Cardiologists view of recent diabetes outcome trials:
translational considerations
CAROLINA
TECOS Pending
Stable T2DM Acute coronary syndrome
EXAMINE** SAVOR**
Yearly CV
event rate ACS-7-8% maybe Stable-2-4% maybe
** No CV benefit found
DPPIV inhibitors
All type 2 DM
38 year old Hispanic male
Fight with son
Develop mild chest pressure
History of T2DM – 6 years
2/6/2014
3
48 y/o
Type 2 diabetes
The trials
Meta-analysis of DPP-4 Inhibitors predicted a
cardiovascular protective effect
52% reduction in risk for CV events compared to other oral agents or placebo.
Patil Am J Cardiol. 2012;110(6):826-833.
First Author DPP4i Comparator Risk Ratio
M-H, Random, 95% CI
Risk Ratio
M-H, Random, 95% CI Events Total Events Total Weight
Aschner 1 528 3 522 3.7% 0.33 (0.03, 3.16)
Bosi E 1 300 2 294 3.3% 0.49 (0.04, 5.37)
Chan 10 65 12 26 37.7% 0.33 (0.16, 0.67)
Defronzo 2 264 0 64 2.1% 1.23 (0.06, 25.54)
Foley 0 546 0 546 Not estimable
Foley Je 0 29 0 30 Not estimable
NCT00316082 4 291 3 74 8.6% 0.34 (0.08, 1.48)
NCT00374907 0 20 1 16 1.9% 0.27 (0.01, 6.21)
NCT00698932 4 284 0 284 2.2% 9.00 (0.49, 166.39)
NCT00918879 0 107 0 106 Not estimable
NCT01263496 5 391 0 83 2.3% 2.36 (0.13, 42.22)
Pfuntzer 2 335 7 328 7.7% 0.28 (0.06, 1.34)
Pi-Sunyer 0 262 0 92 Not estimable
Rosenstock 11 306 3 95 11.9% 1.14 (0.32, 4.00)
Rosenstock J 0 396 0 202 Not estimable
Schweitzer 2 169 2 166 4.9% 0.98 (0.14, 6.89)
Schweitzer A 0 526 2 254 2.0% 0.10 (0.00, 2.01)
Williams-Herman
3 179 11 364 11.7% 0.55 (0.16, 1.96)
Total (95% CI) 4998 3546 100.0% 0.48 (0.31,0.75)
Total events 45 46
Heterogeneity: Tau2 = 0.00; Chi2 = 11.22, df = 12 (P = 0.51); I2 = 0% Test for overall effect: Z = 3.28 (P = 0.001)
0.001
DPP4i better
0.1 1 10 1000
DPP4i worse
SAVOR-TIMI EXAMINE
Population Established CV disease, age ≥ 40
OR
Multiple CV risk factors: age ≥55 (male) or
≥60 (female) and at least one of the
following: dyslipidemia, hypertension or
active smoking
Acute coronary syndrome within
15-90 days, age ≥ 18
Sample Size N=16,492 N= 5,380
A1C Range 6.5%-12.0% 6.5%-11.0%
Baseline A1C 8.0% 8.0%
Primary Endpoint Composite of CV death,
nonfatal MI, nonfatal stroke
Composite of CV death, nonfatal
MI, nonfatal stroke
Planned/Actual #
Events
1040/1222 650/621
Median Duration of
Follow-up
2.1 years 1.5 years
Scirica BM Am Heart J 2011;162:818-825.e6
White WB, et al. Am Heart J. 2011;162:620-626.
More hospitalizations for heart failure in saxagliptin-
treated group (SAVOR)
Saxagliptin
(N=8,280)
Placebo
(N=8,212) HR
p value for
superiority
CV Death 3.2 2.9 1.03 (0.87-1.22) 0.72
MI 3.2 3.4 0.95 (0.80-1.12) 0.52
Ischemic Stroke 1.9 1.7 1.11 (0.88-1.39) 0.38
Hosp for Cor. Revasc 5.2 5.6 0.91 (0.80-1.04) 0.18
Hosp for UA 1.2 1.0 1.19 (0.89-1.60) 0.24
Hosp for Heart
Failure 3.5 2.8 1.27 (1.07-1.51) 0.007
All-Cause Mortality 4.9 4.2 1.11 (0.96-1.27) 0.15
ITT Population 2-year KM rate (%)
n engl j med 369;14:1317
Highest NT-proBNP predicts increased risk
for HF hospitalizations in SAVOR
0
2
4
6
8
10
12
Quartile 1(<64BNP)
Quartile 2 Quartile 3 Quartile 4(>333 BNP)
0.1 1.10
2.20
10.90
0.1 0.30
2.00
8.90 Saxagliptin
Placebo
Ho
sp
ita
liza
tio
n f
or
he
art
fa
ilu
re (
%)
P<0.024
No increase in mortality
Best predictor of HF is prior history
N=387 HF events
Hazard ratio 1.27 ;( 95%CI 1.07-1.51)
(p<0.007)
n engl j med 369;14:1317
EASD 2013
EXAMINE-post ACS
Fix and then enroll 15-90 days
Alogliptin-2701
Placebo-2679
N Engl J Med 2013;369:1327-35
Baseline
BMI
Duration of DM
Hypertension
Prior HF
Prior MI
Prior revascularization
Mean HbA1c
GFR >60 cc/min
ASA
Statins
ACEI
N Engl J Med 2013;369:1327-35
Alogliptin Control
28 28
7.1 years 7.3 years
82% 83%
28% 27%
77% 77%
74% 74%
8.0 8.0
71% 70%
91% 91%
90% 90%
82 82
Saxagliptin Control
31 31
10.3 years 10.3 years
81% 82%
12.8% 12.8%
38% 37%
43% 43%
8.0 8.0
84% 84%
75% 76%
78% 78%
? ?
