Module D Evaluating CV safety and potential for CV risk reduction with newer T2D agents ACROSS T2D educational slide modules 2 3 Ongoing CVOTs DPP4 inhibitors GLP1 receptor agonists SGLT2 inhibitors ID: 809967
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Slide1
EDUCATIONAL SLIDE MODULES
Module D:
Evaluating CV safety and potential for CV risk reduction with newer T2D agents
Slide2ACROSS T2D educational slide modules
2
Slide33
Ongoing CVOTs
DPP4 inhibitors
GLP1 receptor agonists
SGLT2 inhibitors
Completed and ongoing CVOTs
Slide4A closer look at CV effects of 21st century
T2D agents
4
Adapted from 1. Kirby.
Br
J Diabetes
Vasc
Dis
2012;12:315–20
.
2. Lantus® SPC. FDA 2015.19501960
1970198019902000
2010
2012
2013
Lente class of insulins produced
SUs first used
Metformin introduced in the UK
Recombinant human insulin produced
2nd generation SUs available
Three new classes introduced:
-glucosidase inhibitors, meglitinides and TZDs
Glimepiride:
3rd generation SU
DPP4 inhibitors
GLP1 receptor agonists
SGLT2 inhibitors
Insulin
degludec
Older T2D agents
Newer T2D agents
Insulin glargine
available
2
Slide5CV safety trials are being conducted for each compound within the newer classes
5
Timings represent estimated completion dates as per ClinicalTrials.gov.
Adapted from Johansen. World J Diabetes
2015;6:1092–96. (references 1–19
expanded in slide notes
)
CANVAS-R
8
(n = 5700)
Albuminuria
2013
2014
20152016
2017
2018
2019
SAVOR-TIMI 53
1
(n = 16,492)
1,222 3P-MACE
EXAMINE
2
(n = 5380)
621 3P-MACE
TECOS
4
(n = 14,724)
≥ 1300 4P-MACE
LEADER
6
(n = 9340)
≥ 611 3P-MACE
SUSTAIN-6
7
(n = 3297)
3P-MACE
DECLARE-TIMI 58
15
(n = 17,150)
≥ 1390 3P-MACE
EMPA-REG OUTCOME®
5
(n = 7034)
≥
691 3P-MACE
CANVAS
10
(n = 4365)
≥ 420 3P-MACE
CREDENCE
17
(n = 3700)
Renal
+ 5P-MACE
CAROLINA
®
11
(n =
6000)
≥ 631 4P-MACE
ITCA CVOT
9
(n = 4000)
4P-MACE
EXSCEL
14
(n = 14,000)
≥ 1591 3P-MACE
DPP4 inhibitor CVOTs
SGLT2 inhibitor CVOTs
GLP1 CVOTs
Ertugliflozin
CVOT
18
(n = 3900)
3P-MACE
OMNEON
13
(n = 4000)
4P-MACE
CARMELINA
12
(n = 8300)
4P-MACE
+
renal
REWIND
16
(n = 9622)
≥ 1067 3P-MACE
2021
ELIXA
3
(n = 6068)
≥ 844 4P-MACE
HARMONY Outcomes
19
(n = 9400) 3P-MACE
Slide66
Slide7DPP4 inhibitors: Mechanism of action
Adapted
from
Drucker.
Expert
Opin
Invest
Drugs 2003;12:87–100
and
Ahrén Curr Diab Rep. 2003;3:365–372.
Food intake
Glucose-dependent insulin secretion
Increases glucose
utilisation
by muscle and adipose tissue
Decreases hepatic glucose release improving overall glucose control
Glucose-dependent glucagon suppression
β
-cells
α-cells
DPP4
Active
GLP1
(
7-36)
Inactive
GLP1
(9-36)
amide
2
amino acids
cleaved from
amino terminus
Pancreas
DPP4 inhibitors
Intestine
7
Slide8Selected mechanistic trials indicate potential CV effects of the DPP4 inhibitor class
8
1. Ye et al. Am J
Physiol
Heart
Circ
Physiol 2010;298:H1454–65. 2. Hocher
et al. Int J
Cardiol 2013;167:87–93. 3. van Poppel et al. Diabetes Care 2011;34:2072–77. 4. Kröller-Schön et al. Cardiovasc
Res 2012;96:140–9. 5. Ta et al. J Cardiovasc Pharmacol 2011;58:157–66. 6. Sauvé et al. Diabetes 2010;59:1063–73.
7. Read et al. Circ Cardiovasc Imaging 2010;3:195–201. 8. Matikainen et al. Diabetologia 2006;49:2049–57.
Endothelialfunction3
Atherosclerotic plaque volume5
Left
ventricular
function
6,7
Myocardial
infarct size
1,2
Triglycerides
8
Inflammation and
oxidative stress
4
Slide9*Ongoing.
1.
Scirica et al. N
Engl
J Med 2013;369:1317–26. 2. White et al. N
Engl
J Med 2013;369:1327–35. 3. Green et al. N Engl J Med 2015; DOI:
10.1056/NEJMoa1501352. 4. Marx et al. Diabetes Vasc Dis Res 2015;12:164–74. 5. NCT01897532. 6.
Scirica et al. Am Heart J 2011;162:818–25.e6. 7. Data on file (BI trial no. 1218.22 trial protocol). 8. NCT01243424.Summary of CV outcomes
trials with DPP4 inhibitors9
SAVOR-TIMI 531 EXAMINE2TECOS
3CAROLINA®4CARMELINA®5Intervention
Saxagliptin/ placeboAlogliptin/ placeboSitagliptin/ placeboLinagliptin/ glimepiride
Linagliptin/ placeboMain inclusion criteriaHistory of or multiple risk factors for CVDACS within 15–90 days before randomisationCVD≥ 2 specified traditional CV risk factors or manifest CVD
High risk of CV events (e.g. albuminuria,
prior CVD)
No. of patients
16,492
5380
14,671
6041
8300
Primary
outcome
3P-MACE
3P-MACE
4P-MACE
4P-MACE
4P-MACE
Key secondary outcome
Expanded MACE
4P-MACE
3P-MACE
3P-MACE
3P-MACE; renal composite
Target no.
of events
1040
6
650
1300
631
625
7
Median follow-up (y)
2.1
1.5
3.0
6–7*
4*
7
Estimated completion
Completed
Completed
Completed
2018
8
2018
Link to study design +
data
Link to study design +
data
Link to study design +
data
Link to study design + baseline data
Link to study design + baseline data
Slide10DPP4 inhibitor CVOTs: baseline characteristics
10
Data are provided for the DPP4 inhibitor treatment arm. Mean values show unless otherwise indicated.
– indicates that the data are not reported.
*Median.
1.
Scirica
et al. N
Engl J Med 2013;369:1317–26. 2. White et al. N Engl J Med 2013;369:1327–35. 3. Green et al. N Engl J Med 2015;
DOI: 10.1056/NEJMoa1501352. 4. Marx et al. Diabetes Vasc Dis Res 2015;12:164–74. 5. NCT01897532.
SAVOR-TIMI 531 EXAMINE2TECOS
3CAROLINA®4CARMELINA®5
Mean age, years65.161.0*65.464.0
–% with prior MI38.087.542.7
13.8
–
% with prior HF
12.8
27.8
17.8
–
–
% with prior CVD
78.4
–
73.6
34.5
Diabetes
duration
, y
10.3*
7.3*
11.6
6.2*
–
HbA
1c
,%
8.0
8.0
7.2
7.2
–
Statin use, %
78.3
90.6
79.8
64.1
–
T2D therapy,
%
Naive
Metformin
SU
TZD
Insulin
4.1
69.9
40.5
6.2
41.6
Naive
Metformin
SU
TZD
Insulin
1.1
65.0
46.9
2.5
29.4
Naive
Mono
Dual
TZD
Insulin
–
47.7
51.4
–
23.5
Naive
Mono
Dual
TZD
Insulin
9.2
66.0
23.8
–
Ex.–
Slide11Summary of completed DPP4 inhibitor CVOTS
11
*Upper boundary of 1-sided repeated CI.
1.
Scirica
et al
. N Engl J Med 2013;369:1317–26.
2. White et al. N Engl
J Med 2013;369:1327–35. 3. Green et al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352.
SAVOR-TIMI 53
1 Primary endpoint Hazard ratioCVD or CRFsHbA1c 6.5–12.0%n = 16,492Saxagliptin
Placebo3P-MACE
1.00(95% CI 0.89–1.12)p = 0.99(superiority)
2.1 year median follow-upEXAMINE2
ACS
HbA
1c
6.5–11.0%
n = 5380
Alogliptin
Placebo
3P-MACE
0.96
(upper CI
*
1.16)
p = 0.32
(superiority
)
1.5 year median follow-up
Randomisation
1
2
3 years of median follow-up
TECOS
3
CVD
HbA
1c
6.5–8.0%
n = 14,735
Sitagliptin
Placebo
4P-MACE
0.98
(95%
CI 0.89–1.08)
p = 0.65
(superiority)
3.0 year median follow-up
Slide1212
Slide13GLP1 has various potential effects on the CV system:
Data derived from non-clinical and mechanistic proof-of-concept studies
13
1. Jax. Clin Res Cardiol
2009;98:75–9. 2. Grieve. Br J Pharmacol 2009;157:1340–51 (modified).
