSTAIN 8SUSTAIN 3 SUSTAIN 10 SUSTAIN 4 SUSTAIN 5SUSTAIN 9

Trial design SUSTAIN 7

Adapted from Figure S1.*Semaglutide dose escalation from starting dose of 0.25 mg, dose doubled every 4 weeks until trial maintenance dose achieved. Dulaglutide 0.75 mg and 1.5 mg dosed once weekly without dose escalation. eGFR, estimated glomerular filtration rate; MTD, maximum tolerated dose.

Semaglutide 1.0 mg

Semaglutide 0.5 mg

Dulaglutide 0.75 mg

Treatment duration 40 weeks

Dose escalation*4–8 weeks

Dulaglutide 1.5 mg

Follow-up5 weeks

Randomisation(1:1:1:1)

Treatment maintenance 32–36 weeks

1,201 patients with T2D

• Age ≥18 years

• HbA1c 7.0–10.5%

• Stable treatment with metformin (≥1,500 mg/day or MTD) for 90 days prior to screening

• eGFR ≥60 mL/min/1.73 m2

Trial information

• Randomised, open-label, active-controlled, parallel-group, multicentre, multinational, four-armed, phase 3b trial

• Conducted in 16 countries in Europe plus Hong Kong, India and USA

SUSTAIN 7

6,0

6,5

7,0

7,5

8,0

8,5

HbA

1c(%

)

Time since randomisation (Week)

Semaglutide 0.5 mg Dulaglutide 0.75 mg Semaglutide 1.0 mg Dulaglutide 1·5 mg

ETD: –0.41[–0.57;–0.25]

p<0.0001

ETD: –0.40 [–0.55;–0.25]

p<0.0001

Values are estimated means with associated ETDs and 95% confidence intervals from a mixed model for repeated measurements analysis using data from all randomised patients exposed to at least one dose of trial product (full analysis set) using data obtained while on treatment and prior to onset of rescue mediation. Dashed line indicates the overall mean value at baseline. ETD, estimated treatment difference.

Overall mean at baseline: 8.2%

4 8 12 16 28 400

-1.5

-1.1

-1.8

-1.4

-2,0

-1,5

-1,0

-0,5

0,0

Semaglutide0.5 mg

Dulaglutide0.75 mg

Semaglutide1.0 mg

Dulaglutide1·5 mg

Cha

nge

from

bas

elin

e (%

)

Pratley et al. Lancet Diabetes Endocrinol, 2018; 6(4): 275-286

SUSTAIN 7

Change in HbA1cSUSTAIN 7

ETD: –3.55 [–4.32;–2.78]

p<0.0001

ETD: –2.26 [–3.02;–1.51]

p<0.000188

90

92

94

96

Bod

y w

eigh

t (k

g)

Time since randomisation (Week)

Semaglutide 0.5 mg Dulaglutide 0.75 mg Semaglutide 1.0 mg Dulaglutide 1.5 mg

Change in body weightSUSTAIN 7

Values are estimated means with associated ETDs and 95% confidence intervals from a mixed model for repeated measurements analysis using data from all randomised patients exposed to at least one dose of trial product (full analysis set) using data obtained while on treatment and prior to onset of rescue medication. Dashed line indicates the overall mean value at baseline. ETD, estimated treatment difference.

Overall mean at baseline: 95.2 kg

4 8 12 16 28 400

-4.6

2.3

-6.5

-3.0

-8

-7

-6

-5

-4

-3

-2

-1

0

Semaglutide0.5 mg

Dulaglutide0.75 mg

Semaglutide1.0 mg

Dulaglutide1.5 mg

Cha

nge

from

bas

elin

e (k

g)

Pratley et al. Lancet Diabetes Endocrinol, 2018; 6(4): 275-286

SUSTAIN 7

SUSTAIN 6Semaglutide and Cardiovascular Outcomes

in Patients with Type 2 Diabetes

Marso SP et al. N Engl J Med 2016;375:1834–44

SUSTAIN 6: rationale and trial information

*Dose escalation from a starting dose of 0.25 mg, dose doubled each step until trial dose achieved. www.ClinicalTrials.gov (NCT01720446). CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; FDA, Food and Drug Administration; MI, myocardial infarction; NYHA, New York Heart Association; OAD, oral antidiabetic drug.1. FDA. Guidance for Industry: Diabetes Mellitus Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 2008. Available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. Accessed January 2018; 2. Marso SP et al. N Engl J Med 2016;375:1834–44.

