1--PCE_Nashville_Dyslipidemia_Lillo

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					    2008       Symposia
               Series 2




    Radisson Hotel at Opryland
      Nashville, Tennessee
          May 31, 2008
1
           Dyslipidemia:
       When Statins Alone Fail
                Joseph L. Lillo, DO
    Assistant Professor of Family Medicine and
                  Adjunct Faculty
     Arizona College of Osteopathic Medicine
              Midwestern University
                 Glendale, Arizona
             Scottsdale Family Health
                Scottsdale, Arizona

2
    Faculty Disclosure
     Dr Lillo: speakers bureau: Abbott Laboratories/
      Solvay Pharmaceuticals, GlaxoSmithKline, Novartis,
      Oscient Pharmaceuticals, Pfizer Inc, Sepracor Inc




3
    What percentage of your patients with
    dyslipidemia who are receiving statin therapy
    alone achieve their LDL-C goal?

    1.    ≤25%                                           41%
    2.    26%-50%
    3.    51%-75%                                              31%

    4.    76%-100%                                 24%




                                                                     4%
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                                                   1      2     3     4   7
    LDL-C = low-density lipoprotein cholesterol.

4
    Learning Objectives
     Identify patients who would benefit from
      combination therapy for dyslipidemia based on
      results of recent clinical trials
     Develop optimal treatment strategies for lowering
      LDL-C and raising HDL-C levels in patients with
      mixed dyslipidemia
     Educate patients on the benefits and long-term
      safety data associated with combination drug
      therapy for dyslipidemia

    HDL-C = high-density lipoprotein cholesterol.

5
    Case Study



6
    History and Physical Findings
     65-year-old white man
     History of CABG surgery (1 year prior), hypertension
     Physical findings
           Height: 1.83 m (6 ft); weight: 107 kg (236 lb);
            waist circumference: 103 cm (40.6 in); BMI: 32 kg/m2
           BP: 118/78 mm Hg
     Current medications
           Ramipril (10 mg once daily)
           Atorvastatin (20 mg once daily)

    BMI = body mass index; BP = blood pressure;
    CABG = coronary artery bypass graft.

7
    Laboratory Results
     Lipid profile
          TC: 173 mg/dL
          LDL-C: 80 mg/dL
          Non–HDL-C: 136 mg/dL
          HDL-C: 38 mg/dL
          TG: 280 mg/dL
     FPG level: 138 mg/dL (120 mg/dL at last visit)



    FPG = fasting plasma glucose; TC = total cholesterol; TG = triglyceride.

8
    What is this patient’s CHD
    risk category?

    1.    Very high
                                          43%
    2.    High
    3.    Moderately high
                                                30%
    4.    Moderate
    5.    Low                       18%


                                                      8%
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                                                           1%

                                    1     2      3    4     5
                                                                7
    CHD = coronary heart disease.

9
     AHA/NHLBI 2005 Scientific Statement:
     The Metabolic Syndrome
      Diagnosis is established by the presence of ≥3 risk factors
                                                          Defining Level
     Risk Factor                              Women                     Men                  Case
                                              >88 cm                 >102 cm                103 cm
     Waist circumference*
                                              (>35 in)               (>40 in)              (40.6 in)
     TG†                                                   ≥150 mg/dL                     280 mg/dL
     HDL-C†                                 <50 mg/dL               <40 mg/dL             38 mg/dL
     BP†                                              ≥130/≥85 mm Hg                    ACE inhibitor
     Fasting glucose†                                      ≥100 mg/dL                     138 mg/dL
     *Lower cutpoints (≥90 cm in men and ≥80 cm in women) for Asian Americans.
     †Or drug treatment for elevated TG or glucose levels, hypertension, or reduced HDL-C levels.

     ACE = angiotensin-converting enzyme; AHA = American Heart Association; NHLBI = National
     Heart, Lung, and Blood Institute.
     Grundy SM, et al. Circulation. 2005;112;2735-2752.

10
     Framingham Risk Scoring (Men)
     Step 1: Age (y)               Step 2: TC
     Age (y)       Points                 TC                                          Age (y)
      20-34            -9              (mg/dL)           20-39        40-49        50-59         60-69   70-79
      35-39            -4                <160               0           0              0           0      0
      40-44            0               160-199              4           3              2           1      0
      45-49            3               200-239              7           5              3           1      0
      50-54            6               240-279              9           6              4           2      1
      55-59            8                 280              11           8              5           3      1
      60-64           10           Step 3: HDL-C
      65-69           11            HDL-C
                                                                60            50-59             40-49   <40
      70-74           12            (mg/dL)
      75-79           13            Points                      -1                0               1       2

     Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
     JAMA. 2001;285:2486-2497.


