Post on 05-Oct-2020
Clinical trials in T2DM & CVD: Review of
key outcomes with GLP-1 RA and SGLT2i
Eduard Montanya, MDBarcelona, Spain
Cardio Diabetes Master ClassNovember 16 - 17, 2018 - Dubai, UAE
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, PhDHospital Universitari Bellvitge
IDIBELL
CIBERDEM
University of Barcelona
Shifting gears in the management of diabetes and CVD 15-16 November 2018, Dubai, UAE
Cardiovascular 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 COMPLETED
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
Completion Q4 2018
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 COMPLETED
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
Completion Q4 2018
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
SGLT-2i 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
Trial Event-driven Time-driven
Median duration of follow-up,
years
N
EMPA-REG ✓ 3.1 7,028
CANVAS ✓ 2.4 10,142
DECLARE ✓ 4.2 17.160
PatientsBaseline
Age, yearsDiabetes duration,
yearsBMI, kg/m2 HbA1c, %
CANVAS 63 14 32.0 8.2
EMPA-REG 63 NR 30.6 8.1
DECLARE 64 12 32.1 8.3
EMPA-REG, CANVAS and DECLARE population and design
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
CVD and Non-CVD proportion in CVOTs of SGLT-2i
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
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 COMPLETED
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
Completion Q4 2018
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 therapies 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 patientsExenatide 7356 7101 6893 6580 5912 4475 3595 3053 2281 1417 727Placebo 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
0,25 0,5 1 2
p-value
Primary endpoint 0.01 for superiority
CV Death 0.007
Non-fatal MI 0.11
Non-fatal stroke 0.30
Liraglutide: LEADER results
0 6 18 24 30 36 42 48 540
5
10
15
20
12
Months from randomisation
HR: 0.87 [0.78; 0.97]95% CI,p<0.001 for non-inferiority,p=0.01 for superiority
Pat
ien
ts w
ith
an
ev
ent
(%)
Favours placebo →← Favours liraglutide
Semaglutide: SUSTAIN-6 results
Marso et al. New Engl J Med 2016;375:1834–44.
Weeks from randomisation
Pat
ien
ts w
ith
an
eve
nt
(%)
0
5
10
15
20
0 8 16 24 32 40 48 56 64 72 80 88 96 104
HR: 0.74 [0.58; 0.95]95% CI,p<0.001 for non-inferiority,p=0.02 for superiority (not pre-specified)
Favours placebo →← Favours semaglutide
0,25 0,5 1 2
p-value
Primary endpoint
<0.001 (non-
inferiority)
CV Death 0.92
Non-fatal MI 0.12
Non-fatalStroke
0.04
Pati
en
ts w
ith
an
even
t (%
)
Albiglutide: HARMONY outcomes
HR: 0.78 (95% CI: 0.68; 0.90)Event rate per 100 person-years: albiglutide 4.57; placebo 5.87p<0.0001 for non-inferiorityp=0.0006 for superiority
Time to first occurrence of CV death, MI or stroke
Time from randomisation (months)
0 4 8 12 16 20 24
10
16
14
12
0
8
6
4
2
28
No. at risk
Albiglutide
Placebo
4731 4503 3148 1064
4732 4460 3074 1030
4613
4603
4239
4208
2142
2077
-
-
Hernandez AF et al. Lancet 2018; http://dx.doi.org/10.1016/S0140-6736(18)32261-X [Epub ahead of print]
HARMONY OUTCOMES
*CV death, myocardial infarction, stroke and urgent revascularisation for unstable angina; Hernandez AF et al. Lancet 2018; http://dx.doi.org/10.1016/S0140-6736(18)32261-X [Epub ahead of print]
Secondary endpoints and all-cause death
Albiglutide(N=4731)
Placebo(N=4732) Hazard ratio (95% CI)
p-value†
3-point MACE (primary outcome)
338 428 0.78 (0.68; 0.90)<0.0001, 0.0006
4-point MACE* 373 468 0.78 (0.69; 0.90) 0.0005
CV death 122 130 0.93 (0.73; 1.19) 0.578
Myocardial infarction 181 240 0.75 (0.61; 0.90) 0.003
Stroke 94 108 0.86 (0.66; 1.14) 0.300
CV death or hospitalisation for HF 188 218 0.85 (0.70; 1.04) 0.113
All-cause death 196 205 0.95 (0.79; 1.16) 0.644
Favours placeboFavours albiglutide
0,5 1.0 2.01.5
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, last accessed Nov 11, 2018
• SGLT2 inhibitors have shown CV safety
• Empagliflozin and canagliflozin have shown reduction in risk of MACE inpatients with ACVD (secondary prevention). SGLT-2i have not shownreduction in MACE in patients with multiple risk factors (primary riskfactors)
• CV death and death from any cause reduced by liraglutide
• SGLT-2i prevent hospitalization for heart failure, both in patients with andwithout established ACVD
SGLT-2i have a more robust and consistent effect on prevention of heartfailure (and renal outcomes) than on atherosclerotic cardiovascular events
• 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).
• CV death and death from any cause reduced by liraglutide
• 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.