Why should cardiologist be concerned about cardio metabolic risk?

Prof. D John BetteridgeUniversity College London

Slide lecture prepared and held by:

Master Class: Advanced CV Risk management in cardiologyJune 17-18, 2011, London

Presentation topic

Intra-Abdominal (Visceral) Fat

Visceral

Subcutaneous

Abdominal obesity: a major underlying cause of acute myocardial

infarction (MI)

Yusuf et al, 2004

PAR

(%)a

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

Abdominal obesity predicts the risk of CVD beyond BMI

Cardiometabolic risk factors in the INTERHEART Study

0

20

40

60

18

Hypertension

10

Diabetes

20

AbdominalObesity

49

Abnormal Lipids

High waist circumference is associated with multiple cardio

vascular risk factors30

20

10

0 LowHDL-Ca

HighTGb

HighFPGc

HighBPd

>2 riskfactorse

Prev

alen

ce o

f hig

h wa

istcir

cum

fere

nce

asso

ciate

d wi

th (%

)

US population age >20 years

NHANES 1999–2000 cohort

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 Eventsin Metabolic Syndrome, a Meta-

AnalysisIncident CAD Events in Patients Without Prevalent CVD

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

Study RR1.401.281.521.621.483.921.411.484.901.74

1.49

Girman (b)GodslandHolvöetMcNeillPyöräläRidkerSattarSchillaciTenkanenSummaryExcluding outlierssummary

Decreased risk Increased risk0.1 0.2 0.5 1 2 5 10

Adipose Tissue:A Major Secretory Organ

Adiposetissue

IL-6

Adiponectin

Leptin

TNFα

Adipsin(Complement D)

Plasminogenactivator inhibitor-1

(PAI-1)

Resistin

Free fatty Acids

Angiotensinogen

Lipoprotein lipase

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

IL-1βMCP 1

Vascular Endothelial Growth Factor

Dyslipidaemia in Type 2 Diabetes and Metabolic

SyndromeTriglycerides

Small, dense LDL

Insulin resistance

Remnants HDL2

Characteristics of LDL Subclasses

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

Large, buoyant LDL Small, dense LDLGAG-binding segments(3147–3157) (3359–3367)

apo B-100

Free cholesterolPhospholipids

• 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

Large, buoyantparticles

Small, denseparticles

Apo B More apo B

The Absolute Concentration of LDL-C Can be Misleading in Subjects with

Small, Dense LDL?At the same LDL-C level, the number of LDL particles is increased, if small and denseEach LDL particle contains one molecule of apo BApo B concentration increases in direct relation to number of LDL particlesSniderman AD et al Ann Intern Med 2001

LDL Subfractions “Control” vs Patient with Insulin

Resistance

Increasing densityDecreasing size

III

IIIDJB-TG 0.9 mmol/l

DM-TG 2.95 mmol/l

UKPDS:Risk Factors for MI.

• LDL cholesterol• HDL cholesterol• HbA1c • Systolic blood pressure• Smoking Baseline Epidemiology Data

Turner et al BMJ 1998

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

Temporal Mortality Trends Patients with and without Diabetes

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

CHD Prevention Trials with Statins in Diabetic Patients Subgroup Analyses.

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)

CHD % Risk Reduction Overall Diabetes

Secondary prevention

GREACE Atorvastatin 313 51 58 (p<0.0001)

Time to First Major Cardiovascular Event Patients With Diabetes

TNT StudyHR = 0.75 (95% CI 0.58, 0.97) P=0.026

Atorvastatin 10 mgAtorvastatin 80 mg

0 1 2 3 4 5 6Time (years)

0.20

0.10

0.15

0.05

0

Cum

ulat

ive

inci

denc

e of

maj

or

card

iova

scul

ar e

vent

s*

Relative risk reduction = 25%

Atorvastatin 80mg

Atorvastatin 10mg

Shepherd et al Diabetes Care 2006

HR = 0.75 (95% CI 0.58, 0.97) P=0.026

Relative risk reduction = 25%

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;

Non Diabetes

Event Rate

Diabetes n=978

No Diabetes n=3184

0%

5%

10%

15%

20%

25%

30%

Pravastatin

Atorvastatin

HR 0.75 p= 0.03

HR 0.76 p= 0.002

Ahmed et al European Heart Journal Sept 5th 2006

Implications of Recent Trials Adult Treatment Panel III Guidelines

Diabetes

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

With metabolic syndrome Without metabolic syndrome

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)

4417 (44%)5584 (56%)22% with DM

Deedwania et al Lancet In Press

TNT Time to First Major Cardiovascular Event Patients With Metabolic Syndrome

0 1 2 3 4 5 6Time (years)

