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Cardiovascular Safety of DPP IV
Antagonists: A Cardiologist’s View
Jonathan Howlett MD FRCPC FACC
Clinical Professor of Medicine
Libin Cardiovascular Institute
University of Calgary
Faculty/Presenter Disclosure
• Faculty: Jonathan Howlett
• Relationships with commercial interests:
• Grants/Research Support: AstraZeneca,
•
Merck,
Servier, Medtronic
Consulting Fees: AstraZeneca, Novartis, Merck,
Servier, Pfizer, Medtronic, Abbott
• I DO PLAN TO DISCUSS OFF LABEL USE OF
MEDICATIONS!!
Jon’s
• Review findings of the
SAVOR TIMI-53 Study
• Review findings of the
EXAMINE Study
• Discuss importance of
HF hospitalization as an
outcome
• Consider impact of
SAVOR and EXAMINE in
context
SAVOR-TIMI 53: Background Information
• Saxagliptin is a selective DPP-4 inhibitor1,2
– Indicated as an adjunct to diet and exercise to improve glycemic control in
adults with T2DM in multiple clinical settings2
– Reduces fasting and postprandial glucose concentrations and HbA1c in
T2DM patients2,3
• Pooled data from 8 Phase 2/3 studies with >4600 patients
demonstrated a reduction in CV events with saxagliptin vs
comparators; 0.7% vs 1.4% (RR: 0.44; 95% CI: 0.24-0.82)4
– CV events were not adjudicated; overall event rate was low (41 events)
• SAVOR-TIMI 53 was designed to meet an FDA postmarketing
requirement to assess long-term CV impact of all antidiabetic
agents approved since 20085,6
CI: confidence interval; CV: cardiovascular; DPP-4: dipeptidyl peptidase-4; FDA: US Food and Drug Administration;
HbA1c: hemoglobin A1c; RR: relative risk; T2DM: type 2 diabetes mellitus.
4
1. Augeri DJ, et al. J Med Chem. 2005;48;5025-5037; 2. Onglyza [prescribing information]; May 2013;
3. Scirica BM, et al. Am Heart J. 2011;162:818-825; 4. Frederich R, et al. Postgrad Med. 2010;122:16-27;
5. FDA. Guidance for Industry. 2008.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. Accessed Aug
2013; 6. Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684.
Study Design
N≈16,500
patients
Documented T2DM
and established CVD (secondary prevention) or multiple CV risk
factors (primary prevention)
RANDOMIZE 1:1 DOUBLE BLIND
SAXAGLIPTIN
2.5 mg/d or 5 mg/d
Dosing based on eGFR
PLACEBO
All other diabetes therapy per
treating doctors
Follow-up visits
Q6 months
Duration
Event driven;
≈1040 events required
Final Visit
Primary endpoint
CV death, non-fatal MI,
non-fatal ischemic
stroke
CVD: cardiovascular disease; eGFR: estimated glomerular filtration rate
Scirica BM, et al. Am Heart J. 2011;162:818-825. (Permission requested)
Key Inclusion and Exclusion Criteria
Inclusion Criteria1
Documented T2DM and HbA1c 6.5% and <12.0%; AND
Multiple risk factors:
History of Established CVD
• 40 yrs
OR
• Documented atherosclerosis
(coronary, cerebrovascular, PV)
• 55 yrs (male) or 60 yrs (female)
• 1 additional risk factor
(dyslipidemia, HTN, smoking)
Exclusion Criteria1,2
•Current or previous (within 6 months) incretin-based therapy†
•Acute vascular (cardiac or stroke) event <2 months before randomization
•Uncontrolled CV or metabolic risk factors
•Chronic dialysis, renal transplant, or serum creatinine >6 mg/dL
†Includes
other DPP-4 inhibitors and GLP-1 agonists
GLP-1: glucagon-like peptide 1; PV: peripheral vascular ; HTN = hypertension
1. Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684; 2. Scirica BM, et al. Am Heart J. 2011;162:818-825.