Key endpoints2

• Primary: time to first occurrence of death from CV causes, non-fatal MI or non-fatal stroke

• Secondary: time to first occurrence of each component of the primary endpoint, revascularisation, unstable angina requiring hospitalisation, hospitalisation for heart failure or all-cause death

Key inclusion criteria2

• HbA1c ≥7.0%• Previously on 0–2 OADs, basal or pre-mix insulin ± 0–2 OADs• ≥50 years of age with established CVD (prior CV, cerebrovascular or

peripheral vascular disease, chronic heart failure [NYHA Class II–III]), or CKD Stage 3 or worse

• ≥60 years of age with at least one CV risk factor

Semaglutide 1.0 mg

Semaglutide 0.5 mg

Placebo 1.0 mg

Treatment duration 104 weeks

Dose escalation*

4–8 weeks

Placebo 0.5 mg

Follow-up5 weeks

Randomisation(1:1:1:1)

Treatment maintenance 96–100 weeks

N=3,297

“…a new antidiabetic therapy to treat type 2 diabetes is not

associated with an unacceptable increase in cardiovascular risk”

US FDA guidance on assessing CV risk of new therapies1

SUSTAIN 1–7Baseline characteristics

Exenatide ER, exenatide extended release; Iglar, insulin glargine.1. Sorli C et al. Lancet Diabetes Endocrinol 2017;5:251–60; 2. Ahrén B et al. Lancet Diabetes Endocrinol 2017;5:341–54; 3. Ahmann AJ et al. Diabetes Care 2018;41:258–66; 4. Pratley RE et al. Lancet Diabetes Endocrinol 2018;6:275–86; 5. Aroda VR et al. Lancet Diabetes Endocrinol 2017;5:355–66; 6. Rodbard HW et al. J Clin Endocrinol Metab 2018;103:2291–301; 7. Novo Nordisk. Data on file; 8. Marso SP et al. N EnglJ Med 2016;375:1834–44.

Subjects in SUSTAIN 6 were older with longer diabetes duration and higher HbA1c

MonotherapySUSTAIN 11,7

Vs sitagliptinSUSTAIN 22,7

Vs exenatide ER

SUSTAIN 33

Vs dulaglutideSUSTAIN 74,7

Vs IGlarSUSTAIN 45

Add-on to basal insulin

SUSTAIN 56

Mean Mean Mean Mean Mean Mean

Age, years 53.7 55.1 56.6 56.0 56.5 58.8

HbA1c, % 8.1 8.1 8.3 8.2 8.2 8.4

Diabetes duration, years 4.2 6.6 9.2 7.4 8.6 13.3

Body weight, kg 91.9 89.5 95.8 95.2 93.5 91.7

BMI, kg/m2 32.9 32.5 33.8 33.5 33.0 32.2

Add-on to SOC

SUSTAIN 68

Mean

64.6

8.7

13.9

92.1

32.8

SUSTAIN 6Primary outcome

Kaplan─Meier plot for first event adjudication committee-confirmed CV death, non-fatal MI and non-fatal stroke using ‘in-trial’ data from subjects in the full analysis set. *Not prespecified. CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction. Marso SP et al. N Engl J Med 2016;375:1834–44;.

0

5

10

15

0 8 16 24 32 40 48 56 64 72 80 88 96 104Time since randomisation (weeks)No. at risk

Semaglutide 1,648 1,619 1,601 1,584 1,568 1,543 1,524 1,513

Placebo 1,649 1,616 1,586 1,567 1,534 1,508 1,479 1,466

HR: 0.74 [95% CI: 0.58;0.95]Events: 108 semaglutide; 146 placebop<0.001 for non-inferiorityp=0.02 for superiority*

Semaglutide, 6.6%

Placebo, 8.9%

109

Sub

ject

s w

ith

an e

vent

(%

)

