Trial Evaluating

Cardiovascular
Outcomes With
Sitagliptin (TECOS)
Cardiovascular
Muh A Sungkar
Safety
Trial

Cardiology Division, Department Internal Medicine

Diponegoro University / Kariadi Hospital
 Agenda
CV outcome trials in diabetic
patients
FDA guidelines for CV safety of
anti-diabetic drugs
Selected Cardiovascular Outcome
Trials Among DPP-4 Inhibitors
Trial Evaluating Cardiovascular
Outcomes With Sitagliptin
ARDIOVASCULAR OUTCOME
IN PATIENS WITH DIABETES
 Diabetes Is Associated With
Increased Risk of CV Disease
Diabetes confers an increased risk for MI,
stroke, and
PAD1-3
It is not clear whether diabetes should be
considered a
cause or a comobidity of heart failure4
- Diabetes is associated with an increased
risk of
developing HF in patients with other causes
(eg, acute
merging Risk Factors Collaboration. Lancet.2010;2215-22. 2. American Diabetes Association. Diabetes Care.2003;26:333
MI)Association.
American Diabetes and Diabetes
is believed to 4.promote
Care.2014;37:S14-S80.
Gregg EW et el. Ann Int.Med.2007;147:149-56.
McMurray JJV et al.diastolic
Lancet Diabete Endocrinology.201

dysfuntion
 Heart failure in patient with type 2
Diabetes1
Retrospective cohort study to Incidence of CHF
(cases per 1,000 person-years)
update 35
estimates of CHF in patients 30 30.9
with
25
T2DM
20 P<0.001
- Follow-up of up to 73
months 15
12.4
1,167 of 8,231 patients with 10
T2DM
5
had incidence CHF, vs 536
0
of 8.845
patients without T2DM Without Diabetes
With Diabetes

Patients with T2DM

experience CHF
A GUIDELINES FOR CV SAFE
OF ANTI-DIABETIC DRUGS
 FDA Guidance for Industry to
Evaluate CV Risk in New
Antihyperglycemic Medications
July 2008: In order to establish the safety
1

of a new antihyperglycemic medication to

treat T2DM, FDAs Endocrinologic and
Metabolic Drugs Advisory Committee
provided guidance on risk assessment
Effects on CV risk to be more thoroughly addressed
during antihyperglycemic medication development
Recommendation to demonstrate that therapy will
not result in unacceptable increase in CV risk
Key areas to be addressed by study sponsors
(inclusion of patients with a higher risk of CV events
[eg, patients with advanced CV disease, elderly
patients,
FDA = Food and Drug Administration; T2DM = type and patients
2 diabetes mellitus; CV = cardiovascular.with impaired renal function],
1. Center for Drug Evaluation and Research. Guidance for Industry: Diabetes MellitusEvaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes.
study duration 2 years)
December 2008. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. Accessed September 12, 2014.
 FDA Statistical Criteria for Approval1
Five hypothetical examples of possible HRs, and regulatory consequences
Noninferiority Noninferiority
Boundary Boundary
HR 1.3 HR 1.8
BEST
Approvable; Superiority
CV safety study
post approval
may not be required Noninferiority

Approvable; need for

Noninferiority
CV safety study

Inferiority
Not approvable
Underpowered

0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2
Hazard ratio
FDA = Food and Drug Administration; HR = hazard ratio; CV = cardiovascular.
1. Reproduced with permission from Hirshberg B et al. Diabetes Care. 2011:34 (Suppl 2);S101S106.
LECTED CV OUTCOME TRIAL
AMONG DPP-4 INHIBITORS
ose of CV Outcomes Trials With DPP-4 inhib

outcomes trials for DPP-4 inhibitors are designed to

monstrate no increased CV risk vs placebo when use
rt of usual care1-3,a
outcomes trials for DPP-4 inhibitor are not designed
valuate a CV benefit of HbA1c reduction3-5
bA1c is intended to be similar between the two groups throug
adjusment of antihyperglycemic medications according to lo
treatment guidelines
CV safety and CV benefit can be evaluated independently of
HbA1c

