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Master Class : Advanced CV Risk management in cardiology June 17-18, 2011, London. Presentation topic. Why should cardiologist be concerned about cardio metabolic risk?. Slide lecture prepared and held by:. Prof. D John Betteridge U niversity College London.

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slide1

MasterClass:

Advanced CV Risk management in cardiology

June 17-18, 2011, London

Presentation topic

Why should cardiologist be concerned about cardio metabolic risk?

Slide lecture prepared and held by:

Prof. D John Betteridge

University College London

slide2

Intra-Abdominal (Visceral) Fat

Visceral

Subcutaneous

abdominal obesity a major underlying cause of acute myocardial infarction mi

49

20

10

Diabetes

Abdominal

Abnormal

Lipids

Obesity

Abdominal obesity: a major underlying cause of acute myocardial infarction (MI)

Cardiometabolic risk factors in the INTERHEART Study

60

Abdominal obesity predicts the

risk of CVD beyond BMI

40

PAR (%)a

18

20

0

Hypertension

aProportion of MI in the total population attributable to a specific risk factor

Yusuf et al, 2004

high waist circumference is associated with multiple cardio vascular risk factors
High waist circumference is associated with multiple cardio vascular risk factors

US population age >20 years

30

20

Prevalence of high waistcircumferenceassociated with (%)

10

0

LowHDL-Ca

HighTGb

HighFPGc

HighBPd

>2 riskfactorse

NHANES 1999–2000 cohort

the metabolic syndrome prevalence in the usa
The Metabolic Syndrome:Prevalence in the USA

Prevalence of Metabolic Syndrome

ATP III NCEP clinical definition

22%

Ford et al.

Prevalence of the Metabolic Syndrome among US adults: Findings from the 3rd National Health and Nutrition Survey.

JAMA 2002; 287:356-359.

increased cad events in metabolic syndrome a meta analysis
Increased CAD Eventsin Metabolic Syndrome, a Meta-Analysis

Incident CAD Events in Patients Without Prevalent CVD

RR

Study

1.40

1.28

1.52

1.62

1.48

3.92

1.41

1.48

4.90

1.74

1.49

Girman (b)

Godsland

Holvöet

McNeill

Pyörälä

Ridker

Sattar

Schillaci

Tenkanen

Summary

Excluding outliers

summary

0.1 0.2 0.5 1 2 5 10

Decreased risk Increased risk

GAMI AS et al. J Am Coll Cardiol 49:403, 2007

adipose tissue a major secretory organ
Adipose Tissue:A Major Secretory Organ

Leptin

IL-6

IL-1β

Plasminogenactivator inhibitor-1(PAI-1)

MCP 1

TNFα

Free fatty Acids

Adiposetissue

Resistin

Lipoprotein lipase

Adiponectin

Adipsin(Complement D)

Vascular Endothelial Growth Factor

Angiotensinogen

Lyon 2003; Trayhurn et al 2004; Eckel et al 2005

dyslipidaemia in type 2 diabetes and metabolic syndrome
Dyslipidaemia in Type 2 Diabetes and Metabolic Syndrome

Triglycerides

Insulin resistance

Small, dense LDL

Remnants

HDL2

characteristics of ldl subclasses
Characteristics of LDL Subclasses

Large, buoyant LDL

Small, dense LDL

GAG-binding segments

(3147–3157) (3359–3367)

Phospholipids

Free cholesterol

apo B-100

  • Polar lipids: 63.3%
  • Accessible apo B-100: 36.7
  • Low GAG affinity
  • Polar lipids: 35.6%
  • Accessible apo B-100: 64.4
  • High GAG affinity

Hurt-Camejo E et al Curr Opin Lipidol 2000;11:465

the absolute concentration of ldl c can be misleading in subjects with small dense ldl

Apo B

More apo B

The Absolute Concentration of LDL-C Can be Misleading in Subjects with Small, Dense LDL?