3. Robinson et al. BMJ Open 2013;3:pii e001986.
↑
Insulin sensitivity (direct or indirect?)
↑
Insulin secretion
↓ Glucagon secretion↑ Insulin biosynthesis↑
β-cell proliferation↓ β -cell apoptosis↓ Appetite
↑ Neuroprotection
↓ Glucose output
Brain
Pancreas
Liver
Muscle
and
adipose tissue
↑ Endothelial function
↑ Nitric oxide production
↑ ↓ Myocardial
contractility (data conflict)
↑ Systolic function in myocardial infarction
↑ Systolic function in cardiomyopathy
↓ Infarct
size
↑
Ischaemic pre-conditioning
↑
Post-ischaemic
recovery
↑ Myocardial glucose uptake
Heart
Incretin hormone
1,2
Clinical trial data show that GLP1 receptor agonists are associated
with
small increases
in heart rate and modest reductions in body weight and blood
pressure
3
Slide14Summary of CV outcomes trials with GLP1 receptor agonists
14
*Once weekly.
1. NCT01147250. 2.
Bentley-Lewis
et al. Am Heart J
2015;0:1-8.e7. 3. Marso
et al. Am Heart J 2013;166:823–30.e5. 4. NCT01720446. 5. NCT01144338. 6. NCT01394952. 7.
NCT02465515
Intervention
Main inclusion criteriaNo. of patientsPrimary outcomeKey 2° outcomeTarget no.of events
Estimated follow-upEstimated completionELIXA1,2Lixisenatide/ placeboHistory of
ACS60684P-MACEExpanded MACE8442.1 years median
CompletedLEADER®3Liraglutide/ placeboVascular disease, or risk factors, or CRF, or CHF9340
3P-MACE
Expanded MACE
> 611
Up to ~5 years
Nov-15
SUSTAIN-6
™4
Semaglutide/ placebo
Evidence of CV disease
3297
3P-MACE
Expanded MACE
Not specified
Up to ~3 years
Jan-16
EXSCEL
5
Exenatide ER*/ placebo
No CV criteria specified
14,000
3P-MACE
All-cause mortality; HHF
Not specified
Up to ~7.5 years
Apr-18
REWIND
6
Dulaglutide
/ placebo
Pre-existing vascular disease or
≥
2 CV risk factors
9622
3P-MACE
Microvascular composite
Not specified
Up to ~6.5 years
Apr-19
HARMONY OUTCOMES
7
Albiglutide/ placebo
Established CVD
9400
3P-MACE
Expanded MACE
Not specified
3–5
years
May-19
Link to study
+
baseline data
Link to study design + data
Slide15Summary of ELIXA findings
15
1
.
Pfeffer
et al. ADA, 8 Jun 2015, Boston,
USA (oral presentation).
Randomisation
1
2
3 years of median follow-up
ELIXA1ACSHbA1c 5.5–11%n = 6068Placebo
4P-MACE 1.02(95% CI 0.89–1.17)
No difference in 4P-MACE
with lixisenatide vs placebo
HR
1.02
(95%
CI 0.89–1.17)
No
difference in HHF with lixisenatide vs placebo
HR 0.96 (95
%
CI 0.75–1.23)
No
difference in
CV
death + HHF with lixisenatide vs
placebo
HR 0.97 (95
% CI 0.82–1.16)
2.1 year median follow-up
Lixisenatide
Slide16Summary of completed T2D CVOTS for newer T2D agents
16
*Upper boundary of 1-sided repeated CI.
1
.
Scirica
et al. N
Engl J Med 2013;369:1317–26. 2. White et al. N
Engl J Med 2013;369:1327–35. 3. Green et al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352. 4. Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).
SAVOR-TIMI 53
1 CVD or CRFsHbA1c 6.5–12.0%n = 16,492Saxagliptin
Placebo3P-MACE 1.00
(95% CI 0.89–1.12)p = 0.99
2.1 year median follow-upEXAMINE2
ACS
HbA
1c
6.5–11.0%
n = 5380
Alogliptin
Placebo
3P-MACE
0.96
(upper CI* 1.16)
p = 0.315
1.5 year median follow-up
Randomisation
1
2
3 years of median follow-up
TECOS
3
CVD
HbA
1c
6.5–8.0%
n = 14,735
Sitagliptin
Placebo
4P-MACE
0.98
(95%
CI
0.88–1.09
)
p = 0.645
(superiority)
3.0 year median follow-up
ELIXA
4
ACS
HbA
1c
5.5–11%
n = 6068
Placebo
4P-MACE
1.02
(95%
CI
0.89–1.17
)
2.1 year median follow-up
Primary endpoint
Hazard
ratio
Lixisenatide
Slide17For the primary outcome, all completed CVOTs fall within the FDA mandated upper 95% CI limit of 1.3
17
*Upper boundary of 1-sided repeated
CI.
†Total event rate, %.
1.
Scirica et al
. N Engl J Med 2013;369:1317–26. 2. White et al. N
Engl J Med 2013;369:1327–35. 3. Green et al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352. 4. Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).
1.0
2.00.80.6HR (95% CI)
1.3FDA mandated upper 95% CI for CV safety
Number of events(event rate, % per 100 person-years)Placebo+ usual care
Comparator + usual care DPP4 inhibitor trials SAVOR-TIMI 531
609 (3.7%)
613 (3.7%)
GLP1 agonist trials
ELIXA
4
406 (13.4
†
%)
399 (13.2
†
%)
EXAMINE
2
316 (11.8%
†
)
305 (11.3%
†
)
TECOS
3
851 (4.17%)
839 (4.06%)
Favours comparator
Favours placebo
*
Slide18Hospitalisation for heart failure (HHF) data for all completed CVOTs
18
Analysis 1 = as
component of
expanded MACE.
Analysis 2 =
as component of post-hoc composite
of
CV death and HHF.1. Scirica et al. N Engl
J Med 2013;369:1317–26. 2. White et al. N Engl J Med 2013;369:1327–35. 3. Green et al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352. 4. Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).
1.02.00.80.6
HR (95% CI)Number of events (%)
Placebo+ usual care Comparator + usual care
Favours comparatorFavours placebo
SAVOR-TIMI 53 (
HHF)
1
EXAMINE (HHF analysis 1)
2
EXAMINE (HHF analysis 2)
2
TECOS (HHF)
3
TECOS (HHF + CV death)
3
ELIXA (HHF)
4
ELIXA (HHF + CV
death)
4
228 (2.8)79 (2.9)
89 (3.3)229 (3.1)525 (7.2)
127 (4.2)253 (8.3)
289 (3.5)85 (3.1)106 (3.9)
228 (3.1)538 (7.3)122 (4.0)248 (8.2
)
Slide1919
Slide20Urinary glucose excretion via SGLT2 inhibition
1
20
1
.
Bakris
et al. Kidney Int 2009;75;1272–7.
SGLT2
SGLT2
inhibitor
SGLT1
SGLT2 inhibitors reduce glucose
reabsorption
in the proximal tubule, leading to
urinary glucose excretion
*
and osmotic diuresis
Filtered glucose load > 180 g/day
Slide21Pharmacological properties of available
SGLT2 inhibitors
21
*For the 300 mg dose.
Data from http://www.ema.europa.eu/ (
Jardiance
SPC, Forxiga SPC , Invokana
PI, Invokana
SPC, all accessed June 2015); 1. Sha et al. Diab Obes Metab 2015;17:188–97.
EmpagliflozinDapagliflozinCanagliflozinTherapeutic dose (mg/day)Starting dose
10–25105–1010100–300100
AdministrationQDWith or without foodQDWith or without food
QDBefore first meal Peak plasma concentration (hours post-dose)1.5
Within 2
1–2
Absorption
(mean oral bioavailability)
≥ 60%
~ 78%
~ 65%
Metabolism
Primarily
g
lucuronidation - no active metabolite
Elimination
(half-life, hours)
Hepatic:renal
43:57
[12.4]
Hepatic:renal
22:78
[12.9]
Hepatic:renal 67:33
[13.1]*
Selectivity over SGLT1
1:5000
> 1:1400
>
1:160
1
Glucose
excretion
with
higher dose
(g/day)
78
~ 70
119
Link to SGLT2 clinical data
Slide22 SNS
activity (?)
SGLT2 inhibitors modulate a range of factors
related to CV
risk
Based on clinical and mechanistic studies
22
Inzucchi
et al.
Diab
Vasc Dis Res 2015;12:90‒100.
Weight Visceral adiposity
Blood pressure Arterial stiffness
Glucose Insulin
Albuminuria
Uric Acid
Novel
Pathways (?)
LDL-C
HDL-C
Triglycerides
Oxidative
stress
SNS
activity (?)
