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.