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					                                                                                                                                         Drug Treatment
         “Hypercholesterolemia:
                                                                                                            Anti-hyperlipidemic Agents
    Pathophysiology and Therapeutics”                                                                            • HMG-CoA Reductase Inhibitors: STATINS
                                                                                                                 • Fibrates (gemfibrozil, fenofibrate)
                                                                                                                 • Niacin (immediate vs. sustained release)
                          Robert J. Straka, Pharm.D. FCCP
                                                                                                                 • Cholesterol Absorption Inhibitors (Ezetimibe)
                                       Associate Professor
                                                                                                                 • Omega 3- Fatty Acids
                                       College of Pharmacy                                                       • Combination agents
                                    University of Minnesota
                                        Strak001@umn.edu




              HMG-CoA Reductase Inhibitors                                                                        Statins Approved in the U.S.
                                               "Statins"
      Agents                                                                                                                                                 Recommended                 Max daily dose
                                                                                                                                                           starting dose (mg)                (mg)
       1. Lovastatin - Mevacor® (Merck)
       2. Pravastatin - Pravachol® (BMS)
                                                                                                     Atorvastatin—(Lipitor; Pfizer)                                 10 - 20                   80
       3. Simvastatin - Zocor® (Merck)
       4. Fluvastatin - Lescol® (Novartis)                                                           Fluvastatin—(Lescol; Novartis)                                 20 – 40                   80
       5. Atorvastatin - Lipitor® (Pfizer)
       6. Rosuvastatin - Crestor® (Astra-Zeneca)                                                     Lovastatin—(Mevacor; Merck)                                    20 – 40                   80

      MOA                                                                                            Pravastatin—(Pravachol; BMS)                                   10 – 80                   80
           • Block the rate limiting step in cholesterol synthesis (HMG-
             CoA mevalonate)                                                                         Rosuvastatin-(Crestor; AZ)                                      5 – 40                   40
           • Increase LDL-C receptor density
           • Other (pleiotropic) effects                                                             Simvastatin—(Zocor; Merck)                                     20 – 40                   80




                                                                                                                     Pleiotropic Effects of Statins
          Pharmacologic Therapy: Statins                                                                •   Endothelial function (NO regulation)
                                                                                                        •   Atherosclerotic plaque stabilization
    • Inhibit cholesterol synthesis                                                                     •   Inhibition of LDL-C oxidation
                                                                                                        •   Effects on VSMC growth
• Beneficial effects on all lipid parameters                                                            •   Platelet inhibition and antithrombosis
    • LDL-C ↓ 22%-63%                                                                                   •   Reduced leukocyte adhesiveness
                                                                                                        •   Effects on circulatory clotting factors
    • HDL-C ↑ 5%-16%                                                                                         –   Tissue factor
    • TG              ↓ 7%-30%                                                                               –   Fibrinogen
                                                                                                             –   hs-CRP
•   24%-40% relative reduction in coronary events                                                            –   PAI-1/Lp(a)
                                                                                                             –   Effects on blood viscosity and flow
•   Potential side effects: myopathy, ↑ liver enzymes
                                                                                                        •   BP effects
•   Contraindications: liver disease, pregnancy                                                         •   Reduced ischemia-reperfusion injury (cardiac and cerebral)
•   Precautions: use with certain drugs                                                                 •   Enhanced angiogenesis
                                                                                                  Rosensen RS, et al. JAMA. 1998;279:1643-1650; Gotto AM, et al. Curr Opin Lipidology.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA.   2001;12:391-394; Maron DJ, et al. Circulation. 2000;101:207-213; White CM. J Clin
2001;285:2486.                                                                                    Pharmacol. 1999;39:111-118.
                    Recommendations From ATP III                                                                                                                                                                             Statins: Effect on LDL-C:
                                                                                                                                                                                                                                     Package Insert Data
                                                                                                                                                                                          Daily                   Fluvastatin      Lovastatin       Pravastatin    Simvastatin       Atorvastatin   Rosuvastatin
                                                                                                                                                                                          Dose (mg)                  20 40 80     10 20 40 80      10 20 40 80    10 20 40 80        10 20 40 80    5 10 20 40
                                  When LDL-C lowering drug                                                                                                                                                 0

