The concept of Diabetes & CV risk:A lifetime risk challenge

The Clinical Significance of LDL-Cholesterol: No Longer a Hypothesis?

John J.P. Kastelein, MD PhDAcademic Medical Center University of AmsterdamDept. Vascular MedicineAmsterdam, The Netherlands

Master Class Lipid InnovationsPrague, Czech RepublicMay 27-28, 2011

Slide lecture prepared and held by:

Presentation topic

Mortality from Ischemic Heart Disease and Cholesterol 3,020 Deaths

Prospective Studies Collaboration. Lancet 2007;370:1829

128

64

32

16

8

4

2

1

1.0 1.5Usual HDL-C (mmol/L) Usual non-HDL-C (mmol/L) Usual total/HDL-C (mmol/L)

3.0 4.0 5.0 6.0 3.0 4.0 5.0 6.0 7.00.5

A. HDL-C B. non-HDL-C C. Total/HDL-CAge at risk(years)

70-89

60-69

40-69

Age at risk(years)

70-89

60-69

40-69

70-89HR 0.69(0.63-0.74)

60-69HR 0.60(0.56-0.64)

40-69HR 0.56(0.51-0.60)

Age at risk(years)

Discoveryof statins

Discoveryof LDLreceptors

Endo, 1976 Brown andGoldstein,1974

Statins raise LDLreceptors in the liver

Plasma LDL is reduced

Primary prevention trials

Secondary prevention trials

50 70 110 130 150 170 19090 210 % P

atie

nts

with

CH

D E

ven

t

LDL cholesterol

CARE-Rx

4S-Rx

LIPID-PL

4S-PL

CARE-PL

LIPID-Rx

AFCAPS-Rx

WOSCOPS-Rx

WOSCOPS-PL

AFCAPS-PL

25

20

15

10

5

0

ASCOT-PL

ASCOT-Rx

HPS-Rx

HPS-PL

HPS

LRC-PLLRC-Rx

POSCH-PL

POSCH-Rx

non statin trials

Statin trials

(mg/dL)

1.3 1.8 2.3 2.8 3.4 3.9 4.4 4.9 5.4 (mmol/L)

TNT-80A

TNT-10A

Clear Cardiovascular Benefits of Intensive Lipid-Lowering Therapy

Correlation Between LDL-C Lowering and Decreased CHD Risk According to Treatment Modality in a Meta-Regression Analysis

Adapted from Robinson JG, et al. J Am Coll Cardiol. 2005;46(10):1855–1862

LDL-C Reduction, %4025 30 3515 20

Nonfa

tal M

I and C

HD

D

eath

Rela

tive R

isk

Reduct

ion,

%

–20

100

80

60

40

20

0

LondonOsloMRCLos AngelesUpjohnLRC NHLBIPOSCH4Sa

WOSCOPSa

CAREa

LIPIDa

AF/TexCapsa

HPSa

ALERTa

PROSPERa

ASCOT-LLAa

CARDSa

CTTC: 23% reduction in major vascular events for 1mmol/L lower LDL-C with statins

Deaths Due to Suicide, Cancer, and Hemorrhagic Stroke

Number (%) of patients

Quintile 1<64 mg/dL(114/1722)*

Quintile 264–<77 mg/dL

(529/1403)*

Quintile 377–<90 mg/dL

(1019/968)*

Quintile 490–<106 mg/dL

(1515/515)*

Quintile 5106 mg/dL(1718/266)*

Suicide 1 (0.1) 0 (0.0) 1 (0.1) 1 (0.0) 1 (0.1)

Cancer 21 (1.1) 37 (1.9) 34 (1.7) 32 (1.6) 30 (1.5)

Hemorrhagic stroke† 6 (0.3) 5 (0.3) 6 (0.3) 8 (0.4) 7 (0.4)

*Number of patients: atorvastatin 10 mg/atorvastatin 80 mg†Fatal and non-fatal

Cardiovascular events occurred in 22 (10%) of 227 patients with abnormal liver tests who received statin (3·2 events per 100 patient-years) and 63 (30%) of 210 patients with abnormal liver tests who did not receivestatin (10·0 events per 100 patient-years; 68% relative risk reduction, p<0·0001). This cardiovascular disease benefit was greater (p=0·0074) than it was in patients with normal liver tests

Lancet, 2010; 376; 9756

GREACE: Enzyme Activity in Patients with Raised Liver Enzymes. A) On Statins B) Not On Statins

Lancet, 2010; 376; 9756

Lancet, 2010; 376; 9756

Study Treatment comparison

N Target population

Entry lipid criteria

PROVE-IT A 80 vs. P 40 4162 ACS TC ≤240 mg/dL

A to Z S 40 then S 80 vs. placebo then S 20

4497 ACS TC ≤250 mg/dL

TNT A 80 vs. A 10 10,001 Prior CHD LDL-C 130-250 mg/dL TG ≤600 mg/dL

IDEAL A 80 vs. S 20-40 8888 Prior CHD TG ≤600 mg/dL

SEARCH S 80 vs. S 20 12,064 Prior CHD TC ≥4.5 mmol/L or ≥3.5 if on statins

Second CTT Cycle: More vs Less Intensive Statin Therapy

Study Treatment comparison

N Target population Entry lipid criteria

ALLIANCE A 10-80 (until LDL <80 mg/dL) vs. usual care

2442 Prior CHD LDL-C 110-200 mg/dL on lipid lowering drugs, 130-250 mg/dL if not

4D A 20 vs. placebo 1255 Type 2 DM + haemodialysis

LDL-C 80-190 mg/dLTG <1000 mg/dL

ASPEN A 10 vs. placebo 2410 Type 2 DM + CHD or risk factors

LDL-C <150, TG ≤445 mg/dL with CHD; LDL-C <159, TG ≤600 mg/dL without

MEGA P 10-20 vs. usual care

8214 Primary prevention TC 220-270 mg/dL

JUPITER R 20 vs. placebo 17 802 Primary prevention (but CRP>2 mg/dL)