Baseline Demographic and Clinical Characteristics
Characteristic
Age, yrs - mean (SD)
Age ≥75 yrs - n (%)
Females - n (%)
Race - n (%)
White
Hispanic
Established atherosclerotic disease - n (%)
Hypertension - n (%)
Dyslipidemia - n (%)
Prior MI - n (%)
Prior heart failure - n (%)
Prior coronary revascularization - n (%)
Saxagliptin
Placebo
(N = 8,280)
65.0 (8.5)
1169 (14.1)
2768 (33.4)
(N = 8,212)
65.0 (8.6)
1161 (14.1)
2687 (32.7)
6241 (75.4)
1778 (21.5)
6494 (78.4)
6725 (81.2)
5895 (71.2)
3147 (38.0)
1056 (12.8)
3566 (43.1)
6166 (75.1)
1763 (21.5)
6465 (78.7)
6767 (82.4)
5844 (71.2)
3090 (37.6)
1049 (12.8)
3557 (43.3)
Yrs: years; SD: standard deviation; IQR: inter-quartile range; BMI: body-mass index
Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684.
Baseline Renal Function: Overall and Subgroups
Saxagliptin
Placebo
(N = 8,280)
(N = 8,212)
72.5 (22.6)
6986 (84.4)
1122 (13.6)
172 (2.1)
72.7 (22.6)
6930 (84.4)
1118 (13.6)
164 (2.0)
Albumin/creatinine ratio, mg/mmol –median (IQR) 1.8 (0.7–7.5)
1.9 (0.7–7.9)
eGFR, mL/min – mean (SD)
>50 mL/min – n (%)
30–50 mL/min – n (%)
<30 mL/min – n (%)
Albumin/creatinine ratio – n (%)
<3.4 mg/mmol
3.4–33.9 mg/mmol
>33.9 mg/mmol
Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684.
4867 (61.5)
2217 (28.0)
832 (10.5)
4829 (61.6)
2209 (28.2)
806 (10.3)
Kaplan-Meier Rates of the Primary Composite
Endpoint – CV Death, MI, or Stroke
Patients With Endpoints (%)
14
12
Saxagliptin: 7.3%*
10
Rate/100 person-yrs – 3.7
HR 1.00; 95% CI, 0.89–1.12
8
P≤0.001 (NI)
6
P=0.99 (superiority)
4
Placebo: 7.2%*
Rate/100 person-yrs – 3.7
2
0
0
Placebo
180
360
8212
7983
7761
Saxagliptin 8280
8071
7836
Days
540
720
900
7267
4855
851
7313
4920
847
*K-M event rates are presented after 2 yrs.
HR: hazard ratio; K-M: Kaplan-Meier; Pbo: placebo; Saxa: saxagliptin
Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684.
9
Primary and Secondary Endpoints
Saxagliptin
Placebo
n (%; rate)* n (%; rate)*
(N = 8,280) (N = 8,212)
Primary endpoint
CV death, MI, or
stroke
Secondary endpoint
CV death, MI,
stroke, hosp for UA,
HF, or coronary
revasc
All-cause mortality
HR
(95% CI)
P value P value
NI Superiority
613
(7.3; 3.7)
609
(7.2; 3.7)
1.00
<0.001
(0.89-1.12)
1059
(12.8; 6.6)
1034
1.02
(12.4; 6.5) (0.94-1.11)
0.66
420 (4.9)
378 (4.2)
1.11
(0.96-1.27)
0.15
0.99
*% = K-M event rate at 2 yrs ; rate = rate/100 person-yrs
HF: heart failure; hosp: hospitalization: revasc: revascularization; UA: unstable angina
Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684.
