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					Modern Management of Cholesterol
          in the High-Risk Patient
Overview Presentation
• Who are at risk
  – Secondary prevention
  – Primary prevention - Diabetes Mellitus type 2
• Lowering Cholesterol
  – Secondary prevention
  – Primary prevention
• Beyond cholesterol lowering
• How low should we go
• Guidelines
Priorities for Lipid lowering

• Secondary prevention
• Patients with diabetes mellitus type 2
• Patients with genetic dyslipidemia's
• Patients with multiple risk factors
SECONDARY
PREVENTION
Consequences 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



                                         20
                                                             25 X
          Deaths per 1000 person-years




                                                                                     19.15
                                         15

                                                                         12 X


                                         10




                                         5
                                                 0.77                  1.64


                                                No CHD                  CHD            CHD        LDL cholesterol level
                                               <130 mg/dl            <130 mg/dl     >160 mg/dl
                                              (3.4 mmol/l)          (3.4 mmol/l)   (4.1 mmol/l)



TikkanenJ. et al. N Engl J Med 1990:322(24):1700 - 1707
Cholesterol/AMI Link in Low TC Population


                                                          500
                     100,000 screened subjects in 3 yr.
                      Cumulative incidence of AMI per



                                                                     Men
                                                                     Women
                                                          400



                                                          300



                                                          200



                                                          100



                                 0
                            Range                               <167 (4.2)   168-191 (4.3-4.9)   192-217 (4.9-5.5)   >218 (5.6)
                            Mean                                149 (3.7)        180 (4.6)       204 (5.2)           245 (6.3)
                                                                                Serum cholesterol mg/dl (mmol/l)


Wakugami K., et al. Jpn Cir J. 1998;52:7-14
 PRIMARY
PREVENTION
Diabetes Mellitus type 2
‘With an excess of fat diabetes
 begins and from an excess of
      fat diabetics die…’


        Elliott P. Joslin MD 1927
Atherosclerosis in Diabetes

• ~80% of all diabetic mortality
   – 75% from coronary atherosclerosis
   – 25% from cerebral or peripheral vascular disease
• >75% of all hospitalizations for diabetic
 complications
• >50% of patients with newly diagnosed
 type 2 diabetes have CHD


National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995.
Framingham study:
DM type 2 and cardiovascular mortality

                                                18
 Annual cardiovascular                          16
 mortality per 1000 persons                     14
                                                12
                                                10
                                                 8
                                                 6
                                                 4
                                         DM+
                                                 2
                                         DM -
                                                 0
                                                     men   women
Kannel et al, JAMA 241: 2035 - 38 1979
MRFIT: DM type 2 and CVD mortality


                       160
                       140
 10.000 person years




                                                                                                 Diabetes
   CV mortality per




                       120                                                                       No diabetes
                       100
                        80
                        60
                        40
                        20
                         0
                             < 4.7   4.7-5.1   5.2-5.7   5.8-6.2   6.3-6.7   6.8-7.2    7.3   mmol/l
                                                 total cholesterol

Stamler J et al. Diabetes Care 16(2): 434 - 444, 1993
Impact of CHD Risk Factors in Patients with DM type 2


                                      % risk increase

 HbA1C per 1 %                              +11

 Systolic blood pressure per 10 mm Hg.      +15

 HDL-cholesterol per 0.1 mmol/l             -15
 LDL-cholesterol per 1 mmol/l               +57


UKPDS BMJ 1998
   8 year CV mortality in Finnish DM (n=1059) and
   non-DM (n=1378) subjects following MI




                                      non DM               DM
                                    MI +          MI -   MI +   MI -

    CV events (%)                   18.8          3.5    45     20.2
    Strokes (%)                     7.2           1.9    19.5 10.3


Haffner et. al. NEJM July 23 1998 (Vol 339: 229-334)
Women, Diabetes, and CHD

• Diabetic women are at high risk for CHD
• Diabetes eliminates relative cardioprotective effect
   of being premenopausal
    – risk of recurrent MI in diabetic women is three times that of
      nondiabetic women
• Age-adjusted mean time to recurrent MI or fatal
   CHD event is 5.1 yr for diabetic women vs 8.1 yr
   for nondiabetic women


 Kannel WB. Am Heart J. 1985;110:1100-1107.
 Abbott RD et al. JAMA. 1988;260:3456-3460.
Diabetes Mellitus and Reduction of CHD in the US

 1971
 9639 individuals (670 DM+)                                30%
                                                                                              23%
 Age: 35 – 74 years
 9 year follow-up                                          20%               15%
                                                                                                              11%

 1982                                Reduction mortality   10%
                                                                                      -13%            -17%
 8463 individuals (637 DM+)                                           -1%
 Age: 35 – 74 years                                         0%
 8 year follow-up
                                                           -10%
                                                                         -13%
                                                           -20%
                                                                  -21%                                     -20%
             Men no DM                                     -30%                            -27%
             Men DM +                                                               -36%
                                                           -40%
             Women no DM
                                                                                                    -44%
             Women DM +                                    -50%
                                                                  Total mortality   CVD mortality   CHD mortality