                               therapy is employed, intensity of                                                                                                                                        -10

                                therapy should be sufficient to                                                                                                                                         -20


                                 achieve AT LEAST a 30-40%                                                                                                                                   Mean %
                                                                                                                                                                                             Change
                                                                                                                                                                                                        -30
                                                                                                                                                                                             in LDL-C   -40
                                  reduction in LDL-C levels.                                                                                                                                            -50

                                                                                                                                                                                                        -60

                                                                                                                                                                                                        -70
                                                                                                                                                                                                       Adapted from Package insert data reviewed 06/07
                                                                                                                   Grundy et al. Circulation. 2004;110:227-239.




                                    Pharmacologic Therapy:                                                                                                                                             Statins: General Effects on HDL-C:
                                      Statins—Rule of 6
                                                                                                                                                                                           Daily               Fluvastatin    Lovastatin     Pravastatin     Simvastatin Atorvastatin Rosuvastatin
                                                 Majority of LDL-C Reduction Is                                                                                                            Dose (mg)           20 40 80      10 20 40 80   10 20 40 80     10 20 40 80 10 20 40 80 5 10 20 40

                                                  Achieved With Starting Dose                                                                                                                            16                                                                      *
                                                                                                              Doubling
                                                                                                                                                                                                         14                                                                *
                                                                                                                                                                                                         12
                                                                                                                                                                                                         10
                                                                                                                                                                                          Mean %
                                                                                                                                                                                          Change           8
                                                                                                                                                 3-Step                                   in HDL-C
                                      Statin – starting dose                                          1st           2nd            3rd                                                                     6
                                                                                                                                                 Titration
                                                                                                                                                                                                           4
                                                                                                                                                                                                           2
                                             19% - 45%                                                5%-            5%-          5%-                                                                      0
                                                                                                      6%             6%           6%                                                                                                                                    10
                                                   % Reduction in LDL-C
                                                                                                                                                                                                *      13 and 16% Refers to a sub-study where TG: 300-700mg/dL, otherwise values
                                                                                                                                                                                                       of +8-9% are generally observed
    Adapted from Illingworth. Med Clin North Am. 2000;84:23.                                                                                                                                           Adapted from Package insert data reviewed 06/07




