Clinical Benefit of Hyperlipidaemia Treatment

1
Clinical Benefit of Hyperlipidaemia Treatment

Russell S Scott Clinical Professor of
Medicine Lipid and Diabetes Research Christchurch
New Zealand 08/2002
2
Epidemiology Predicting a global rise in CVD

• Populations are aging
• Obesity and insulin resistance is increasing and
  will cause CVD rates to rise
• Diabetes rates will double in 10 years and CVD is
  the major health risk of DM
• Hypertension is prevalent and is a major risk
  factor for CVD
• What is the role of lipid management in
  preventing TIA, stroke, fatal / non-fatal MI,
  angina and revascularization procedures

3
Prevention of adverse CVD outcomes through Lipid
Treatment

• CHD Prevention in Patients with High Absolute
  Risk ( eg gt 15)
• CHD Prevention in Patients with Lower Absolute
  Risk
• Reducing rates of Revascularisation
• Special categories
• The Elderly
• Women
• Stroke
• Diabetes
• Peri infarction treatment

4
CHD Prevention in Patients with High Absolute
Risk ( eg gt 15)

• Main Studies
• CARE
• LIPID
• 4S
• HPS
• VA-HIT
• BIP

5
Statin Sudies Mechanism of Action of Statins
VLDL
Cholesterol synthesis
Apo B
LDL receptor (BE receptor) synthesis
LDL receptormediated hepatic uptake of LDL and
VLDL remnants
Apo E
Intracellular Cholesterol
Apo B
Serum LDL-C
Serum VLDL remnants
Serum IDL
Systemic Circulation
Hepatocyte
Reduce hepatic cholesterol synthesis, lowering
intracellular cholesterol, which stimulates
upregulation of LDL receptor and increases the
uptake of non-HDL particles from the systemic
circulation.
6
Statins and PPAR? activation
Statins
PPAR? activators
Activated PPAR?
Activation or repression
Inflammatory mediators
Tissue factor
ApoA-I
Endothelial dysfunction,parietal
inflammation and thrombogenicity
7
CARE STUDY
Placebo
Treated

• DM 304
• non DM 1774
• total 2078

• DM 282
• non DM 1799
• total 2081

8
CARE STUDYoverall event rates ()
PLACEBO
TREATED

• 13.2

• 10.2

Excess risk 3.0 events / 100 persons
Risk reduction 24 (9 - 36)
Placebo minus Treated
9
LIPID STUDY
Placebo
Treated

• DM 386
• non DM 4116
• total 4502

• DM 396
• non DM 4116
• total 4512

10
LIPID STUDYoverall event rates ()
PLACEBO
TREATED

• 15.9

• 12.3

Excess risk 3.6 events / 100 persons
Risk reduction 25 (15 to 32)
Placebo minus Treated
11
4S
Placebo
Treated

• DM 97
• non DM 2126
• total 2223

• DM 105
• non DM 2116
• total 2221

12
4Soverall event rates ()
PLACEBO
TREATED

• 28.0

• 19.4

Excess risk 8.6 events / 100 persons
Event rates are CHD death or non fatal MI
Risk Reduction 34 (23 to 40)
Placebo minus Treated

13
Placebo
Treated

• DM 2981
• non DM 7288
• total 10269

• DM 2982
• non DM 7285
• total 10267

Numbers may be /- 2 for DM
14
Heart Protection Studyoverall event rates ()
PLACEBO
TREATED

• 11.8

• 8.7

Excess risk 3.1 events / 100 persons
Risk reduction 27 (21 to 33)
Placebo minus Treated
15
CHD Prevention Trials with Statins
Note Risk reductions shown are for CHD death,
non fatal MI
16
CHD Death and non fatal MI Event Rates in Lipid
treatment trials
mmol/l
125
150
175 mg/dl
17
Fibrates PPAR alpha ligands
Retinoic acid
PPAR?
PPAR?
Ligand
PPAR
RXR
Adipose tissue
Liver
PPRE
Target gene
Control of genesinvolved in lipid transport and
oxidation
LipogenesisFat cell differentiation
18
Effects of Fibrates

• Increase HDL
• Decrease Triglycerides
• Alter size of LDL
• small to larger
• reduce inflammatory markers
• CRP
• fibrinogen