Link to SGLT2 clinical data
Slide23EMPA-REG OUTCOME
®
1
CANVAS
2
CANVAS-R
3
CREDENCE
4
DECLARE-
TIMI 585Ertugliflozin CVOT6InterventionsEmpagliflozin/ placeboCanagliflozin/
placeboCanagliflozin/placeboCanagliflozin/placebo
Dapagliflozin/ placeboErtugliflozin/placeboMain inclusion criteriaEst. vascular complications Est. vascular complications or ≥ 2 CV risk factors
Est. vascular complications or ≥ 2 CV risk factorsStage 2 or 3 CKD + macroalbuminuriaHigh risk for CV eventsEst. vascular complicationsNo. of patients70344339
5700
3627
17,150
3900
Primary outcome
3P-MACE
3P-MACE
Progression of albuminuria
ESKD,
S-creatinine doubling, renal/CV death
3P-MACE
3P-MACE
Key secondary outcome
4P-MACE
Fasting insulin secretion, progression of albuminuria
Regression of albuminuria, change in
eGFR
4P-MACE + HHF
4P-MACE + HHF +
revascularisation
4P-MACE
Target no.
of events
691
≥ 420
TBD
TBD
1390
TBD
Estimated median FU
~3 years
6–7 years
3 years
~4 years
4–5 years
5–7
years
Estimated completion
2015
Apr 2017
2017
2019
2019
2021
Summary of CV
outcome
trials with SGLT2
inhibitors
23
Adapted from Inzucchi et al. Diabetes
Vasc
Dis Res 2015;12:90
‒
100. 1
. Zinman et al.
Cardiovasc
Diabetol
2014;13:102.
2. NCT01032629. 3. NCT01989754. 4. NCT02065791. 5. NCT01730534. 6. NCT01986881.
Link to study design
Link to study design
Link to study design
Link to study design
Link to study design
Will report
EASD 2015
Slide24Patients
7034
Long-term CV safety of empagliflozin is being evaluated in a large, multicentre Phase IV trial (EMPA-REG OUTCOME
®
)
24
*Cumulative percentage for North America, Australia and New Zealand.
1.
Zinman
et al.
Cardiovasc Diabetol 2014;13:102. 2. NCT01131676.Countries
42592
Clinical sites
Countries
with study centres involved in the
EMPA-REG
OUTCOME
®
trial
41%
19%
Asia
Europe
North
America /
Western Pacific
20%
15%
Latin America
4%
Africa
*
Slide25EMPA-REG OUTCOME
®
: Study design
25
Zinman et al.
Cardiovasc
Diabetol
2014;13:102.
Placebo
run-in
2 weeks
Empagliflozin 10 mg QD + usual care
Empagliflozin 25 mg QD + usual care Placebo + usual care
Screening (n = 11,507)
Background therapy adjustment
allowed after Week 12
12 weeks of stable background glucose-lowering therapy
Visit 1
Week
4
8
12
16
28
40
52
0
-2
-3
Visit 3
Visits
4–7
every
4 weeks
Visits 8–10
every 12
weeks
Visits every
14
weeks
Visit 2
Follow-up
R
End of
study visit
+30
days
Aim Compound-specific
To determine CV safety of empagliflozin
vs placebo + usual care for glycaemic control and
CV risk in
patients with
T2D
and high CV risk
Slide26EMPA-REG OUTCOME
®
: Inclusion criteria
26
Zinman et al.
Cardiovasc
Diabetol 2014;13:102.
Adults with insufficient glycaemic control
High risk of CV events (≥1 of the following)
Age ≥ 18 years HbA1c
≥ 7% and ≤ 10% if on background glucose-lowering therapy, or≥ 7% and ≤ 9% if drug-naïveBMI ≤ 45 kg/m2 History of MI (> 2 months prior to enrolment)Evidence of single/multi-vessel CAD Unstable angina > 2 months prior to consent with evidence of single- or multi-vessel CADHistory of stroke (ischaemic or haemorrhagic) > 2 months prior to consent
Occlusive peripheral artery disease
Slide27EMPA-REG OUTCOME
®
: Primary endpoint
Target number of events:
≥
691
Non-inferiority and superiority of empagliflozin vs placebo will be assessed (hierarchical testing)
90% power to demonstrate non-inferiority for the primary (3P-MACE) and key secondary (4P-MACE) outcome
≥ 80% power to detect hazard ratio of 0.785 for primary (3P-MACE) outcome27
Zinman et al. Cardiovasc Diabetol 2014;13:102.
Primary endpoint: time to 1st occurrence of any of the following adjudicated components of the primary composite endpoint (3P-MACE)1. CV death (including fatal stroke and fatal MI)2. Non-fatal MI (excluding silent MI)3. Non-fatal stroke
Slide28EMPA-REG OUTCOME
®
: Secondary endpoints
28
Zinman
et al.
Cardiovasc Diabetol 2014;13:102.
Key secondary outcome
Additional secondary outcomes
Expanded primary outcome (4P-MACE)3P-MACE + hospitalisation for unstable angina
Occurrence of and time to new onset of:Albuminuria (UACR ≥ 30 mg/g) Macroalbuminuria (UACR ≥ 300 mg/g)Occurrence of and time to a composite microvascular outcome, comprising:Initiation of laser therapy for retinopathy,
vitreous haemorrhage, diabetes-related blindness and new or worsening nephropathy as defined by:New-onset macroalbuminuria
Doubling of serum creatinine accompanied by eGFR ≤ 45 mL/min/1.73 m2
Initiation of renal replacement therapyDeath due to renal diseaseIndividual components of this compositeFurther CV outcomes
Individual components of the 4P-MACE
Individual occurrence of and time to:
Silent MI
Heart failure requiring hospitalisation
All-cause mortality
Transient
ischaemic attack
Coronary revascularisation procedures
Slide29EMPA-REG OUTCOME
®
: Other outcomes of interest
Efficacy
Change from baseline in:
HbA
1c, fasting plasma glucose, weight, waist circumference and blood pressure
Proportion of patients that obtain the composite endpoint of: HbA
1c reduction ≥ 0.5%, systolic blood pressure reduction > 3 mmHg and body weight reduction > 2%Sub-studiesImpact on renal and CV biomarkers (cystatin C, hs-CRP and
hs-troponin T)Pharmacogenomics (potential genetic variations associated with drug responses) SafetyAEs, clinical laboratory tests, vital signs, 12-lead ECG, physical examination, use of rescue medication, confirmed hypoglycaemia*, volume depletion, bone fracture, hepatic events, malignancies, UTI and GIs
29*Plasma glucose ≤ 70mg/dL (3.9 mmol/L) and/or requiring assistance. Zinman et al. Cardiovasc Diabetol 2014;13:102.
Slide30EMPA-REG OUTCOME
®
: Demographics
30
Zinman et al.
Cardiovasc
Diabetol 2014;13:102.
Treated set (n = 7034)
A
ge, years, mean (SD)
63.1 (8.6)≥ 75 y, n (%)652 (9)Male, n (%)5026 (72)
Race, n (%) White Asian Black/African American
Other5089 (72)1518 (22)357 (5)70 (1)
Ethnicity, n (%) Hispanic or Latino1268 (18)
Smoking
history, n (%)
Current
Ex-smoker
930 (13)
3216
(46)
Time
since T2D diagnosis, n (%)
≤ 5 years
> 5–10
years
> 10 years
1265
(18)
1754 (25)
4015 (57)
Slide31EMPA-REG OUTCOME
®
: Baseline metabolic characteristics
31
Data are mean (SD) unless otherwise stated.
Zinman et al.
Cardiovasc
Diabetol 2014;13:102.
Treated set (n = 7034)
HbA1c, %8.1 (0.8)HbA1c < 8.5%, n (%)
4811 (68)FPG, mmol/L8.5 (2.4)
BMI, kg/m2 30.6 (5.3)≥ 35, n (%)1426 (20)
Weight, kg86.4 (18.9)Waist circumference, cm105 (14)
eGFR,
mL/min/1.73 m
2
(MDRD)
74 (21)
≥ 90, n (%)
1534 (22)
60
to
< 90,
n (%)
3671 (52)
30
to
< 60,
n (%)
1796 (26)
Median (Q1, Q3)
ACR
albumin ratio, mg/g
17.7 (7.1,
72.5)
Slide32EMPA-REG OUTCOME
®
: Baseline CV characteristics
32
Data are mean (SD) unless otherwise stated.
Zinman et al.
Cardiovasc
Diabetol 2014;13:102.
Treated set (n = 7034)
History of CVD (any of the below), n (%)
6978 (99) History of stroke1631 (23) History of MI
3275 (47) Peripheral occlusive arterial disease1449 (21) CABG
1738 (25) Single-vessel CAD743 (11) Multi-vessel CAD
3285 (47)SBP/DBP, mmHg135 (17) / 77 (10)Lipids (mmol/L)
Total cholesterol
4.2 (1.1)
LDL-cholesterol
2.2 (0.9)
HDL-cholesterol
1.2 (0.3)
Triglycerides
1.9 (1.4)
Slide33EMPA-REG OUTCOME
®
: Background therapies
33
*Data on file.
Zinman
et al. Cardiovasc Diabetol 2014;13:102.