11
      Framingham Risk Scoring (Men) (cont’d)
      Step 4: Systolic Blood Pressure                             Step 7: Calculate Risk of CHD
      Systolic BP            Points               Points            Points       10-y Risk       Points   10-y Risk
        (mm Hg)            (Untreated)           (Treated)           <0            <1%             5          2%
      <120                      0                    0
                                                                      0             1%             6          2%
      120-129                   0                    1
                                                                      1             1%             7          3%
      130-139                   1                    2
                                                                      2             1%             8          4%
      140-159                   1                    2
                                                                      3             1%             9          5%
      160                      2                    3
                                                                      4             1%            10          6%
      Step 5:                                                                                      11         8%
                                                     Age (y)
      Smoking                                                                                     12         10%
      Status                20-39         40-49        50-59        60-69        70-79            13         12%
       Nonsmoker               0             0            0            0            0             14         16%
        Smoker                 8             5            3            1            1             15         20%
      Step 6: Add Up the Points                                                                   16         25%
     BP = blood pressure.                                                                         17       30%
     Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
     JAMA. 2001;285:2486-2497.

12
     Framingham Risk Scoring (Women)
     Step 1: Age (y)                Step 2: TC
     Age (y)       Points                 TC                                          Age (y)
      20-34            -7              (mg/dL)           20-39        40-49        50-59          60-69   70-79
      35-39            -3                <160               0           0              0              0    0
      40-44            0               160-199              4           3              2              1    1

      45-49            3               200-239              8           6              4              2    1
                                       240-279             11           8              5              3    2
      50-54            6
                                         280              13           10             7              4    2
      55-59            8
      60-64           10
                                    Step 3: HDL-C
      65-69           12
                                   HDL-C
                                                                60            50-59             40-49    <40
      70-74           14           (mg/dL)
      75-79           16           Points                       -1                0               1        2
     Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
     JAMA. 2001;285:2486-2497.

13
     Framingham Risk Scoring (Women) (cont’d)
     Step 4: Systolic Blood Pressure                             Step 7: Calculate Risk of CHD
     Systolic BP           Points             Points                     Points        10-y Risk   Points   10-y Risk
      (mm Hg)            (Untreated)         (Treated)                     <9             <1%       14         2%
     <120                       0                 0                         9              1%       15         3%
     120-129                    1                 3                        10              1%       16         4%
     130-139                    2                 4                         11             1%       17         5%
     140-159                    3                 5                        12              1%       18         6%
     160                       4                 6                        13              2%       19         8%
                                                                                                    20        11%
     Step 5:
     Smoking                                     Age (y)                                            21        14%
     Status              20-39        40-49       50-59        60-69       70-79                    22        17%
     Nonsmoker              0            0            0           0           0                     23        22%
       Smoker               9            7            4           2           1                     24        27%
     Step 6: Add up the Points                                                                      25      30%
     Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
     JAMA. 2001;285:2486-2497.

14
     NCEP ATP III 2004 Update: Risk Categories
       Risk Category                                                     Criteria
                                          CVD + multiple risk factors (especially diabetes),
        Very high (New)                    severe/poorly controlled risk factors, metabolic
                                              syndrome, or acute coronary syndromes
                                                         CHD or CHD risk equivalents;
                  High
                                                             10-year risk >20%
                                                                  ≥2 risk factors;
         Moderately high
                                                               10-year risk 10%-20%
                                                                      ≥2 risk factors;
              Moderate
                                                                     10-year risk <10%
                  Low                                                  0-1 risk factor
     CVD = cardiovascular disease; NCEP ATP III = National Cholesterol Education Program Adult
     Treatment Panel III.
     Adapted from Grundy SM, et al. Circulation. 2004;110:227-239.

15
     NCEP ATP III 2004 Update: LDL-C
     Goals and Cutpoints
                                                        LDL-C Level (mg/dL)
         Risk                                             Initiate
       Category                       Goal                         Consider Drug Therapy*
                                                            TLC
       Very high                   <100
                                                              ≥100                    ≥100
        (New)                 (optional <70)
       High                        <100                       ≥100                    ≥100
     Moderately                    <130
                                                              ≥130                    ≥130
       high                  (optional <100)
       Moderate                       130                    ≥130                    ≥160
           Low                        160                    ≥160                    ≥190
     *In patients with moderate or higher risk, use therapy sufficient to achieve at least a 30%-40% reduction
     in LDL-C levels.
     TLC = therapeutic lifestyle changes.
     Adapted from Grundy SM, et al. Circulation. 2004;110:227-239.

16
                                                      DECISION POINT    ?
     What would be your next step in treating
     this patient?
     1.   Increase atorvastatin dose to
          40 mg once daily
                                                56%
     2.   Add a glucose-lowering agent
          and a fibrate to his current
          atorvastatin regimen
          (20 mg once daily)
     3.   Add omega-3 fatty acids
          (3-4 g/d) to his current
          atorvastatin regimen
          (20 mg once daily)
     4.   Add extended-release niacin     17%         17%
          (1000 mg/d) to his current                         11%
          atorvastatin regimen
          (20 mg once daily)

     Use your keypad to vote now!                                   7
                                          1      2      3       4



17
     Treatment Decision (Option 1)
     What would be your next step in treating this patient?
     1. Increase atorvastatin dose to 40 mg once daily
     2. Add a glucose-lowering agent and a fibrate to his
        current atorvastatin regimen (20 mg once daily)
     3. Add omega-3 fatty acids (3-4 g/d) to his current
        atorvastatin regimen (20 mg once daily)
     4. Add extended-release niacin (1000 mg/d) to his current
        atorvastatin regimen (20 mg once daily)