First occurrence of CV death, non-fatal MI or non-fatal stroke

No. of patients with an event/Total no. of subjects (%)

HR [95% CI] Interactionp value

SUSTAIN 6 Semaglutide Placebo

Prespecified analysis: primary endpoint 108/1,648 (6.6) 146/1,649 (8.9) 0.74 [0.58;0.95] N/A

Post hoc analysis:Established CV disease** 97/1,262 (7.7) 124/1,271 (9.8) 0.78 [0.60;1.01]

0.2219*CV risk factors 11/386 (2.8) 22/378 (5.8) 0.48 [0.23;0.99]

Post hoc analysis:Prior MI/stroke 66/673 (9.8) 88/694 (12.7) 0.76 [0.55;1.05]

0.7541*No prior MI/stroke 42/975 (4.3) 58/955 (6.1) 0.70 [0.47;1.04]

SUSTAIN phase 3a trials Semaglutide Comparators

Post hoc meta-analysis‡ 13/3,150 (0.4) 8/1,657 (0.5) 0.85 [0.35;2.06] 0.7258†

0,2 2,0

HR

Risk of MACE across CV risk subgroups in SUSTAIN 6(Leiter LA et al. 2019)

*Subgroup interaction p value for MACE by prior MI/stroke or CV risk factors/established CV disease. ** Established CV disease in the subgroup was defined differently (Prior stroke, ischaemic heart disease (including MI), peripheral arterial disease, ≥50% arterial stenosis (any artery), coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft) or heart failure) vs the primary SUSTAIN 6 publication in order to exclude chronic kidney disease from this group. People were included in the CV risk factors subgroup if they did not have any manifestations.of CV diseaseCI, confidence interval; CV, cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular event; MI, myocardial infarction; N/A, not applicable.Leiter LA et al. Cardiovasc Diabetol. 2019 Jun 6;18(1):73. doi: 10.1186/s12933-019-0871-8

Favours placebo/comparatorsFavours semaglutide

1.0

Individual and expanded composite outcomesSUSTAIN 6

Kaplan–Meier plot for first event adjudication committee-confirmed CV death, non-fatal MI and non-fatal stroke using ‘in-trial’ data from subjects in the full analysis set. Expanded composite CV outcome was first occurrence of CV death, non-fatal MI, non-fatal stroke, revascularisation, unstable angina requiring hospitalisation or hospitalisation for heart failure.CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction. Marso SP et al. N Engl J Med 2016;375:1834–44; Novo Nordisk, data on file..

0

1

2

3

4

5

0 8 16 24 32 40 48 56 64 72 80 88 96 104Time since randomisation (weeks)

CV deathHR: 0.98 [95% CI: 0.65;1.48]Events: 44 semaglutide; 46 placebop=0.92

Placebo, 2.8%Semaglutide, 2.7%

0

1

2

3

4

5

0 8 16 24 32 40 48 56 64 72 80 88 96 104Time since randomisation (weeks)

109 109

Placebo, 3.9%Semaglutide, 2.9%

0

1

2

3

4

5

0 8 16 24 32 40 48 56 64 72 80 88 96 104Time since randomisation (weeks)

Sub

ject

s w

ith a

n ev

ent

(%)

Placebo, 2.7%Semaglutide, 1.6%

109

Non-fatal strokeHR: 0.61 [95% CI: 0.38;0.99]Events: 27 semaglutide; 44 placebop=0.04

No. at risk

Semaglutide 1,648 1,634 1,627 1,617 1,607 1,589 1,579 1,572

Placebo 1,649 1,637 1,623 1,617 1,600 1,584 1,566 1,558

0

5

10

15

20

0 8 16 24 32 40 48 56 64 72 80 88 96 104Time since randomisation (weeks)

Expanded composite CV outcomeHR: 0.74 [95% CI: 0.62;0.89]Events: 199 semaglutide; 264 placebop=0.002

Sub

ject

s w

ith a

n ev

ent

(%)

109

Semaglutide, 12.1%Placebo, 16.0%

Sub

ject

s w

ith a

n ev

ent

(%)

Sub

ject

s w

ith a

n ev

ent

(%)