Treated set (n = 7034)
Glucose-lowering therapy, n (%)
No therapy128 (1.8)Monotherapy
2055 (29.2)Metformin (% of monotherapy)745 (36.3)Insulin (% of monotherapy)
954 (46.4)Dual combination therapy3188 (45.3)Metformin + sulphonylurea (% of dual combination
therapy)1383 (43.4)Metformin + insulin (% of dual combination therapy)1420 (44.5) Total metformin
5205 (74.0)*
Total insulin
3446 (48.2)*
Anti-hypertensive
therapy, n (%)
6641
(94.4)
Blockers
of the renin–angiotensin system
5651 (80.3)
β-blockers
4537 (64.5)
Any diuretic
3015 (42.9)*
Calcium
channel blockers
2114
(30.1)
Other therapies,
n (%)
Acetylsalicylic
acid
5990 (85.2)
Statins
5387 (76.6)
Fibrates
630
(9.0)
Slide34Module D: Summary
FDA guidance from 2008 requests CV outcome trials (CVOTs) to demonstrate CV safety of all new glucose-lowering compounds
1
CVOTs designed to assess impact of drugs on CV outcomes (MACE) vs placebo on top of usual care for glucose and CV risk factor management
Not designed to assess impact of differences between treatment arms in, for example, HbA
1c
on CV outcomes
Completed CVOTs in DPP4 inhibitor and GLP1 class report neutral effects on CV outcomes confirming CV safety as defined by FDA2-6
Ongoing CVOTs will provide further clarity on the CV safety of individual glucose-lowering agents34
1. FDA Guidance for Industry. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. 2. Scirica et al. N Engl J Med 2013;369:1317–26. 3. White et al. N Engl
J Med 2013;369:1327–35. 4. Zannad et al. Lancet 2015;385:2067–76. 5. Green et al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352. 6. Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).
Slide35APPENDIX
Slide36+
U
sual care
for
Type 2 Diabetes
N = 6068; duration of follow-up 2.1 years
Main inclusion
criteria
1. Age ≥ 30 years old
2. Type 2
Diabetes3. History of acute coronary syndrome
Primary endpoint: time to first occurrence of:Placebo
Lixisenatide 10 g (0.1 mL injection)vsELIXA: Study design
361. NCT01147250. 2. Katz P. Diabetes Vasc Dis Res 2014;11:395–409. 3. Bentley-Lewis et al. Am Heart J 2015;0:1-8.e7.4. Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).
Non-fatal stroke
Non-fatal MI
CV-related death
Unstable angina requiring hospitalisation
Aim Compound-specific
To assess CV morbidity and mortality associated with lixisenatide vs placebo
Back
Next
Slide37ELIXA: Baseline characteristics
37
Bentley-Lewis
et al. Am Heart J
2015;0:1-8.e7.
Randomised population
(N = 6068)
Age,
years (mean ± SD)
60.3 ± 9.7Male, n (%)4207 (69.3)Race, n (%)
AsianBlackWhite Other768 (12.7)221 (3.6)4563 (75.2)516 (8.5)
Ethnicity, n (%)Hispanic1768 (29.1)BMI, kg/m2 n (%)
Mean ± SD18.5–24.925.0‒29.9≥ 3030.2 ± 5.71017 (16.8)2297 (37.9)2734 (45.1)
Cholesterol, mg/
dL
(mean ± SD)
Total
Triglycerides
HDL-C
LDL-C
153
± 44
164 ± 113
43 ± 11
78 ± 35
Fasting plasma glucose,
mg/
dL
(mean ± SD)
148
± 52
HbA
1c
, %,
(mean ± SD)
7.7 ± 1.3Qualifying ACS event
STEMI
Non-STEMI
UA2667 (44.0)
2346 (38.7)1042 (17.2)
Next
Back
Slide38ELIXA: Lixisenatide was
non-inferior to
placebo on primary 4P-MACE endpoint
Outcome
Placebo
(n = 3034)
Lixisenatide
(n
= 3034)HR (95% CI)
4-P MACE399 (13.2%)
406 (13.4%)1.02 (0.89–1.17)Individual componentsCV mortality
158 (5.2%)2.4/100 pt-y156 (5.1%)2.3/100 pt-y0.98 (0.78–1.22)MI (fatal/non-fatal)261 (8.6%)4.1/100 pt
-y270 (8.9%)4.2/100 pt-y1.03 (0.87–1.22)Stroke (fatal/non-fatal60 (2.0%)0.9/100 pt-y67 (2.2%)1.0/100 pt-y1.12 (0.79–1.58)Unstable angina
10 (0.3%)0.1/100 pt-y11 (0.4%)0.2/100 pt-y1.11 (0.47–2.62)38Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).
Next
Back
Slide39ELIXA:
HHF was not significantly increased with
lixisenatide vs placebo
Outcome
Placebo
(n = 3034)
Lixisenatide
(n
= 3034)HR (95% CI)MACE + HHF
469 (15.5%)7.6/100 pt-y456 (15.0%)7.3/100 pt
-y0.97 (0.85–1.10)MACE + HHF + Coronary Revascularisation659 (21.7%)11.2/100 pt-y661 (21.8%)11.1/100 pt-y1.00 (0.90–1.11)HHF127 (4.2%)1.9/100 pt-y122 (4.0%)1.8/100 pt
-y0.96 (0.75–1.23)CV death + HHF253 (8.3%)3.9/100 pt-y248 (8.2%)3.8/100 pt-y0.97 (0.82–1.16)39
Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).Back
Slide40+ Usual care for T2D
N =
9340
; expected duration of follow-up 3.5–5 years
Main inclusion
criteria
1.
Type
2
Diabetes
2. Patients with prior CVD (e.g., MI, stroke, CHF, CRF) and age ≥ 50 years, or patients without prior CVD and ≥ 60 years old at screening with ≥ 1 CV risk factors
PlaceboLiraglutide 0.6–1.8 mg daily SC
vsLEADER: Study design401. Marso et al. Am Heart J 2013;166:823–30.e5. 2. NCT01179048.
Non-fatal strokeNon-fatal MI
CV-related death
Aim Compound-specific
To
assess the
CV safety
of
liraglutide relative to current usual care
Primary endpoint: time to first occurrence of primary major adverse cardiac events
Non-fatal stroke
CV
death
Non-fatal
MI
Results anticipated 2016
Next
Back
Slide41LEADER: Baseline characteristics
41
Total population
(N = 9340)
Age,
years (mean ± SD)
64.3 ± 7.2
Male,
n (%)
6003 (64.3)
Race, n (%)
WhiteAsianBlackOther7237 (77.5)922 (9.9)775 (8.3)406 (4.3)Ethnicity, n (%)
Hispanic or Latino1135 (12.2)BMI, kg/m2 (mean ± SD)32.5 ± 6.3
Cholesterol, mg/dL (mean ± SD)TotalTriglyceridesHDL-CLDL-C170.4 ± 45.3182.5 ± 140.0
45.5 ± 12.3
89.5 ± 35.5
HbA
1c
, %,
(mean ± SD)
8.7
± 1.5
Previous CVD, n (%)
7592
(81.3
)
No previous CVD, n (%)
1748 (18.7)
Hypertension, n (%)
8408 (90.0)
Hyperlipidaemia, n (%)
7191 (77.0)
Coronary artery disease, n (%)
5303 (56.8)
Congestive heart failure, n (%)
1599 (17.1)
Peripheral artery disease, n (%)
1644 (17.6)
Diabetes duration, years
12.7 ± 8.0
Marso et al. Am Heart J 2013;166:823–30.e5.
Back
Slide42SAVOR-TIMI 53: Study design
42
1.
Mosenzon
et al. Diabetes
Metab
Res Rev 2013;29:417–26. 2.
Scirica et al. N Engl
J Med 2013;369:1317–26.
+ Usual care for T2D
N = 16,492; median follow-up, 2.1 years (maximum, 2.9 years)Main inclusion criteria1. Patients with T2D2. HbA
1c > 6.5%, < 12.0%3. High-risk for CV events – established CVD and/or multiple risk factors
Primary endpoint: time to first occurrence of primary composite endpoint:Placebo
Saxagliptin 2.5 or 5 mgvs
Non-fatal stroke
CV
death
Non-fatal
MI
Aim Compound-specific
To determine whether saxagliptin reduces risk of CV events
when used
alone or added to other diabetes medications
Back
Next
Slide43No.
at
risk
Placebo
8212
7983
7761
7267
4855
851
Saxagliptin
8280
8071
783673134920847
0
180
360
540
720
900
14
12
10
0
2
4
6
8
Saxagliptin
Placebo
HR 1.00
(95
% CI 0.89–1.12
)
p < 0.001
for
non-inferiority
p = 0.99
for superiority
Patients with primary endpoint (%)
SAVOR-TIMI 53: Saxagliptin was non-inferior
to placebo on primary 3P-MACE endpoint
43
Scirica
et al. N
Engl
J Med
2013;369:1317–26.
Days
Back
Next
Slide44SAVOR-TIMI 53: Increased risk of
hospitalisation for heart failure in saxagliptin arm
Scirica
et
al.
