DM medications and Cardiovascular Safety

1. 1
DM and CVD
Cardiovascular Outcome Trials
Does it matter?
Dr. Mohammad Daoud
Consultant Endocrinologist
KAMC/ NGHA - Jeddah –Saudi Arabia

2. Objectives
To Understand :
DM and CV Risk
Glycemic Control and CV outcomes
The evidence ?
DM Medications and CVD ?
Medications CV Safety

3. Questions
-Does lowering A1c below a target (<7.0 % - 6.5% )
translate in reduction in CVD Risk ?
-Does it matter which intervention /treatment
is used to achieve this objective ?
( target A1c / CVD risk reduction ?)
-Could a medication cause more harm then benefit ?
The target The intervention

4. HbA1c Is Associated With Outcomes
 Increases in HbA1c are correlated with both microvascular and
macrovascular disease complications1,2
 However, in clinical trials, interventions to lower HbA1c have only reduced
microvascular complications1,3,4
UKPDS = United Kingdom Prospective Diabetes Study.
1. Stratton IM et al. BMJ. 2000;321:405–412. 2. Gerstein HC et al. Diabetologia. 2010;53:2509–2517. 3. ADVANCE Collaborative Group et al. N Engl J Med. 2008;358:2560–2572. 4.
Ismail-Beigi F et al. Lancet. 2010;376:419–430.
HazardRatio
Updated Mean HbA1c
UKPDS: Fatal and Nonfatal
Myocardial Infarction1
0.5
1
5
0 5 6 7 8 9 10
14% increase per 1% increase in
HbA1c P<0.0001
11
1
10
15
0 5 6 7 8 9 10 11
UKPDS: Microvascular
End Points1
37% increase per 1% increase in
HbA1c P<0.0001
0.5

5. Compared with subjects without diabetes, people with
diabetes* have…
Diabetes increases CV risk
> 2  risk of
heart disease1
> 2  risk
of stroke1
*Type 1 or Type 2.
1. NIDDK. http://diabetes.niddk.nih.gov/dm/pubs/stroke/ accessed May 2013.
2. Inzucchi SE, et al. Diabetes Care. 2012;35:1364–1379.
Reducing CV risk is a major focus of diabetes management2

6. Diabetes → Increased Risk of Heart Failure
Independent of Ischemia
 Diabetic cardiomyopathy
 2 to 4-fold increase incidence
of heart failure in DM
 Asymptomatic abnormalities of
ventricular systolic and diastolic
function, independent of ischemic
heart disease or systemic
hypertension
 Independent risk factors for CHF
 Elevated A1C
 Micro-albuminuria
Nichols G A et al. Dia Care 2004;27:1879-1884

8. Lower HbA1c levels are associated with
reduced micro- and macrovascular risk
Risk reduction with 1% decline in annual mean HbA1c
1
All, p < 0.0001 p = 0.035 p = 0.016 p = 0.0001
Microvascular
disease
37%
PVD
43%
Stroke
14% 12%
Heart
failure
Cataract
extraction
16%
19%
0%
15%
30%
45%
Myocardial
infarction
PVD, peripheral vascular disease (lower extremity amputation or fatal peripheral vascular disease);
UKPDS, UK Prospective Diabetes Study
1. Stratton IM, et al. BMJ. 2000;321:405–412.
UKPDS observational study

9. 0
5
10
15
20
25
30
35
40
45
50
Myocardial
Infarction
Stroke CV Death
Nondiabetic –MI (n=1,304)
Diabetic +MI (169)
Nondiabetic +MI (n=69)
Diabetic –MI (n=890)
P<0.001*
P<0.001*
P<0.001*
CV = cardiovascular; -MI = no prior myocardial infarction; +MI = prior myocardial
infarction
*For diabetes vs. no diabetes and prior MI vs. no prior MI
Increased Risk of Cardiovascular Events Over 7
Years in Patients With Type 2 Diabetes
Haffner SM, et al. N Engl J Med. 1998;339:229–234.