s enrolled in CV outcomes trial with DPP-4 inhibitors have a high risk of CV events(ie, have established CV diseae or multiple CV risk factors.)
WB et al. Am Heart J. 2011;162:620-6.e7. 2.Scirica BM et al. Am Heart J. 2011;162:818-25.e6.3.Green JB etal.Am Heart J.2013;166:983-9.e7.
WB et al. N Engl J Med. 2013;369:1327-35. 5.Scirica BM et al. N Engl J Med. 2013;369:1317-26
Traditional CV Outcome Trials vs
DPP-4 Inhibitor CV Outcome Trials
itional CV outcome trials1,2
onstate CV benefit (lower CV risk vs placebo or active comparator)
4 inhibitor CV outcome trials3-5
onstrate CV safety (no increased CV risk vs placebo as part of standart
aditiona (eg, LDL-C) CV Outcome Trials DPP-4
1,2
Inhibitor CV Outcome Trials
nitiation of blinded treatment or placeboInitiation of blinded treatment or placebo
No adjusment Adjusment
to maintain to maintain
LDL-C levels the HbA1c levels the
same in booth
groups same in both
groups
Difference in LDL-C Small or no difference in
between treatment and HbA1c
placebo between treatment and
placebo
CV benefit of treatment demonstrated by No increased CV risk (CV safety) of
significant reduction in CV outcomes
Treatment demonstrated by no inferiority
CV = cardiovascular; DPP-4 = dipeptidyl peptidase-4; LDL-C = low density lipoprotein cholesterol.
1. Heart Protection Study Collaborative Group. Lancet. 2002;360:722. 2. Heart Protection Study Collaborative Group. Lancet. 2003;361:20052016. 3. White WB et al. N Engl J Med.
2013;369:13271335. 4. Scirica BM et al. N Engl J Med. 2013;369:13171326. 5. Green JB et al. Am Heart J. 2013;166:983989.e7.
seline Risk of Patients Populations Enrolled in
fety Trials of DPP-4Inhibitors

Risk Factors Stable CAD-CVD-PAD Post ACS patients

Alogliptin EXAMINE Presented
(N=5.380)1 Sept.2013
ACS within 15-90 days
Saxagliptin SAVOR-TIMI (n=16.492)2 Presented
Pre-existing CVD or multiple risk factor for CVD Sept.2013

Sitagliptin TECOS (N= 14.000)3

End Dec..2014
Pre-existing CVD

Linagliptin CARMELINA (N=8.300)4

Pre-existing CVD + albuminuria or impairement End Dec..2018
renal function

Vildagliptin does not have an ongoing CV outcomes trial

WB et al. N Engl J Med. 2013;369:1327-35,2. Scirica BM et al. N Engl J Med. 2013;369:1317-26.3.Green JB etal.Am Heart J.2013;166:983-9.e7.
ELINA: Cardiovascular and renal microvascular outcome study with linagliptin in patiens with type 2 diabetes at high vascular risk.
AL EVALUATING CARDIOVASCUL
COMES WITH SITAGLIPTIN (TEC
TECOS: Study Objective1
assess cardiovascular outcomes and clinical safety of long-term treatme

h sitagliptin used as part of usual care compared with usual care without

agliptin in patients with type 2 diabetes and a history of cardiovascular

sease and inadequate glycemic control

COS will primarily test the hypothesis that sitagliptin, when used as part

usal diabetes care, is noninferior to usual care without sitagliptin with re

the risk of significant confirmed cardiosvacular outcomes

sitagliptin is found to be noninferior to usual care without sitagliptin, an

sessment of superiority will be performed

TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin

Green JB et al. Am Heart J. 2013;166:983-9.e7
TECOS: Study Design1
andomized, double blind, placebo-controlled safety study
pproximately 14,000 patients with type 2 diabetes
vent-drivent trial that will continue until 1,300 confirmed CV events have
ccurred
tegrted study design with no interruption of usual care a
Sitagliptin vs placebo will be added to the ongoing care regimen
esired outcome of glycemic equipoise between treatment arms to asses
ffects of sitagliptin independent of glucose-lowering effects
nce daily sitagliptin 50-100 mg oral tablet at randomization, dose
pendent on renal functiom
Dose could be reudeuced to 50 mg or 25 mg once daily during the study

re defined as stable-dose monotherapy or dual combinstion therapy with metformin, pioglitazone, or a sulfonylurea
udes stable dose of insuline, either alone or combination with a stable dose of metformin for at least 3 months
JB et al. Am Heart J. 2013;166:983-9.e7
ECOS: Selected Inclusion Criteria:1
lusion criteria included:
Aged 50 years with type 2 diabetes
Documented vascular disease in the coronary, cerebral, or
peripheral arteries
Patients with inadequate control (HbA1c of 6.5%-8.0%) for at
3 months despite:
Stable-dose monotherapy or dual combination with therapy with metfo
pioglitazone, and/or a sulfonylurea
Stable dose of insuline as monotherapy or in combination with stable do
of metformin

