Ways to Improve The

Macrovascular Outcomes in Type

2 Diabetes Therapy
23rd Jakarta Diabetes Meeting
ShangriLa Hotel, Jakarta
December, 20-21, 2014

Wismandari Wisnu, MD

Division of Endocrinology and Metabolism

Department of Internal Medicine
Faculty of Medicine Universitas Indonesia
Cipto Mangunkusumo National Referral Hospital
Jakarta, Indonesia
2014

Outlines
Background
Significance of Cardiovascular
Outcomes in Patients With Diabetes
Multifactorial approach in lowering CV
outcomes
Intensive HbA1c lowering in reducing
CV events
CV Outcome Trials of DPP-4 Inhibitors

Background

Glucose (mg/dL)

350
300
250
200
150
100
50

Relative -cell
function (%)

The natural progression of type 2

diabetes
Post-meal BG
DIAGNOSIS

250

Fasting BG

Insulin resistance

200
150
100

-cell failure

50
0

Obesity

IGT

Diabetes

MACROVASCULAR CHANGES

Clinical
features

Years

Uncontrolled
hyperglycaemia

MICROVASCULAR CHANGES
-10

-5

10

15

Adapted from Type 2 Diabetes BASICS. International Diabetes Center; 2000.

20

25

30

Insulin
level

The goal of diabetes management is to secure

optimal glycemic control to avoid complications
Microvascular

Macrovascular

Diabetic
retinopathy

Stroke
1.2- to 1.8-fold
increase in stroke3

Leading cause
of blindness
in working-age
adults1

Cardiovascular
disease
75% diabetic patients
die from CV events4

Diabetic
nephropathy
Leading cause of
end-stage renal
disease2

Diabetic
neuropathy
Leading cause of
non-traumatic lower
extremity amputations5

Erectile Dysfunction
The most secretive
Complication of DM

Diabetic Foot
Fong DS, et al. Diabetes Care 2003;e 26 (Suppl.1):S99S102. 2Molitch ME, et al. Diabetes Care 2003; 26 (Suppl.1):S94S98. 3Kannel WB, et al. Am Heart J
1990; 120:672676. 4Gray RP & Yudkin JS. Textbook of Diabetes 1997. 5Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl.1):S78S79.
1

Dyslipidemia

Hypercoagulabil
ity

Hypertensio
n

Type 2
DM
Proinflammatory
state

Obesity

CVD

Significance of
Cardiovascular Outcomes
in Patients With Diabetes

Diabetes Is Associated With

Increased Risk of CV Disease
Diabetes confers an increased risk for MI, stroke, and
PAD13
It is not clear whether diabetes should be considered a
cause or a comorbidity of heart failure4
Diabetes is associated with an increased risk of
developing HF in patients with other causes (eg, acute
MI) and is believed to promote diastolic dysfunction

Diabetes is associated with a 2- to 3-fold increase in

the risk of CV and all-cause mortality5
CV = cardiovascular; MI = myocardial infarction; PAD = peripheral artery disease; CHD = coronary heart disease; HF = heart failure.
1. Emerging Risk Factors Collaboration. Lancet. 2010;375:22512222. 2. American Diabetes Association. Diabetes Care. 2003;26:33333341. 3. American Diabetes Association. Diabetes
Care. 2014;37:S14S80. 4. McMurray JJV et al. Lancet Diabetes Endocrinol. 2014; DOI 10.1016/S2213-8587(14)70031-2. 5. Gregg EW et al. Ann Int Med. 2007;147:149156.

Heart Failure in Patients With

Type 2 Diabetes
Retrospective cohort study to update
estimates of CHF rate in patients with T2DM
Follow-up of up to 72 months

Incidence of CHF
(cases per 1,000 person-years)

1,167 of 8,231 patients with T2DM had

incident CHF, vs 526 of 8,845 patients
without T2DM
Patients with T2DM experienced CHF at 2.5
times the rate of comparison subjects
without T2DM
(rate ratio: 2.5 [95% CI 2.32.7])

CHF = congestive heart failure; T2DM = type 2 diabetes mellitus; CI = confidence interval
.
1. Nichols G et al. Diabetes Care. 2004;27:18791884.