19
Bezafibrate Infarction Prevention (BIP) Study
Placebo
Treated

• DM 154
• non DM 1388
• total 1542

• DM 155
• non DM 1393
• total 1548

20
Bezafibrate Infarction Prevention overall event
rates ()
PLACEBO
TREATED

• 15.0

• 13.6

Excess risk 1.4 events / 100 persons
Risk reduction 9.4 (nsd)
Placebo minus Treated
21
BIP Study ? Effect of Bezafibrate in patients
with Triglyceride Levels lt200 mg/dl (2.25
mmol/l)
Triglycerides lt200 mg/dl (2.25 mmol/l)
Bezafibrate (n1314) Placebo (n1317)
P0.86
0
1
2
3
4
5
6
BIP Study Group Circulation 200010221-27.
22
BIP Study ? Effect of Bezafibrate in patients
with Triglyceride Levels gt200 mg/dl (2.25
mmol/l)
Triglycerides gt200 mg/dl (2.25 mmol/l)
Bezafibrate (n 234) Placebo (n225)
39.5 risk reduction
P0.02
0
1
2
3
4
5
6
BIP Study Group Circulation 200010221-27.
23
VA-HIT
Placebo
Treated

• DM 318
• non DM 949
• total 1267

• DM 309
• non DM 955
• total 1264

Only males were included
24
VA-HIToverall event rates ()
PLACEBO
TREATED

• 21.7

• 17.3

Excess risk 4.4 events / 100 persons
Event rates are CHD death or non fatal MI
Risk Reduction 22 (9 to 40)
Placebo minus Treated
25
CHD Death and non fatal MI Event Rates in Lipid
treatment trials
mmol/l
125
150
175 mg/dl
26
CHD Prevention in Patients with Lower Absolute
Risk ( eg lt 10)

• Main Studies
• AFCaps/TexCaps
• WOSCOPS

27
CHD Prevention Trials with Statins in lower risk
subjects
CHD Risk Reduction (overall)
Absolute Risk Reduction
Drug
Study
No.
Primary Prevention
2.3
40
3583
Lovastatin
AFCAPS/TexCAPS
2.4
31
6595
Pravastatin
WOSCOPS
Note Risk reductions shown are for CHD death,
non fatal MI
28
Comparison of Studies
Primary prevention Secondary prevention
29
HPS with MAJOR VASCULAR EVENT by upper
lower thirds of on study LDL
30
25
with major vascular events
20
15
1.5
2.0
2.5
3.0
3.5
4.0
143
104
70
mg/dl
Average LDL cholesterol (mmol/l)
30
Reducing rates of Revascularisation

• Main Studies
• HPS
• Post CABG

31
HEART PROTECTION STUDYPATIENT NUMBERS
Category
Number of Patients ()
13386 (66)
PRIOR CHD
8510 (42) includes 1126 with DM
MI
Other CAD
4876 (24) includes 855 with DM
NO PRIOR CHD
7150 (34)
CVA
PVD
Diabetes
Approximately 1500 patients overlapped in this
group
32
Heart Protection Study Revascularisation rates
Risk ratio and 95 CI
Placebo (n10,267)
Simvastatin (n10,269)
Statin better
Statin worse
7.1
5.0
Coronary Revasc
Non Coronary
5.2
4.4
Revascularisation
Any Revascularisation
N939
N1205
0.76(0.66-0.85) (2P lt0.001)
11.7
9.1
0.76(0.72-0.81) (2P lt0.0001)
Any vascular event
N2585 (25.2)
N2033 (19.8)
Lancet 360 (7) 2002.
33
Post CABG Trial

• Aim
• Post CABG, do patients have better outcomes with
  aggressive LDL lowering therapy ?
• Intervention
• Lovastatin Cholestyramine if needed
• End Points
• angiographic outcome
• Combined end point death from CVD, or non fatal
  MI / CVA, or CABG or angioplasty
• LDL Treatment objectives
• 60-85 mg/dl (1.6-2.2 mmol/l) for aggressive
  treatment group
• 130-140 mg/dl (3.4-3.6 mmol/l) for less intensive
  bgroup.