 K. Gu, et al. JAMA 1999; 281:1291
Overview Presentation
• Who are at risk
  – Secondary prevention
  – Primary prevention - Diabetes Mellitus type 2
• Lowering Cholesterol
  – Secondary prevention
  – Primary prevention
• Beyond cholesterol lowering
• How low should we go
• Guidelines
Major HMG-CoA Trials
          Placebo MI rate per 100 subjects per 5 years




                                                                                            With CHD +
                                                                                 4S         high cholesterol
                                                         22.6                 n=4,444
                                                                            TC 6.8 mmol/l



                                                         15.9/13.2      LIPID         CARE           With CHD +
                                                                       n=9,014       n=4,159         normal cholesterol
                                                                     TC 5.6 mmol/l TC 5.4 mmol/l

                                                                                                               Without CHD +
                                                         7.9                    WOS                            high cholesterol
                                                                        n=6,595 TC 7.0 mmol/l
                                                                             TexCAPS                               Without CHD +
                                                         2.8            n=6,605 TC 5.7 mmol/l                      low HDL


WOS : NEJM 1995; 333 : 1301-1307
CARE : NEJM 1996; 335 : 1001-1009
LIPID : NEJM 1998; 339: 1349-1357
4S : Lancet 1994; 344 : 1383-1389
TexCAPS: JAMA 1998; 279: 1615-1622
‘Numbers Needed to Treat’
Major Coronary Events (MACE)

             High


                      4-S     WOS
   LDL cholesterol




                     nnt 13   nnt 43


                     LIPID
                     nnt 26   AFCAPS
                     CARE      nnt 59
                     nnt 33
              Low
Ischemic Events
                                                                -36% difference*
                            25                                         (p = 0.048)
                                                                                             21%
                            20
   % of patients
      with an
     ischemic               15                      13%
       event
                            10


                              5


                              0
                                               Atorvastatin                             Angioplasty/UC
                                               n = 22 of 164                             n = 37 of 177
*p=0.048 vs an adjusted significance level of p=0.045 atorvastatin vs angioplasty/UC.
Pitt B et al. N Engl J Med. 1999;341:70-76.
AVERT: Incidence of First Ischemic Event by Time
                                                      Atorvastatin
                     20                               Angioplasty/UC
                                                                           46%
                                 24% difference                        difference
                     15

   % of patients                                                              11%
                                                10%
     with an         10
    ischemic                        7%
      event                                                        6%
                       5



                       0
                                    0-6 months                     >6-18 months


  Pitt B et al. N Engl J Med. 1999;341:70-76.
Time to First Ischemic Event

                       25
                                        Angioplasty/UC (n=177)
                       20               Atorvastatin (n=164)


                       15
                                                                                          p=0.027
    Cumulative
     incidence
        (%)
                       10



                         5



                         0
                             0                             6                      12                18
                                                               Time since randomization
                                                                       (months)

Data on file. Parke-Davis, Morris Plains, NJ, Study 981-068.
Start of Statin Therapy in Secondary Prevention

                Acute coronary event

                       0    3m     6m    9m     1y     2y     3y       4y
  Primary prevention       Secondary prevention

                                                       4S
     WOSCOPS
     AFCAPS                                   LIPID

                                           CARE
                            MIRACL : unstable a.p. and non-Q infarct
                            FLORIDA: AMI ( ischemie)
                            A-Z: standard vs. aggressive care
Ischaemic Stroke

    Ischaemic Stroke Reduction in Statin Trials
                                          placebo   treated   reduction
Primary prevention
  Woscop                                    51       46        10%
Secondary prevention
  CARE                                      78       54        31%
  4S                                        98       70        30%




  Hebert et al JAMA 1997; 278: 313 - 21
Effects of Statins on Stroke Events: A Meta-analysis
of Primary- and Secondary-Prevention Trials


               0
                                                                      1° Prevention (-42 to -27)†
                                                                      2° Prevention (13-45)†
             -10                                                      Combined (11-40)†

  Relative
 reduction                -15
             -20
  in rates
    (%)
             -30                                               -27*

                                            -32*

             -40


   *P=0.001.
   †95% confidence interval of percentage of relative reduction.

   Crouse JR et al. Arch Intern Med. 1997;157:1305-1310.
Cholesterol Reduction and Stroke
Pre Statin Trials (1965 - 1992)

    Intervention                                                                        Odds Ratio of Stroke
    Cholestyramine
    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

                                      -1                           0                                1

 Cholesterol Reduction and the Risk for Stroke in Men. David Atkins et al. Ann. Intern. Med. 1993;119:136-145

				
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