18
     Treatment Decision (Option 1)
      Increasing the statin dose will lower LDL-C
       and non–HDL-C levels about 5%-6% but will
       have minimal effect on TG and HDL-C levels
      This may have little benefit on his residual CHD risk




19
       Residual CHD Risk in Major Statin Trials
                              CHD events occur in patients treated with statins
     Major CHD Events (%)
     Patients Experiencing




                                                         Placebo           Statin
                             28.0

                                    19.4
                                           15.9
                                                           13.2                 11.8
                                                  12.3             10.2                                             10.9
                                                                                       8.7         7.9
                                                                                                          5.5              6.8


                              4S1          LIPID2              CARE3              HPS4         WOSCOPS5 AFCAPS/
                                                                                                        TexCAPS6
                  N           4444           9014               4159             20,536           6595     6605
                 LDL         -35%           -25%               -28%              -29%            -26%     -25%
                                            Secondary                           High Risk                       Primary
     1. 4S Group. Lancet. 1994;344:1383-1389.                   4. HPS Collaborative Group. Lancet. 2002;360:7-22.
     2. LIPID Study Group. N Engl J Med. 1998;339:1349-1357.    5. Shepherd J, et al. N Engl J Med. 1995;333:1301-1307.
     3. Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.      6. Downs JR, et al. JAMA. 1998;279:1615-1622.


20
       Residual CVD Risk in Patients Treated
       With Intensive Statin Therapy
                                   Statistically significant reductions,
                                  but significant residual CVD risk remains
     Major CVD Events (%)
     Patients Experiencing




                                    Moderate statin therapy          Intensive high-dose statin therapy




                             PROVE IT-TIMI 221                 IDEAL2                             TNT3
             N         4162                                       8888                         10,001
     LDL-C* (mg/dL) 95      62                              104          81                  101      77
     *Mean or median LDL-C after treatment.
       1. Cannon CP, et al. N Engl J Med. 2004;350:1495-1504; 2. Pedersen TR, et al. JAMA. 2005;294:2437-2445;
       3. LaRosa JC, et al. N Engl J Med. 2005;352:1425-1435.

21
        Residual CVD Risk in Patients
        With Diabetes Treated With Statins
                                           HPS1: n = 5963*                                              CARDS2: N = 2838
     Major Vascular Event Rate (%)




                                     30                                                            16




                                                                        Acute CVD Event Rate (%)
                                            25.1                                                   14      13.4
                                     25
                                                            22% Risk
                                                     20.2                                          12                      32% Risk
                                     20                     Reduction
                                                                                                   10                9.4   Reduction
                                     15                                                            8

                                                            Residual                               6
                                     10                                                                                    Residual
                                                            CVD Risk                               4                       CVD Risk
                                     5
                                                                                                   2
                                     0                                                             0
                                          Placebo Simvastatin                                            Placebo Atorvastatin
       *Patients with diabetes. (HPS also enrolled 14,573 high-risk patients without diagnosed diabetes.)

     1. Collins R, et al. Lancet. 2003;361:2005-2016; 2. Colhoun HM, et al. Lancet. 2004;364:685-696.

24
       Lipids in Patients With Premature CHD
                                             Men                                                              Women
                             200                   *                                        250                     †
     Concentration (mg/dL)




                                                   177                                                              219




                                                                    Concentration (mg/dL)
                             180
                             160                         Controls                           200                           Controls
                                   138 139   141         CHD                                                              CHD
       Plasma Lipid




                             140




                                                                      Plasma Lipid
                                                                                                        152
                             120                                                            150   134
                             100                                                                              110
                              80                                                            100
                              60                                                                                               †
                                                                                                                          57
                              40
                                                         45   *
                                                              35                             50
                                                                                                                               47

                              20
                               0                                                              0
                                   LDL-C      TG         HDL-C                                    LDL-C        TG         HDL-C

       *P <.005 compared with controls.
       †P <.05 compared with controls.



          Genest JJ Jr, et al. Circulation. 1992;85:2025-2033.

26
     Independent risk factors for CVD in
     patients with diabetes and the metabolic
     syndrome include:

     1. Low TG levels and high                        85%
          LDL-C levels
     2.   Low TG levels and high
          HDL-C levels
     3.   High TG levels and low
          LDL-C levels
     4.   High TG levels and low
          HDL-C levels
     Use your keypad to vote now!               13%
                                    2%   1%
                                                            7
                                    1    2       3     4

27
     Atherogenic Dyslipidemia in Patients With
     Diabetes and the Metabolic Syndrome
      High TG levels (independent CVD risk factor)
           
          TG-rich remnant lipoproteins (VLDL)
         Altered metabolism (lipolysis) of LDL and HDL particles
      Absolute levels of LDL-C are commonly not significantly
       increased, but other LDL parameters significantly change
         ↑ Number of LDL particles (↑ LDL-P and Apo B)
             Predominantly small, dense LDL-P
      Low levels of HDL-C (major independent CVD risk factor)
         May reduce reverse cholesterol transport

     Apo B = apolipoprotein B; LDL-P = LDL particle; VLDL = very low-density lipoprotein.