Green JB et al. Am Heart J. 2013;166:983-9.e7

ECOS: Exclusion Criteria Include:1

Type 1 diabetes e GFR <30

mellitus or mL/min/1.73m2
ketoacidosis Planned or
2 episodes of severe anticipated
hypoglycemia revascularization
requiring procedure
assistance 12 month Cirrhosis of liver
prior to diasease
enrollment Pregnancy or planned
Use of approved or
investigational DPP-4 pregnancy
inhibitor, Known allergy or
TECOS: Outcome1
Primay outcome was time from randomization to the first adjudicated a:
CV-related death
Nonfatal MI
Nonfatal stroke
Unstable angina requiring hospitalization
Secondary outcomes
Composite end point of : time to first adjudicated confirm CV-related death, non
nonfatal stroke
Time to the occurrence of the individual components of the primary end point
Time to all-cause mortality
Time to hospital admission for adjudicated congestive heart failure

Other prespecified outcome include:

Change from baseline in urinary albumin:creatinine ratio, eGFR, Hb A 1c , body w
Time to initiation of additional antihyperglycemic therapy and/or initiation of ch
insulin
Counts of outpatients visits and hospitalizations
V events will be adjudicated by independent committee, blinded to study therapy.
een JB t al. Am Heart J. 2013;166:983-989.e7
 TECOS: Analysis1
imary outcome analysis is designed to demonstrate
oninferiory of usual care with sitagliptin vs usual car
without sitagliptin
If sitagliptin is found noninferior to placebo, an assessment
superiority will be performed
edian follow-up of approximately 4 years is anticipat
Study will continue until 1,300 confirmed cardiovascular ev
have occoured

Green JB t al. Am Heart J. 2013;166:983-989.e7

ECOS: Exclusion Criteria Include:1

Type 1 diabetes mellitus e GFR <30

or mL/min/1.73m2
ketoacidosis Planned or anticipated
2 episodes of severe revascularization
hypoglycemia requiring procedure
assistance 12 month Cirrhosis of liver
prior to diasease
enrollment Pregnancy or planned
Use of approved or pregnancy
investigational DPP-4 Known allergy or
inhibitor, intolerance to sitagliptin
Greenthan
JB et al.pioglitazone 3
Am Heart J. 2013;166:983-9.e7
TECOS: Study Objective1
assess cardiovascular outcomes and clinical safety of long-term treatme

h sitagliptin used as part of usual care compared with usual care without

agliptin in patients with type 2 diabetes and a history of cardiovascular

sease and inadequate glycemic control

COS will primarily test the hypothesis that sitagliptin, when used as part

usal diabetes care, is noninferior to usual care without sitagliptin with re

the risk of significant confirmed cardiosvacular outcomes

sitagliptin is found to be noninferior to usual care without sitagliptin, an

sessment of superiority will be performed

TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin

Green JB et al. Am Heart J. 2013;166:983-9.e7
 TECOS CV Safety Trial: Patient
North
Recruitment 1
December 2008 July 2012
America
2,594, Western
17.7% Europe
2,076, 14.2%

Eastern
Europe
3,965, 27.0%

Asia Pacific
4,565,
31.1%
Latin
America
1,471,10.0%

Total
14,671a = country involved in
a
Intention-to-treat population.
TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular TECOS
1. Green JB et al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352.
 TECOS CV Safety Trial:
Patient Disposition1
14,735
randomize
d 64 excluded from all
analyses
11 did not consent
53 at one site
14,671 excluded
included in ITT analysis for GCP deviations

7,332 Sitagliptin ITT 7,339 Placebo ITT

7,180 (97.9%) vital status 7,123 (97.0%) vital status
known known
6,972 (95.1%) completed 6,905 (94.1%) completed
61 (0.8%) lost to follow-up 71 (1.0%) lost to follow-up
29 (48%) vital status known 33 (46%) vital status known
299 (4.1%) withdrawn 363 (4.9%) withdrawn
179 (60%) vital status 185 (51%) vital status
known known
TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; GCP = good clinical
practice; ITT = intention-to-treat.
1. Green JB et al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352.
 TECOS CV Safety Trial:
Baseline Patient Characteristics1
Baseline Sitagliptin Placebo
Characteristica N=7,332 N=7,339
Age, y 65.47.9 65.58.0
Female sex, n (%) 2134 (29.1) 2163 (29.5)
Race/Ethnicity, n
(%)
White 4955 (67.6) 5002 (68.2)
Asian 1654 (22.6) 1611 (22.0)
Other 517 (7.1) 485 (6.6)
Black 206 (2.8) 241 (3.3)
Hispanic or Latino 886 (12.1) 912 (12.4)