Non-fatal MIHR: 0.74 [95% CI: 0.51;1.08]Events: 47 semaglutide; 64 placebop=0.12

No. at risk

Semaglutide 1,648 1,623 1,609 1,595 1,582 1,560 1,543 1,535

Placebo 1.649 1,624 1,598 1,587 1,562 1,542 1,516 1,502

No. at risk

Semaglutide 1,648 1,630 1,619 1,606 1,593 1,572 1,558 1,558

Placebo 1,649 1,629 1,611 1,597 1,571 1,548 1,528 1,521

No. at risk

Semaglutide 1,648 1,599 1,560 1,535 1,510 1,477 1,446 1,427

Placebo 1,649 1,595 1,550 1,515 1,466 1,420 1,373 1,352

CVOTs with GLP-1RAs have varying results

p-values for superiority/noninferiority are for the primary endpoint.CI, confidence interval; CV, cardiovascular; CVOT, cardiovascular outcomes trial; GLP-1RA, glucagon-like peptide-1 receptor agonist; HR, hazard ratio; MACE, major adverse cardiovascular event; MI, myocardial infarction. 1. Holman RR et al. N Engl J Med 2017;377:1228–39; 2. Pfeffer MA et al. N Engl J Med 2015;373:2247–57; 3. Husain M et al. N Engl J Med 2019. doi 10.1056/NEJMoa1901118 [Epub ahead of print]; 4. Marso SP et al. N Engl J Med 2016;375:311–22; 5. Marso SP et al. N Engl J Med 2016;375:1834–44; 6. Gerstein HC et al. Lancet 2019 doi 10.1016/S0140-6736(19)31149-3 [Epub ahead of print].

MACE

CV death

Non-fatal stroke

Non-fatal MI

0,3 HR [95% CI] 2.0

SUSTAIN 65 Favours semaglutide Favours placebo

p=0.02 for superiorityp<0.001 for noninferiority

MACE

CV death

Non-fatal stroke

Non-fatal MI

0,3 HR [95% CI] 2.0

LEADER4 Favours liraglutide Favours placebo

p=0.01 for superiorityp<0.001 fornoninferiority

MACE

CV death

Non-fatal stroke

Non-fatal MI

0,3 HR [95% CI] 2.0

REWIND6 Favours dulaglutide Favours placebo

p=0.026 for superiority

MACE

Unstable angina

CV death

Fatal and non-fatal stroke

Fatal and non-fatal MI

0,3

ELIXA2

HR [95% CI] 2.0

Favours lixisenatide Favours placebo

p=0.81 for superiorityp<0.001 for noninferiority

MACE

CV death

Non-fatal stroke

Non-fatal MI

0,3 HR [95% CI] 2.0

EXSCEL1 Favours exenatide Favours placebo

p=0.06 for superiorityp<0.001 for noninferiority

MACE

CV death

Non-fatal stroke

Non-fatal MI

0,3 HR [95% CI] 2.0

PIONEER 63 Favours oral semaglutide Favours placebo

p=0.17 for superiorityp<0.001 for noninferiority

Potential mode of action for GLP-1 to impact cardiovascular disease

GLP-1, glucagon-like peptide-1; GLP-1R, glucagon-like peptide-1 receptor; LV, left ventricularDrucker DJ. Cell Metab 2016;24:15–30

↑ Cardioprotection

Heart

↓ Coagulation

Platelets

↑ Natriuresis

↑ Diuresis

Kidney

↓ Inflammation

Fat & other

tissues

↓ Blood pressure

Blood vessel

↓ Body weight

Brain

Intestine↓ Postprandial lipids

↓ Glucagon secretion

↑ Insulin secretion

↑ Insulin biosynthesis

↓ Apoptosis

a-cell

b-cell

Pancreas

↓ Glucose ↓ HypoglycaemiaGLP-1

Ø Anti-atherosclerotic effects

Ø Anti-inflammatory effects

Ø Reduced platelet aggregation

SUSTAIN 6: nephropathy outcomes

Kaplan–Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy (A) or EAC-confirmed diabetic retinopathy complication (B) using ‘in-trial’ data from subjects in the full analysis set. HR is from a proportional hazard model. CI, confidence interval; Cr, creatinine; CrCl, creatinine clearance; EAC, (external) event adjudication committee; HR, hazard ratio; MDRD, modification of diet in renal disease. Marso SP et al. N Engl J Med 2016;375:1834–44.