Large, buoyant

particles

Small, dense

particles

At the same LDL-C level,

the number of LDL

particles is increased,

if small and dense

Each LDL particle

contains one molecule

of apo B

Apo B concentration

increases in direct

relation to number of

LDL particles

Sniderman AD et al Ann Intern Med 2001

ldl subfractions control vs patient with insulin resistance
LDL Subfractions “Control” vs Patient with Insulin Resistance

DM-TG 2.95 mmol/l

DJB-TG 0.9 mmol/l

III

I

II

Increasing density

Decreasing size

ukpds risk factors for mi
UKPDS:Risk Factors for MI.
  • LDL cholesterol
  • HDL cholesterol
  • HbA1c
  • Systolic blood pressure
  • Smoking

Baseline Epidemiology Data

Turner et al BMJ 1998

slide14

Temporal Mortality Trends

Patients with and without Diabetes

Suffering a Myocardial Infarction

(a comparison of 1762 patients in 1995 with 1642 patients in 2003)

Cubbon RM et al. Eur Heart J 2007; 28: 540–545

chd prevention trials with statins in diabetic patients subgroup analyses
CHD Prevention Trials with Statins in Diabetic Patients Subgroup Analyses.

CHD % Risk Reduction

Secondary prevention

CARE Pravastatin 586 23 25 (p=0.05)

4S Simvastatin 202 32 55 (p=0.002)

LIPID Pravastatin 782 24 19 (NS)

4S reanalysis Simvastatin 483 32 42 (p=0.001)

HPS Simvastatin 3050 24 18.4 (p<0.0001)

Diabetes

Overall

51

Atorvastatin

313

GREACE

58 (p<0.0001)

time to first major cardiovascular event patients with diabetes tnt study

Atorvastatin 10 mg

Atorvastatin 80 mg

Time to First Major Cardiovascular Event Patients With DiabetesTNT Study

HR = 0.75 (95% CI 0.58, 0.97)

P=0.026

0.20

Atorvastatin 10mg

HR = 0.75 (95% CI 0.58, 0.97)

P=0.026

0.15

Cumulative incidence of major cardiovascular events*

Atorvastatin 80mg

0.10

0.05

Relative risk reduction = 25%

Relative risk reduction = 25%

0

0 1 2 3 4 5 6

Time (years)

Shepherd et al Diabetes Care 2006

slide17
Acute Coronary Syndromes and Diabetes. Is Intensive Lipid Lowering Therapy Beneficial? Results of the PROVE IT-TIMI 22 Trial

Population: 978 ACS patients with DM LDL 101mg/dl. 734 clinical history; 219 fasting glucose >126mg/dl (7mmol/l) 25 HbA1c>7%. 3184 without diabetes LDL 108mg/dl

Diabetic patients older, more often female, more CVD morbidity, hypertension, PVD but smoked less often

Design: RCT of standard (pravastatin 40mg; LDL 81mg/dl; 18% ) vs intensive statin (atorvastatin 80mg; LDL 57mg/dl; 44%) therapy in patients treated early after ACS

Secondary endpoint: Death, MI, unstable angina;

HR 0.75

p= 0.03

HR 0.76

p= 0.002

Event

Rate

Non

Diabetes

Diabetes

n=978

No Diabetes

n=3184

Ahmed et al European Heart Journal Sept 5th 2006

implications of recent trials adult treatment panel iii guidelines diabetes
Implications of Recent Trials Adult Treatment Panel III GuidelinesDiabetes

Diabetes plus CVD:

Initiate statin therapy regardless of

baseline LDL-C;

LDL goal <70mg/dl (1.8mmol/L)

Circulation 2004;110 227

tnt study prevalence of metabolic syndrome
TNT StudyPrevalence of Metabolic Syndrome

With metabolic syndrome Without metabolic syndrome

5584 (56%)

4417 (44%)

22% with DM

2005 NCEP-based criteria (Circulation 2005 112: 2735)

  • BMI 28
  • Triglycerides 150 mg/dL (1.7 mmol/L)
  • HDL-C: Men <40 mg/dL (<1.0 mmol/L); Women <50 mg/dL (<1.3 mmol/L)
  • Blood pressure 130/85 mm Hg
  • Fasting glucose 100 mg/dL (5.6 mmol/L)

Deedwania et al Lancet In Press

tnt time to first major cardiovascular event patients with metabolic syndrome

Atorvastatin 10 mg

Atorvastatin 80 mg

TNT Time to First Major Cardiovascular Event Patients With Metabolic Syndrome

0.20

HR 0.71 (95%CI 0.61,0.84)

p<0.0001

HR = 0.71 (95% CI 0.61, 0.84)

P < 0.0001

0.15

Atovastatin 10mg/day

Proportion of patients experiencing major cardiovascular event*

0.10

Atovastatin 80mg/day

0.05

Relative risk reduction 29%

0

0 1 2 3 4 5 6

Time (years)

Deedwania et al 2006 Lancet In Press

cards collaborative atorvastatin diabetes study
CARDS:Collaborative AtoRvastatin Diabetes Study