30.9
P<0.001

12.4

HbA1c Is Associated With

Outcomes

Increases in HbA1c are correlated with both

microvascular and macrovascular disease
complications1,2

15

However, in clinical trials, interventions to lower HbA1c

1,3,4
have only
reduced microvascular UKPDS:
complications
UKPDS:
Microvascular
Fatal and
End Points

Hazard Ratio

10

Nonfatal
Myocardial Infarction1

37% increase per 1% increase in

HbA1c
P<0.0001

0.5

0 5

10

11

14% increase per 1% increase in

HbA1c
P<0.0001
0.5

0 5

10

11

Updated Mean HbA1c

UKPDS = United Kingdom Prospective Diabetes Study.

1. Reproduced with permission from Stratton IM et al. BMJ. 2000;321:405412. 2. Gerstein HC et al. Diabetologia. 2010;53:25092517. 3. ADVANCE Collaborative Group et al. N Engl J
Med. 2008;358:25602572. 4. Ismail-Beigi F et al. Lancet. 2010;376:419430.

Tight Glycaemic Control Reduces

Complications
Epidemiological extrapolation showing benefit of a 1% reduction in mean
HbA1c
21%

37%

HbA1C
1%

*P<.0001
**P=.035
Stratton IM et al. UKPDS 35. BMJ 2000; 321: 405412

Deaths related to
diabetes*
Microvascular
complications (eg,
kidney disease and
blindness)*

14%

Heart attack*

43%

Amputation or fatal
peripheral blood
vessel disease*

12%

Stroke**

Multifactorial
approach in lowering
CV outcomes

Smoking and diabetes

There are clear benefits to smoking cessation
in people with diabetes stop as soon as
possible
Several features contribute to mortality
Number of cigarettes smoked
Duration of smoking
Number of years since cessation
The benefit of smoking cessation on
cardiovascular mortality may be even greater
in men with diabetes vs. men without diabetes
(3 to 5 fold difference)
Padmawati et al Smoking among diabetes patients in Yogyakarta, Indonesia: cessation efforts are urgently needed Trop Med Int Health
2009 14(4):412-9

All cause mortality in diabetes

patients who smoke
1.56

1.58

NS

NS

1.44
1.25

Never smoked
<20 cigarettes/day
*p<0.05
NS- not statistically
>20 cigarettes/day
significant

Chaturvedi et al Which Features of Smoking Determine Mortality Risk in Former Cigarette Smokers With Diabetes? Diabetes Care

Hypertension
Treatment of hypertension reduces
macrovascular risk in people with diabetes
ACCORD-BP achieved an SBP target of <120
mmHg
increased incidence of side-effects
no further reduction in CV events other than
stroke
Targets differ among major bodies (e.g. ADA
target is 140/80 mmHg vs. 140/90 mmHg in
JNC-8)
Achieving blood pressure control is more
important than the particular agent used

UKPDS group Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998
Patel et al Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the
ADVANCE trial): a randomised controlled trial. Lancet 2007;370:829840
Hansson et al Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment
(HOT) randomised trial. Lancet 1998;351:17551762
Cushman et al ACCORD Study Group Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:15751585

Most patients require combination therapy for

Lipid-lowering therapy

Who should be on statin therapy?

ADA recommendations 2014 for people with diabetes

Those with overt CVD, or > 40 years old with

one or more other CVD risk factors
Consider in;
those with no overt CVD and <40 years if
LDL >100 mg/dl despite lifestyle therapy
those <40 years , with no overt CVD, but
with multiple CVD risk factors
Target LDL <100 mg/dl, consider goal of <
70mg/dl in overt CV

erican Diabetes Association Standards of medical care in diabetes Diabetes Care 2014 37 S14-S80

AHA guidelines for statin therapy

in people with diabetes
CVD

No CVD
LDL-C
(mg/dl)

Age 2140

Age 40-75
10-year CV
risk < 7.5%

10-year CV
risk 7.5%

Age >
75

Age 21-74

Age > 75

190

High
High
High
High
intensit intensit intensit intensit
y*
y*
y*
y*

High
intensity*

Moderate
** or high
intensity*

70189

Discuss

High
intensity*

Moderate
** or high
intensity*

High
intensity*

Moderate
** or high
intensity*

<70

Discuss

Modera
Highte
intensit
intensit
y*
y**

Discuss

Discuss

Discuss

Discuss

No recommendations for or against specific LDL or HDL targets

*High intensity- dose that reduces LDL approx 50% or more (e.g. Atorvastatin 40-80mg, Rosuvastatin 20mg)
**Moderate intensity- dose that reduces LDL 30-50% (e.g. Atorvastatin 10mg, Rosuvastatin 10mg, Simvastatin
20-40mg, Pravastatin 40mg)
Stone et al 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults
Circulation 2014; 129: S1-S45