10. Submission with NDA
• Meta-analysis of important CV events across controlled Phase II and III studies to
calculate the risk ratio
• If the upper bound of the 2-sided 95% CI for the estimated risk ratio is:
– > 1.8, inadequate data to support approval
– 1.3–1.8,* postmarketing CV trial(s)
needed to show definitively < 1.3
– < 1.3,* postmarketing CV trial(s) generally not necessary
(*With a reassuring point estimate.)
• Studies included in the meta-analysis must be appropriately designed, and include
patients at higher CV risk so that sufficient endpoints are obtained to allow a
meaningful estimate of risk
Regulatory requirements
for CV outcome data
FDA: Guidance for industry (Dec 2008)
Diabetes Mellitus: Evaluating Cardiovascular Risk in New Antidiabetic Therapies in Type 2
Diabetes1
1. FDA Guidance for Industry.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf.
2. EMA Guidelines. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf.

11. 11
Superiority
Noninferiority
Approvable;
CV safety study
postapproval may not
be required
Noninferiority
Boundary
HR 1.3
Noninferiority
Boundary
HR 1.8
0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2
Hazard ratio
HR = hazard ratio; CV = cardiovascular; CI = confidence interval.
1. Hirshberg B et al. Diabetes Care. 2011:34;S101–S106.
FDA Statistical Hurdles for Approval1
Hypothetical examples of possible HRs, and regulatory consequences
If the upper bound of two-sided 95% CI for HR is <1.3, a postmarketing CV
trial may not be required under normal conditions.

12. 12
Non-inferiority
Boundary
HR 1.3
Non-inferiority
Boundary
HR 1.8
0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2
FDA Statistical Hurdles for Approval1
Hypothetical examples of possible HRs, and regulatory consequences
Non-inferiority
Inferiority
Underpowered
Approvable; need for full
postapproval CV safety study
(~600 events)
Not approvable
If upper bound of two-sided 95% CI for HR is between 1.3 and 1.8, a
postmarketing full CV safety trial will be required to definitively assess whether
upper bound is <1.3.
HR = hazard ratio; CV = cardiovascular; CI = confidence interval.
1. Hirshberg B et al. Diabetes Care. 2011:34;S101–S106.
Hazard ratio

13. 13
Non-inferiority
Boundary
HR 1.3
Non-inferiority
Boundary
HR 1.8
0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2
Hazard ratio
FDA Statistical Hurdles for Approval1
Hypothetical examples of possible HRs, and regulatory consequences
Non-inferiority
Inferiority
Underpowered
Approvable; need for full
postapproval CV safety study
(~600 events)
Not approvable
If the upper bound of the two-sided 95% CI for HR is >1.8, the drug is not
approvable and a full safety trial is required prior to approval.
HR = hazard ratio; CV = cardiovascular; CI = confidence interval.
1. Hirshberg B et al. Diabetes Care. 2011:34;S101–S106.

14. 14
CI = confidence interval; HR = hazard ratio; CV = cardiovascular.
1. Hirshberg B et al. Diabetes Care. 2011:34;S101–S106.
FDA Statistical Hurdles for Approval1
 If the upper bound of the two-sided 95% CI for HR is <1.3 (after
interim analysis) and the overall risk-benefit analysis supports
approval, a postmarketing CV trial may not be needed
 If the upper bound of the two-sided 95% CI for HR is between 1.3
and 1.8, a postmarketing trial will be required to definitively assess
whether upper bound is <1.3 before obtaining approval
 If the upper bound of the two-sided 95% CI for HR is >1.8, the drug is
not approvable