LDL-C <130 mg/dL, TG <500 mg/dL

GISSI-HF R 10 vs. placebo 4574 CHF None

AURORA R 10 vs. placebo 2773 Haemodialysis None

Second CTT Cycle: Additional Trials of Statin vs Control

Absolute Effect of Statin Therapy onMAJOR VASCULAR EVENTS

0 1 2 3 4 5

05

1015

20

LDL cholesterol, mmol/L

Fiv

e ye

ar r

isk

of a

maj

orva

scul

ar e

vent

, %

Control

21% relative riskreduction per mmol/LStatin

15% relative riskreduction per 0.5 mmol/LMore statin

Combined evidence:~33% relative risk reductionper 1.5 mmol/L

Less statin

Proportional Effects on MAJOR VASCULAR EVENTS per mmol/L Reduction in LDL Cholesterol

0.4 0.6 0.8 1 1.2 1.4

No. of events (% pa)Statin/

More statinContr ol/

Relative risk (CI)

Statin/morestatin better

Control/lessstatin better

Nonfatal MI

CHD death

Any major coronary event

CABG

PTCA

Unspecified

Any coronary revascularisation

Ischaemic stroke

Haemorrhagic stroke

Unknown stroke

Any stroke

Any major vascular event

3485 (1.0)

1887 (0.5)

5105 (1.4)

1453 (0.4)

1767 (0.5)

2133 (0.6)

5353 (1.5)

1427 (0.4)

257 (0.1)

618 (0.2)

2302 (0.6)

10973 (3.2)

4593 (1.3)

2281 (0.6)

6512 (1.9)

1857 (0.5)

2283 (0.7)

2667 (0.8)

6807 (2.0)

1751 (0.5)

220 (0.1)

709 (0.2)

2680 (0.8)

13350 (4.0)

0.73 (0.69 - 0.78)

0.80 (0.74 - 0.87)

0.76 (0.73 - 0.78)

0.75 (0.69 - 0.82)

0.72 (0.65 - 0.80)

0.76 (0.70 - 0.82)

0.75 (0.72 - 0.78)

0.79 (0.72 - 0.87)

1.12 (0.88 - 1.43)

0.88 (0.76 - 1.01)

0.84 (0.79 - 0.89)

0.78 (0.76 - 0.80)

99% or 95% CI

Proportional effects on ALL CAUSE MORTALITY per mmol/L LDL-C Reduction

0.5 0.75 1 1.25 1.5

No. of events (% pa)Statin/

More statinControl/

Less statinRelative risk (CI)

Statin/morestatin better

Control/lessstatin better

Statin vs control

More vs less statin

First cycle (14 trials)

A to Z PROVE-IT

ALLIANCE

ASPEN

TNT

4D

MEGA

IDEAL SEARCH

JUPITER GISSI-HF AURORA

3832 (1.9)

104 (2.7)50 (1.2)

121 (2.3)

70 (1.6)

284 (1.2)

297 (16.8)

63 (0.3)

366 (1.8)964 (2.4)

198 (1.0)657 (8.2)

636 (13.5)

4354 (2.2)

130 (3.4)69 (1.7)

127 (2.4)

68 (1.6)

282 (1.1)

320 (17.9)

82 (0.4)

374 (1.8)970 (2.4)

247 (1.2)644 (8.0)

660 (14.0)

0.88 (0.84 - 0.91)

Subtotal (21 trials) 5874 (2.2) 6502 (2.4) 0.90 (0.87 - 0.93)

Subtotal (5 trials) 1768 (1.9) 1825 (2.0) 0.94 (0.82 - 1.08)

Total (26 trials) 7642 (2.1) 8327 (2.3) 0.90 (0.87 - 0.93)

Difference between more vs less and statin vs control:c12= 0.4, p=0.53

99% or 95% CI

Proportional Effects on CANCER INCIDENCE per mmol/L Reduction in LDL Cholesterol

0.5 0.75 1 1.25 1.5

No. of patients

Statin/More statin

ControlLess statin

Relative risk (CI)

Statin/morestatin better

Control/lessstatin better

0-1 year 1-2 years 2-3 years 3-4 years 4-5 years 5+ years All groups

982 (1.2%)1088 (1.3%)982 (1.4%)873 (1.4%)680 (1.3%)455 (1.5%)

5060 (6.0%)

997 (1.2%)1056 (1.3%)999 (1.4%)878 (1.4%)645 (1.3%)489 (1.6%)

5064 (6.0%)

0.98 (0.87 - 1.11)1.03 (0.92 - 1.16)0.98 (0.86 - 1.10)0.97 (0.85 - 1.10)1.05 (0.90 - 1.22)0.98 (0.80 - 1.21)1.00 (0.96 - 1.04)

Trend c12= 0.01; p=0.94

99% or 95% CI