Kidney disease as a risk factor

Lower eGFR and microalbuminuria is
associated with higher CVD mortality
worldwide, and in in Asia
High prevalence of microalbuminuria in Asian
populations with diabetes (almost 60%)
Patients with microalbuminuria are at high
CVD risk

Wu et al An alarmingly high prevalence of diabetic nephropathy in Asian type 2 diabetic patients: the
MicroAlbuminuria Prevalence (MAP) Study Diabetologia 2005 48(1):17-26

Lower eGFR and microalbuminuria

associated with higher CVD mortality
CKD Prognosis Consortium meta-analysis

Diabetes
No Diabetes

Fox et al Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality: a
collaborative meta-analysis of general population cohorts Lancet 2012; 380(9854): 16621673

Antiplatelet therapy

Low-dose aspirin for primary CVD prevention in people with diabetes

Effective for secondary prevention - 1.5% absolute

reduction serious CV events (18% relative
reduction) Primary prevention less clear, both for
general population and people with diabetes
Not recommended for low CVD risk adults with
diabetes
men <50 years, women <60 years with no major
additional CVD risk factors,10-year CVD risk <5%
Consider for those with diabetes at intermediate
CVD risk
younger patients with one or more risk
factorsolder patients with no risk factors, 10-year
Antithrombotic Triallists collaboration Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of
individual participant data from randomised trials Lancet 2009; 373(9678) 18491860
CVD
riskPrevention
of 510%
Pignone et al
Aspirin for Primary
of Cardiovascular Events in People With Diabetes - A position statement of the ADA, a scientific
statement of the AHA, and an expert consensus document of the ACCF Diabetes Care 2010 33 (6) 1395-1402

Intensive HbA1C
lowering in reducing
CV events

Impact of Intensive vs Conventional

Glycemic-Lowering Strategies on Risk
of Cardiovascular Outcomes Is Unclear
Lowering of HbA1c has been shown to
reduce microvascular disease1,2
Reduction of macrovascular risk has
not been consistently observed35
The impact of antihyperglycemic
medications on HbA1c may not reflect
the effect on overall risk of CV events6
1. American Diabetes Association. Diabetes Care. 2014;37:S14S80.
2. McMurray JJV et al. Lancet Diabetes Endocrinol. 2014; DOI 10.1016/S2213-8587(14)70031-2.
3. ADVANCE Collaborative Group et al. N Engl J Med. 2008;358:25602572.
4. Gerstein HC et al. N Engl J Med. 2008;358:25452559.
5. Duckworth W et al. N Engl J Med. 2009;360:129139.
6. Ban K et al. J Am Soc Hypertension. 2009;3:245259

Meta-Analysis: Probability of events of CHD with

intensive glucose-lowering vs standard treatment
Intensive treatment/
standard treatment

Weight of
study size

Odds ratio
(95% CI)

Odds ratio
(95% CI)

Participants

Events

3071/1549

426/259

8.6%

0.75 (0.541.04)

PROactive* 2605/2633

164/202

20.2%

0.81 (0.651.00)

ADVANCE 5571/5569

310/337

36.5%

0.92 (0.781.07)

UKPDS

VADT

892/899

77/90

9.0%

0.85 (0.621.17)

ACCORD

5128/5123

205/248

25.7%

0.82 (0.680.99)

100%

0.85 (0.770.93)

Overall

17267/15773 1182/1136

0.6
0.8 1.0 1.2 1.41.6
Intensive
Standard
treatment better
treatment better
* Included non-fatal myocardial infarction and death from all-cardiac mortality

Ray KK et al. Lancet 2009;373:176572

Impact of Intensive vs Conventional Glycemic-Lowering

Strategies on Risk of CV Outcomes Is Unclear
Lowering HbA1c may prevent macrovascular disease if
started early,
but the effects may not be apparent for a very long
time
Diabetes
Duration
(mean)