15. Impact of Intensive DM Control

16. STUDY POPULATION GLUCOSETARGET
PRIMARY
ENDPOINT
RESULT HYPOGLYCEMIA
Van den Berghe—1 SICU (n = 1548) 80-110 versus 180-200 ICU death 42% RRR 7.2% (<40 mg/dL)
Van den Berghe—2 MICU (n = 1200) 80-110 versus 180-215 Hospital death No difference
18.7% (mean 32
mg/dL)
VISEP* MICU, sepsis (n = 488) 80-110 versus 180-200 28-day death
↑ Mortality
trend
17.0% (<40 mg/dL)
GIST-UK* Stroke ICU (n = 933)
72-126 versus usual
care
90-day death No difference 15.7% (<70 mg/dL)
European
Glucontrol*
MICU (n = 1101) 80-110 versus 140-180 Hospital death
↑ Mortality
trend
8.6% (<40 mg/dL)
NICE-SUGAR MICU 81-108 versus <180 90-day death 14% ↑ Mortality 6.8% (<40 mg/dL)
RandomizedTrials Comparing Normalization of Blood Glucose Concentration with
Insulin Infusion, Compared with Standard of Care in aVariety of ICU Settings

17. NICE-SUGAR
Normoglycemia in Intensive Care Evaluation
Survival Using Glucose Algorithm Regulation
6104 patients ; 1/3 (surgical) and 2/3( medical)
Only 20% had known diabetes
Intensive-Rx
Group
Conventional
Group
Subjects received IV
insulin
97% 69%
Mean BG achieved 115 mg/dL. 144 mg/dL.
Mortality rate at 90
days
27.5%
14% higher mortality rate
OR 1.14 (85% CI, 0.4 to 4.8)
24.9%
Severe hypoglycemia 6.8% 0.5%
(P<0.001) (BG ≤40 mg/dL)

18. Steno-2 Study
Multifactorial Intervention for Type 2 DM
Gaede P, et al. N Engl J Med. 2008;358:580–591. Copyright
© 2008 Massachusetts Medical Society. All rights reserved.
0
10
20
30
40
50
60
70
80
CumulativeIncidence
CardiovascularEvent(%)
Years of Follow-up
0 1 2 3 5 7 8 11 13
Intensive Therapy
No. at Risk
Intensive Therapy
Conventional Therapy
80
80
72
70
65
60
61
46
56
38
50
29
47
25
31
14
4 6 9 1210
Conventional Therapy
P<0.001
Lower risk of death from CV causes
(HR 0.43; 95% CI, 0.19 to 0.94; P = 0.04)
Lower CV events
(HR, 0.41; 95% CI, 0.25 to 0.67; P<0.001)
160 patients …Rx for 7.8
Follow up 5.5 yrs
Total 13.3 yrs

19. Aa Aa

20. Study
Number of events
(annual event rate, %)
Difference in
HbA1c (%)
Favours
intensive
therapy
Favours
less
intensive
therapy
Hazard ratio
(95% CI)
More
intensive
Less
intensive
ACCORD 198 (1.18) 245 (1.51) –1.01 0.77 (0.64, 0.93)
ADVANCE 310 (1.18) 337 (1.28) –0.72 0.92 (0.79, 1.07)
UKPDS 150 (1.20) 76 (1.40) –0.66 0.81 (0.62, 1.07)
VADT 72 (16.5) 87 (1.99) –1.16 0.83 (0.61, 1.13)
Overall 730 745 –0.88 0.85 (0.76, 0.94)
Intensive glycaemic control may
reduce risk of myocardial infarction
Meta-analysis of ACCORD, ADVANCE, VADT and UKPDS suggests intensive
glucose control reduces the risk of myocardial infarction by 15%
Turnbull FR, et al. Diabetologia. 2009;52:2288–2298.
00.5 2.0

