Clinical trials in T2DM & CVD: Review of key outcomes with GLP-1 … · 2019. 4. 23. · Clinical trials in T2DM & CVD. Review of key outcomes with GLP-1 RA and SGLT2i Eduard Montanya,

Clinical trials in T2DM & CVD: Review of

key outcomes with GLP-1 RA and SGLT2i

Eduard Montanya, MDBarcelona, Spain

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

implications

Cardio Diabetes Master ClassFebruary 22-23, 2019 - Barcelona, Spain

Clinical trials in T2DM & CVD.Review of key outcomes with GLP-1 RA and SGLT2i

Eduard Montanya, MD, PhDHospital Universitari Bellvitge

IDIBELL

CIBERDEM

University of Barcelona

Shifting gears in the management of diabetes and CVD 22-23 February 2019, Barcelona

• 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

CVOTs in Diabetes: CV risk with new therapies

FDA, U.S. Food and Drug AdministrationFDA, 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

Contemporary CVOTs in diabetes

ClinicalTrials.gov. Accessed 08 October 2018

20192015 20202013 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 yrsQ3 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 yrsCompletion Q3 2019

GLP-1RA

ELIXA(Lixisenatide, GLP-1RA)

n=6068; follow-up ~2 yrsQ1 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 yrsQ2 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 yrsQ2 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 yrsQ3 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 yrsQ4 2014 – RESULTS

CARMELINA(Linagliptin, DPP-4i)

n=7003; duration ~4 yrs Q3 2018 – RESULTS

ALECARDIO(Aleglitazar, PPAR-αγ) n=7226;

follow-up 2 yrsTermin. 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 yrsCompletion Q2 2021

SOLOIST-WHF (Sotagliflozin , SGLT-1i & SGLT-2i)

n=4000; duration ~2.7 yrsCompletion Q1 2021

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


20192015 20202013 2014 2016 2017 2018 2021

SGLT-2i




Q2 2017 – RESULTS


n=17,276; duration ~6 yrsQ3 2018 - RESULTS


Q2 2017 – RESULTS



(+ve efficacy)



GLP-1RA




Q3 2018 TOPLINERESULTS




Q3 2017 – RESULTS




Q3 2018 - RESULTS


Q4 2018 COMPLETED

2022




Q3 2016 – RESULTS





SGLT2i CVOTs

CVOTs in diabetes: SGLT-2i

20192015 20202013 2014 2016 2017 2018 2021

SGLT-2i




Q2 2017 – RESULTS


n=17,276; duration ~6 yrsQ342018 - RESULTS


Q2 2017 – RESULTS



(+ve efficacy)



2022







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 Placebo0.0

–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

Ch

an

ge i

n H

bA

1c

fro

m

baselin

e (

%)

StudyDapagliflozin (Dapa)1

52-week dataCanagliflozin (Cana)2

52-week dataEmpagliflozin (Empa)3

24-week data

Study armDapa

(5 mg)n=137

Dapa10 mgn=135

Placebo

n=137

Cana100 mgn=368

Cana300 mgn=367

Sita100 mgn=366

Empa10 mgn=217

Empa25 mgn=213

Placebo

n=207

Baseline HbA1c (%) 8.2 7.9 8.1 7.9 7.9 7.9 7.9 7.9 7.9

Comparison of SGLT-2 inhibitors: Body weight

These are not head-to-head trials SGLT-2, sodium–glucose cotransporter-2; sita, sitagliptin1. 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 Placebo0.0

–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

Ch

an

ge i

n b

od

y w

eig

ht

fro

m b

aselin

e (

kg

)Study

Dapagliflozin (Dapa)1

52-week dataCanagliflozin (Cana)2

52-week dataEmpagliflozin (Empa)3

24-week data

Study armDapa

(5 mg)n=137

Dapa10 mgn=135

Placebo

n=137

Cana100 mgn=368

Cana300 mgn=367

Sita100 mgn=366

Empa10 mgn=217

Empa25 mgn=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

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 combinedASCVD, 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

66

4034

60

100

80

60

40

20

0

EMPA-REG DECLARE

%

CANVAS

CVD non-CVD

CVD 7,020 pt’sCVD 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

SGLT2i CVOTs: primary outcomes

CI, confidence interval; CVOT, cardiovascular outcomes trial; HR, hazard ratio; MACE, major adverse cardiovascular event; SGLT2, sodium-glucose co-transporter 21. 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

0

0 180 360 540 720 900 1080 1260 1440

HR: 0.9395% CI: 0.84; 1.03p=0.17 for superiority

Time from randomisation (days)