Study

Antihyperglycemic
Medicationa

UKPDS1

Follow-up
(median)
10 years

Newly
diagnosed

SU/insulin or metformin vs
dietary restriction

8 years

Intensive glucose control

including gliclazide vs
standard treatment

5 years

ACCORD4,5

10 years

Multiple drugs in both arms

3.4 years

VADT6

11.5 years

Multiple drugs in both arms

5.6 years

UKPDS
Long-term
follow-up2
ADVANCE

10 years post
intervention

HbA1c: Baseline,
Between-arm
Difference
7.1% (all patients)b,
0.9%c
No difference in
HbA1c between
treatment armsd

Microvascular

CVD

Mortality

7.5% (both arms)b,

0.8%d

8.1% (both arms)e,

1.1%c
9.4% (both arms)b,
1.5%d

Obese patients; bMean baseline HbA1c; cMedian between-arm difference; dMean between-arm difference;
e
Median baseline HbA1c.
CV = cardiovascular; UKPDS = United Kingdom Prospective Diabetes Study (UKPDS); ADVANCE = Action in
Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; ACCORD =
Action to Control Cardiovascular Risk in Diabetes; VADT = Veterans Affairs Diabetes Trial.
a

1. UKPDS Group. Lancet. 1998;352:837853. 2. Holman RR et al. N Engl J Med. 2008;359:15771589. 3. ADVANCE Collaborative Group et al. N Engl J Med. 2008;358:25602572. 4. Gerstein
HC et al. N Engl J Med. 2008;358:25452559. 5. Ismail-Beigi F et al. Lancet. 2010;376:419430. 6. Duckworth W et al. N Engl J Med. 2009;360:129139.

CV Outcome Trials of
DPP-4 Inhibitors

What Now.
Traditionally, diabetes medications have been
approved based upon efficacy in lowering HbA1C, a
biomarker accepted by most as a surrogate for
about DPP-4
reduction in How
risk of microvascular
complications
and hyperglycemic
symptoms.
inhibitor
as a new
The new FDA and EMAdrug
guidelines emphasize that
for new medications to gain approval, clinical trials
????
data must exclude a clinically important excess of
drug- associated cardiovascular risk.
Trials should include persons at sufficiently high
cardiovascular risk, eg, patients who are elderly,
have multiple cardiovascular risk factors, and/or
CVD, or some degree of renal dysfunction

Incretins Modulate Insulin and Glucagon to

Decrease Blood Glucose During
Hyperglycemia15
Ingestion
of food

GI tract

Glucosedependent
Pancreas

Release of
active incretins
GLP-1 and GIP
DPP-4
inhibitor

DPP-4
enzyme

Inactive
GLP-1

Inactive
GIP

Insulin from
beta cells
(GLP-1 and GIP)

Beta cells
Alpha cells
Glucosedependent
Glucagon
from alpha cells
(GLP-1)

Peripheral
glucose
uptake

Blood glucose in
fasting and
postprandial states

Hepatic
glucose
production

Incretin hormones GLP-1 and GIP are released by the intestine throughout the day; their
levels increase in response to a meal.
DPP-4=dipeptidyl peptidase-4; GI=gastrointestinal; GIP=glucose-dependent insulinotropic polypeptide; GLP-1=glucagon-like peptide-1.
1. Drucker DJ. Diabetes Care. 2003;26(10):29292940. 2. Brubaker PL et al. Endocrinology. 2004;145(6):26532659. 3. Zander M et al. Lancet. 2002;359(9309):824930. 4. Ahrn B. Curr
Diab Rep. 2003;3(5):365372. 5. Buse JB et al. In: Williams Textbook of Endocrinology, 11th ed. Saunders; 2008:13291389.