21. 21
Impact of Intensive vs Conventional Glycemic-Lowering
Strategies on Risk of CV Outcomes Is Unclear
Study
Diabetes
Duration
(mean)
Antihyperglycemic
Medicationa
Follow-up
(median)
HbA1c: Baseline,
Between-arm
Difference
Microvascular CVD Mortality
UKPDS1
Newly
diagnosed
SU/insulin or metformina vs
dietary restriction
10 years
7.1% (all patients)b,
–0.9%c ↓ ↔ ↔
UKPDS
Long-term
follow-up2
10 years post
intervention
No difference in
HbA1c between
treatment armsd
↓ ↓ ↓
ADVANCE3 8 years
Intensive glucose control
including gliclazide vs
standard treatment
5 years
7.5% (both arms)b,
–0.8%d ↓ ↔ ↔
ACCORD4
,5 10 years Multiple drugs in both arms 3.4 years
8.1% (both arms)e,
–1.1%c ↓ ↔ ↑
VADT6 11.5 years Multiple drugs in both arms 5.6 years
9.4% (both arms)b,
–1.5%d ↔ ↔ ↔
aObese patients; bMean baseline HbA1c; cMedian between-arm difference; dMean between-arm difference; eMedian 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.
1. UKPDS Group. Lancet. 1998;352:837–853. 2. Holman RR et al. N Engl J Med. 2008;359:1577–1589. 3. ADVANCE Collaborative Group et al. N Engl J Med. 2008;358:2560–2572. 4. Gerstein HC et al. N
Engl J Med. 2008;358:2545–2559. 5. Ismail-Beigi F et al. Lancet. 2010;376:419–430. 6. Duckworth W et al. N Engl J Med. 2009;360:129–139.
Lowering HbA1c may prevent macrovascular disease if started early,
but the effects may not be apparent for a very long time

23. The Look AHEAD Research Group
> 5000 Patients

24. The Look AHEAD Research Group
Stopped early on the basis of futility analysis
at about 9.6 yrs (was scheduled for 13 + yrs )

26. Reductions in MI (15% Su/ InsulinVs 33% MFN)
All-cause mortality (13% and 27%, respectively)
N Engl J Med 2008;359:1577–1589

27. Veterans Affairs
• 6,185 with CHF & DM
• Oral antihyperglycemic:
- With metformin (n=1,561)
- Without metformin
• Statistically adjusted for
co-variables
Death: 0.76 (0.63-0.92) p < 0.01
CHF hospitalization: 0.93 (0.74-1.18) p = 0.56
Total hospitalization: 0.94 (0.83-1.07) p = 0.35
Survivalestimates
1.00
0.95
0.90
0.75
0.85
0.80
Time (days)
0 700100 200 300 600400 500
Metformin
No metformin
p = 0.01
Aguilar D, et al. Circ Heart Fail 2011;4:53-8.
Metformin Use in Heart
Failure Patients
24 % RRR in MORTALITY

28. Aim: the impact of the use different insulin
secretagouges (ISs) on long-term major clinical
outcomes (Mortality & CV risk) in type 2 diabetes.
Method : 107,806 diabetic patients with or without MI
(Danish residents)
 Initiating single (IS) agent or Metformin
 between 1997 and 2006 followed up for 9 years
Schramm study

29. Schramm study
Agent W/O prior MI W prior MI
Glimepiride 1.32 (1.24-1.40) 1.30 (1.11-1.44)
Glibenclamide 1.19 (1.11-1.28) 1.47 (1.22-1.76)
Glipizide 1.27 (1.17-1.38) 1.53 (1.23-1.89)
Tolbutamide 1.28 (1.17-1.39) 1.47 (1.17–1.84)
Gliclazide 1.05 (0.94–1.16) 0.90 (0.68–1.20)
Repaglinide 0.97 (0.81–1.15) 1.29 (0.86–1.94)
Compared with Metformin (H.R/ 95% confidence intervals)

30. Schramm Study :Results
Schramm study
Conclusion
Most used ISs, including Glimepiride, Glibenclamide, Glipizide, and
Tolbutamide, seems to be associated with
increased mortality and cardiovascular risk
Metformin ,Gliclazide and Repaglinide
appear to be asso. with a lower risk than other ISS