     Garvey WT, et al. Diabetes. 2003;52:453-462; Haffner SM. Diabetes Care. 2003;26 (suppl 1):S83-S86.

28
     TG Level Is Significant CVD Risk Factor:
     Recent Meta-Analysis of 29 Studies
        Groups                               CHD Cases
                                                                                     N = 262,525
        Duration of follow-up
          ≥10 years                             5902
          <10 years                             4256
        Sex
          Male                                  7728
          Female                                1994
        Fasting status
          Fasting                               7484
          Nonfasting                            2674
        Adjusted for HDL
          Yes                                   4469
          No                                    5689
                                                                            1.72 (1.56-1.90)
     *Individuals in top vs bottom third
     of usual log-TG values; adjusted for at least age,    1                 2
     sex, smoking status, and lipid concentrations; also       CHD Risk Ratio* (95% CI)
     adjusted for BP (in most studies).

     Sarwar N, et al. Circulation. 2007;115:450-458.

29
     Risk of CHD by TG Level:
     PROCAM Study
                                               8-Year Follow-Up                                   N = 4639 men with no
                                                                                                  history of MI or stroke
      Elevated TG levels
                                                                                                               P = .001
       significantly increase CHD risk                                          3
                                                                                                                  2.6




                                                           Relative CHD Risk
      Significant correlation remains                                         2.5                P = .01
       between TG level and CHD                                                 2
       risk after adjustment for LDL-C                                                               1.6
                                                                               1.5   Comparator
       and HDL-C                                                                        1.0
      6-fold increased CHD risk in                                             1
       patients with TG >200 mg/dL                                             0.5
       and LDL-C:HDL-C >5                                      0
                                                 TG Level (mg/dL)                      <105
                                                                                        <105        105-166
                                                                                                     105-166     >166
                                                                                                                  >166


                                             Coronary Event Rate                       3.2%           5.2%       8.3%


     Assmann G, et al. Am J Cardiol. 1996;77:1179-1184.

30
     TG Level Remains CVD Risk Factor in Patients
     Treated With Statins: CARE and LIPID
                                                                       N = 13,173
                                   30       Slope = .018
                                                                                           Placebo
                                               P = .02
             CVD Event Rate (%)*




                                   25                                                      Pravastatin



                                   20

                                             Slope = .029
                                               P <.001
                                   15
                                              <98      99-126    127-158 159-207    >207
                                        0      1            2        3      4        5
                                                           TG Level (mg/dL)
     *CHD death, nonfatal MI, CABG, PTCA.
     Sacks FM, et al. Circulation. 2000;102:1893-1900.

31
     NCEP ATP III: TG-Rich Remnant
     Lipoproteins Are Atherogenic
      Elevated TG levels are a marker for elevated levels
       of atherogenic remnant lipoproteins
      VLDL-C is the most readily available measure of
       atherogenic remnant lipoproteins for clinical practice
      When TG levels are elevated, non–HDL-C
       (TC − HDL-C) better represents the concentrations
       of all atherogenic lipoproteins than LDL-C alone
      Non–HDL-C should be a secondary target of
       therapy when TG levels are ≥200 mg/dL
     VLDL-C = very low-density lipoprotein cholesterol.

     NCEP ATP III. Circulation. 2002;106:3143-3421.

32
     Non–HDL-C in Predicting CHD Risk
      Within non–HDL-C levels,
       no association was found                                       2.5
       between LDL-C and the




                                                  Relative CHD Risk
       risk for CHD                                                    2

      In contrast, a strong
                                                                      1.5
       positive and graded
       association between non–                                        1
       HDL-C and risk for CHD
       occurred within every level                                    0.5
       of LDL-C                                                                                             ≥190
                                                                       0                                160-189
      Non–HDL-C is a stronger                                                                       <160
                                                                            <130   130-159    ≥160
       predictor of CHD risk than                                             LDL-C (mg/dL)           Non–HDL-C
       LDL-C                                                                                           (mg/dL)


     Liu J, et al. Am J Cardiol. 2006;98:1363-1368.

33
     NCEP ATP III: HDL-C Is an
     Independent Risk Factor for CHD
      A low HDL-C level is strongly and inversely associated
       with CHD risk
      Independent relationship holds after correction for other
       risk variables in multivariate analysis
      A low HDL-C level often correlates with elevations
       of serum TG and remnant lipoproteins
      HDL may be antiatherogenic
         Promotes reverse cholesterol transport
         Antioxidant and anti-inflammatory properties inhibit
           atherogenesis
     NCEP ATP III. Circulation. 2002;106:3143-3421.