EXAMINE-ACS SAVOR-Stable CAD
Comparison of demographics
Primary endpoint by components Alogliptin Placebo Hazard ratio
Primary EP:
Death, MI, CVA
11.3% 11.8% NS
CV death 3.3% 4.1% NS
Non fatal MI 6.9% 6.5% NS
Non fatal CVA 1.1% 1.2% NS
Alogliptin Placebo Hazard ratio
All cause death 3.9% 4.9% NS
HF
hospitalization
3.1% 2.9% NS
Hx of HF 18.1% 22.3% NS
Exploratory adjudicated components
EXAMINE N Engl J Med 2013;369:1327-35
Hospitalization for heart failure
Naveed Sattar
13% of patients had heart failure at baseline in SAVOR
NT pro-BNP (333 to 44000 pg/ml) SAVOR
0
0.5
1
1.5
2
2.5
3
3.5
4
Saxagliptin Placebo Placebo Alogliptin
3.5
2.8 2.9
3.8
% hospitalization for heart failure
Saxagliptin
Placebo
Placebo
Alogliptin
% incid
ence o
f hospitaliz
ations f
or
heart
failu
re
EXAMINE Prior history of heart failure-28%
SAVOR Prior history of heart failure-13%
Percent hospitalizations for heart failure
Diabetes and heart failure is complex
14
Co-occurrence with
heart failure?
Hyperglycemia / IR
Etiology of HF?
Systolic / dysfunction
Myofibrosis
↑ oxidative stress
↑ renal dysfunction
↑ autonomic dysfunction
Impaired gas exchange
↓ functional status
Other unknown
Insulin
resistance
Glucose
toxicity
Chilton 2014 pending publication
Heart failure is common in type 2
diabetes
Retrospective cohort
study. PharMetrics
integrated claims
database, Medicaid,
Medicare and 60 pvt
health care HMO
N=50 million lives
>1995
Incidence rates of
CV events in type 2
diabetes patients on
insulin
0
50
100
150
200
250
MI Stroke Heart failure
97
151
243
per 10,000 person-years
Duration of diabetes- positively associated
with the incidence rate of
fatal CVD both type 1 and 2 diabetes
Pharmacoepidemiology and drug safety 2009; 18: 497–503
1513 patients
were enrolled
Randomized,
double-blind
Type 2 diabetes
Losartan (50 to
100 mg once
daily) with
placebo
3.4 yr follow up
16
EFFECTS OF LOSARTAN ON RENAL AND CARDIOVASCULAR OUTCOMES
IN PATIENTS WITH TYPE 2 DIABETES AND NEPHROPATHY (RENAAL)
Hazard ratio for mortality was 5·98
(95% CI 3·90–9·17, p<0·0001)
Circulation. 2006;113:1588
Lancet Diabetes Endocrinol 2014 pending
Diabetes with heart failure
Diabetes no heart failure
Translational science considerations with DPP-4 inhibitors
Vulnerable plaques in
type 2 diabetes
8 months later
30 y/o/ Hispanic
type 2 DM male
A1c 8.5
NIRS-IVUS
Cellular pleotrophic effects of
DPP IV inhibitors
Increase phosphorylation of
endothelial NO synthase (eNOS)
Proliferation
Senescence /apoptosis
Atheroprotective
Anti-thrombotic
Circ J 76:2497
Circ 97:2494
↑ cAMP/protein kinase A
JACC 59:265
Atheroprotective
↑ GLP-1 & other pathways
Mol Cell Endo 325:26
Anti-inflammatory effects of
DPP IV inhibitors
J Clin Endo Metab 2012;97:3333
DPP-4 inhibitors: Non heart failure model and heart failure model
DPP-4 inhibition significantly reduces DPP-4
activity in insulin resistant animals
Insulin resistant Zucker lean (ZL) and ZO obese rats known to have diastolic dysfunction
DPP 4 inhibitor vs control
2D echo and heart cath 16 wks
Aroor-Sowers et at Endocrinology May 7,
2013 as doi:10.1210/en.2013-1096
DPP-4 inhibition improves diastolic dysfunction
Insulin resistant
obese rats
known to have
diastolic
dysfunction
DPP IV inhibitor
vs control
Aroor-Sowers et at
Endocrinology May 7, 2013
doi:10.1210/en.2013-1096
DPP 4I
DPP-4 inhibitors: atherosclerosis