31. Cardiovascular safety of sulfonylureas:
Meta-Analysis of randomized clinical trials.
Diabetes Obes Metab. 2013 Oct;15(10):938-53.
115 selected trials
Mortality was significantly increased with SUs
(OR: 1.22 [1.01-1.49], p = 0.047)
CONCLUSIONS
SU .. increased mortality and a higher risk of stroke
Safety of SU cannot be considered established unless it is
evaluated in long-term CV outcomes trials.

32. Risk of acute coronary events associated with
Glyburide Vs. Gliclazide use in patients with type 2
DM a nested case-control study.
.
Diabetes Obes Metab 2014 Jan;16(1):22-9.
observational study , over 5.5 yrs
> 21, 000 patients
4239 patients had an ACS-related admission / death
(adjusted OR 1.14; 95% CI 1.06-1.23) (N.N.Harm: 50).
CONCLUSION
Glyburide Vs. Gliclazide
a 14% higher risk of ACS events.

33. Aa Aa

34. Aa Aa

35. Secondary
endpoints

38. SELECTED OUTCOMES TRIALS
DPP-4 INHIBITORS

39. 39
Vildagliptin does not have an ongoing CV outcomes trial
Linagliptin CARMELINA (N=8,300)4
Pre-existing CVD + albuminuria or impaired renal function
End Jan 2018
Risk Factors Stable CAD-CVD-PAD Post ACS patients
Sitagliptin TECOS (N=~14,000)3
Pre-existing CVD
End Dec 2014
Alogliptin EXAMINE (N=5,380)1
ACS within 15–90 days
Presented
Sept 2013
Saxagliptin SAVOR-TIMI (N=16,492)2
Pre-existing CVD or multiple risk factors for CVD
Presented
Sept 2013
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;369:1327–1335. 2. Scirica BM et al. N Engl J Med. 2013;369:1317–1326. 3. Green JB et al. Am Heart J 2013;166:983–989.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.
Baseline Risk of Patient Populations Enrolled
in CV Outcome Trials of DPP-4 Inhibitors

41. FOR INTERNAL USE
No. at risk
Placebo 2679 2299 1891 1375 805 286
Alogliptin 2701 2316 1899 1394 821 269
CI, confidence interval; CV, cardiovascular; CVD, CV disease; HR, hazard ratio; MI, myocardial infarction.
†The primary endpoint occurred in 11.3% of alogliptin patients and 11.8% of placebo patients;
HR = 0.96 (1-sided repeated CI bound, 1.16).
Source: White WB, et al. N Engl J Med. 2013;369:1327–1335.
Placebo
246 12 18
100
90
80
70
60
50
40
30
20
10
0
24
18
12
0 30
Months
Cumulativeincidenceofprimary
endpointevents(%)
6
0
0 6 12 18 24 30
Alogliptin
HR = 0.96
(upper boundary of the 1-sided repeated CI, 1.16)
EXAMINE:
Alogliptin was non-inferior versus placebo for the composite primary
endpoint†(death from CVD, non-fatal MI, non-fatal stroke)

42. 42
EXAMINE and SAVOR-TIMI:
Primary Safety End Point (Composite of CV Death, Nonfatal MI, Nonfatal Stroke)
SAVOR-TIMI2
Saxagliptin
n=8,280
Placebo
n=8,212
HR (95% CI)
1° Endpt 7.3% 7.2% 1.00 (0.89–1.12)
EXAMINE1
Alogliptin
n=2,701
Placebo
n=2,679
HR
(upper limit of 95% CI)
1° Endpt 11.3% 11.8% 0.96 (1.16)
Alogliptin and saxagliptin
were non-inferior for the
primary composite end
point1,2
CV = cardiovascular; MI = myocardial infarction; 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; HR = hazard ratio; CI = confidence interval.
1. White WB et al. N Engl J Med. 2013;369:1327–1335; 2. Scirica BM et al. N Engl J Med. 2013;369:1317–1326.