10
Individual Components of the Composite Endpoints
Efficacy endpoint
Saxagliptin
Placebo
n (%)*
n (%)*
(N = 8,280)
(N = 8,212)
HR (95% CI)
P value
CV death
269 (3.2)
260 (2.9)
1.03 (0.87–1.22)
0.72
MI
265 (3.2)
278 (3.4)
0.95 (0.80–1.12)
0.52
Ischemic stroke
157 (1.9)
141 (1.7)
1.11 (0.88–1.39)
0.38
Hosp for UA
97 (1.2)
81 (1.0)
1.19 (0.89–1.60)
0.24
Hosp for HF
289 (3.5)
228 (2.8)
1.27 (1.07–1.51)
0.007
Hosp for
coronary revasc.
423 (5.2)
459 (5.6)
0.91 (0.80–1.04)
0.18
*K-M event rates are presented after 2 yrs.
Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684.
Adjudicated Causes of CV Death
Saxagliptin
Type
Placebo
n (%)*
(N = 8,280)
n (%)*
(N = 8,212)
269 (3.2)
260 (2.9)
Any CV death
HF
Acute MI
Cerebrovascular
Sudden cardiac death
Other
Presumed CV death
44 (0.5)
23 (0.3)
22 (0.3)
131 (1.6)
14 (0.2)
35 (0.4)
HR (95% CI)
1.03 (0.87-1.22)
40 (0.5)
19 (0.2)
35 (0.4)
109 (1.3)
15 (0.2)
42 (0.4)
*Event rates are presented after 2 yrs.
Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684.
P value
0.72
Changes in Antidiabetic and CV Medications Over Time
%
Baseline
Saxa
Pbo
n=
Metformin
SU
TZD
Insulin
Other
None
8280
69.9
40.5
6.2
41.6
0.6
4.1
8212
69.2
40.0
5.7
41.2
0.6
4.8*
n=
8280
8212
75.5
78.3
53.6
28.2
61.6
75.0
78.4
54.9
27.6
61.6
Aspirin
Statin
ACEi
ARB
β-blockers
Year 1
Year 2
Saxa
Pbo
Saxa
Pbo
Antidiabetic medications
7999
7943
5101
5059
69.6
70.1
70.0
69.9
39.7
40.4
39.2
39.5
5.4
5.2
4.7
4.7
42.3
43.6
42.5
45.8†
0.6
0.5
0.6
0.4
4.4
4.3
5.0
4.7
CV medications
7512
7405
3695
3603
77.3
80.8
52.8
29.7
62.6
77.3
80.8
54.2
29.8
62.5
72.7
77.1
52.9
29.7
58.3
72.4
78.7
53.1
31.3
57.2
*P = 0.0496; †P = 0.0008; P = not significant for all other endpoints shown.
Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684.
End of treatment
Saxa
Pbo
8041
69.4
39.8
4.9
43.8
0.7
4.5
8007
70.0
40.2
4.7
46.4†
0.6
4.0
7539
7498
77.7
80.5
51.8
30.0
62.8
78.0
81.1
52.4
30.3
62.4
Summary of Findings
• The SAVOR-TIMI 53 study of saxagliptin versus placebo
when added to standard of care in patients with T2DM
at high CV risk demonstrated:
– No increased risk of CV death, MI, or ischemic stroke
– Significantly improved glycemic control
– Prevented of deterioration in microalbuminuria
– Increased risk of hospitalization for HF
– Increased risk of hypoglycemia
– Rates of pancreatitis and pancreatic cancer similar to placebo
Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684.