34
     Low HDL-C Increases CVD Risk Even
     If LDL-C Levels Are Well Controlled:
     TNT Study
               Patients with LDL-C <70 mg/dL (n = 2661)                           Hazard Ratio (95% CI) versus Q1
                                10                                                Q2 0.85 (0.57-1.25)
      5-Year Risk of Major CV




                                 9                                                Q3 0.57 (0.36-0.88)
                                 8                                                Q4 0.55 (0.35 -0.86)
                                 7                                                Q5 0.61 (0.38-0.97)
            Events (%)




                                 6
                                 5
                                 4
                                 3
                                 2
                                 1
                                 0
                                      Q1         Q2              Q3                Q4              Q5
                                     (<37)   (37 to <42)     (42 to <47)       (47 to <55)        (55)
                                               Quintile of HDL-C* (mg/dL)
     No. of Events                     57        50                 34                34             35
     No. of Patients                  473       525               550                569            544
     *On-treatment level (3 months). Barter P, et al. N Engl J Med. 2007;357:1301-1310.

36
     CVD Risk Associated With Low HDL-C Level
     Remains in Patients Treated With Statins
                                High HDL-C + statin                          Low HDL-C + statin
                          30                                                 30
                                                                                  25.8             25.8
     CVD Event Rate (%)




                                                        CVD Event Rate (%)
                                      22.6

                          20                           18.5 20                           18.5
                               17.0                                                                                       17.0



                          10                                                 10



                          0                                0
                                  HPS                  CARE/LIPID                        CARE/LIPID                          H
     HPS Collaborative Group. Lancet. 2002;360:7-22.                  Sacks FM, et al. Circulation. 2000;102:1893-1900.



37
     In patients with diabetes who receive
     statin therapy to reduce LDL-C levels:

     1. Residual CVD risk remains      89%
          high
     2.   Residual CVD risk is low
     3.   Residual CVD risk has no
          impact on event rates
     4.   Residual CVD risk from low
          HDL-C levels is not
          clinically significant

     Use your keypad to vote now!
                                                       7%
                                             2%   2%
                                                            7
                                       1     2     3    4

38
     Key Points
      Residual CVD risk remains after patients are treated with statins to
       reduce LDL-C and is particularly high in patients with diabetes who
       are treated with statins
      Atherogenic dyslipidemia contributes to residual risk for
       atherosclerosis and CVD risk
         Increased levels of TG and TG-rich remnant lipoproteins
         Increased levels of non–HDL-C
         Increased numbers of Apo B–containing particles, including
          small, dense LDL
         Decreased levels of HDL-C
      The combination of high TG with low HDL-C and/or high LDL-C
       synergistically increases CHD risk


39
     Treatment Decision (Option 2)
     What would be your next step in treating this patient?
     1. Increase atorvastatin dose to 40 mg once daily
     2. Add a glucose-lowering agent and a fibrate to his
        current atorvastatin regimen (20 mg once daily)
     3. Add omega-3 fatty acids (3-4 g/d) to his current
        atorvastatin regimen (20 mg once daily)
     4. Add extended-release niacin (1000 mg/d) to his current
        atorvastatin regimen (20 mg once daily)




40
     Treatment Decision (Option 2):
     3-Month Follow-up
      Visit 1
         TLC   (diet, exercise) reinforced
         Glucose-lowering agent and fenofibrate
          (145 mg/d) prescribed as add-on to
          statin therapy
      Visit 2
         Improvements in lipid profile and glucose level
         No musculoskeletal side effects; no hepatic
          or renal laboratory abnormalities




41
     Treatment Decision (Option 2):
     3-Month Follow-up (cont’d)
      After 3 months’ therapy with atorvastatin plus fenofibrate
        and a glucose-lowering agent

     Lipid Profile              Visit 1      Visit 2 (3-month follow-up)
     TC (mg/dL)                   173            141 (19% reduction)
     LDL-C (mg/dL)                80             69 (14% reduction)
     Non–HDL-C (mg/dL)            136            97 (29% reduction)
     HDL-C (mg/dL)                38              44 (16% increase)
     TG (mg/dL)                   280            140 (50% reduction)
     Glucose Level              Visit 1      Visit 2 (3-month follow-up)
     FPG (mg/dL)                  138            95 (31% reduction)



42
     Treating Beyond LDL-C: Other Targets
     of Lipid-Lowering Therapy
      Lipoproteins other than LDL are involved in atherogenesis
       (pro: VLDL, IDL; anti: HDL)1
      NCEP ATP III concluded (on the basis of several types of
       data) that an elevated non–HDL-C in patients with
       hypertriglyceridemia will impart increased risk even after the
       goal of LDL-C has been reached1
      NCEP ATP III 2004 update: “For those high-risk patients
       who have elevated triglycerides or low HDL-C levels,
       addition of a fibrate or nicotinic acid to LDL-lowering
       therapy can be considered.”2

     IDL = intermediate-density lipoprotein.