Nephropathy outcomes

Semaglutide Placebo

HR(95% CI)

P valueN

(%)Incidence rate per 100 PYR

N(%)

Incidence rate per100 PYR

New or worsening nephropathy 62

(3.8) 1.86 100 (6.1) 3.06 0.64

(0.46; 0.88) 0.005

Persistent macroalbuminuria 44

(2.7) 1.31 81 (4.9) 2.47 0.54

(0.37; 0.77) 0.001

Persistent doubling of serum Cr level and CrCl per MDRD <45 ml/min/1.73 m2

18 (1.1) 0.53 14

(0.8) 0.41 1.28(0.64; 2.58) 0.48

Need for continuous renal-replacement therapy 11

(0.7) 0.32 12 (0.7) 0.35 0.91

(0.40; 2.07) 0.83

0

2

4

6

8

0 8 16 24 32 40 48 56 64 72 80 88 96 104

Sub

ject

s w

ith

an e

vent

(%

)

Weeks since randomisation

Semaglutide,3.8%

HR: 0.64 [95% CI: 0.46;0.88]Events: 62 semaglutide; 100 placebop=0.005

109

Placebo,6.1%

No. at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

New or worsening nephropathy

SUSTAIN 6: diabetic retinopathy complications

*Defined as Snellen visual acuity of 20/200 (6/60) or less, or visual field of less than 20 degrees, in the better eye with best correction possible. CI, confidence interval; E, number of events. HR, hazard ratio. Four subjects had unknown history of diabetic retinopathy at baseline.Vilsbøll T et al. Diabetes Obes Metab 2018;20:889–97.

0

2

4

6

8

0 8 16 24 32 40 48 56 64 72 80 88 96 104

Sub

ject

s w

ith

an e

vent

(%

)

Weeks since randomisation

Diabetic retinopathy complications

HR: 1.76 (95% CI: 1.11;2.78)Events: 50 semaglutide; 29 placebop=0.02

Placebo,1.8%

Semaglutide,3.0%

109

No. at riskSemaglutide 1,648 1,622 1,612 1,595 1,570 1,548 1,535 1,648

Placebo 1,649 1,617 1,605 1,545 1,576 1,558 1,539 1,649

Diabetic retinopathy outcomes

Semaglutide Placebo

HR(95% CI)

P valueN

(%)Incidence rate per 100 PYR

N(%)

Incidence rate per100 PYR

Diabetic retinopathy complications

50(3.0) 1.49 29

(1.8) 0.86 1.76(1.11;2.78) 0.02

Need for retinal photocoagulation

38(2.3) 1.13 20

(1.2) 0.59 1.91(1.11;3.28) 0.02

Need for treatment with intravitreal agents

16(1.0) 0.47 13

(0.8) 0.38 1.23(0.59;2.56) 0.58

Vitreous haemorrhage 16(1.0) 0.47 7

(0.4) 0.21 2.29(0.94;5.57) 0.07

Onset of diabetes-related blindness*

5(0.3) 0.15 1

(0.1) 0.03 5.01(0.59;42.88) 0.14

COMPARED WITH THE OVERALL TRIAL POPULATION

SUSTAIN 6: subjects with events of diabetic retinopathy complications

Data from full analysis set. EAC, (external) event adjudication committee.Vilsbøll T et al. Diabetes Obes Metab 2018;20:889–97.

Diabetes duration (years) 13.9 17.5HbA1c (%) 8.7 9.4Treated with insulin at baseline (%) 58.0 75.9

Overall populationN=3,297

EAC-confirmedeventsN=79

Medical history of diabetic retinopathy (%) 29.4 83.5Medical history of proliferative retinopathy (%) 6.1 29.1Medical history of proliferative retinopathy and treatment with laser therapy or intravitreal agents (%)

3.4 17.7

More progressed

diabetes

More had a medical

history of diabetic

retinopathy

NEW Ozempic® reimbursement conditionsREVISED CRITERIA AS OF 1-JULY-2019

www.riziv.be accessed July 2019