Cardiovascular Outcomes With Alogliptin
in Patients With Type 2 Diabetes Mellitus
and Recent Acute Coronary Syndrome
William B. White, MD
for the EXAMINE Investigators
Cardiology Center, University of Connecticut School
of Medicine, Farmington, Connecticut USA
Sept-13 EUCAN/ALO/2013-10101
Objectives and End Points of EXAMINE
Primary objective: To demonstrate that major CV event rates are not higher
with alogliptin than with placebo in type 2 diabetes patients with recent ACS
who are receiving standard of care for diabetes and secondary CV prevention
– Primary end point: Composite of first occurrence of CV death, nonfatal
MI, and nonfatal stroke
Secondary objectives:
Superiority assessment: If non-inferiority is proven to demonstrate that
major CV event rates were lower on alogliptin than with placebo
Secondary end point: Evaluate the time from randomization to the first
occurrence of the expanded MACE:
– Composite of CV death, nonfatal MI, nonfatal stroke, and urgent
revascularization due to UA
– Major exploratory end points: all CV deaths, all-cause mortality
ACS=acute coronary syndrome; CV=cardiovascular; MI=myocardial infarction; UA=unstable angina.
White WB, et al. N Engl J Med. 2013. [Epub ahead of print]
Study Design
• Randomized, double-blind, placebo-controlled study of
alogliptin with diabetes standard of care versus placebo with
diabetes and cardiovascular standard of care
Alogliptina QD + standard of care (N=2701)
Treatment period (4.5 years)
Placebo QD + standard of care (N=2679)
Days –14
to –1
Day 1
Month 1
Month 12
Visits at months 3, 6, and 9
Screening
visit
End of
study
Visits every 4 months
Baseline/
randomization
QD=once daily.
aAt
randomization, patients assigned to receive 25, 12.5, or 6.25mg QD based on renal function. After
randomization, dose adjustments were allowed on the basis of changes in renal function.
White WB, et al. Am Heart J. 2011;162(4):620–626.
2-Week
follow-up
Study Patients
• Diagnosis of type 2 diabetes and receiving antihyperglycemic
therapy (single or combination therapies)
• Acute coronary syndrome* within 15 to 90 days before
randomization
• Receiving local standard of care for type 2 diabetes care and
secondary CV prevention (excluded were DPP-4 inhibitors and
GLP-1 agonists)
• Patients with unstable cardiovascular conditions or those on
dialysis within 14 days of planned randomization were excluded
*Myocardial infarction or hospitalized unstable angina
White WB, et al. N Engl J Med. 2013. [Epub ahead of print]
Baseline Patient Characteristics
Duration of diabetes
Median, years
BMI
Median, kg/m2
HbA1C level
Mean ± SD, %
Qualifying index ACS event
for trial entry, No. (%)
Myocardial infarction (MI)
Procedure-related MI
Unstable angina requiring hospitalization
Time from index ACS to randomization
Median, days
Alogliptin
(N=2701)
Placebo
(N=2679)
7.1
7.3
28.7
28.7
8.0 ± 1.1
8.0 ± 1.1
2084 (77)
180 (7)
609 (23)
2068 (77)
188 (7)
605 (23)
44
46
White WB, et al. N Engl J Med. 2013. [Epub ahead of print]
Baseline Cardiovascular Therapies
Alogliptin
(N=2701)
Placebo
(N=2679)
Medications administered at baseline, No. (%)
2630 (97)
Antiplatelet agents
Aspirin
2448 (91)
Thienopyridine
2155 (80)
2602 (97)
2433 (91)
2165 (81)
Statins
2446 (91)
2420 (90)
β-Blockers
2208 (82)
2203 (82)
Renin-angiotensin
system blockers
2201 (82)
2210 (83)
White WB, et al. N Engl J Med. 2013. [Epub ahead of print]
Time to Primary End Point
(CV Death, Nonfatal MI, Nonfatal Stroke)
Cumulative Incidence of the
Primary End Point (%)
Hazard ratio, 0.96 (* one-sided repeated CI bound, 1.16)
Events, No. (%)
Placebo: 316 (11.8)
Alogliptin: 305 (11.3)
Months
Placebo (n):
Alogliptin (n):
2679
2701
2299
2316
1891
1899
1375
1394
* Using alpha=0.01.