Circulation 2014;130:1579–88.
HR 1.27 (05% CI 1.07–1.51); p
=
0.007
0
8212
8280
180
8036
8064
Days
0
1
2
3
Hospitalisation for heart failure (%)
4
360
7856
7867
720
4959
4978
540
7389
7375
Placebo
Saxagliptin
2.8%
3.5%
Placebo
Saxagliptin
Back
44
Slide45EXAMINE: Study design
45
*Depending on renal function.
1. White et al
.
Am Heart J 2011;162:620–26.e1. 2. White et al. N
Engl
J Med 2013;369:1327–35.
+
Usual care for T2D
N = 5380; median follow-up = 18 months (maximum 40 months) Main inclusion criteria1. Patients with T2D2. HbA
1c ≥ 6.5%, ≤ 11.0% (if on oral or combination); HbA1c ≥ 7.0%, ≤ 11.0% (if treatment includes insulin) 3. History of acute coronary syndrome within 15–90 days pre-randomisation
Primary endpoint: time to first occurrence of primary major adverse cardiac events Placebo
Alogliptin 6.25–25 mg daily*vs
Non-fatal stroke
CV
death
Non-fatal
MI
Aim Compound-specific
To demonstrate non-inferiority of
alogliptin
vs
placebo with respect to
CV
events in patients at high CV risk
Next
Back
Slide46Risk of
HHF occurring
as
the first
event
in pre-specified exploratory extended MACE endpoint did
not differ significantly between
groups
Risk
of events assessed as component of post-hoc composite endpoint
of CV death and HHF was not significantly different between groupsEXAMINE: HHF was not significantly increased with alogliptin vs placebo46Zannad
et al. Lancet 2015;385:2067–76.Alogliptin (n = 2701)Placebo (n = 2679)HR (95% CI)
p valueHospital admission for heart failure85 (3.1%)79 (2.9%)1.07 (0.79–1.46)0.657Alogliptin (n = 2701)
Placebo (n = 2679)HR (95% CI)p valueHospital admission for heart failure106 (3.9%)89 (3.3%)1.19 (0.90–1.58)0.220Next
Back
Slide47No. at risk
Placebo
2679
2299
1891
1375
805
286
Alogliptin
2701
2316
1899
1394
821
296
Placebo
24
6
12
18
100
80
60
40
20
0
24
18
12
0
30
Months
Cumulative incidence of primary endpoint events (%)
6
0
0
6
12
18
24
30
Alogliptin
HR 0.96
(upper boundary of
the 1-sided repeated CI 1.16)
p < 0.001 for non-inferiority; p = 0.32 for superiority
EXAMINE: Alogliptin was non-inferior to placebo on primary 3P-MACE endpoint
47
1. White et al. N
Engl
J Med
2013;369:1327–35,
Back
Slide48TECOS: Study design
48
*
50
mg daily if the baseline eGFR
was
≥ 30
and < 50 mL per
minute per 1.73 m2.Green et al. N Engl J Med 2015; DOI 10.1056/NEJMoa1501352
+ Usual care for T2D
N = 14,671; median follow-up 3.0 years
Main inclusion criteriaPatients aged ≥ 50 years with T2DHbA1c 6.5–8.0% receiving stable oral glucose-lowering therapy and/or
insulin*3. Pre-existing vascular diseasePrimary endpoint: time to first occurrence of:
PlaceboSitagliptin 100 mg daily*
vs
Non-fatal stroke
Non-fatal MI
CV-related death
Unstable angina requiring hospitalisation
Aim Compound-specific
To determine CV outcomes associated with long-term
sitagliptin
Next
Back
Slide49TECOS: Baseline characteristics
49
Values
mean
±
SD if not specified n (%).
Green et al. N Engl J Med 2015; DOI 10.1056/NEJMoa1501352
Characteristic
Sitagliptin
n = 7332
Placebon = 7339Age, years65.4 ± 7.965.5 ± 8.0Women, n (%)
2134 (29.1)2163 (29.5)Race, n (%) White
Black Asian Other4955 (67.6)206 (2.8)
1654 (22.6)517 (7.1)5002 (68.2)241 (3.3)
1611 (22.0)
485 (6.6)
Hispanic or Latino
886 (12.1)
912 (12.4)
BMI (kg/m
2
)
(mean ± SD)
30.2
± 5.6
30.2
± 5.7
eGFR
(mL/min/1.73 m
2
)
74.9 ± 21.3
74.9 ± 20.9
HbA1c
7.2
± 0.5
7.2
± 0.5
CV risk management
Systolic blood pressure (mmHg)
135
± 16.9
135
± 17.1
Diastolic blood pressure (mmHg)
77.1 ± 10.3
77.2
± 10.6
Total cholesterol (mg/
dL
)
166.1
± 44.8
165.4
± 45.9
LDL-C (mg/
dL
)
91.2
± 63.8
90.7
± 51.2
HDL-C (mg/
dL
)
43.5
± 12.0
43.4
± 13.0
Triglycerides (mg/
dL
)
166.0
± 101.0
164.8
± 98.8
Aspirin use, n (%)
5764 (78.6)
5754 (78.4)
Statin use, n (%)
5851 (79.8)
5868 (80.0)
Next
Back
Slide50TECOS: Baseline CV risk factors
50
*Enrolled participants could have one or more prior
CV event.
Green
et al. N
Engl J Med 2015; DOI 10.1056/NEJMoa1501352.
Characteristic, n (%)
Sitagliptin
n = 7332
Placebon = 7339Prior CV disease*5397 (73.6)5466 (74.5)
Myocardial infarction3133 (42.7)3122 (42.5) PCI
2814 (38.9)2900 (40.1)CABG
1845 (25.2)1819 (24.8)≥ 50% stenosis in a coronary artery3804 (51.9)
3883 (52.9)
Prior cerebrovascular disease
1806 (24.6)
1782 (24.3)
Stroke
1297 (17.7)
1258 (17.1)
TIA
280 (3.8)
286 (3.9)
≥ 50% stenosis in a carotid artery
431 (5.9)
429 (5.8)
Peripheral arterial disease
1217 (16.6)
1216 (16.6)
History of heart failure
1303 (17.8)
1340 (18.3)
Next
Back
Slide51TECOS: Diabetes characteristics at baseline
51
Values are mean ±SD or median (IQR) for continuous variables
or
n (%)
for categorical variables.
Green et al. N Engl J Med 2015; DOI 10.1056/NEJMoa1501352.
Characteristic
Sitagliptin
n = 7332
Placebon = 7339
Duration of diabetes, years
11.6 ± 8.1
11.6 ± 8.1
HbA
1c
,
%
7.2 ± 0.5
7.2 ± 0.5
Medication taken alone or in combination
Metformin
5936 (81.0)
6030 (82.2)
Sulphonylurea
3346 (45.6)
3299 (45.0)
Thiazolidinedione
196 (2.7)
200 (2.7)
Insulin
1724 (23.5)
1684 (22.9)
Median daily dose (units)
50 (33, 80)
50 (32, 80)
Monotherapy
3496 (47.7)
3498 (47.7)
Dual combination therapy
3766 (51.4)
3768 (51.3)
Next
Back
Slide52TECOS:
Sitagliptin was non-inferior
to placebo on primary 4P-MACE
endpoint
*CV
death,
non-fatal MI, non-fatal stroke, hospitalisation
for unstable angina.Green et
al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352.
Sitagliptin
72576857
65196275
59315616
39192896
1748
1028
Placebo
7266
6846
6449
6165
5803
5421
3780
2743
1690
1005
100
8
0
60
4
0
20
0
0
4
8
12
18
24
30
36
42
48
Months in the trial
Patients with an event (%)
Patients at risk:
0
0
4
8
12
18
24
30
36
42
48
5
10
15
Sitagliptin
Placebo
HR (95% CI): 0.98 (0.88–1.09)
p < 0.001
Next
Back
52
Slide53TECOS:
No significant difference in rate of
hospitalisation for heart failure (ITT analysis)
Outcome
Placebo
Sitagliptin
HR (95% CI)
HHF
*
228 (3.1%)1.07/100 pt-y
228 (3.1%)1.09/100 pt-y1.00 (0.83–1.20)p = 0.98CV Death + HHF*525 (7.2%)2.50/100 pt-y
538 (7.3%)2.54/100 pt-y1.02 (0.90–1.15)p = 0.7453
ITT population. Adjusted for history of heart failure at baseline
*Pre-specified analyses Green et al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352Back
Slide54CAROLINA
®
will evaluate CV safety of linagliptin compared with glimepiride in patients with T2D
54
1.
Rosenstock
et al. Diab
Vasc Dis Res 2013;10:289–301. 2. Marx et al. Diabetes
Vasc Dis Res 2015;12:164–74.