Baseline Risk of Patient Populations

Enrolled in CV Outcome Trials of DPP-4
Inhibitors
Risk Factors

Stable CAD-CVD-PAD

Post ACS patients

Alogliptin EXAMINE (N=5,380)1
ACS within 1590 days

Saxagliptin SAVOR-TIMI (N=16,492)2

Pre-existing CVD or multiple risk factors for CVD

Sitagliptin TECOS (N=~14,000)3

Pre-existing CVD

Linagliptin CARMELINA (N=8,300)4

Pre-existing CVD + albuminuria or impaired renal function

Presented
Sept 2013
Presented
Sept 2013
End Dec 2014
End Jan 2018

Vildagliptin does not have an ongoing CV outcomes trial

CV = cardiovascular; DPP-4 = dipeptidyl peptidase-4; CAD = coronary artery disease; CVD = cardiovascular disease;
PAD = peripheral artery disease; ACS = acute coronary syndrome; ACS = acute coronary syndrome; EXAMINE =
Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus
and Acute Coronary Syndrome; SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients
With Diabetes Mellitus Trial-Thrombolysis in Myocardial Infarction; TECOS = Trial Evaluating Cardiovascular Outcomes
With Sitagliptin; CARMELINA = Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients
With Type 2 Diabetes Mellitus at High Vascular Risk.
1. White W et al. N Engl J Med. 2013;369:13271335. 2. Scirica BM et al. N Engl J Med. 2013;369:13171326. 3. Green JB et al. Am Heart J 2013;166:983989.e7. 4. CARMELINA:
Cardiovascular and renal microvascular outcome study with linagliptin in patients with type 2 diabetes mellitus at high vascular risk. ClinicalTrials.gov web site. http://clinicaltrials.gov/ct2/show/
NCT01703298. Accessed September 12, 2014.

EXAMINE, SAVOR-TIMI, and

TECOS
EXAMINE1

SAVOR-TIMI2

TECOS3

Alogliptin vs
Placebo

Saxagliptin vs
Placebo

Sitagliptin vs
Placebo

Sample size, N

5,380

16,492

~14,000

Median duration of
diabetes, y

7.2

10.3

N/A

Baseline HbA1c, %

8.0

8.0

6.58.0

Number of events

621

1,222

>1,300

Median duration of
exposure, y

1.5

2.1

Up to 4.0

EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2
Diabetes Mellitus and Acute Coronary Syndrome; SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes
Recorded in Patients With Diabetes Mellitus Trial-Thrombolysis in Myocardial Infarction; TECOS = Trial
Evaluating Cardiovascular Outcomes With Sitagliptin.
1. White WE et al. N Engl J Med. 2013:369:13271335. 2. Scirica BM et al. N Engl J Med. 2013:369:13171326. 3. Green JB et al. Am Heart J 2013;166:983989.e7.

EXAMINE: Results Summary

Alogliptin was noninferior for the
primary composite end point of CV
death, nonfatal MI, and nonfatal stroke
Alogliptin 11.3% vs placebo 11.8%; HR
(upper bound of 95% CI) = 0.96 (1.16)
Treatment with alogliptin did not significantly
increase the incidence of pancreatitis or pancreatic
cancer compared with placebo
Alogliptin and placebo groups did not differ
significantly with respect to the incidence of serious
adverse events, including hypoglycemia, cancer,
angioedema, elevated serum aminotransferase
values, and changes in eGFR
EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary
Alogliptin 33.6% vs placebo 35.5%; P=0.14
Syndrome; CV = cardiovascular; MI = myocardial infarction; HR = hazard ratio; CI = confidence interval; eGFR = estimated glomerular filtration rate.
1. White WB, et al. N Engl J Med. 2013;369:13271335.

SAVOR-TIMI: Results Summary

Saxagliptin was non inferior for the primary
composite end point of CV death, nonfatal MI,
and nonfatal stroke
Saxagliptin 7.3% vs placebo 7.2%; HR (95%
CI) = 1.00 (0.891.12)
Treatment with saxagliptin did not significantly increase the
incidence of pancreatitis or pancreatic cancer compared with
placebo
Saxagliptin was associated with an increase in hypoglycemia
compared with placebo (15.3% vs 13.4%; P<0.001)
Treatment with saxagliptin did not significantly increase the
incidence of thrombocytopenia, lymphocytopenia, infections,
cancers, hypersensitivity or skin reactions, bone fractures, or
SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial-Thrombolysis in
liver
abnormalities
Myocardial
Infarction;
CV = cardiovascular; MI = myocardial infarction; HR = hazard ratio; CI = confidence interval.
1. Scirica BM et al. N Engl J Med. 2013;369:13171326.