White WB, et al. N Engl J Med. 2013. [Epub ahead of print]
805
821
286
296
Primary End Point by Components
Hazard Ratio for
Alogliptin Group
(95% CI)
Alogliptin
(N=2701)
Placebo
(N=2679)
305 (11.3)
316 (11.8)
0.96
(≤1.16)*
CV death
89 (3.3)
111 (4.1)
0.79
(0.60 to 1.04)
Nonfatal MI
187 (6.9)
173 (6.5)
1.08
(0.88 to 1.33)
Nonfatal stroke
29 (1.1)
32 (1.2)
0.91
(0.55 to 1.50)
Primary end point: CV
death, nonfatal MI, or
nonfatal stroke, No. (%)
*99% one-sided confidence interval, P<0.001 for non-inferiority
White WB, et al. N Engl J Med. 2013. [Epub ahead of print]
Other End Points
Any CV Death
Hazard ratio, 0.85 (95% CI = 0.66 to 1.10)
Secondary End Point
Hazard ratio, 0.95 (*one-sided repeated CI bound, 1.14)
All-Cause Mortality
Hazard ratio, 0.88 (95% CI = 0.71 to 1.09)
* Using alpha=0.01.
White WB, et al. N Engl J Med. 2013. [Epub ahead of print]
Summary
• Rates of major adverse cardiovascular events were similar with
alogliptin compared with placebo in patients with type 2
diabetes and recent acute coronary syndromes
• This observation occurred in the following context:
– Significantly lower HbA1C level (–0.36%) with alogliptin
– High overall CV event rate (11% over the median follow-up of 18
months)
– High levels of standard of care for both diabetes and cardiovascular
prevention
• Outcomes were similar for the secondary end point (composite
of CV death, nonfatal MI, nonfatal stroke, urgent
revascularization due to UA)
White WB, et al. N Engl J Med. 2013. [Epub ahead of print]
The meaning of these trials
• Not all HF outcomes are the same
– Type of New diagnosis
– Admission
– HF Death
• Biomarker profile
• Pre-event outcomes
• Post-event outcomes
Arnold et al, ACC 2012
The Major Types of Heart Failure
Hospitalizations
Worsening chronic
heart failure (75%)
De novo
heart failure (23%)
Advanced/ end-stage
heart failure (2%)
Fonarow GC. Rev Cardiovasc Med. 2003; 4 (Suppl. 7): 21
Cleland JG et al. Eur Heart J. 2003; 24: 442
Mechanisms for inflammatory
immune activation in CHF
Adrenergic nervous system
RV LV
LPS
Pro-inflammatory
Tissue injury
Translocation
Bowel wall
oedema
Hypoxia
Immune activation
Tissue
underperfusion
Anker SD, von Haehling S. Heart 2004; 90: 464-70
cytokine activation
Myocardial production
HF Evolution:
Daily mortality rate and log NT-BNP level
Hospital Admission
Circulation. 2012;126:65-75
EJHF (2011) 13, 142–147
Circulation. 2000;102:1127-1131
All-Cause Mortality Increases
With Each Hospitalization
Adapted from Setoguchi S et al. Am Heart J. 2007;154:260-266.
How Do SAVOR and EXAMINE Measure Up?
SAVOR TIMI 53
– Stable patients
EXAMINE
– Post ACS patients
• HF specifically separated • HF NOT specifically
mentioned
– Mechanism unknown
– Further data needed
• Isolated CV event noted
in past (PPARs)
– HF signal then did not
portend worse prognosis
– Need further data
• No conclusions vs. SAVOR
until HF data known
• Real world registry data
needed
Implications for a Cardiologist
• These results will not concern most cardiologists
– CV safety of these two DPP IV agents has been
established
• No further CV reduction is present
• Reasonable reduction in BS noted
• Most Cards support the most recent CDA relaxation of BS
control guidelines
– The HF signal needs further work
• What happens to biomarkers
• Is there an increased event rate in the future