     1. Grundy SM. Circulation. 2002;106:2526-2529; 2. Grundy SM, et al. Circulation. 2004;110:227-239.

43
     American Diabetes Association
     Standards of Medical Care in Diabetes:
     Dyslipidemia Management
                                         First Priority                          Second Priority

      LDL-C Lowering                TLC                              Niacin, ezetimibe, bile acid
      Goal: <100 mg/dL*             Statins                           sequestrants, or fenofibrate

      HDL-C Raising                   TLC                            Niacin‡ or fibrates
      Goal: >40 mg/dL†

      TG Lowering                   TLC                            Fibrates (fenofibrate, gemfibrozil)
      Goal: <150 mg/dL              Glycemic control               Niacin‡

                                                                    Statins (if LDL-C is also high)


      Combined                        Glycemic control +           Glycemic control + statin + fibrate
      Hyperlipidemia                   high-dose statin             Glycemic control + statin + niacin‡

     *An LDL-C goal <70 mg/dL is an option in patients with overt CVD. † An HDL-C goal >50 mg/dL
     should be considered for women. ‡ At high doses, niacin may increase blood glucose levels.
     American Diabetes Association. Diabetes Care. 2004;27:S68-S71.
     American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4-S41.

44
     Lipid Management in Patients With
     Diabetes* or Metabolic Syndrome
     Statin therapy to achieve LDL-C <100 mg/dL (<70 mg/dL with CHD)

     TG ≥500 mg/dL                        Fibrate
                                          Omega-3 fatty acids

     TG ≥150-500 mg/dL                    Fibrate (with slightly low or normal HDL-C)
                                          Niacin (with very low HDL-C)

     TG <150 mg/dL and                     Niacin
     Low HDL-C†

     *Well-controlled diabetes; A1C <7.0%.
     †HDL-C <40 mg/dL in men or <50 mg/dL in women.



     Adapted from American Diabetes Association. Diabetes Care. 2004;27:S68-S71.
     Adapted from American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4-S41.
     Adapted from Physicians’ Desk Reference. 61st ed. Montvale, NJ: Thomson PDR; 2007:2725-2727.

45
     Outcomes in Fibrate Trials: Patients
     With Diabetes or Metabolic Syndrome
                                                        Major CVD
                                                       Event Rate
       Trial                                     N    Control   Drug                     RRR              P
       Primary Prevention
         HHS1*                                  292   13.0%             3.9%             71%           <.005
         FIELD2†                               7664   10.8%             8.9%             19%            .004
       Secondary Prevention
         BIP3‡                                 1470   18.4%            14.1%             25%             .03
         VA-HIT4§                               769   29.4%            21.2%             32%            .004
     *Patients with TG >204 mg/dL and an LDL:HDL >5
     (may or may not have had diabetes or metabolic                 1Manninen   V, et al. Circulation. 1992;85:37-45.
     syndrome).                                                      2Keech A,
     †Patients with diabetes and no prior CVD.                                  et al. Lancet. 2005;366:1849-1861.
                                                       3Tenenbaum A, et al. Arch Intern Med. 2005;165:1154-1160.
     ‡Patients with metabolic syndrome.
                                                          4Rubins HB, et al. Arch Intern Med. 2002;162:2597-2604.
     §Patients with diabetes.



46
     VA-HIT: CVD Risk Reduction in
     Diabetics Compared With Nondiabetics
                                  Combined              Nonfatal           CHD
                                  End Point               MI               Death               Stroke
                             0
                             5
     Cumulative Event Rate




                                                                                      3
                             10                                                    P = .88
                                                                                                         10
         Change (%)




                             15                                                                         P = .67

                             20              18
                             25              P = .07     22      21
                                                       P = .17 P = .09
                             30
                             35    32
                                  P = .004                DM
                             40                           No DM
                                                                          41                  40
                             45      P = .26                             P = .02             P = .046


     DM = diabetes mellitus.
     Rubins HB, et al. Arch Intern Med. 2002;162:2597-2604.

47
     FIELD: Primary and
     Secondary End Points
                                                                        11% Reduction
                                                                           P = .035
                           Placebo
                           Fenofibrate

                                                                                        21% Reduction
      Event Rate (%)




                       11% Reduction                                                       P = .003
                          P = .16
                                         24% Reduction
                                            P = .01
                                                         19% Increase
                                                            P = .22




                       CHD Events*        Nonfatal MI     CHD Death       Total CVD        Coronary
                         (Primary                                          Events†      Revascularization
                        End Point)                                       (Secondary
                                                                          End Point)
     *Nonfatal MI and CHD death. †CHD events, stroke, CVD death, revascularizations.
     Keech A, et al. Lancet. 2005;366:1849-1861.

48
     FIELD: End Points in Patients With No
     Prior CVD (78% of Study Population)
                                                       CHD Events          Total CVD
                                                        (n = 7664)         (n = 7664)
                            Risk Reduction (%)    0

                                                  -5

                                                 -10

                                                 -15

                                                 -20                          -19
                                                                             P = .004
                                                 -25
                                                            -25       Secondary End Point
                                                 -30      P = .014

                                                       Primary End Point

     Keech A, et al. Lancet. 2005;366:1849-1861.