EXAMINE and SAVOR-TIMI:

Hospitalization for Heart
Failure
EXAMINE1,2

HHFa

Alogliptin
n=2,701

Placebo
n=2,679

HR (95% CI)

3.9%

3.3%

1.19 (0.891.58)

SAVOR-TIMI3

HHF

Saxagliptin
n=8,280

Placebo
n=8,212

HR (95% CI)

3.5%

2.8%

1.27 (1.071.51)

EXAMINE: In a post-hoc analysis, there was

a trend (P=NS) for increased hospitalization
for HF with alogliptin compared with
placebo2
SAVOR-TIMI: Hospitalization for HF was
significantly increased with saxagliptin
compared with placebo3
Mortality due to HF was not significantly
different between saxagliptin and placebo
(0.5% for both)3

Post-hoc analysis.
EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary
Syndrome; SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial-Thrombolysis in Myocardial
Infarction; HHF = hospitalization for heart failure; HR = hazard ratio; CI = confidence interval; HF = heart failure.
a

1. Reproduced with permission from White WB et al. N Engl J Med 2013;369:13271335. 2. Sanon VP et al. Clin Diabetes. 2014;32:121126. 3. Reproduced with permission from Scirica
BM et al. N Engl J Med 2013;369:13171326.

DPP-4 Inhibitor CV Outcome Trials Were Not

Designed to Demonstrate CV Risk Reductions Based
on Differences in Glycemic Control
EXAMINE and SAVOR-TIMI1,2
Differences in HbA1c in the DPP-4 inhibitor arms vs placebo
arms were small because usual care was pursued in both study
arms by the use of additional antihyperglycemic medications
TECOS3
Design permits rapid equalization of glycemic control between
groups
Glycemic equality between groups will permit assessment of
the CV effects of sitagliptin independently of its glucoselowering effects

DPP-4 = dipeptidyl peptidase-4; CV = cardiovascular; EXAMINE = Examination of Cardiovascular

Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute
Coronary Syndrome; SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes Recorded in
Patients With Diabetes Mellitus Trial-Thrombolysis in Myocardial Infarction; TECOS = Trial
Evaluating Cardiovascular Outcomes With Sitagliptin.
1. White WB et al. N Engl J Med. 2013;369:13271335. 2. Scirica BM et al. N Engl J Med 2013;369:13171326. 3. Green JB et al. Am Heart J. 2013;166:983989.e7.

EXAMINE, SAVOR-TIMI, and TECOS

HbA1c
Range, %

Primary
End point

Duration of Treatment (as part of usual care)

Alogliptin

EXAMINE1

SAVORTIMI2

6.511.0

CV death,
Nonfatal MI, or
Nonfatal stroke

Placebo
Saxagliptin
6.512.0

CV death,
Nonfatal MI, or
Nonfatal stroke

Placebo

CV death,
Nonfatal MI,
Nonfatal stroke, or UA
req. hospitalization

Sitagliptin

TECOS3

6.58.0

Placebo
Randomization

Year 1

Year 2

Year 3

Median Duration of Follow-upa

Up to
Year 4

Approximate median duration of follow-up for TECOS, based on the expected event rate at study
initiation.
a

CV = cardiovascular; MI = myocardial infarction; UA = unstable angina.

1. White WB et al. N Engl J Med. 2013;369:13271335. 2. Scirica BM et al. N Engl J Med 2013;369:13171326. 3. Green JB et al. Am Heart J. 2013;166:983989.e7.

CV Outcome Trials With DPP-4

Inhibitors
Completed Trials
Alogliptin
EXAMINE1

Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and
Acute Coronary Syndrome (N=5,380)
Primary End Point: Composite end point of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke
Results: Alogliptin was noninferior to placebo. [Median duration of exposure to alogliptin was 1.5 year]

Saxagliptin
SAVOR2

Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial (N=16,492)
Primary End Point: Composite end point of CV death, nonfatal MI, or nonfatal ischemic stroke
Results: Saxagliptin was noninferior to placebo. [Median follow-up period was 2.1 years (range, 1.8 to 2.3) and the
maximum follow-up time was 2.9 years]

Ongoing Trials
Sitagliptin
TECOS3,4

Start: Dec 2008

Projected completion:
End of 2014
N=14,724

Trial Evaluating Cardiovascular Outcomes With Sitagliptin

Primary Outcome: Time to first confirmed occurrence of CV event , a composite defined as
CV-related death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization.
[Expected median follow-up of approximately 4 years]

Linagliptin
CAROLINA5

Start: Oct 2010

Projected completion:
Mid-2018
N=6,000

Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Patients With Type 2 Diabetes

Primary Outcome: Time to first occurrence of any component of the composite end point: CV
death, nonfatal MI, nonfatal stroke, and hospitalization for unstable angina pectoris.
[A complementary placebo-controlled CV trial CARMELINA was required by FDA]

Vildagliptin

Vildagliptin does not have an ongoing cardiovascular outcomes trial.