Patient Population

  • Type 2 diabetes (40-75y)
  • No prior MI or CVD
  • Other risk factors +
  • Lipid profile:
    • LDL-C <159 mg/dL (4.14 mmol/L)
    • TG <600 mg/dL (6.78 mmol/L)
  • Collaboration in the UK

with Diabetes UK, NHS R&D and Pfizer

d/b PBO

2,838Patients

Atorvastatin 10 mg

304 events Expected completion 2005

Actual termination June 2003 after

2nd interim analysis 210 events

  • Primary Endpoint
  • Time to first major CVD event

Colhoun et al. Diabetic Med 2002; 32: 259-264.

median lipid levels by treatment
Median Lipid Levels by Treatment

Total cholesterol (mmol/L)

LDL cholesterol (mmol/L)

Average difference 40%

1.20 mmol/L (46mg/dL) p<0.0001

Average difference 26%

1.40 mmol/L (54mg/dL) p<0.0001

6

4

3

4

2

2

1

0

0

0

1

2

3

4

4.5

0

1

2

3

4

4.5

Years of Study

Years of Study

Placebo

Atorvastatin

median lipid levels by treatment1
Median Lipid Levels by Treatment

Triglycerides (mmol/L)

HDL cholesterol (mmol/L)

Average difference 19%

0.39 mmol/L, 35mg/dL p<0.0001

Average difference 1%

0.02 mmol/L,0.8mg/dL p=0.0002

1.4

2

1.2

1

.8

1

.6

.4

.2

0

0

0

1

2

3

4

4.5

0

1

2

3

4

4.5

Years of Study

Years of Study

Placebo

Atorvastatin

slide24
CARDSPrimary Prevention of CVD in Type 2 Diabetes with Atorvastatin 10mgCumulative Hazard for Primary Endpoint

15

Relative Risk -37% (95% CI: -52, -17)

Placebo

127 events

P=0.001

10

Atorvastatin

83 events

Cumulative Hazard (%)

5

0

0

1

2

3

4

4.75

Years

Number at risk

Placebo

1410

651

1351

1306

305

1022

Atorva

1428

694

1392

1361

328

1074

treatment effect on primary endpoint in cards

HR* 0.63

(95% CI: 0.45, 0.91)

Treatment Effect on Primary Endpoint in CARDS

Number of first events

18 38 55 71 86 97 106 117 124

Placebo

17 26 34 40 45 52 63 68 74

Atorva

Colhoun et al Diabetologia 2005

cumulative hazard for stroke
Cumulative Hazard for Stroke

Relative Risk -48% (95% CI: -69, -11)

0.04

Placebo

39 events

0.03

Atorvastatin

21 events

Cumulative Hazard (%)

0.02

0.01

0

Years

0

1

2

3

4

4.75

Number at risk

1410 1370 1342 1061 677 321

Placebo

1428 1402 1378 1093 716 344

Atorva

cumulative hazard for primary endpoint in older people

15

Placebo

Atorvastatin 10 mg

10

Cumulative hazard (%)

5

0

0

1

2

3

4

Years

Cumulative Hazard for Primary Endpoint in Older People

62 events

≥65 years

Relative Risk -38% (95% CI -58, -8)P=0.017

41 events

65 events

42 events

<65 years

Relative Risk-37% (95% CI-57,-7)

P=0.019

slide28

Objective:

Does atorvastatin 10mg/day affect kidney status in the CARDS study and does

the effect of atorvastatin on CVD events vary by kidney status?

Population:

2838 patients with type 2 diabetes and no prior CVD.

Outcomes:

Estimated glomerularfitration rate (eGFR), albuminuria and CVD events.

Measurements:

Baseline and follow-up GFR estimated using the Modification of Diet in Renal

Disease study equation. Urinary albumin measured on spot urines

Results:

Atorvastatin therapy led to a small but significant improvement in annual change in

eGFR, 0.18mL/min/1.73m2/year (95% CI 0.04-0.32, p=0.01)

No effect on albuminuria incidence or regression to normoalbuminuria

In 970 patients with eGFR 30-60mL/min/1.73m2atorvastatin reduced major

CVD events by 42% with 61% reduction in stroke

slide29

Yearly mean within person change in estimated GFR

(MDRD) by treatment group and baseline albuminuria

Mean within

person change in

est GFR from

baseline

Net effect

0.38ml/min/1.73m2/year

p=0.03

MDRD: Modification of Diet in Renal Disease

joint british societies guidelines on prevention of cardiovascular disease in clinical practice
Joint British Societies’ Guidelines on Prevention of Cardiovascular Disease in Clinical Practice