Inclusion if ≥ 1 of the following is fulfilled:
Previous vascular complications Evidence of end-organ damage, e.g., albuminuriaAge ≥ 70 years≥ 2 specified traditional CV risk factors
With or without metformin background therapy (including patients with contraindication to metformin use in renal impairment)N = 6041; approximate 6–7 year follow-up
Primary endpoint: time to first occurrence of primary composite endpoint:Glimepiride 1–4 mg
Linagliptin 5 mgvs
Active comparator trial
CV death (including fatal stroke and fatal
MI)
Non-fatal MI
Non-fatal stroke
Hospitalisation for UA
Next
Back
Slide55Total
(n =
6041*)
Group A:
Previous CV
events
†
(
n = 2084, 34.5% of total)
Group B: Retinopathy/ albuminuria(n = 513, 8.5% of total)Group C:Age > 70 years (n = 1163,
19.3% of total)Group D:≥ 2 CV risk factors (n = 2252,37.3% of total)
Age, years (mean ± SD)64.0 ± 9.564.6 ± 8.965.6 ± 9.7
74.0 ± 3.458.0 ± 7.2≥ 75 y, %
14.0
14.3
21.2
37.9
0.0
Sex, male, n (%)
3622 (
60.0)
1511 (
72.5)
284 (
55.4)
593 (
51.0)
1219 (
54.1)
Race, n (%)
White
4408 (
73.0)
1489 (
71.4)
367 (
71.5)
911 (
78.3)
1634 (
72.6)
Asian
1061 (
17.6)
427 (20.5)
85 (
16.6)
145 (
12.5)
402 (
17.9)
Black/African
American
331 (
5.5)
101 (
4.8)
32 (
6.2)
40 (
3.4)
157 (
7.0)
Other
‡
241 (
4.0)
67 (
3.2)
29 (
5.7)
67 (
5.8)
59 (
2.6)
Ethnicity, n (%)
Hispanic or Latino1033 (17.1)309 (14.8)
96 (18.7)260 (22.4)368 (16.3)
Smoking: Current/ex-smoker, %
19.5/33.716.3/46.2
14.4/30.2
6.6/32.8
30.7/23.6Time since T2D
diagnosis, years (median, IQR)6.2 (2.9, 11.0)5.8(2.7, 10.4)
6.6(3.6, 11.3)7.7(4.3, 12.0)
5.8(2.6, 10.7)Time since T2D diagnosis, %
≤ 5 years40.643.736.1
30.5
44.2> 5–10 years28.2
29.1
30.4
30.5
25.9
> 10
years
30.9
27.2
33.5
39.0
29.9
CAROLINA
®
: Baseline characteristics
55
*A few patients had no reliable CV risk categorisation.
†
Myocardial infarction 13.8%, coronary artery disease 17.1%,
stroke 7.8%, peripheral arterial occlusive disease 5.5%.
‡
American Indian/Native, Alaskan/Native, Hawaiian/Pacific Islander.
Marx et al. Diabetes
Vasc
Dis Res 2015;12:164–74.
Back
Slide56CARMELINA
®
will evaluate CV and renal safety of linagliptin in patients with T2D at high CV and renal risk
56
NCT01897532.
N = 8300; ~ 4-year follow-up
I
nclusion criteria
T2D
with HbA
1c ≥ 6.5% and ≤ 10.0%Stable background anti-diabetes medication, excluding GLP1, DPP4 inhibitors, SGLT2 inhibitorsHigh risk of CV,
defined by: 1) albuminuria (micro or macro) and previous macrovascular disease 2) and/or impaired renal function with predefined UACRPrimary CV endpoint: time to first occurrence of primary composite endpoint:
PlaceboLinagliptin 5 mg
vsCV death (including fatal stroke and fatal MI)
Non-fatal MI
Renal endpoint: time to first occurrence of the composite
endpoint:
Renal death, ESRD, and sustained decrease of ≥ 50%
eGFR
This study addresses the CV safety requirements from the FDA,
as well as investigates the potential renal effects of the drug
Non-fatal stroke
Hospitalisation for UA
Back
Slide57CANVAS: Study design
57
1. Neal et al. Am Heart J 2013;166:217–223.e11. 2
.
NCT01032629.
In addition to usual care for T2D, patients
randomised
1:1:1 to
Stable dose of background
antihyperglycaemic
agents administered for 8 weeks prior to screeningN = 43652; expected duration of follow-up 6-7 yearsMain inclusion criteria1
1. Patients with T2D2. Age ≥ 30 years with history of symptomatic atherosclerotic vascular disease or ≥ 50 years with 2 or more risk factors for CVD
Primary endpoint: time to first occurrence of1:Placebo
Canagliflozin (100 mg)Non-fatal MI
CV-related death
Non-fatal stroke
Aim Compound-specific
To determine CV risk associated with
canagliflozin
Canagliflozin
(300
mg)
Back
Slide58CANVAS-R: Study design
58
NCT01989754.
N = 5700; expected duration of follow-up 3 years
Main inclusion
criteria
Established
CV disease or multiple risk factors
Age ≥ 30 years
T2D
Primary endpoint:
Number of participants with progression of albuminuria Aim Compound-specificEffects of canagliflozin on renal endpoints in adults with T2D and at high CV risk
+ Usual care for T2DPlacebo
Canagliflozin (100 or 300 mg)vs
Other endpoints:
CV
safety data will be evaluated as
3P-MACE
Although primarily a renal study, CANVAS-R will prospectively collect adjudicated CV outcomes, as required by the FDA mandate
Back
Slide59CREDENCE: Study design
59
*CV
death, non-fatal
MI,
non-fatal stroke,
hospitalised congestive heart failure and hospitalised
unstable angina.NCT02065791.
N = 3700; expected duration of follow-up ~4 years
Main inclusion
criteriaStage 2 or 3 CKD and macroalbuminuriaOn ACE inhibitor or ARBAge ≥ 30 yearsPrimary endpoint: time to first occurrence of:
End-stage kidney diseaseSerum creatinine doubling
Aim Compound-specificTo determine whether canagliflozin has a renal/vascular protective effect vs placebo + Usual care for T2D
PlaceboCanagliflozin (100 mg)
vs
Renal
or CV death
Other endpoints:
Composite CV safety endpoint*
Although primarily a renal study, CREDENCE will prospectively collect adjudicated CV outcomes, as required by the FDA mandate
Back
Slide60DECLARE-TIMI 58: Study design
60
1. http://www.timi.org/index.php?page=declare-timi-58. Accessed March 2015. 2
.
NCT01730534.
N = 17,150; expected duration of follow-up ~4.5 years
Main inclusion
criteria
High risk for CV events
Age ≥ 40 years
T2DPrimary endpoint: time to first occurrence of:
CV deathMyocardial infarction
Aim Compound-specificTo determine whether dapagliflozin reduces CV events vs placebo + Usual care for T2DPlacebo
Dapagliflozin (10 mg)vs
Ischaemic
stroke
Back
Slide61Ertugliflozin CVOT: Study design
61
NCT01986881.
N = 3900; expected duration of follow-up up to 6.3 years
Main inclusion
criteria
Evidence or a history of atherosclerosis (coronary, cerebral or peripheral)
Age ≥ 40 years
T2D
Primary endpoint: time to first occurrence of:
CV
deathNon-fatal MIAim Compound-specificTo determine whether ertugliflozin reduces CV events
vs placebo + Background therapy for T2DPlacebo
Ertugliflozin (5 or 15 mg)vs
Non-fatal
stroke
Back
Slide62Clinical profile of SGLT2 inhibitors
62
Back
Slide63Pooled data
Empagliflozin pooled Phase III placebo-corrected change from
baseline
in
HbA
1c
*
63
*
All statistically significant.
†Error bar represents 95% CI.1. Hach et al. Diabetes 2013;62(suppl 1A):A21(P69-LB). 2. Roden et al. Lancet Diabetes Endocrinol 2013;1:208‒19. 3. Häring et al. Diabetes Care 2014;37:1650–9. 4. Kovacs et al. Diabetes Obes
Met 2014;16:147‒58. 5. Häring et al. Diabetes Care 2013;36:3396‒3404. 6. Rosenstock et al. Diabetes 2013;(suppl 1):(1102-P). 7. Barnett et al. Lancet Diabetes Endocrinol 2014;2:369‒84
Pooled1Monotherapy2MET
3PIO4MET + SU5
Insulin
78-week
6
Mild RI
7
Patients, n
831
821
224
224
217
213
165
168
225
216
169
155
98
97
BL HbA
1c
(%)
7.98
7.96
7.87
7.86
7.94
7.86
8.07
8.068.07
8.10
8.278.278.027.96
Adjusted mean (SE) difference
vs placebo
in
change from baseline in HbA
1c
(%)
†
†
†
†
†
†
Empagliflozin 10 mg QD
Empagliflozin 25 mg QD
Back
Slide64Empagliflozin pooled Phase III placebo-corrected change from
baseline
in body weight*
64
Pooled data
Pooled
1
Monotherapy
2
MET
3
PIO4MET + SU5Insulin
78-weekMild RI6N/AN/A
Adjusted mean (SE) difference vs placebo in change from baseline in body weight (kg)Patients, n
831
821
224
224
217
213
165
168
225
216
N/A
N/A
98
97
BL BW
(kg)
78.8
79.1
78.4
77.8
81.6
82.2
78.0
78.9
77.1
77.5
91.6
94.7
92.1
88.1
†
†
†
†
†
†
*All statistically significant.