49
     Treatment Decision (Option 3)
     What would be your next step in treating this patient?
     1. Increase atorvastatin dose to 40 mg once daily
     2. Add a glucose-lowering agent and a fibrate to his
        current atorvastatin regimen (20 mg once daily)
     3. Add omega-3 fatty acids (3-4 g/d) to his current
        atorvastatin regimen (20 mg once daily)
     4. Add extended-release niacin (1000 mg/d) to his current
        atorvastatin regimen (20 mg once daily)




50
     Treatment Decision (Option 3)
      Prescription omega-3 fatty acids at 3-4 g/d
       are indicated for patients with severe
       hypertriglyceridemia (TG >500 mg/dL)
      This reduces TG up to 40%, but there is little change
       in HDL-C levels, and LDL-C levels may increase




51
      Efficacy of Omega-3 Fatty Acids for
      Patients With Severe Hypertriglyceridemia*
                                       †
         Change From Baseline (%)


                                                                        Placebo
                                                                        Omega-3 fatty acids 4 g
                                                                   †




                                                            †

                                                                            †
                                    LDL-C     VLDL-C            HDL-C      TG
     *TG level: 500-2000 mg/dL, N = 42.
     †P <.02 vs placebo.


     Harris WS, et al. J Cardiovasc Risk. 1997;4:385-391.

52
           Omega-3 Fatty Acids/Statin Combination
           Therapy in Insulin-Resistant Obese Men
                                     Atorvastatin 40 mg
     Change From Baseline (%)




                                     Omega-3 fatty acids 4 g       *
                                     Combination




                                                                       *   *

                                                                                *
                                          *   *        *
                                * LDL-C       Non–HDL-C        HDL-C       TG           Insulin
     N = 48                                                                           Resistance
     *P <.05 vs placebo.
     HOMA = homeostasis model assessment.
                                                                                    (HOMA Score)
     Chan DC, et al. Diabetes. 2002;51:2377-2386.

53
     Treatment Decision (Option 4)
     What would be your next step in treating this patient?
     1. Increase atorvastatin dose to 40 mg once daily
     2. Add a glucose-lowering agent and a fibrate to his
        current atorvastatin regimen (20 mg once daily)
     3. Add omega-3 fatty acids (3-4 g/d) to his current
        atorvastatin regimen (20 mg once daily)
     4. Add extended-release niacin (1000 mg/d) to his current
        atorvastatin regimen (20 mg once daily)




55
     Treatment Decision (Option 4):
     3-Month Follow-up
      Visit 1
         TLC (diet, exercise) reinforced
         Glucose-lowering agent and extended-release
         niacin (1000 mg at bedtime) prescribed as
         add-on to statin therapy
      Visit 2
         Improvements in lipid profile and glucose level
         No musculoskeletal side effects; no hepatic or
         renal laboratory abnormalities



56
     Treatment Decision (Option 4):
     3-Month Follow-up (cont’d)
      After 3 months’ therapy with atorvastatin plus
        extended-release niacin and a glucose-lowering agent

     Lipid Profile              Visit 1      Visit 2 (3-month follow-up)
     TC (mg/dL)                  173             164 (5% reduction)
     LDL-C (mg/dL)                80             72 (10% reduction)
     Non–HDL-C (mg/dL)           136            118 (13% reduction)
     HDL-C (mg/dL)                38             46 (21% increase)
     TG (mg/dL)                  280            180 (36% reduction)
     Glucose Level              Visit 1      Visit 2 (3-month follow-up)
     FPG (mg/dL)                 138            120 (13% reduction)



57
     CDP: Macrovascular Outcomes*
                        15% Reduction                                  Placebo (n = 2789)
                            P <.05                                     Niacin (n = 1119)
       Event Rate (%)




                                          26% Reduction
                                              P <.05      24% Reduction
                                                              P <.05
                                                                            47% Reduction
                                                                                P <.05




                        CHD Death/         Nonfatal MI    Stroke/TIA        CV Surgery†
                        Nonfatal MI
     *Total follow-up experience (mean, 6.2 years)
     †5-year incidence

     TIA = transient ischemic attack.
     CDP Research Group. JAMA. 1975;231:360-381.

58
          CDP: Reduction in Recurrence of MI*
          by Baseline FPG Level
     Nonfatal MI Event Rate (%)



                                    Placebo
                                                                                Interactive P value = NS
                                    Niacin

                                  30% Reduction                                      57% Reduction
                                                                    25% Reduction
                                                  24% Reduction




                                      <95           95-104            105-125             ≥126
                                                  Baseline FPG Level (mg/dL)
           *6-year follow-up.
           ‡American Diabetes Association definition of diabetes.

     Canner PL, et al. Am J Cardiol. 2005;95:254-257.

59
      COMPELL: Lipid Effects of
      Niacin ER/Statin Combination Therapy
                                    Atorvastatin 40 mg + niacin ER 2 g   Simvastatin 40 mg + ezetimibe 10 mg
                                    Rosuvastatin 20 mg + niacin ER 1 g   Rosuvastatin 40 mg

                                                                                                          *
         Change From Baseline (%)




                                                             * *                                     *




                                                                                     *
                                                                                *

                                    LDL-C               HDL-C                 TG                  Lp(a)
     Lp(a) = lipoprotein (a); niacin ER = niacin extended-release.       N = 292; 12 weeks.
     McKenney JM, et al. Atherosclerosis. 2007;192:432-437.              *P <.05 vs atorvastatin + niacin ER.

