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
ClinicalTrials.gov. Accessed 08 October 2018
20192015 20202013 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 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 TOPLINERESULTS
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
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 yrsCompletion Q2 2021
SOLOIST-WHF (Sotagliflozin , SGLT-1i & SGLT-2i)
n=4000; duration ~2.7 yrsCompletion Q1 2021
SGLT2i CVOTs
CVOTs in diabetes: SGLT-2i
20192015 20202013 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 yrsQ342018 - 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
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 yrsCompletion Q2 2021
SOLOIST-WHF (Sotagliflozin , SGLT-1i & SGLT-2i)
n=4000; duration ~2.7 yrsCompletion Q1 2021
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
(%)
HR: 0.8695% CI: 0.74; 0.99p=0.04 for superiority
EMPA-REG1
Empagliflozin
Placebo
Time from randomisation (weeks)
0 52 260 312104 156 20826
78
130
182 234 286338
20
15
10
5
0
HR: 0.8695% CI: 0.75; 0.97p=0.02 for superiority
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
ClinicalTrials.gov. Accessed 08 October 2018
20192015 20202013 2014 2016 2017 2018 2021
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
Q4 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
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 yrsCompletion Q2 2021
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
SerTyrLeuGluGlyAlaAla GlnLys
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
His Gly Thr Thr SerPheGlu GlyAsp
Leu
Ser
LysGlnMetGluGluAlaVal GluArg
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
SerTyrLeuGluGlyAlaAla GlnLys
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
SerTyrLeuGluGluAlaAla GlnLys
Ser
His Gly Thr Thr SerPheGlu Gly Asp Val
IgG
Albiglutide2
(73.0 kDa)Lys
His Gly Thr Thr SerPheGlu GlyAsp
Val
Ser
SerTyrLeuGluGlyAlaAla GlnLys
Phe
Glu
Ile Ala Trp Leu Val Gly Arg His
Lys
Gly Thr Thr SerPheGlu GlyAsp
Val
Ser
SerTyrLeuGluGlyAlaAla GlnLys
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
SerTyrLeuGluGluAlaAla GlnLys
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
97% amino-acid homology to human GLP-1
Liraglutide4
His Ala Thr Thr SerPheGlu Gly AspVal
Ser
SerTyrLeuGluGlyAlaAla GlnLys
Phe
Glu
Ile Ala Trp Leu GlyVal GlyArg
Glu
Arg
C-16 Fatty acid
Exenatide1
HisGly Thr ThrSerPheGluGly AspLeu
Ser
LysGlnMetGluGluAlaVal GluArg
Phe
Leu
Ile GluTrpLeu ProLys GlyGlyAsp SerSerGlyAlaProProProSer
~ 50% amino-acid homology to human GLP-1
Lixisenatide6–8
HisGly Thr ThrSerPheGluGly AspLeu
Ser
LysGlnMetGluGluAlaVal GluArg
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
94% amino-acid homology to human GLP-1
C-18 Fatty di-acid chain
spacer
His Aib Thr ThrSerPheGluGly AspVal
SerSer
TyrLeuGluGlyAlaAla GlnLys
Phe
Glu
Ile Ala TrpLeu GlyVal GlyArgArg
Exenatide1–3
97% amino-acid homology to human GLP-1
Albiglutide10
Lys
HisGly Thr ThrSerPheGluGly AspVal
Ser
SerTyrLeuGluGlyAlaAla GlnLys
Phe
Glu
IleAlaTrpLeuVal GlyArgHis
Lys
Gly Thr ThrSerPheGluGly AspVal
Ser
SerTyrLeuGluGlyAlaAla GlnLys
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
Time from randomisation (months)
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
Time from randomisation (months)
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,
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
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 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