DPP-4 inhibitors repress foam cell formation by inhibiting
scavenger receptors (recognize oxLDL)
Scavenger receptors
LOX-1 (macrophages)
CD-36
DPP-4 inhibitors
Sitagliptin
NVPDPP728
THP-1 macrophages studied in
presence and absence of
oxidized LDL
Scavenger receptors are a group of receptors that recognize
modified low-density lipoprotein (LDL) by oxidation or acetylation
Acta Diabetol-2014 print
DOI 10.1007/s00592-013-0541-3
oxLDL added
Control
Foam cell formation
1
2
3
4 Relative protein expression Anti-inflammatory: expression
of IL-6 was significantly inhibited
Improving metabolic inflexibility
with DPP IV inhibitor
New information
Diabetes and heart failure assumed to be
ischemic…now new evidence direction
relation to T2DM
○ Diabetes Metab 1997;23:213
○ Ann Epidemiol 1994;4:67-74
18F-FDG-PET/computerized
tomographic (CT) scans
12 patients-non ischemic CM
Glucose Fatty acids Myocardial insulin
needed to have
substrate switch
Insulin resistance states impairs shift
Hypertension
Ischemia
Diabetes
Others
JACC 51:93
Circ 105:1727
Circ 106:2043
Myocardial glucose uptake
Patient 1-non responder
Patient 2-responder
Baseline
DPP 4 inh
Baseline
DPP 4 inh
18F-FDG-PET
J Cardiac Fail 2012;18:804
Incretins reduce prothrombosis risk: DPP-4
Inhibitor reduces platelet aggregation
N=50 T2DM
patients
N=10 controls
Platelet
aggregation
testing
Platelet inhibitors
NO, prostacyclin (PGI2)
and reduce cellular Ca++
levels
0
10
20
30
Baseline 1 month 3 months
Type 2DM
% i
nh
ibit
ion
DPP 4 inhibition
Sitaglipin significantly inhibited
platelet aggregation-(dose
dependency- 40% @ 10 ug/ml)
P<0.0001
Gupta et al Platelets 2012: Sept 5 early
Closing comments
Ongoing, prospective clinical trials of DPP-4 inhibitors
with cardiovascular outcomes
DPP-4
inhibitor
Trial name Trial design Patient
characteristics
Primary end
point
Linagliptin CARdiOvascular
outcome study
of LINAagliptin
versus
glimepiride in
patients with
type 2 diabetes
(CAROLINA)
n=6,000
5mg vs
glimepiride 1–
4mg
Noninferiority
and
superiority trial
HbA1c 6.5–8.5%
High
cardiovascular
risk
Time to the first
occurrence of
nonfatal MI,
nonfatal stroke,
hospitalization for
unstable
angina, or
cardiovascular
death
Sitagliptin Trial Evaluating
Cardiovascular
Outcomes with
Sitagliptin
(TECOS)
n=14,000
50mg or 100mg
vs placebo
Noninferiority
trial
HbA1c 6.5–8.0%
History of
cardiovascular
disease
Time to first
confirmed
cardiovascular
event (nonfatal MI,
nonfatal stroke, or
hospitalization
for unstable
angina)
Pending publication-Chilton
TECOS Am Heart J 2013;166:983-989.e7
DPP-4 inhibitor considerations
Class Effect?
Don’t use in patients with diastolic
dysfunction?
Don’t use if history of HF?
Measure NT proBNP first?
Wait for TECOS?
Translational
considerations
Play of chance?
GLP-1
GIP
Improved diastolic relaxation in animals
Improved substrate utilization
J Physiol 2011;589:3309
ACEI drug interaction
DPP4 inhibition neuropeptide Y Vasoconstriction of microcirculation increases circulating blood volume
Pharmacological differences?
Figure 8
Closing comments
CV overview-2014
CRP LDL BP PPG Weight
loss
CV
events
Side
effects
SGLT2
Inhibitor
? yes
Statins 0 ?/ 0 YES
ARR 3-
4%
yes
TZD ++/- + /- yes
DPP 4
Inhibitor
+ /- +/- 0 No (HF?) yes
10%
weight
loss
ARR 1-
2%
Hunger
Endo-
barrier
? ? + / - ? ? yes
Gastric
bypass
YES /
SOS
yes
30
Thank you
Texas and Murmur