43. 43
EXAMINE and SAVOR-TIMI:
Hospitalization for Heart Failure
SAVOR-TIMI3
Saxagliptin
n=8,280
Placebo
n=8,212
HR (95% CI)
HHF 3.5% 2.8% 1.27 (1.07–1.51)
EXAMINE1,2
Alogliptin
n=2,701
Placebo
n=2,679
HR (95% CI)
HHFa 3.9% 3.3% 1.19 (0.89–1.58)
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
aPost-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.
1. White WB et al. N Engl J Med 2013;369:1327–1335. 2. Sanon VP et al. Clin Diabetes. 2014;32:121–126. 3. Scirica BM et al. N Engl J Med 2013;369:1317–1326.
EXAMINE: In a post-hoc analysis, there
was a trend (P=NS) for increased
hospitalization for HF with alogliptin
compared with placebo2

44. 44
TECOS: Analysis1
 Primary outcome analysis is designed to demonstrate
noninferiority of usual care with sitagliptin vs usual care without
sitagliptin for the primary composite end point of time from
randomization to the first adjudicated CV-related death, nonfatal MI,
nonfatal stroke, or unstable angina requiring hospitalization
– If sitagliptin is found noninferior to placebo, an assessment of superiority will be
performed
 Median follow-up of up to 4 years is anticipated
– Study achieved 1,300 confirmed CV events
TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; MI = myocardial infarction.
1. Green JB et al. Am Heart J. 2013;166:983–989.e7.

45. FOR INTERNAL USE
TECOS: Study design
+ Standard of care for Type 2 Diabetes
N = 14,724; expected median follow-up ~ 4 years
Main inclusion criteria
1. Patients aged ≥ 50 years with Type 2 Diabetes
2. HbA1c 6.5–8.0% receiving stable oral glucose-lowering therapy* and/or insulin
3. Cardiovascular disease
Primary endpoint: time to first occurrence of 1 of the following:
1. CV-related death
2. Unstable angina requiring hospitalisation
3. Non-fatal stroke
4. Non-fatal MI
PlaceboSitagliptin 100 mg daily versus
*Monotherapy or dual combination therapy with metformin, pioglitazone or a sulphonylurea;
or insulin monotherapy or in combination with metformin for  3 months prior to enrolment.
Regulatory requirement for recruitment of ≥ 2000 patients receiving metformin monotherapy at baseline
Source: Green JB, et al. Am Heart J. 2013;166:983–989; Bethel MA, et al. IDF Congress 2013.
Poster P-700; ClinicalTrials.gov NCT00790205.

46. 46
TECOS: Secondary and Other Prespecified
Outcomes1
 Secondary outcomes
– Composite end point of time to first adjudicateda confirmed CV-related death, nonfatal MI, 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 outcomes include:
– Changes from baseline in urinary albumin:creatinine ratio, eGFR, HbA1c,
body weight
– Time to initiation of additional antihyperglycemic medications and/or initiation of chronic insulin
– Counts of outpatient visits and hospitalizations
aCV events will be adjudicated by an independent committee, blinded to study therapy.
TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; MI = myocardial infarction; eGFR = estimated glomerular filtration
rate.
1. Green JB et al. Am Heart J. 2013;166:983–989.e7.