0.05

0Prop

ortio

n of

pat

ient

s exp

erie

ncin

g

maj

or c

ardi

ovas

cula

r eve

nt*

Relative risk reduction 29%

Atorvastatin 10 mgAtorvastatin 80 mg

0.20

0.10

0.15

HR = 0.71 (95% CI 0.61, 0.84)P < 0.0001

HR 0.71 (95%CI 0.61,0.84) p<0.0001

Atovastatin 80mg/day

Atovastatin 10mg/day

Deedwania et al 2006 Lancet In Press

304 events Expected completion 2005

Atorvastatin 10 mg

2,838Patients

d/b PBO

CARDS:Collaborative AtoRvastatin Diabetes

StudyPatient 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

Primary EndpointTime to first major CVD event

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

Actual termination June 2003 after 2nd interim analysis 210 events

Median Lipid Levels by Treatment Total cholesterol

(mmol/L)LDL cholesterol

(mmol/L)

0 2 3 41 4.5 2 3 41 4.5

Years of Study

Years of Study

00

1

2

3

4

0

2

4

6

Placebo Atorvastatin

Average difference 26%1.40 mmol/L (54mg/dL) p<0.0001

Average difference 40%1.20 mmol/L (46mg/dL) p<0.0001

Median Lipid Levels by Treatment

HDL cholesterol (mmol/L)

Triglycerides (mmol/L)

0 2 3 41 4.5 2 3 41 4.5

Years of Study

Years of Study

00

1

21.4

0

.2

.4

.6

.8

1

1.2

Placebo Atorvastatin

Average difference 1%0.02 mmol/L,0.8mg/dL p=0.0002

Average difference 19% 0.39 mmol/L, 35mg/dL p<0.0001

CARDSPrimary Prevention of CVD in Type 2 Diabetes with

Atorvastatin 10mgCumulative Hazard for Primary Endpoint

Relative Risk -37% (95% CI: -52, -17) P=0.001

AtorvaPlacebo

Years

328305

694651

10741022

13611306

13921351

14281410

Placebo127 events

Atorvastatin83 events

Cum

ulat

ive

Haz

ard

(%)

0

5

10

15

0 1 2 3 4 4.75Number at risk

0

0.5

1

1.5

2

0 1 2 3 4 4.5Study time (years)

Haz

ard

ratio

(95%

CI)

Treatment Effect on Primary Endpoint in

CARDS

18 38 55 71 86 97 106 117 124

17 26 34 40 45 52 63 68 74Atorva

PlaceboNumber of first events

HR* 0.63 (95% CI: 0.45, 0.91)

Colhoun et al Diabetologia 2005

Cumulative Hazard for Stroke Placebo39 events

Atorvastatin21 events

Number at risk

AtorvaPlacebo

0 1 2 3 4 4.75

Years

1410 1370 1342 1061 677 3211428 1402 1378 1093 716 344

0

0.01

0.02

0.03

0.04

Cum

ulat

ive

Haza

rd (%

)

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

0

5

10

15

40 2 31

Cum

ulat

ive

haza

rd (%

)

Years

PlaceboAtorvastatin 10 mg

<65 yearsRelative Risk-37% (95% CI-57,-7)P=0.019

65 events

42 events

≥65 yearsRelative Risk -38% (95% CI -58, -8)P=0.017 41 events

62 events

Cumulative Hazard for Primary Endpoint in Older People

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 glomerular fitration 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 normoalbuminuriaIn 970 patients with eGFR 30-60mL/min/1.73m2 atorvastatin reduced major CVD events by 42% with 61% reduction in stroke

Mean within person change in est GFR from baseline

Yearly mean within person change in estimated GFR (MDRD) by treatment group and baseline albuminuria

Net effect0.38ml/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 Indications for Statin Therapy in DiabetesAged >40yrs type 2 or type 1Aged 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

Heart, 2005; 91 Suppl V

Targets Total chol <4mmol/lLDL-chol <2mmol/l

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 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 Vasc Dis Res 2008; 5: 177-183

CARDS: Safety Overview Atorvastatin Placebo 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 Vasc Dis Res 2008; 5: 177-183

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 Vasc Dis Res 2008; 5: 177-183

CARDS: Safety OverviewMuscle-related Adverse Events

Atorvastatin Placebo 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 Vasc Dis Res 2008; 5: 177-183

h Association between Statin Therapy and Incident Diabetes in 13 Major Cardiovascular Trials

Odds Ratio 1.09 (1.02-1.17)

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

for 4years resulted in one extra case of diabetes

Objective:To characterize IVUS defined coronary atherosclerosis progression in diabetic patients

Methods:Systematic analysis, 2,237 subjects in RCTs ofatherosclerosis 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.