Benefits of intensive multiple risk factor

intervention

Potential benefits of multifactorial approaches

Adherence to multiple therapies is more likely if initiated simultaneously

Early aggressive therapy targeting multiple risk factors could potentially have a major impact

on CVD prevention

Chapman RH et al. Arch Intern Med. 2005;165:1147-1152. Wald NJ, Law MR. BMJ. 2003;326:1419.

MRFIT: CVD mortality by diabetes status and number of baseline risk factors

0

20

40

60

80

100

120

140

none one only two only all three

Ag

e ad

just

ed C

VD

dea

th r

ate

per

10

,000

per

son

yea

rs

Nondiabetic

Diabetic

Stamler J et al. Diabetes Care 1993;16:434-443

FPG (mmol/L)

HbA1C (%)

SBP (mmHg)

DBP (mmHg)

Tot-C (mmol/L)

LDL-C (mmol/L)

TG (mmol/L)

Conventional–1.0

+0.2

–3

–8

+0.2

–0.3

+0.1

Intensive–2.9

–0.5

–14

–12

–1.1

–1.2

–0.5

p<0.001

<0.001

<0.001

0.006

<0.001

<0.001

0.015

Gaede P et al. NEJM 2003;348:383-93

Evidence base for multiple risk factor intervention: the STENO-2 study

Hazard ratio and 95% CI

Cardiovascular disease

Autonomic neuropathy

Retinopathy

Nephropathy

0 0.2 0.4 0.6 0.8 1.0

Gaede P et al. NEJM 2003;348:383-93

STENO-2 study: Clinical outcomes

*From nonfatal MI, CABG, PCI, nonfatal stroke, amputation, or surgery for PAD .

Prim

ary

Com

posi

te E

nd P

oint

* (%

)

0 3612

966048 847224

60

30

40

20

10

50

Intensive therapy

Conventional Therapy

Months of Follow-up

P = 0.007

Hazard ratio = 0.47 (95 percent CI., 0.24 to 0.73; P = 0.008)

Intensive Risk Management in Patients With Diabetes

Gaede P, et al. NEJM 2003; 348: 383-93

STENO-2 study: Residual CV risk

Risk factors for coronary artery disease

Potentially modifiable p LDL cholesterol <0.0001 HDL cholesterol 0.0001 HbA1C 0.0022 Systolic blood pressure 0.0065 Smoking 0.056

Stepwise selection of major risk factors for 280 coronaryartery disease events in 2,693 UKPDS patients followed for 10 years

Age and gender were also significant risk factors but not body mass index, fasting plasma insulin, waist/hip ratio or microalbuminuria

Turner RC et al. BMJ 1998;316:823-8

Summary

Type 2 diabetes is characterised by a complex and evolving pathophysiology

Most patients die from a cardiovascular cause, but microvascular complications are also important

Integrated strategies to control multiple risk factors are crucial to improve patient outcomes

Approaches to CVD prevention in diabetes

Lipidmodification

Lifestyle intervention

BPlowering

Glucose lowering

OptimalCV risk

Reduction ?

The problem

Patients routinely underestimate their

own CV risk

CV complications start to develop early in disease

course

Patients pick and choose which pills to

take

Complications are usually already

present at diagnosis

Abnormal insulin sensitivity, haemostasis, BP, vascular

function, weight, lipids, all drive adverse outcomes

The prevention of CV complications: a complex and multifactorial problem

Dysfunctional microcirculation and

macrocirculation

Drug Therapy Primary Indication

Statins Dyslipidaemia

Antihypertensives Blood pressure

Oral antidiabetics Glucose control

Long-acting insulins Glucose control

Frequently used therapies in diabetes

Key findings from recent lipid-lowering trials

2002 2003 2004 2005

HPS Benefit in CVD and DM

regardless of baseline LDL-C

ASCOT-LLABenefit in high-risk HTN regardless of baseline

LDL-C

CARDSBenefit in DM

TNTBenefit of

intensive vsmoderate

lipid loweringin stable CAD

ALLHAT-LLTNeutral effect in HTN

with mild lipid lowering

PROVE IT-TIMI 22 Early and late benefit of intensive vs moderate lipid lowering in ACS

Primary preventionSecondary prevention (ACS)Secondary prevention (stable CAD)

4D Neutral effect

in ESRD

A to Z Late benefit of

intensive vs moderate lipid lowering in ACS

IDEAL Benefit of intensive vs

moderate lipid lowering in stable CAD

Statins reduce all-cause death: Meta-analysis of 14 trials

CTT Collaborators. Lancet. 2005;366:1267-78

Cause of death

3.4 0.81

0.910.950.93

Vascular causes:

StrokeOther vascular

Any vascular

Any non-CHD vascular

0.60.61.2

4.7

2.40.20.11.13.8

8.5 9.7

4.01.20.10.32.4

5.7

1.30.70.6

4.4

Nonvascular causes:Cancer

Respiratory

0.83

1.010.820.890.870.95

0.88

TraumaOther/unknown

Any nonvascular

Any death

Events (%)Treatment(n = 45,054)

Control(n = 45,002) Treatment

betterControlbetter

1.51.00.5

CHD

Relative risk

Benefits of aggressive LDL-C lowering in diabetes

Shepherd J et al. Diabetes Care 2006; Sever PS et al. Diabetes Care 2005; HPS Collaborative Group. Lancet 2003; Colhoun HM et al. Lancet 2004.

