modern management of cholesterol in the high-risk patient
TRANSCRIPT
Overview PresentationOverview Presentation
• Who are at risk Who are at risk – Secondary preventionSecondary prevention– Primary prevention - Diabetes Mellitus type 2Primary prevention - Diabetes Mellitus type 2
• Lowering CholesterolLowering Cholesterol– Secondary preventionSecondary prevention– Primary preventionPrimary prevention
• Beyond cholesterol loweringBeyond cholesterol lowering• How low should we goHow low should we go• GuidelinesGuidelines
Priorities for Lipid loweringPriorities for Lipid lowering
• Secondary preventionSecondary prevention
• Patients with diabetes mellitus type 2Patients with diabetes mellitus type 2
• Patients with genetic dyslipidemia'sPatients with genetic dyslipidemia's
• Patients with multiple Patients with multiple rriskisk factorsfactors
04/19/23 17:53P0168.PFIZER.Lipitor.Slide_Kit.A.dh07
Consequences of CHDConsequences of CHD
• 50 % of all MI’s in patients with previous MI
• 70 % of all fatal MI’s in patients with previous MI
• 4 -7 x increased risk of MI compared to people
without CHD
Mortality in Hypercholesterolemic Men With CHD
LDL cholesterol levelLDL cholesterol level
55
1010
1515
2020
De
ath
s p
er
10
00
pe
rso
n-y
ea
rsD
ea
ths
pe
r 1
00
0 p
ers
on
-ye
ars
25 X25 X
12 X12 X
CHDCHD>160 mg/dl>160 mg/dl(4.1 mmol/l)(4.1 mmol/l)
19.1519.15
CHDCHD<130 mg/dl<130 mg/dl(3.4 mmol/l)(3.4 mmol/l)
1.641.64
No CHDNo CHD<130 mg/dl<130 mg/dl(3.4 mmol/l)(3.4 mmol/l)
0.770.77
TikkanenJ. et al. N Engl J Med 1990:322(24):1700 - 1707TikkanenJ. et al. N Engl J Med 1990:322(24):1700 - 1707
168-191 (168-191 (4.3-4.9)4.3-4.9)180 180 (4.6)(4.6)
192-217 192-217 (4.9-5.5)(4.9-5.5)204 204 (5.2)(5.2)
>218 >218 (5.6)(5.6)245 245 (6.3)(6.3)
<167 <167 (4.2)(4.2)149 149 (3.7)(3.7)
Serum cholesterol mg/dl Serum cholesterol mg/dl (mmol/l)(mmol/l)
RangeRangeMeanMean
Cu
mu
lati
ve
in
cid
en
ce
of
AM
I p
er
Cu
mu
lati
ve
in
cid
en
ce
of
AM
I p
er
10
0,0
00
sc
ree
ne
d s
ub
jec
ts i
n 3
yr.
10
0,0
00
sc
ree
ne
d s
ub
jec
ts i
n 3
yr.
100100
00
400400
200200
300300
500500
MenMenWomenWomen
Cholesterol/AMI Link in Low TC Population
Wakugami K., et al. Jpn Cir J. 1998;52:7-14Wakugami K., et al. Jpn Cir J. 1998;52:7-14
04/19/23 17:53P0168.PFIZER.Lipitor.Slide_Kit.A.dh07
‘With an excess of fat diabetes begins and from an excess of
fat diabetics die…’
Elliott P. Joslin MD 1927
National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995.