a
All values are mean SD unless otherwise specified.
TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; SD = standard deviation.
1. Green JB et al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352.
 TECOS CV Safety Trial: Baseline Disease Characteristics 1
Sitagliptin Placebo
Baseline Characteristicsa
N=7,332 N=7,339
Duration of diabetes, yb 11.68.1 11.68.1
HbA1c, % 7.20.5 7.20.5
Body mass index, kg/m2 30.25.6 30.25.6
Systolic BP, mmHg 13516.9 13517.1
Diastolic BP, mmHg 77.110.3 77.210.6
eGFRc, mL/min/1.73m2 74.921.3 74.920.9
eGFRc <50 mL/min/1.73m2, n (%) 686 (9.4) 683 (9.3)
Median urine albumin:creatinine ratio, 10.3 (3.5, 11.4 (3.6,
mg/g (Q1, Q3)d 34.6) 36.2)
Total cholesterol, mg/dL 166.144.8 165.445.9
LDL cholesterol, mg/dL 91.263.8 90.751.2
HDL cholesterol, mg/dL 43.512.0 43.413.0
Triglycerides, mg/dL 166.0101.0 164.898.8
a
All values are mean SD unless otherwise specified.
b
Duration = (year of randomization year of diagnosis) + 1.
c
MDRD formula used to calculate eGFR. Sitereported values are presented.
d
Urinary albumin:creatinine ratio data available for only 5148 patients (n= 2606 for sitagliptin, n=2542 for
placebo).
TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; BP = blood pressure;
 TECOS CV Safety Trial:
Baseline Disease Characteristics
(continued)1
Baseline Characteristics Sitagliptin Placebo
N=7,332 N=7,339
Prior cardiovascular disease, n (%) 5397 (73.6) 5466 (74.5)
Myocardial infarction 3133 (42.7) 3122 (42.5)
50% coronary 3804 (51.9) 3883 (52.9)
stenosis
Prior PCI 2814 (38.9) 2900 (40.1)
CABG 1845 (25.2) 1819 (24.8)
Prior cerebrovascular disease, n (%) 1806 (24.6) 1782 (24.3)
Prior peripheral artery 1216 (16.6)
1217 (16.6)
disease, n (%)
Prior congestive heart failure, n (%) 1303 (17.8) 1340 (18.3)
NYHA class 3 or higher 171 (2.3) 202 (2.8)
Current smoker, n (%) 865 (11.8) 813 (11.1)

TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; PCI = percutaneous
coronary intervention; CABG = coronary artery bypass graft; NYHA = New York Heart Association.
1. Green JB et al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352.
 TECOS CV Safety Trial: Baseline Medication Use
Sitagliptin Placebo
Baseline Medication use, n (%)
N=7,332 N=7,339
Antihyperglycemica
Metformin 5936 (81.0) 6030 (82.2)
Sulfonylurea 3346 (45.6) 3299 (45.0)
Thiazolidinedione 196 (2.7) 200 (2.7)
Insulin 1724 (23.5) 1684 (22.9)
Antihypertensive
Beta blocker 4647 (63.4) 4675 (63.7)
ACE inhibitor or ARB 5743 (78.3) 5812 (79.2)
Calcium channel blocker 2444 (33.3) 2517 (34.3)
Diuretic 2976 (40.6) 3044 (41.5)
Antiplatelet
Aspirin 5764 (78.6) 5754 (78.4)
Other antiplatelet 1593 (21.7) 1594 (21.7)
Lipid-lowering
Statin 5851 (79.8) 5868 (80.0)
Ezetimibe 386 (5.3) 375 (5.1)

a
Medications taken alone or in combination.
TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; ACE = angiotensin-
converting enzyme; ARB = angiotensin receptor blocker.
1. Green JB et al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352.
 TECOS CV Safety Trial: Glycemic
First 4 months: AHA doseControl
stability recommended 1

Subsequently: Physicians counseled to implement individualized

standard of care consistent with local/regional guidelines, with a
resulting narrowing of HbA1c between arms2