Indications for Statin Therapy in Diabetes

Aged >40yrs type 2 or type 1

Aged 18-39yrs type 2 or type 1 and

Significant retinopathy

Nephropathy

Poor glycaemic control (HbA1c> 9%)

Hypertension

Cholesterol >6mmol/l

Features of metabolic syndrome: Trig >1.7mm0l/l; HDL < 1.0 in men, < 1.2mmol/l in women

Family history of premature CVD in first degree relative

Targets

Total chol <4mmol/l

LDL-chol <2mmol/l

Heart, 2005; 91 Suppl V

slide31

Objective:

To explore the relationship between drug

adherence and mortality in survivors of

acute myocardial infarction

Design:

Population-based, observational, longitudinal

study of 31,455 elderly MI survivors

1999-2003 in Ontario, Canada.

Patient adherence: 80%, 40-79% and <40%

days covered.

Main Outcome Measure:

Long-term mortality, mean follow-up 2.4years

assessed by multivariate survival models

cards safety overview
CARDS: Safety Overview

Atorvastatin

n=1428 (%)

Patients with ≥ one AE

All cause 1390 (97.3)

Treatment associated 328 (23.0)

Discontinuations due to AEs

All cause 122 (8.5)

Treatment associated 41 (2.9)

Dose interruptions due to AEs

All cause 201 (14.1)

Treatment associated 34 (2.4)

Patients with serious AEs

All cause 421 (29.5)

Treatment associated 15 (1.1)

Newman et al Diabetes VascDis Res 2008; 5: 177-183

cards safety overview1
CARDS: Safety Overview

AtorvastatinPlacebo

n=1428 (%) n=1410 (%)

Patients with ≥ one AE

All cause 1390 (97.3) 1376 (97.6)

Treatment associated 328 (23.0) 358 (25.4)

Discontinuations due to AEs

All cause 122 (8.5) 145 (10.3)

Treatment associated 41 (2.9) 48 (3.4)

Dose interruptions due to AEs

All cause 201 (14.1) 172 (12.2)

Treatment associated 34 (2.4) 23 (1.6)

Patients with serious AEs

All cause 421 (29.5) 431 (30.6)

Treatment associated 15 (1.1) 16 (1.1)

Newman et al Diabetes VascDis Res 2008; 5: 177-183

cards safety overview muscle related adverse events
CARDS: Safety OverviewMuscle-related Adverse Events

Atorvastatin

n=1428 (%)

Myalgia

All cause 57 (4)

Treatment associated 14 (1)

Leg Cramps

All cause 70 (4.9)

Treatment associated 11 (0.8)

Myopathy

All cause 1 (0.1)

Treatment associated 1 (0.1)

Newman et al Diabetes VascDis Res 2008; 5: 177-183

cards safety overview muscle related adverse events1
CARDS: Safety OverviewMuscle-related Adverse Events

AtorvastatinPlacebo

n=1428 (%) n=1410 (%)

Myalgia

All cause 57 (4) 67 (4.8)

Treatment associated 14 (1) 17 (1.2)

Leg Cramps

All cause 70 (4.9) 61 (4.3)

Treatment associated 11 (0.8) 10 (0.7)

Myopathy

All cause 1 (0.1) 1 (0.1)

Treatment associated 1 (0.1) 0

Newman et al Diabetes VascDis Res 2008; 5: 177-183

slide36
h

Association between Statin Therapy and Incident Diabetes

in 13 Major Cardiovascular Trials

Treatment of 255 (95%CI 150-852) patients with statins

for 4years resulted in one extra case of diabetes

Odds Ratio 1.09 (1.02-1.17)

slide38

Objective:

To characterize IVUS defined coronary

atherosclerosis progression in diabetic patients

Methods:

Systematic analysis, 2,237 subjects in RCTs of

atherosclerosis progression, Reversal, Camelot,

Activate, Asteroid and Illustrate .

All patients had CAD, at least one lumen

narrowing >20% on diagnostic arteriogram.

The pattern of disease progression was compared

in subjects with and without diabetes

Diabetic patients had a greater percent atheroma

volume 40.2 ± 0.9% vs 37.5 ± 0.8% on multivariate

analysis, p<0.0001 at baseline.