Atherosclerosis in DiabetesAtherosclerosis in Diabetes
• ~80% of all diabetic mortality~80% of all diabetic mortality– 75% from coronary atherosclerosis75% from coronary atherosclerosis
– 25% from cerebral or peripheral vascular disease25% from cerebral or peripheral vascular disease
• >75% of all hospitalizations for diabetic >75% of all hospitalizations for diabetic
complicationscomplications
• >50% of patients with newly diagnosed >50% of patients with newly diagnosed
type 2 diabetes have CHDtype 2 diabetes have CHD
04/19/23 17:53P0168.PFIZER.Lipitor.Slide_Kit.A.dh07
1818
1616
1414
1212
1010
88
66
44
22
00menmen womenwomen
Framingham study: Framingham study: DM type 2 and cardiovascular mortalityDM type 2 and cardiovascular mortality
Annual cardiovascular Annual cardiovascular mortality per 1000 personsmortality per 1000 persons
DM+DM+
Kannel et al, JAMA 241: 2035 - 38 1979Kannel et al, JAMA 241: 2035 - 38 1979
DM -DM -
04/19/23 17:53P0168.PFIZER.Lipitor.Slide_Kit.A.dh07
MRFIT: DM type 2 and CVD mortalityMRFIT: DM type 2 and CVD mortality
Stamler J et al. Diabetes Care 16(2): 434 - 444, 1993Stamler J et al. Diabetes Care 16(2): 434 - 444, 1993
00
2020
4040
6060
8080
100100
120120
140140
160160
< 4.7< 4.7 4.7-5.14.7-5.1 5.2-5.75.2-5.7 5.8-6.25.8-6.2 6.3-6.76.3-6.7 6.8-7.26.8-7.2 7.37.3 mmol/lmmol/l
CV
mort
ality
per
CV
mort
ality
per
10.0
00 p
ers
on
years
10.0
00 p
ers
on
years
DiabetesDiabetesNo diabetesNo diabetes
total cholesteroltotal cholesterol
04/19/23 17:53P0168.PFIZER.Lipitor.Slide_Kit.A.dh07UKPDS BMJ 1998UKPDS BMJ 1998
Impact of CHD Risk Factors in Patients with DM type 2 Impact of CHD Risk Factors in Patients with DM type 2
% risk increase% risk increase
HbAHbA1C1C per 1 % per 1 % +11+11
Systolic bloodSystolic blood pressure per 10 mm Hg.pressure per 10 mm Hg. +15+15
HDL-cholesterol per 0.1 mmol/lHDL-cholesterol per 0.1 mmol/l -15 -15
LDL-cholesterol per 1 mmol/lLDL-cholesterol per 1 mmol/l +57+57
8 year CV mortality in Finnish DM (n=1059) and 8 year CV mortality in Finnish DM (n=1059) and non-DM (n=1378) subjects following MInon-DM (n=1378) subjects following MI
non DMnon DM DM DMMI +MI + MI -MI - MI + MI + MI -MI -
CV events (%)CV events (%) 18.818.8 3.53.5 4545 20.220.2
Strokes (%)Strokes (%) 7.27.2 1.91.9 19.519.5 10.310.3
Haffner et. al. NEJM July 23 1998 (Vol 339: 229-334)Haffner et. al. NEJM July 23 1998 (Vol 339: 229-334)
Kannel WB. Am Heart J. 1985;110:1100-1107.Abbott RD et al. JAMA. 1988;260:3456-3460.
Women, Diabetes, and CHDWomen, Diabetes, and CHD
• Diabetic women are at high risk for CHDDiabetic women are at high risk for CHD• Diabetes eliminates relative cardioprotective effect Diabetes eliminates relative cardioprotective effect
of being premenopausalof being premenopausal– risk of recurrent MI in diabetic women is three times that of risk of recurrent MI in diabetic women is three times that of
nondiabetic womennondiabetic women
• Age-adjusted mean time to recurrent MI or fatal Age-adjusted mean time to recurrent MI or fatal CHD event is 5.1 yr for diabetic women vs 8.1 yr CHD event is 5.1 yr for diabetic women vs 8.1 yr for nondiabetic womenfor nondiabetic women
Diabetes Mellitus and Reduction of CHD in the USDiabetes Mellitus and Reduction of CHD in the US
-21%
-1%
-13%
15%
-36%
-13%
-27%
23%
-44%
-17%
-20%
11%
-50%
-40%
-30%
-20%
-10%
0%
10%
20%
30%
Red
uct
ion m
ort
alit
y
Total mortality CVD mortality CHD mortality
Men no DMMen DM +Women no DMWomen DM +
197119719639 individuals (670 DM+)9639 individuals (670 DM+)
Age: 35 – 74 yearsAge: 35 – 74 years
9 year follow-up9 year follow-up
198219828463 individuals (637 DM+)8463 individuals (637 DM+)
Age: 35 – 74 yearsAge: 35 – 74 years
8 year follow-up8 year follow-up
K. Gu, et al. JAMA 1999; 281:1291 K. Gu, et al. JAMA 1999; 281:1291
Overview PresentationOverview Presentation