Overall LS mean between-arm

Baseline HbA1c:
difference:
7.2%
8.5 0.29% (95% CI, 0.32, 0.27)

8.0

Placebo
HbA1c, %

7.5

7.0 Sitagliptin
6.5

6.0
0.0
0 4 8 12 24 36 48
No. at Risk Month
Sitagliptin 7325 6779 6485 6454 6110 3524
1434
Placebo 7331 6746 6422 6390 59803443 1386

TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; AHA =

antihyperglycemic; LS = least-squares.
1. Green JB et al. Am Heart J. 2013;166:983989.e7. 2. Green JB et al. [published online ahead of print June 8,
2015] N Engl J Med. doi: 10.1056/NEJMoa1501352.
 TECOS CV Safety Trial:
Primary Composite CV Outcome1
The TECOS CV Safety Trial achieved its
primary CV end point of noninferiority of
sitagliptin added to usual care vs placebo
added to usual care
Primary Composite CV Outcomea , n/N HR (95%
Sitagliptin Placebo
(%) CI)
0.98
695/7,257 695/7,266
Per-protocol (PP) population (0.88,
(9.6) (9.6)
1.09)
PP was primary analysis for primary
P value for noninferiority: P<0.001b
composite CV outcome

y composite CV outcome was a composite endpoint of time to CV death, nonfatal stroke, nonfatal MI, and hospitalization
table angina. bNoninferiority P-value for a margin of 1.30 in hazard ratio.
= Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; HR = hazard ratio;
nfidence interval.
B et al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352
 TECOS CV Safety Trial: Primary
Composite CV Outcome (ITT)1
Primary Composite CV Outcome: Intention-to-
Treat Population Placebo
100 11.6%
(n=851)
Patients with Event,

15
80
Sitagliptin
10 11.4%
60 (n=839)
%

5
40 HR (95% CI) 0.98
(0.89, 1.08)
0
20 0 4 8 12 18 24 30 36 42 48

0
0 4 8 12 18 24 30 36 42 48
No. at Risk Month
Sitagliptin7332 7131 6937 6777 6579 6386 4525 3346 2058 1248
Placebo 7339 7146 6902 6751 6512 6292 4411 3272 2034 1234

ween group difference was not statistically significant for superiority: P=0
y P-value for a margin of 1.30 in hazard ratio.
l Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; ITT = intention-to-treat; PP = per protocol; HR = hazard ratio; CI = c
t al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352.
 TECOS CV Safety Trial: Secondary
Composite CV Outcome (ITT)1
Secondary Composite CV Outcome: Intention-to-
Treat Population Placebo
100 10.2%
12.
5
(n=746)
Patients with Event,

80 10.
5 Sitagliptin
10.2%
7.5
60 (n=745)
5.0
%

40 2.5 HR (95% CI) 0.99

(0.89, 1.10)
0
20 0 4 8 12 18 24 30 36 42 48

0
0 4 8 12 18 24 30 36 42 48
No. at Risk Month
Sitagliptin7332 7145 6969 6817 6638 6457 4584 3396 2097 1270
Placebo 7339 7161 6939 6796 6573 6359 4472 3332 2070 1260

ween group difference was not statistically significant for superiority: P=0
y P-value for a margin of 1.30 in hazard ratio.
l Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; HR = hazard ratio; CI = confidence interval; ITT = intention-to-treat;
t al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352.
 TECOS CV Safety Trial: Superiority Analysis for
Primary and Secondary Composite CV Outcomes 1

TECOS CV Safety Trial confirmed that sitagliptin is

noninferior to usual care with regard to the risk of CV
outcomes
Because sitagliptin achieved noninferiority to usual care without
sitagliptin, an assessment of superiority was performed
There were no significant between-group differences for
superiority in the ITT analysis of the primary composite
CV outcome or the secondary composite CV outcome
Sitaglip P-value
Placebo
Intention-to-Treat tin HR (95% for
N=7,33
Population N=7,33 CI) Superiori
9
2 ty
Primary composite CV 839 851
outcome, (11.4) (11.6) 0.98 (0.89
0.65
n (%); rate per 100 patient- ; ; 1.08)
years 4.06 4.17
Secondary composite CV 746
Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; ITT = intention-to-treat; HR = hazard ratio.
745
JB et al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352.
outcome, (10.2) 0.99 (0.89
 TECOS CV Safety Trial:
Hospitalizations for Heart Failure

