1

DM and CVDCardiovascular Outcome Trials

Does it matter?

Dr. Mohammad DaoudConsultant Endocrinologist

KAMC/ NGHA - Jeddah –Saudi Arabia

Objectives

To Understand :DM and CV Risk

Glycemic Control and CV outcomes The evidence ?

DM Medications and CVD ?Medications CV Safety

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

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.

Hazard Ratio

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

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

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

Lower HbA1c levels are associated with reduced micro- and macrovascular risk

Risk reduction with 1% decline in annual mean HbA1c1

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

05

101520253035404550

Inc id

e nce

Rat

e (%

)

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.

Diabetes =

“CHD Risk Equivalent.”

Diabetes is a “CVD ”

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 dataFDA: 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.

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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

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

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 2.2Hazard 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

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

Impact of Intensive DM Control

STUDY POPULATION GLUCOSE TARGET

PRIMARY ENDPOINT RESULT HYPOGLYCEMI

A

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

trend17.0% (<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% ↑

Mortality6.8% (<40

mg/dL)

Randomized Trials Comparing Normalization of Blood Glucose Concentration with Insulin Infusion, Compared with Standard

of Care in a Variety of ICU Settings

NICE-SUGARNormoglycemia 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)

Steno-2 StudyMultifactorial 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.

01020304050607080

Cum

ulat

ive

Incid

ence

Card

iova

scul

ar E

vent

(%)

Years of Follow-up0 1 2 3 5 7 8 11 13

Intensive Therapy

No. at RiskIntensive TherapyConventional Therapy

8080

7270

6560

6146

5638

5029

4725

3114

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

Aa Aa

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 infarctionMeta-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

Impact of Intensive vs Conventional Glycemic-Lowering Strategies on Risk of CV Outcomes Is Unclear

StudyDiabetes Duration (mean)

Antihyperglycemic Medicationa

Follow-up(median)

HbA1c: Baseline, Between-arm

DifferenceMicrovascular CVD Mortality

UKPDS1

Newly diagnosed

SU/insulin or metformina vs dietary restriction

10 years 7.1% (all patients)b, –0.9%c ↓ ↔ ↔

UKPDSLong-term follow-up2

10 years post intervention

No difference in HbA1c between treatment armsd

↓ ↓ ↓ADVANC

E3 8 yearsIntensive 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

The Look AHEAD Research Group> 5000 Patients

The Look AHEAD Research Group

Stopped early on the basis of futility analysis at about 9.6 yrs (was scheduled for 13 + yrs )

Look AHEAD: Lifestyle Intervention Did Not Reduce Hard End Points

Reductions in MI (15% Su/ Insulin Vs 33% MFN)

All-cause mortality (13% and 27%,

respectively)

N Engl J Med 2008;359:1577–1589

Veterans Affairs• 6,185 with CHF & DM• Oral antihyperglycemic:

- With metformin (n=1,561)

- Without metformin• Statistically adjusted for

co-variablesDeath: 0.76 (0.63-0.92) p < 0.01CHF hospitalization: 0.93 (0.74-1.18) p = 0.56Total hospitalization: 0.94 (0.83-1.07) p = 0.35

Surv

ival

est

imat

es

1.00

0.95

0.90

0.75

0.85

0.80

Time (days)0 700100 200 300 600400 500

Metformin

No metforminp = 0.01

Aguilar D, et al. Circ Heart Fail 2011;4:53-8.

Metformin Use in Heart Failure Patients

24 % RRR in MORTALITY

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

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)

Schramm

Study :ResultsSchramm studyConclusion

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

Cardiovascular safety of sulfonylureas: Meta-Analysis of randomized clinical

trials.Diabetes Obes Metab. 2013 Oct;15(10):938-

53.

115 selected trialsMortality was significantly increased

with SUs (OR: 1.22 [1.01-1.49], p = 0.047)

CONCLUSIONSSU .. 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.

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).

CONCLUSIONGlyburide Vs. Gliclazide

a 14% higher risk of ACS events.

RECORD Trial: Rosiglitazone

Aa Aa

RECORD Trial: Rosiglitazone

Aa Aa

Secondary endpoints

SELECTED OUTCOMES TRIALS DPP-4 INHIBITORS

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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

PresentedSept 2013

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

Pre-existing CVD or multiple risk factors for CVD

PresentedSept 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

FOR INTERNAL USE

No. at riskPlacebo 2679 2299 1891 1375 805 286Alogliptin 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

1009080

7060

50

403020

100

24

18

12

0 30

Months

Cum

ulati

ve in

cide

nce

of p

rimar

y en

dpoi

nt

even

ts (%

)

6

00 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

EXAMINE and SAVOR-TIMI: Primary Safety End Point (Composite of CV Death, Nonfatal MI, Nonfatal Stroke)

SAVOR-TIMI2

Saxagliptinn=8,280

Placebon=8,212

HR (95% CI)

1° Endpt 7.3% 7.2% 1.00 (0.89–1.12)

EXAMINE1

Alogliptinn=2,701

Placebon=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.

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EXAMINE and SAVOR-TIMI: Hospitalization for Heart Failure

SAVOR-TIMI3

Saxagliptinn=8,280

Placebon=8,212

HR (95% CI)

HHF 3.5% 2.8% 1.27 (1.07–1.51)

EXAMINE1,2

Alogliptinn=2,701

Placebon=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

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.

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 Diabetes2. HbA1c 6.5–8.0% receiving stable oral glucose-lowering therapy* and/or insulin3. 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 stroke4. 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 baselineSource: Green JB, et al. Am Heart J. 2013;166:983–989; Bethel MA, et al. IDF Congress 2013.

Poster P-700; ClinicalTrials.gov NCT00790205.

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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

TECOSThe Good News

Objectives achieved No excess CV Risk

No higher risk of congestive heart failure

Assuring ….It is not a class effect

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

The Legacy Effect …The Earlier …The Better

Look AHEAD: Earlier Intervention Beneficial?

51

Impact of Intensive vs Conventional Glycemic-Lowering Strategies on Risk of CV Outcomes Is Unclear

StudyDiabetes Duration (mean)

Antihyperglycemic Medicationa

Follow-up(median)

HbA1c: Baseline, Between-arm

DifferenceMicrovascular CVD Mortality

UKPDS1

Newly diagnosed

SU/insulin or metformina vs dietary restriction

10 years 7.1% (all patients)b, –0.9%c ↓ ↔ ↔

UKPDSLong-term follow-up2

10 years post intervention

No difference in HbA1c between treatment armsd

↓ ↓ ↓ADVANC

E3 8 yearsIntensive 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

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 )

Duckworth WC, Abraira C, Moritz TE, et al.; Investigators of the VADT. The duration ofdiabetes affects the response to intensive

glucose control in type 2 subjects: the VA Diabetes Trial. J Diabetes Complications 2011;25:355–361

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 aloneApply the ABCs

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