• Who are at riskWho are at risk– Secondary preventionSecondary prevention– Primary prevention - Diabetes Mellitus type 2Primary prevention - Diabetes Mellitus type 2
• Lowering CholesterolLowering Cholesterol– Secondary preventionSecondary prevention– Primary preventionPrimary prevention
• Beyond cholesterol loweringBeyond cholesterol lowering• How low should we goHow low should we go• GuidelinesGuidelines
22.622.6
15.9/13.215.9/13.2
7.97.9
2.82.8
Pla
ceb
o M
I ra
te p
er 1
00
sub
ject
s p
er
5 ye
ars
Pla
ceb
o M
I ra
te p
er 1
00
sub
ject
s p
er
5 ye
ars
WOS : NEJM 1995; 333 : 1301-1307CARE : NEJM 1996; 335 : 1001-1009LIPID : NEJM 1998; 339: 1349-13574S : Lancet 1994; 344 : 1383-1389TexCAPS: JAMA 1998; 279: 1615-1622
Major HMG-CoA TrialsMajor HMG-CoA Trials
CARECAREn=4,159n=4,159
TC 5.4 mmol/lTC 5.4 mmol/l
LIPIDLIPIDn=9,014n=9,014
TC 5.6 mmol/lTC 5.6 mmol/l
WOSWOSn=6,595 TC 7.0 mmol/ln=6,595 TC 7.0 mmol/l
4S4Sn=4,444n=4,444
TC 6.8 mmol/lTC 6.8 mmol/l
With CHD +With CHD +high cholesterolhigh cholesterol
With CHD +With CHD +normal cholesterolnormal cholesterol
Without CHD +Without CHD +high cholesterolhigh cholesterol
TexCAPSTexCAPSn=6,605 TC 5.7 mmol/ln=6,605 TC 5.7 mmol/l
Without CHD +low HDL
‘‘Numbers Needed to Treat’Numbers Needed to Treat’Major Coronary Events (MACE)Major Coronary Events (MACE)
LD
L c
ho
lest
ero
l
Low
High
4-Snnt 13
LIPIDnnt 26
CAREnnt 33
AFCAPSnnt 59
WOSnnt 43
0
5
10
15
20
25
Atorvastatin Angioplasty/UC
*p=0.048 vs an adjusted significance level of p=0.045 atorvastatin vs angioplasty/UC.
% of patientswith an
ischemic event
13%
21%
-36% difference*
(p = 0.048)
Ischemic Events
n = 22 of 164 n = 37 of 177
Pitt B et al. N Engl J Med. 1999;341:70-76.
0
5
10
15
20
0-6 months >6-18 months
% of patientswith an
ischemic event
Atorvastatin
7%6%
Angioplasty/UC
10%11%
Pitt B et al. N Engl J Med. 1999;341:70-76.
46% difference24% difference
AVERT: Incidence of First Ischemic Event by Time AVERT: Incidence of First Ischemic Event by Time
0
5
10
15
20
25
0 6 12 18
p=0.027Cumulative incidence
(%)
Time since randomization (months)
Time to First Ischemic Event
Data on file. Parke-Davis, Morris Plains, NJ, Study 981-068.
Atorvastatin (n=164)
Angioplasty/UC (n=177)
Acute coronary eventAcute coronary event
WOSCOPSWOSCOPSAFCAPSAFCAPS
Primary prevention Secondary prevention
00 3 m3 m 6 m6 m 9 m9 m 1 y1 y 2 y2 y 3 y3 y 4 y4 y
4 S
CARE
LIPID
MIRACL : unstable a.p. and non-Q infarctMIRACL : unstable a.p. and non-Q infarctFLORIDA: AMI ( ischemie)FLORIDA: AMI ( ischemie)A-Z: standard vs. aggressive careA-Z: standard vs. aggressive care
Start of Statin Therapy in Secondary Prevention
Ischaemic StrokeIschaemic Stroke
placeboplacebo treated treated reductionreduction
Primary preventionPrimary preventionWoscopWoscop 5151 4646 10%10%
Secondary preventionSecondary preventionCARECARE 7878 5454 31%31%4S4S 9898 7070 30%30%
Hebert et al JAMA 1997; 278: 313 - 21
Ischaemic Stroke Reduction in Statin TrialsIschaemic Stroke Reduction in Statin Trials
-15
-32*
-27*
-40
-30
-20
-10
0
Crouse JR et al. Arch Intern Med. 1997;157:1305-1310.
*P=0.001.†95% confidence interval of percentage of relative reduction.
Effects of Statins on Stroke Events: A Meta-analysisof Primary- and Secondary-Prevention Trials
Relativereduction
in rates (%)
1° Prevention (-42 to -27)†
2° Prevention (13-45)†
Combined (11-40)†
-1 0 1
Cholesterol Reduction and StrokeCholesterol Reduction and StrokePre Statin Trials (1965 - 1992)Pre Statin Trials (1965 - 1992)
InterventionCholestyramine
Niacin
Diet
Diet
Diet
Gemfibrozil
Clofibrate and Niacin
Clofibrate
Clofibrate
Multiple
Multiple
Summary Odds ratio (N)
Fatal Stroke - Clofibrate (3)
Fatal Stroke - Other (11)
Fatal Stroke - All (13)
Total Stroke All
Odds Ratio of Stroke
Cholesterol Reduction and the Risk for Stroke in Men. David Atkins et al. Ann. Intern. Med. 1993;119:136-145