†
Error bar represents 95% CI.
N/A, published data not available.
1.
Hach
et
al.
Diabetes
2013;62(
suppl
1A):A21(P69-LB
).
2.
Roden
et al. Lancet Diabetes
Endocrinol
2013;1:208‒19
.
3.
Häring
et
al. Diabetes
Care 2014;37:1650–9
.
4
.
Kovacs
et al. Diabetes
Obes
Met 2014;16:147‒58. 5. Häring et al. Diabetes Care 2013;36:3396‒3404. 6. Barnett et al. Lancet Diabetes Endocrinol 2014;2:369‒84.
Empagliflozin 10 mg QDEmpagliflozin 25 mg QD
BackEmpagliflozin is not indicated for
weight loss. Weight change was a secondary endpoint in clinical trials
Slide65Empagliflozin pooled Phase III placebo-corrected change from baseline in SBP*
65
Pooled data
Pooled
1
Monotherapy
2
MET
3
PIO
4
MET + SU5Insulin78-week
Mild RI6N/AN/A
Adjusted mean (SE) difference vs placebo in change from baseline in SBP (mmHg)Patients, n831
821
224
224
217
213
165
168
225
216
N/A
N/A
98
97
BL SBP (mmHg)
129.6
129.0
133.0
129.9
129.6
130.0
126.5
125.9
128.7
129.3
132.4
132.8
137.4
133.7
†
†
†
†
†
†
Empagliflozin 10 mg QD
Empagliflozin 25 mg QD
*All statistically significant.
†
Error bar represents 95% CI.
N/A, published data not available.
1.
Hach
et
al.
Diabetes
2013;62(
suppl
1A):A21(P69-LB
).
2.
Roden
et al. Lancet Diabetes
Endocrinol
2013;1:208‒19
.
3.
Häring
et
al. Diabetes
Care 2014;37:1650–9
.
4
.
Kovacs
et al. Diabetes
Obes
Met 2014;16:147‒58. 5. Häring et al. Diabetes Care
2013;36:3396‒3404. 6. Barnett et al. Lancet Diabetes Endocrinol 2014;2:369‒84. . BackEmpagliflozin
is not indicated for blood pressure reduction. Change in blood pressure was a secondary
endpoint in clinical trials
Slide6612-week ABPM study with
empagliflozin
in patients with T2D and hypertension: hourly mean SBP (mmHg)
66
FAS
(LOCF-H
). 1.
Tikkanen
et al. Diabetes Care 2015;38:420–8.
Mean (SE) SBP (mmHg)
Week 12Baseline0
12345
HourBackReductions in BP were not associated with increases in pulse rate
Empagliflozin is not indicated for blood pressure reduction. Change in blood pressure
was a
secondary
endpoint
in
clinical
trials
Slide6712-week ABPM study with
empagliflozin
in patients with T2D and hypertension: hourly mean DBP at Week 12
67
Tikkanen
et
al. Diabetes
Care 2015;38:420–8.
Hour
Mean (SE) DBP (mmHg)
0123
45BackReductions in BP were not associated with increases in pulse rate
Empagliflozin is not indicated for blood pressure reduction. Change in blood
pressure was a secondary endpoint in clinical trials
Slide68Empagliflozin pooled Phase III
data:
Change
in lipids (mg/
dL
) from baseline at Week
24
68
*
p <
0.05; **p < 0.001; ***p = 0.008 vs placeboHach et al. Diabetes 2013;62(Suppl 1A):A21 (P69-LB).*****
***
**LDL-C
HDL-CTriglyceridesLDL/HDL-C ratioTotal cholesterol
Mean baseline
101.2
99.2
99.2
48.6
48.6
49.0
164.7
172.7
173.6
2.18
2.11
2.11
181.7
180.6
181.7
Back
Slide69n (%)
Placebo
(n = 3695)
Empagliflozin
10 mg QD
(n = 3806)
25 mg QD
(n = 4782)
Patients with any AE
2621 (70.9)
2686 (70.6)
3499 (73.2)
Patients with AE(s) leading to discontinuationof trial drug
208 (5.6)191 (5.0)255 (5.3)Patients with serious AE(s)494 (13.4)
393 (10.3)
573 (12.0)
One or more severe AE(s)
324 (8.8)
258 (6.8)
373 (7.8)
Deaths
29
(0.8)
19 (0.5)
26 (0.5)
Empagliflozin pooled safety and tolerability data:
Summary of adverse events
Kohler et al. ADA 2015 (poster 1173-P).
Rate per 100 patient-years
69
Back
Slide70Pooled empagliflozin data:
Important
identified safety topics
1. Kohler
et al. ADA
2015 (poster 1173-P). 2.
Data on file.
n
(%)
Placebo(n = 3695)
Empagliflozin 10 mg QD
(n = 3806)25 mg QD(n = 4782)
Urinary tract infection2344 (9.3)374 (9.8)
497 (10.4)Female2Male2
269 (19.3)
75 (3.3)
281 (20.2)
93 (3.8)
360 (20.1)
137 (4.6)
Pyelonephritis
2
4 (0.1)
1 (< 0.1)
3 (0.1)
Pyelonephritis acute
2
3 (0.1)
1 (< 0.1)
2 (< 0.1)
Urosepsis
2
3 (0.1)
2 (0.1)
1 (< 0.1)
Genital
infection
2
41 (1.1)
177 (4.7)
268 (5.6)
Female
2
Male
2
23 (1.6)
18 (0.8)
94 (6.8)
83 (3.4)
156 (8.7)
112 (3.7)
Volume depletion
2
51 (1.4)
57 (1.5)
74 (1.5)
No.
of patients with confirmed
hypoglycaemic AEs
1
567 (15.3)
562 (14.8)
627 (13.1)
Episode requiring assistance (‘severe hypoglycaemic episode’)
1
19 (0.5)
18 (0.5)
18 (0.4)
70
Back
Slide71Pooled empagliflozin data:
Important
potential safety topics
*Based
on 2
MedDRA
preferred terms. †Based on 1 standardized MedDRA query. ‡Based
on 4 standardized MedDRA queries.
§Based on 60 MedDRA preferred terms. 1. Kohler et al. ADA 2015 (poster 1173-P). 2. Data on file.
n
(%)Placebo(n = 3695)Empagliflozin
10 mg QD(n = 3806)
25 mg QD(n = 4782)Events consistent with malignancies*1
36 (1.0)46 (1.2)67 (1.4)Events consistent with malignancies with
an onset after 6 months
of therapy
or later
1
22 (0.9)
30 (1.0)
39 (1.0)
Patients with renal or bladder
cancer
with an onset after 6 months
of therapy
or later
2
2 (<0.1)
2 (<0.1)
1 (<0.1)
Decreased renal function
†1
36 (1.0)
46 (1.2)
64 (1.3)
Serum
creatinine increase ≥ 2x BL and ≥ ULN
2
10 (0.3)
11 (0.3)
14 (0.3)
Hepatic injury
‡1
66 (1.8)
52 (1.4)
82 (1.7)
Events consistent with bone fracture
§1
67 (1.8)
66 (1.7)
63 (1.3)
Events consistent with DKA
1
5 (0.1)
2 (0.1)
1 (< 0.1)
Diabetic
ketoacidosis
2
4 (0.1)
2 (0.1)
1 (< 0.1)
Ketoacidosis
2
1 (< 0.1)
0
0
Acetoanaemia
2
0
0
0
71
Back
Slide72Dapagliflozin: Short-term (Week 24) HbA
1c
change from baseline in Phase III trials
72
*p ≤ 0.0001 vs placebo.
†
Least-squares mean adjusted for baseline value
.
1.
Forxiga 5-mg and 10-mg film-coated tablets [SPC]. Bristol-Myers Squibb/AstraZeneca EEIG, 18 December 2013.
2. Rosenstock et al. Diabetes Care 2012;35:1473–8.7570137 135
401 400145 151108 108
224 223139 140193194
7.798.018.11 7.927.74 7.698.15
8.07
8.24
8.08
7.97
7.90
8.34
8.37
8.46
8.58
HbA
1c
mean change
from baseline (%)
†
*
*
*
*
(Week 52 data)
*
*
*
Add-on
INS
1
Mono-
therapy
1
Add-on
MET
1
Add-on
MET
vs
GLP
1
Add-on
GLM
1
Add-on
PIO
2
Add-on
SU + MET
1
Add-on
SITA ± MET
1
PBO+
SITA ± MET
PBO
PBO
+
MET
GLP + MET
PBO +
GLM
PBO +
PIO
PBO +
INS
PBO+
SU + MET
Comparator
n
BL HbA
1c
(%)
Study
Back
Slide73Dapagliflozin: Short-term (Week
24) body
weight change from baseline in Phase III trials
73
*p < 0.0001 vs
placebo
.
†
Least-squares mean adjusted for baseline value.