47. 47
TECOS
The Good News
 Objectives achieved
 No excess CV Risk
 No higher risk of congestive heart failure
Assuring ….
It is not a class effect

48. 48
Linagliptin Outcome Trial Programme
Comparator PlaceboGlimepiride
Endpoint measures 1. Change from baseline
in HbA1c at Week 24
2. Time weighted
average of
percentage change
from baseline in
UACR at Week 24
Time to first
occurrence of primary
CV composite
endpoint*
Population T2DM patients with
albuminuria on ACEi or
ARB
T2DM patients at high
CV risk
Trial type EfficacyCV outcome
*CV composite endpoint: CV death (including fatal stroke and fatal MI); nonfatal MI; nonfatal stroke;
hospitalization for unstable angina pectoris.
**Renal composite endpoint: renal death; sustained ESRD; sustained decrease of ≥ 50% eGFR.
Source: 1. ClinicalTrials.gov CT01897532; 2. ClinicalTrials.gov NCT01243424; 3. ClinicalTrials.gov
NCT01792518.
1 2 3
Placebo
1. Time to first
occurrence of
primary CV
composite endpoint*
2. Time to first
occurrence of renal
composite endpoint**
T2DM patients with
vascular complications
and albuminuria or
renal-related end-
organ damage
CV and renal
microvascular outcome

49. The Legacy Effect …The Earlier …The Better

51. 51
Impact of Intensive vs Conventional Glycemic-Lowering
Strategies on Risk of CV Outcomes Is Unclear
Study
Diabetes
Duration
(mean)
Antihyperglycemic
Medicationa
Follow-up
(median)
HbA1c: Baseline,
Between-arm
Difference
Microvascular CVD Mortality
UKPDS1
Newly
diagnosed
SU/insulin or metformina vs
dietary restriction
10 years
7.1% (all patients)b,
–0.9%c ↓ ↔ ↔
UKPDS
Long-term
follow-up2
10 years post
intervention
No difference in
HbA1c between
treatment armsd
↓ ↓ ↓
ADVANCE3 8 years
Intensive glucose control
including gliclazide vs
standard treatment
5 years
7.5% (both arms)b,
–0.8%d ↓ ↔ ↔
ACCORD4
,5 10 years Multiple drugs in both arms 3.4 years
8.1% (both arms)e,
–1.1%c ↓ ↔ ↑
VADT6 11.5 years Multiple drugs in both arms 5.6 years
9.4% (both arms)b,
–1.5%d ↔ ↔ ↔
aObese patients; bMean baseline HbA1c; cMedian between-arm difference; dMean between-arm difference; eMedian 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.
1. UKPDS Group. Lancet. 1998;352:837–853. 2. Holman RR et al. N Engl J Med. 2008;359:1577–1589. 3. ADVANCE Collaborative Group et al. N Engl J Med. 2008;358:2560–2572. 4. Gerstein HC et al. N
Engl J Med. 2008;358:2545–2559. 5. Ismail-Beigi F et al. Lancet. 2010;376:419–430. 6. Duckworth W et al. N Engl J Med. 2009;360:129–139.
Lowering HbA1c may prevent macrovascular disease if started early,
but the effects may not be apparent for a very long time

52. VADT
Mortality correlated well with
Duration of DM at study enrollment.
Diabetes duration less than 15 years = Mortality benefit
(Vs. Diabetes duration of ≥20 years )
DuckworthWC, Abraira C, MoritzTE, et al.; Investigators of theVADT.The duration ofdiabetes affects
the response to intensive
glucose control in type 2 subjects: theVA DiabetesTrial. J DiabetesComplications 2011;25:355–361

53. Conclusions
 “Gluco -centric” approach targeting
(HbA1C ) doesn’t tell the whole story
Reducing CV risk in DM patients =
Aggressive management of the standard CV risk
factors rather than intensive glycemic control alone
Apply the ABCs

54.  Uncontrolled DM correlates well with both
macro-vascular ( MI , HF , CVA & PAD and -associated mortality)
and micro-vascular diseases and outcomes
 The impact of DM medications on HbA1c may not reflect
the full effect on overall risk of CV events
 Strict control has less robust impact on macro-vascular
(Vs. microvascular) outcomes
 It takes longer duration of strict control to cash out significant
macro-vascular benefits …but with legacy effect