60
 Fibrate/statin combination therapy
 has the potential to increase the risk of:
     1.   Arrhythmia                     87%
     2.   Myopathy
     3.   Osteoporosis
     4.   Thrombosis




     Use your keypad to vote now!
                                    4%              6%
                                               3%
                                                         7
                                    1     2     3    4

61
      Safety of Fibrate/Statin
      Combination Therapy
       Fibrates improve all components of atherogenic dyslipidemia and
        appear to reduce the risk for CVD; their use in combination with
        statins is particularly attractive1
       Both statins and fibrates have the potential to produce myopathy,
        and the risk for myopathy is enhanced when they are used
        together1
       Clinical and preclinical studies indicate that gemfibrozil interferes
        with catabolism of statins in the liver (ie, inhibits glucuronidation),
        which can raise statin blood levels, thereby predisposing to
        myopathy1-3
       Fenofibrate does not interact adversely with statin catabolism and
        thus may be safer to use in combination therapy with statins1-3
     1. Grundy SM, et al. Circulation. 2004;109:551-556; 2. Davidson MH. Expert Opin Drug Saf. 2006;5:145-156;
     3. Davidson MH. Am J Cardiol. 2002;90:50K-60K.

62
     Number of Cases of Rhabdomyolysis
     in Combination Therapy With Statins*
                                           10
                                           9                                 8.6
               per Million Prescriptions

                                           8
                 No. Cases Reported




                                           7
                                           6
                                           5
                                                       15-Fold Increase
                                           4
                                           3
                                           2
                                           1       0.58
                                           0
                                                Fenofibrate               Gemfibrozil

     *Excludes cases involving cerivastatin.
     Jones PH, et al. Am J Cardiol. 2005;95:120-122.

63
      Safety of Lovastatin/Niacin ER and Niacin
      ER vs Statin Monotherapy (FDA-AERS)
                                                                    30




                                            Million Prescriptions
                                             Serious AERs Per
                                                                    25
                                                                                               *                                              *P <.05 versus L/N
                                                                    20                     *
                                                                    15
                                                                    10
                                                                    5
                                                                    0
                             10                                          L/N
                                                                         L/N
                                                                               N
                                                                               N
                                                                                       L
                                                                                       L
                                                                                           A
                                                                                           A
                                                                                               S
                                                                                               S
                                                                                                                            P
                                                                                                                            P




                                                                                               Per Million Prescriptions
     Million Prescriptions




                                                                                                Rhabdomyolysis AERs
                                                                                                                           10
                             8
       Liver AERs Per




                             6
                                                                                                                           8                        *
                                                                                                                           6
                             4
                                                                                                                           4

                             2                                                                                             2

                             0                                                                                             0
                                                                                                                                L/N   N   L     A   S   P
                                  L/N
                                  L/N   N
                                        N   L
                                            L                       A
                                                                    A     S
                                                                          S        P
                                                                                   P                                            L/N N     L     A   S    P
     A = atorvastatin; AERs = adverse event reports; FDA-AERS = US Food and Drug Administration Adverse
     Event Reporting System; L = lovastatin; N = niacin ER; P = pravastatin; S = simvastatin.
     Alsheikh-Ali AA, et al. Am J Cardiol. 2007;99:379-381.

64
     Ongoing Trials With Fibrate/Statin
     or Niacin/Statin Combination Therapy
                                   End
     Trial         Therapy         Point   N        Patients         Dates
     ACCORD        Simvastatin ±   CVD     10,000   1st and 2nd      ’03-’09
                   Fenofibrate                      prevention         (6 y)
                                                    All have DM
     AIM-HIGH      Simvastatin ±   CVD     3300     2nd prevention   ’06-’10
                   Niacin ER                        ↓HDL and ↑TG       (4 y)
     HPS2-THRIVE   Simvastatin ±   CVD     20,000   2nd prevention   ’07-’11
                   MK524A/niacin                    7000 DM            (4 y)




65
     Q&A




66
     PCE Takeaways



67
     PCE Takeaways
           Lipid abnormalities beyond LDL-C (ie, non–HDL-C, TG, HDL-C)
            should be intensively treated to reduce residual CVD risk
           Fibrate monotherapy is particularly beneficial in reducing CVD
            risk in patients with metabolic syndrome or diabetes
           Niacin is effective therapy for reducing CVD risk; adding niacin
            to statin therapy slows atherosclerosis progression in patients
            with CHD and reduces CVD risk
           Fibrate/statin* and niacin/statin combination therapy correct
            atherogenic lipid abnormalities and appear to be safe



     *Indication not approved by FDA.

68
     Based on the clinical data presented on residual
                                                        KEY QUESTION    ?
     CVD risk, what percentage of your patients with
     dyslipidemia would benefit from statin combination therapy?

     1.   ≤25%                                                48%
     2.   26%-50%                                     42%

     3.   51%-75%
     4.   76%-100%


                                               8%
     Use your keypad to vote now! 2%
                                                                    7
                                        1       2       3       4



69
     2008       Symposia
                Series 2




      Radisson Hotel at Opryland
        Nashville, Tennessee
            May 31, 2008
73

				
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