1. Forxiga
5-mg and 10-mg film-coated tablets [SPC]. Bristol-Myers Squibb/AstraZeneca EEIG, 18 December 2013. 2. Whaley et al. Diabetes Metab Syndr Obes 2012;5:135–48. 3. Rosenstock et al. Diabetes
Care 2012;35:1473–8 . 7570 137135
401400 145151108108
224223 139140 193194
88.8
94.2
87.7
86.3
87.6
88.4
80.9
80.6
90.1
88.6
89.2
91.0
86.4
84.8
94.5
94.5
Body weight mean change
from baseline (kg)
†
*
*
*
*
*
*
*
(Week 52 data)
n
BL BW
(kg)
Study
PBO +
SITA ± MET
PBO
PBO
+ MET
GLP + MET
PBO +
GLM
PBO +
PIO
PBO +
INS
PBO +
SU + MET
Add-on
INS
1,2
Mono-
therapy
1,2
Add-on
MET
1,2
Add-on
MET
vs
GLP
1
Add-on
GLM
1,2
Add-on
PIO
3
Add-on
SU + MET
1
Add-on
SITA ± MET
1
Comparator
Back
Slide74Dapagliflozin: Short-term
(
Week 24) SBP
change from baseline in Phase III trials
*
Least-squares mean adjusted for baseline value.
1
.
Ferrannini
et al. Diabetes Care 2010;33:2217–24. 2. Bailey et al. Lancet 2010;375:2223–33. 3. Nauck et al. Diabetes Care 2011;34:2015–22. 4. Strojek
et al. Diabetes Obes Metab 2011;13:928–38. 5. Jabbour et al. Diabetes Care 2014;37:740–50. 6. Rosenstock et al. Diabetes Care 2012;35:1473–8. 7. Wilding et al. Ann Intern Med 2012;156:405–15.SBP mean change
from baseline (mmHg)*n75 70
119122401400145151
108108 111101139140
193
194
NA
NA
128
126
134
133
133
132
NA
NA
139
141
NA
NA
136
141
Week 8
in patients
with SBP
≥ 130 mmHg at baseline
NA
NA
n
BL SBP
(mmHg)
Study
PBO +
SITA ± MET
PBO
PBO
+ MET
GLP + MET
PBO +
GLM
PBO +
PIO
PBO +
INS
PBO +
SU + MET
Add-on
INS
7
Mono-
therapy
1
Add-on
MET
2
Add-on
MET
vs
GLP
3
Add-on
GLM
4
Add-on
PIO
6
Add-on
SU + MET
Add-on
SITA ± MET
5
Comparator
74
Back
Slide75Dapagliflozin lipid profile (24-week data, SPC)
75
Forxiga
®
10-mg
film-coated tablets [SPC
]. AstraZeneca UK Limited. 2015.
LDL-C
HDL-C
Triglycerides
Total cholesterolBack
Slide76Dapagliflozin: Pooled safety analysis from
12 placebo-controlled trials (12–24 weeks)
1,2
Overall incidence of AEs with dapagliflozin 10 mg was similar to placebo
Few AEs led to treatment discontinuation and were balanced across groups
Most commonly reported events leading to discontinuation with dapagliflozin 10 mg: increased blood creatinine (0.4%), UTIs (0.3%), nausea (0.2%), dizziness (0.2%) and rash (0.2%)
1
76
See notes for Footnotes.1. Forxiga 5-mg and 10-mg film-coated tablets [SPC]. Bristol-Myers Squibb/AstraZeneca EEIG, 18 December 2013. https://www.medicines.org.uk/emc/medicine/27188/SPC/Forxiga+5+mg++%26+10+mg+film+coated+tablets/. Accessed: February 2014.
2. Forxiga (dapagliflozin) tablets. US Prescribing Information; BMS/AstraZeneca, January 2014.
Common AEs2Placebo (n = 1393)Dapagliflozin 5 mg (n = 1145)Dapagliflozin 10 mg
(n = 1193)Genital mycotic infectionsFemale*
1.58.46.9Male†0.32.8
2.7Nasopharyngitis6.26.66.3UTI‡3.75.7
4.3
Back pain
3.2
3.1
4.2
Increased urination
§
1.7
2.9
3.8
Nausea
2.4
2.8
2.5
Influenza
2.3
2.7
2.3
Dyslipidaemia
1.5
2.1
2.5
Constipation
1.5
2.2
1.9
Discomfort with urination
0.71.6
2.1Pain in extremity
1.42.0
1.7Volume depletion¶
0.40.6
0.8Back
Slide77Canagliflozin: HbA
1c
change from baseline in Phase III trials
77
*p < 0.001 vs comparator.
†
Least-squares
mean adjusted for baseline
value
.
Invokana (canagliflozin) tablets Prescribing Information. Janssen Pharmaceuticals, Inc., March 2013.HbA1c mean change from baseline (%)†
****
**nBL HbA1c (%)*
****
*
*
*
Weeks
Add-on
MET + SU vs SITA
52
Mono-
therapy
26
Add-on
MET
26
Add-on
SU
18
Add-on
MET + SU
26
Add-on
MET vs GLM
52
Add-on
MET + PIO
26
Add-on
INS
1
1
8
Placebo-controlled
PBO +
INS
PBO
PBO
+ MET
PBO +
SU
PBO +
SU + MET
GLM + MET
SITA +
MET + SU
PBO +
MET + PIO
Comparator
Active-controlled
192
195
197
183
368
367
45
42
40
156
157
156
115
113
114
565
566
587
482
483
485
378
377
7.97
8.06
8.01
7.96
7.94
7.95
8.49
8.29
8.28
8.12
8.13
8.13
8.007.997.848.20
8.338.277.837.78
7.79
8.138.12
Back
Slide78Canagliflozin: Body weight change from baseline
in Phase III trials
78
*p
< 0.001
vs
comparator.
†
Least-squares
mean adjusted for baseline value.Invokana (canagliflozin) tablets
Prescribing Information. Janssen Pharmaceuticals, Inc., March 2013.Body weight mean change from baseline (kg)†
192195197183368
367156157156
115113114565566
587
482
483
485
378
377
87.5
85.9
86.9
86.7
88.7
85.4
90.8
93.5
93.5
94.0
94.2
94.4
97.7
96.9
96.7
86.6
86.8
86.6
89.6
87.6
*
*
*
*
*
*
*
*
*
*
*
*
*
Weeks
Placebo-controlled
Add-on
INS
1
8
PBO +
INS
Mono-
therapy
26
PBO
Add-on
MET
26
PBO
+MET
Add-on
MET + SU
26
PBO +
SU + MET
Add-on
MET + PIO
26
PBO +
MET + PIO
Add-on
MET vs GLM
52
GLM + MET
Add-on
MET + SU vs SITA
52
SITA +
MET + SU
Comparator
Active-controlled
n
BL BW
(kg)
Back
Slide79Canagliflozin: SBP change from baseline vs comparator in Phase III trials
79
*p < 0.05, **p < 0.001 vs
comparator.
†
Least-squares
mean adjusted for baseline
value
.
1. Stenlof et al. Diabetes
Obes Metab 2013;15:372–82. 2. Invokana (canagliflozin) tablets Prescribing Information. Janssen Pharmaceuticals, Inc., March 2013. 3. Schernthaner et al. Diabetes Care 2013;36:2508–15.SBP mean difference from comparator (mmHg)
†nBL SBP (mmHg)
192195368367
113114
566
587
375
127
129
NA
NA
NA
NA
NA
NA
131
**
**
**
**
**
**
*
*
**
NA
NA
Weeks
Placebo-controlled
Add-on
INS
2
1
8
PBO +
INS
Mono-
therapy
1
26
PBO
Add-on
MET
2
26
PBO
+MET
Add-on
MET + SU
26
PBO +
SU + MET
Add-on
MET + PIO
2
26
PBO +
MET + PIO
Add-on
MET vs GLM
52
GLM + MET
Add-on
MET + SU vs SITA
3
52
SITA +
MET + SU
Comparator
Active-controlled
Back
Slide80LDL-C
HDL-C
Triglycerides
Total
c
holesterol
Canagliflozin lipid profile (pivotal studies, SPC)
80
Invokana
®
100-mg and 300-mg film-coated tablets [SPC]. Janssen-Cilag Ltd. 2015.
Back
Slide81Canagliflozin: General safety profile
Pooled analysis from 4 placebo-controlled trials* at 26 weeks
81
See notes for Footnotes.
Invokana
(canagliflozin) tablets
Prescribing Information.
Janssen Pharmaceuticals, Inc. , March 2013.
Abdominal pain also more commonly reported in patients taking
canagliflozin 100 mg (1.8%) and
300 mg (1.7%) than in patients taking placebo (0.8%)Adverse reactions occurring in ≥ 2% of canagliflozin-treated patients (%)
Placebo (n = 646)Canagliflozin100 mg (n = 833)Canagliflozin300 mg (n = 834)
Genital infections Male†0.64.23.7
Female‡3.210.411.4Urinary tract infection§4.05.9
4.3
Volume depletion
¶
1.5
2.3
3.4
Thirst
#
0.2
2.8
2.3
Constipation
0.9
1.8
2.3
Vulvovaginal
pruritis
0.0
1.6
3.0
Increased
urination
**
0.8
5.34.6
Back