(ITT) 1
Hospitalization for heart failure did not differ between
treatment groups Sitaglip Placeb
HR
Intention-to-Treat tin o P-
(95%
Population N=7,33 N=7,33 value
CI)
2 9
Hospitalization for heart
228 229 1.00
failure,
Composite outcome
n (%); rate
(3.1); (3.1); (0.83, 0.98
per 100of hospitalization for heart failure or
1.07 1.09 1.20)
cardiovascular
patient-yearsa death did not differ between groups
Sitaglip
Placebo HR P-
Intention-to-Treat tin
N=7,33 (95% valu
Population N=7,33
9 CI) e
2
Composite outcome of
hospitalization for heart 538 525 1.02
failure or CV death, (7.3); (7.2); (0.90 0.74
n (%); rate per 100 2.54 2.50
es of hospitalization for heart failure were adjusted for a history of heart failure at baseline.
1.15)
= Trial Evaluating Cardiovascular Outcomes With Sitagliptin; ITT = intention-to-treat CV = cardiovascular; HR = hazard ratio;
patient-yearsa
nfidence interval.
n JB et al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352.
 TECOS CV Safety Trial: Hospitalizations
for Heart Failure (ITT) 1
Hospitalizations for Heart Failure: Intention-to-
Treat Population
100

5
Patients with Event

Placebo
80
4 229 (3.1%)

60 3
Sitagliptin
(%)

2 228 (3.1%)
40 HR (95% CI) 1.00
1
(0.83, 1.20)
0
20 0 4 8 12 18 24 30 36 42 48

0
0 4 8 12 18 24 30 36 42 48

No. at Risk
Month
Sitagliptin7332 7189 7036 6917 6780 6619 4728 3515 2175 1324
Placebo 7339 7204 7025 6903 6712 6549 4599 3443 2131 1315

Between group difference was not statistically significant (P=0.98)

ial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; HR = hazard ratio; CI = confidence interval; ITT = intention-to-trea
et al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352.
 TECOS CV Safety Trial: Total
Mortality (ITT) 1
Total Mortality: Intention-to-Treat
Population

100
1 Placebo
0 537 (7.3%)
Patients with Event

80
8

60 6 Sitagliptin
547 (7.5%)
(%)

4
40 HR (95% CI) 1.01
2
(0.90, 1.14)
0
20 0 4 8 12 18 24 30 36 42 48

0
0 4 8 12 18 24 30 36 42 48

No. at Risk
Month
Sitagliptin7332 7262 7180 7103 7010 6904 4964 3739 2321 1435
Placebo 7339 7271 7176 7098 6982 6864 4891 3673 2293 1412

Between group difference was not statistically significant (P=0.88)

rial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; HR = hazard ratio; CI = confidence interval; ITT = intention-to-tre
B et al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352.
 TECOS CV Safety Trial: Non-CV
Mortality1
Non-CV death rate was the same in both
treatment groups
2.3% for both sitagliptin and placebo

Death due to infection did not differ between

treatment groups
0.6% for sitagliptin vs 0.7% for placebo

S = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular.

een JB et al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352.
 TECOS CV Safety Trial: Limitations1
Enrolled patients with moderate hyperglycemia
(HbA1c 6.5%8.0%) and excluded those with severe
renal insufficiency
Potential biases:
Possible confounding effects on CV outcomes by the small
residual between-group difference in the HbA1c level
Greater use of AHAs in the placebo group
Opportunistic approach to data collection, apart
from the selected values for HbA1c, resulted in
limited acquisition of data regarding UACR
al Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; AHA = antihyperglycemic agent; UACR = urinary albumin:creatinin
et al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352.
 TECOS CV Safety Trial: Summary of
Results1
Sitagliptin met primary end point (no increased CV risk) when added to
usual care in patients with type 2 diabetes and established CV disease
Sitagliptin therapy did not increase all-cause mortality, CV death, or non-
CV death
No between-group difference in hospitalization for heart failure
Sitagliptin treatment not associated with a significant increase in severe
hypoglycemia
Fewer patients receiving sitagliptin treatment required additional
antihyperglycemic agents or initiation of long-term insulin therapy

S = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular.

een JB et al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352.
Thank You
JAMACardiolog April 13,2016
Treatment with sitagliptin is compared with
placebo
Meta-Analysis of SAVOR-TIMI53,EXAMINE,
and TECOS

JAMACardiolog April 13,2016