Cum

ula

tive incid

ence (

%)

DECLARE-TIMI 583

0 6 12 18 3024 4236 48

20

10

5

0

15

Time from randomisation (months)

Patients

with a

n e

vent

(%)


EMPA-REG1

Empagliflozin

Placebo

Time from randomisation (weeks)

0 52 260 312104 156 20826

78

130

182 234 286338

20

15

10

5

0


CANVAS2

Canagliflozin

Placebo

Dapagliflozin

Placebo

0,25 0,5 1 2

p-value

Primary endpoint

p=0.04 for

superiority

CV death <0.001

Non-fatalMI†

0.22

Non-fatalstroke

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

0

10

5

15

0 4830 426 18 24 3612

Pooled Empagliflozin

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

Par

tici

pan

ts w

ith

an

ev

ent

(%)

Heart failure

As compared with placebo, empagliflozin resulted in a significantly lower

risk of hospitalisation for heart failureHR: 0.65

[0.50; 0.85]95% CI, p=0.002

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

0

10

5

15

0 641 3 52

Canagliflozin

Placebo HR: 0.86 [0.75; 0.97]95% CI,p<0.0001 for non-inferiority,p=0.0158 for superiority

Par

tici

pan

ts w

ith

an

eve

nt

(%)

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

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

• 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 patientswith stablished ACVD (secondary prevention).

• SGLT2i have not shown reduction in MACE or CV death in patients with nostablished ACVD (primary prevention)

• SGLT2i prevent hospitalization for heart failure, both in patients with andwithout established ACVD

SGLT2i have shown a more robust and consistent effect on prevention ofheart failure (and renal outcomes) than on atherosclerotic cardiovascularevents

GLP-1RA CVOTs

CVOTs in diabetes: GLP1-RA


20192015 20202013 2014 2016 2017 2018 2021

GLP-1RA




Q4 2018 TOPLINE RESULTS




Q3 2017 – RESULTS




Q3 2018 - RESULTS


Q4 2018 COMPLETED

2022


Q3 2016 – RESULTS



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 1000

Native human GLP-1His Ala Thr Thr SerPheGlu Gly

Asp

Val

Ser

SerTyrLeuGluGlyAlaAla GlnLys

Phe

Glu

Ile Ala Trp Leu GlyVal Gly ArgLys

Time (days)

Once daily†3

Once weekly4

Once daily*2

Long-acting and short-acting GLP-1RAs

*Exendin-based; †GLP-1-basedGLP-1RA, glucagon-like peptide-1 receptor agonist1. 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

Pla

sm

a G

LP-1

RA

4 5310 2 6 7 8

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 1000

Dulaglutide2

(59.7 kDa)

Semaglutide2

(4.1 kDa)

Liraglutide1

(3.8 kDa)

Exenatide2

(4.2 kDa)

Lixisenatide2

(4.9 kDa)