34
Post CABG Trial

• Achieved LDL was 93 - 97 mg/dl (target not quite
  achieved) in the aggressive treatment group vs
  132 - 136 mg/dl in the moderate treatment group
• 7.5 year follow up data
• group comparisons
• 30 decrease re-vascularizations
• 24 decrease in composite end points
• angiographic data at 3 years were different
  between groups

35
Reducing Stroke Events
36
(No Transcript)
37
Pravastatin Pooling Project Stroke Event rates
(number per 1000 py)
LIPID
38
Reducing Vascular Events in Special Groups
39
CVD Event Reduction in Older Persons
Risk ratio and 95 CI
Risk Reduction
Number
Statin better
Statin worse
27
1021
4S (gt65 years)
CARE (65-75 yrs)
39
1283
28
2168
LIPID (65-69 yrs)
HPS (65-69 yrs)
23
4491
19
5816
gt70 years
40
CVD Event Reduction in Women
41
Reducing CVD Events in Diabetic Patients
42
CARE STUDYevent rates for fatal CHD event and
non fatal MI ()
PLACEBO
TREATED
TREATED
PLACEBO

• Non DM
• 12.0

• Diabetes
• 20.4

• Diabetes
• 17.7

• Non DM
• 9.1

Excess risk 2.9 events / 100 persons over
duration of study
Excess risk 2.7 events / 100 persons over
duration of study
rr 13 (-30 to 40) (rr 25 for combined CHD end
points)
rr 26 (10 to 40)
Placebo minus Treated Event Rate
43
LIPID STUDY event rates for fatal CHD event and
non fatal MI ()
PLACEBO
TREATED
TREATED
PLACEBO

• Non DM
• 15.3

• Diabetes
• 22.8

• Diabetes
• 19.2

• Non DM
• 11.7

Excess risk 3.6 events / 100 persons
Excess risk 3.6 events / 100 persons
rr 25 (15 to 33)
rr 19 (-19 to 41)
Placebo minus Treated Event Rate
44
4S event rates for fatal CHD event and non fatal
MI ()
PLACEBO
TREATED
TREATED
PLACEBO

• Non DM
• 27.2

• Diabetes
• 45.4

• Diabetes
• 22.9

• Non DM
• 19.2

Excess risk 8.0 events / 100 persons
Excess risk 22.5 events / 100 persons
rr 32 (23 to 40)
rr 55 (26 to 73)
Placebo minus Treated Event Rate
45
HEART PROTECTION STUDYPATIENT NUMBERS WITH
DIABETES
46
Heart Protection Study Vascular Events in those
with Diabetes
Risk ratio and 95 CI
Placebo
Baseline feature
Simvastatin
Statin better
Statin worse
37.8
Previous MI or
33.4
other CHD (not MI)
No prior CHD
18.6
13.8
No prior CHD or CVD
13.5
9.1
All patients with/out DM
0.80
2585 (25.2)
2033 (19.8)
47
NoteRisk reductions shown are for the specified
outcome for the respective studies HPS CHD
death, non fatal MI, stroke, revascularization CAR
E CHD death, non fatal MI, CABG/PTCA LIPID CHD
death, non fatal MI 4S CHD death, non fatal MI
48
VA-HIT Study Diabetic Subjects
Number with events ()
PLACEBO
TREATED

• Diabetes
• No Diabetes

• Diabetes
• No Diabetes

• 88/309 (28)
• 170/955 (18)

• 116/318 (36)
• 214/949 (23)

• Risk reduction 24 p0.05

• Risk reduction 24 p0.009

49
CHD Prevention Trials with Fibrates in Diabetic
Subjects
Median value Koskinen P et al. Diabetes Care
199215820-825. Rubins HB et al. N Engl J Med
1999341410-418. DAIS Investigators. Lancet
2001357905-910.
50
Lipid Modifying agents after an acute vascular
event
51
MIRACL Worsening Angina with New Objective
Evidence of Ischemia and Urgent Rehospitalization
9
8.4
Placebo
6.2
6
Atorvastatin
Cumulative incidence ()
Relative risk 0.74 P.02 95 CI 0.57-0.95
3
0
0
4
8
12
16
Time since randomization (weeks)
Schwartz GG, et al. JAMA. 20012851711-1718.
52
MIRACL Fatal or Nonfatal Stroke
2
Relative risk 0.50 P.045 95 CI 0.26-0.99
Placebo
1.5
1
Cumulative incidence ()
Atorvastatin
0.5
0
0
4
8
12
16
Time since randomization (weeks)
Schwartz GG, et al. JAMA. 20012851711-1718.
53
Conclusion

• Lipid managemnt is a critical part of a clinical
  approach for reducing stroke, MI and
  revascularisations.
• Stroke and CHD events are reduced across all
  population groups by lipid modifying agents.
• Diabetic subjects, the elderly, females as well
  as males
• regardless of level of LDL
• Statins are the treatment of choice for CVD
  management but Fibrates and other lipid modifyimg
  agents have an important clinical role

54

• No drug treatment will reduce event rates if it
  is not continuedif used with poor complianceif
  it does not produce the expected biochemical
  outcome