Difference in LDL-C

(mg/dL)

Aggressive lipid-lowering

better

Aggressive lipid-loweringworse

0.026

0.036

0.001

<0.0001

0.0003

Primary event rate (%)

17.9

11.9

9.0

12.6

13.5

Control

13.8

9.2

5.8

9.4

9.3

Treatment

0.63

0.67

0.73

P

TNT Diabetes, CHD

ASCOT-LLA Diabetes, HTN

CARDS Diabetes, no CVD

HPS All diabetes

Diabetes, no CVD

* Atorvastatin 10 vs 80 mg/day† Statin vs placebo

Relative risk0.7 0.9 10.5 1.7

0.77

22*

35†

46†

39†

39†

0.75

CARDS: cumulative hazard for any CVD endpoint

Relative Risk = -32% (95% CI -45, -15) p=0.001

Years

306287

663621

1040992

13371275

13721334

AtorvaPlacebo

14281410

Placebo189 events

Atorvastatin134 events

Cum

ulati

ve H

azar

d (%

)

0

5

10

15

20

0 1 2 3 4 4.75

Colhoun H.M. et.al. Lancet 2004; 364: 685-696

Key findings from recent BP-lowering trials

2002 2003 2004 2005

ALLHATBenefit regardless

of drug class

INVESTCCB + ACEI

equivalent to -blocker

+ diuretic in hypertension

+ CAD

VALUEImportanceof promptBP control

ASCOT-BPLABenefit of

CCB + ACEI vs -blocker + diuretic

in high-risk hypertension without CAD

CAMELOTEvidence for BP goal in

hypertension+ CAD

-blocker meta-analysis

Increased risk of stroke vs other

antihypertensives

All-causemortality

CV mortality

CV events

p=0.04

p=0.02

p=0.01

No diabetesDiabetes

No diabetesDiabetes

No diabetesDiabetes

0 0.5-0.5Favours treatment

Adjusted hazard ratio

Greater benefit from hypertension control in type 2 diabetes: Syst-Eur study

Tuomilehto J et al. N Engl J Med 1999;340:677-84

p values comparediabetic vs. non-diabetic

Risk reductions from intervention studies in type 2 diabetes

Clinical Outcomes

Diabetes-related deaths (%)

All-cause mortality (%)

All MI (%)

Fatal MI (%)

All stroke (%)

Fatal stroke (%)

Follow-up (years)

UKPDSCaptoprilAtenololn=1148

32

18

21

28

44

58

8.4

HOPERamipril

n=3577

37

24

22

-

33

-

4.5

HOTFelodipine

Aspirinn=1501

67

43

51

-

30

-

3.8

4SSimva-statinn=202

36

43

55

-

62

-

5.4

UKPDS Group. BMJ 1998; 317: 713-20; HOT Study Group. Lancet 1998; 351(9118): 1755-62;

4S Group. Lancet 1994; 344: 1383-89; HOPE study investigators. Lancet 2000; 355; 253-59.

ADA (USA)1

IDF (Europe)2

AACE (USA)3

FPG (mmol/L)

< 6.7 (120)*

< 6.0 (110)*

< 6.0 (110)*

HbA1C (%)

< 7

< 6.5

< 6.5*mg/dL

Targets for glycaemic control

1American Diabetes Association. Diabetes Care 1999; 22(Suppl 1):S1-S114; 2European Diabetes Policy Group. Diabetic Medicine 1999;16:716-30;

3American Association of Clinical Endocrinologists. Endocrine Pract (2002) 8(Suppl. 1):40-82

Risk reduction in UKPDS 75An intensive glucose control policy HbA1c 7.0 % vs 7.9 % reduces

risk of

– any diabetes-related endpoints 12% p=0.030

– microvascular endpoints 25% p=0.010

– myocardial infarction 16% p=0.052

A tight BP control policy 144 / 82 vs 154 / 87 mmHg reduces risk of

– any diabetes-related endpoint 24% p=0.005

– microvascular endpoint 37% p=0.009

– stroke 44% p=0.013Stratton IM et al. Diabetologia 2006; 1761-9

UKPDS 34: Intensive glucose control and CV protection

UKPDS Group. Lancet. 1998;352:854-65.

n = 1704 overweight, with diabetes; n = 342 metformin group

Favors metforminor intensive

Favors usual care

All-cause mortalityMetformin

Intensive

Myocardial infarctionMetformin

Intensive

StrokeMetformin

Intensive

0.02

0.12

0.08

Aggregate endpoints P*

0 1 2

*Metformin vs other intensive therapy (sulfonylurea or insulin)

Relative risk(95% CI)