His Ala Thr Thr SerPheGlu GlyAsp

Val

Ser


Phe

Glu

Ile Ala Trp Leu GlyVal Gly Arg

Glu

Arg

C-16

Asp

His Gly Thr Thr SerPheGlu GlyAsp

Leu

Ser

LysGlnMetGluGluAlaVal GluArg

Phe

Leu

Ile Glu Trp Leu ProLys Gly Gly

Ser

Ser

Gly

GlyAlaProProSer

Asp


Leu

Ser


Phe

Leu

Ile Glu Trp Leu ProLys Gly Gly

Ser

Ser

Gly

GlyAlaProProLysLys

Lys

Lys

LysLys Lys

His Aib Thr Thr SerPheGlu GlyAsp

Val

Ser


Phe

Glu

Ile Ala Trp Leu GlyVal Gly ArgArg

Spacer

C-18 fatty di-acid

His Gly Thr Thr SerPheGlu Gly Asp Val

Ser

SerTyrLeuGluGluAlaAla GlnLys

Phe

Glu

Ile Ala Trp Leu GlyVal Gly GlyLys

Phe Ile Ala Trp Leu GlyVal Gly GlyLys

Glu


Ser

His Gly Thr Thr SerPheGlu Gly Asp Val

IgG

Albiglutide2

(73.0 kDa)Lys


Val

Ser


Phe

Glu

Ile Ala Trp Leu Val Gly Arg His

Lys

Gly Thr Thr SerPheGlu GlyAsp

Val

Ser


Phe

Glu

Ile Ala Trp Leu Val Gly Arg

rH-albumin

Dulaglutide5

90% amino-acid homology to human GLP-1

His Gly Thr ThrSerPheGluGly AspValSer


Phe

Glu

Ile Ala TrpLeu GlyVal Gly GlyLys

Linker peptide

Modified IgG4 Fc domain

Phe Ile Ala TrpLeu GlyVal Gly GlyLysGlu

SerTyrLeuGluGluAlaAla GlnLysSer

His Gly Thr ThrSerPheGluGly AspVal


Liraglutide4

His Ala Thr Thr SerPheGlu Gly AspVal

Ser


Phe

Glu

Ile Ala Trp Leu GlyVal GlyArg

Glu

Arg

C-16 Fatty acid

Exenatide1

HisGly Thr ThrSerPheGluGly AspLeu

Ser


Phe

Leu

Ile GluTrpLeu ProLys GlyGlyAsp SerSerGlyAlaProProProSer

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

Lixisenatide6–8

HisGly Thr ThrSerPheGluGly AspLeu

Ser


IleGluTrpLeu ProLys GlyGlyAsp SerSerGlyAlaProProProSerLysLys

LysLysLysLys

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


C-18 Fatty di-acid chain

spacer

His Aib Thr ThrSerPheGluGly AspVal

SerSer

TyrLeuGluGlyAlaAla GlnLys

Phe

Glu

Ile Ala TrpLeu GlyVal GlyArgArg

Exenatide1–3


Albiglutide10

Lys

HisGly Thr ThrSerPheGluGly AspVal

Ser


Phe

Glu

IleAlaTrpLeuVal GlyArgHis

Lys

Gly Thr ThrSerPheGluGly AspVal

Ser


Phe

Glu

IleAlaTrpLeuVal GlyArg ALBUMIN

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

Dosage1.5 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

Diabetesduration, 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

p-value

Primary endpointp<.001 for

non-inferiority

CV Death 0.85

MI 0.71

Stroke 0.54

Hospitalisationfor unstable angina

0.75

Lixisenatide: ELIXA results

The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, or hospitalisation for unstable angina1. Pfeffer et al. N Engl J Med 2015;373:2247–57.

0,25 0,5 1 2

Favours placebo →← Favours lixisenatide0

0 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

Part

icip

ants

with a

n

event

(%)

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

Pati

en

ts w

ith

an

even

t (%

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

0

0 1 2 3 4 5

12

0 0,5 1 1,5 2

p-value

Primary endpointp<.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

LEADER1

0

5

10

15

20

0 8 16 24 32 40 48 56 64 72 80 88 96 1040 10 20 30 40 500

5

10

15

20 HR: 0.8795% CI: 0.78; 0.97p<0.001 for non-inferiorityp=0.01 for superiority

Placebo

Liraglutide


Patients

with a

n e

vent

(%) SUSTAIN 62

HR: 0.7495% CI: 0.58; 0.95p<0.001 for non-inferiorityp=0.02 for superiority*

Placebo

Semaglutide

Patients

with a

n e

vent

(%)

Time from randomisation (weeks)

HR: 0.7895% CI: 0.68;0.90p<0.0001 for non-inferiorityp=0.0006 for superiority

0

15

20

5

10

Placebo

Albiglutide


Patients

with a

n e

vent

(%)

0 4 16 20 288 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; lixisenatideand exenatide ER demonstrated CV

safety

Dulaglutide: REWIND

Press Release Results Nov 5

2018

REWIND1

(N=9901)

Dulaglutide

Dosage1.5 mg/week

Mean age, years 66

Gender, % female

46

Diabetesduration, 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,

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

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 superiorityp<0.001 for non-inferiority

MACE

CV death

Non-fatal stroke

Non-fatal MI

SUSTAIN 62


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


Favours albiglutide Favours placebo

p=0.81 for superiorityp<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 infarction1. 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

• GLP-1RAs have different PK/PD and molecular structures, with differentefficacy on glucose control and body weight

• GLP-1RAs inhibitors have shown CV safety

• GLP-1RAs liraglutide, semaglutide, albiglutide, and dulaglutide haveshown CV benefit with MACE reduction in patients with ACVD (secondaryprevention)

• Results suggest that GLP-1RA may have also CV benefit in patients withmultiple risk factors (primary prevention).

GLP-1RA with proven CV efficacy have a more robust and consistent effecton prevention of atherosclerotic events, with more modest effects on renaloutcomes, and safety on heart failure.

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

https://doi.org/10.1007/s00125-018-4729-5

Documents

Clinical trials in T2DM & CVD: Review of key outcomes with GLP-1 … · 2019. 4. 23. · Clinical trials in T2DM & CVD. Review of key outcomes with GLP-1 RA and SGLT2i Eduard Montanya,