CV=cardiovascular; DPP-4=dipeptidyl peptidase-4; MI=myocardial infarction.

1. White W et al. New Engl J Med. 2013;369:13271335. 2. Scirica BM et al. New Engl J Med. 2013;369:13171326. 3. Green JB et al. Am35Heart J. 2013;166:983989.e7. 4. Bethel
MA et al. Poster presented at the International Diabetes Foundation World Congress of Diabetes. Melbourne, Australia December 26, 2013. Abstract PD-0700. 5. NCT 01243424.

Sitagliptin vs Glipizide: Weight

Change and Incidence of
Hypoglycemia1
Body weight at week 104

Hypoglycemia over 104 weeks

Between-groups difference = 2.3 kg

(95% CI: 3.0, 1.6)

Between-groups difference = 28.8%

(95% CI: 33.0, 24.5)
40

n=253

n=261

Patients With
at Least 1 Episode, %

LS Mean (95% CI) Body Weight

Change From Baseline, kg

APaT Population
(Patients Inadequately Controlled on Metformin)

Sitagliptin + metformin
Glipizide + metformin

APaT=all-patients-as-treated; CI=confidence interval; LS=least-squares.

1. Seck T et al. Int J Clin Pract. 2010;64(5):562576.

34.1
30

20

10

5.3
n=588

n=584
All Patients

36

Sitagliptin Was Associated With a

Lower Incidence of Hypoglycemia and
Reduced Body Weight vs Glimepiride1
All patients inadequately controlled on metformin monotherapy (1500 mg/day)
(APaT Population)

(95% CI)
15.0% (19.3, 10.9)
(P<0.001)

n=516

n=518

Body Weight Change at Week 30

LS Mean (95% CI) Change in

Body Weight From Baseline, kg

Patients With 1
Hypoglycemic Episode, %

Hypoglycemia Over 30 Weeks

APaT=all patients as treated; CI=confidence interval; LS=least-squares.

a
Mean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13:160168.
2. Data on file, MSD.

= 2.0 kg
(P<0.001)

n=461
n=465

Sitagliptin 100 mg + metformin

Glimepiridea + metformin
37

Initial Combination of Sitagliptin and Metformin

Produced a Marked Improvement in A1C
Mean baseline A1C = 8.8%
Sita 100 mg q.d.

-0.5

A 1 C (% )*

MF 500 mg b.i.d.

-1.0

MF 1000 mg b.i.d.
-0.8

Sita 50 mg +
MF 500 mg b.i.d.

-1.0

-1.5

-1.3

-2.0

-2.5

Sita 50 mg +
MF 1000 mg b.i.d.

-1.6
-2.1

Placebo change from Baseline = 0.17 %

*Placebo-subtracted LS mean change from baseline at Week 24

tein et al, Diabetes Care: 30; 1979 1987, 2007

Open Label
Sita 50 mg +
MF 1000 mg b.i.d.

Addition of Sitagliptin to Insulin Therapy: HbA 1c

Change From Baseline Over Time
FAS Population (LOCF)

HbA1c LS Mean Change

From Baseline, % (SE)

0.1
0.0

0.03%

0.1

(n=31
2)

0.2

Difference = 0.56%
(P<0.001)

0.3
0.4
0.5

0.59%

0.6

(n=305
)

0.7
0.8
0.8

12
Weeks

18

24

Baseline mean HbA1c: 8.72% for sitagliptin, 8.64% for placebo

FAS=full analysis set; LOCF=last observation carried forward; LS=least squares; SE=standard error.
Diabetes, Obesity and Metabolism 12: 167177, 2010.
a

Sitagliptina
Placeboa

Take Home Messages

The natural progression of T2DM is prolonged

and many key features such as

macrovascular changes occur before
hyperglycaemia develops and therefore before
diagnosis.
Diabetes is associated with a 2- to 3-fold increase in

the risk of CV and all-cause mortality

Early and Multifactorial intervention of

the risk factors in newly diagnosed type 2

diabetes may affect cardiovascular outcomes
40

Take Home Messages

Increases in HbA1c are correlated with
both microvascular and macrovascular
disease complications
However, in clinical trials, interventions
to lower HbA1c have only reduced
microvascular complications
Some studies about DPP-4 inhibitors
demonstrated non inferiority compared
with placebo for the primary composite
safety end point

THANK YOU FOR

YOUR ATTENTION