                               Major Endpoint Lipid Trials                                                                                                                                 Statins-Safety: Myopathy and Hepatotoxicity
                                                                                                          LDL-C Δ                      Placebo                    CHD Risk
Trial                                              Drug                          ↓ LDL-C                 (pla vs rx)                  CHD Rate                   Reduction*
Patients with Multiple CHD Risk Factors                                                                                                                                                   • Myopathy: Muscle pain, tenderness or weakness (myositis)
  LRC-CPPT                         BAR                                             -15%                   205-175                         9.8%                        -19%                  with CK>10X ULN (0-150 U/L) (CK= creatinine kinase)
  WOSCOPS                          Pravastatin 40mg                                -26%                   192-142                         9.3%                        -29%                      • Myopathy may take the form of rhabdomyolysis with or without ARF
  TexCAPS/
                                   Lovastatin 20-40mg                              -25%                   150-115                         5.6%                        -40%                        (acute renal failure), 2o to myoglobinuria
  AFCAPS
  ASCOT                            Atorvastatin 10mg                               -34%                    132-87                         9.4%                        -36%
                                                                                                                                                                                                • Risk of myopathy from clinical studies is dose related and ranges from
                                                                                                                                                                                                  0.02% (20mg S) to 0.3% (80mg S), <0.1% prava, < 0.5% lova, 0.1% rosuva
CHD and CHD Risk Equivalent
   4S                              Simvastatin 40mg                                - 35%                  188-117                        21.8%                        -34%                      • Risk of these events increases with dose escalation or in combination
   POSCH                           Surgery                                         - 40%                  182-110                        30.0%                        -35%
                                                                                                                                                                                                  with fibrates or niacin
   LIPID                           Pravastatin 40mg                                - 25%                  150-112                        15.9%                        -24%                • Hepatotoxicity: LFT’s (liver function tests such as ALT -
   CARE                            Pravastatin 40mg                                - 32%                   139-98                        13.2%                        -24%                  Alanine aminotransferase) are monitored usually at baseline,
   Post-CABG                       Lovastatin/BAR                                  - 39%                   136-93                        13.5%                        -24%                  12 weeks, then periodically thereafter
   HPS                             Simvastatin 40mg                                - 32%                   131-89                        11.8%                        -24%                      •  Usual Incidence of >1 occurrence of >3xULN for ALT (or AST) is <1.2%
   PROVE-IT                        Atorvastatin 80mg                              - 35%                    95-62                         8.3%                        -16%                        prava, 0.2-2.3% for atorva, <1.5% Lova
   A to Z                          Simvastatin 40/80mg†                            -19%                     81-66                      14.4%**                        -11%
                                                                                                                                                                                                • Perspective: In 4S, 4444 pts on simvastatin 20-40mg for 5.4yrs the
   TNT                             Atorvastatin 80mg‼                             -24%‡                    101-77                       8.3%**                        -20%                        frequency of >1 occurrence of LFT>3xULN was the same for Simva as
*Nonfatal MI or CHD death; **composite endpoint;  vs pravastatin 40 mg, †vs simvastatin placebo/20 mg; ‼ vs atorvastatin 10 mg
JAMA. 1984;251:351-164; JAMA. 1998;279:1615-1622; N Engl J Med. 1999;333:1301-1307; Lancet. 2003;361:1149-1158; Lancet. 1994;344:1383-1389; J Am Coll Cardiol.
                                                                                                                                                                                                  Placebo (0.7 vs 0.6%)
1995;26:351-357; N Engl J Med. 1998;339:1349-1357; N Engl J Med. 1996;335:1001-1009; Circulation. 2000;102:157-165; Lancet. 2002;360:7-22; N Engl J Med. 2004;350:1495-1504; JAMA 2004;
292: 1307-1316; N Engl J Med. 2005; 352: 1425-35.
                          Occurrence of CK Elevations > 10x ULN as a                                                                           Selected NLA Recommendations to Health Care
                           Function of Dose and LDL-C Reductions                                                                            Professionals Regarding Muscle Safety With Statin Use
                                                                                                                                             1.                                  “Whenever muscle symptoms or an increased CK level is encountered in a
                                          Cerivastatin (0.2, 0.3, 0.4, 0.8 mg)                 Atorvastatin (10, 20, 40, 80 mg)
                          3.0                                                                                                                                                    patient receiving statin therapy, health professionals should attempt to rule
                                          Pravastatin (20, 40 mg)                              Rosuvastatin (10, 20, 40 mg)
                                                                                                                                                                                 out other etiologies, because these are most likely to explain the findings.
                          2.5             Simvastatin (40, 80 mg)
                                                                                                                                                                                 Other common etiologies include increased physical activity, trauma, falls,
      CK >10 × ULN (%)




                                                                                                                                                                                 accidents, seizure, shaking chills, hypothyroidism, infections, carbon
                          2.0
                                                                                                                                                                                 monoxide poisoning, polymyositis, dermatomyositis, alcohol abuse, and
                          1.5
                                                                                                                                                                                 drug abuse (cocaine, amphetamines, heroin, or PCP).”

                          1.0                                                                                                                2.                                  “Obtaining a pretreatment, baseline CK level may be considered in patients
                                                                                                                                                                                 who are at high risk of experiencing a muscle toxicity (ie, older individuals
                          0.5                                                                                                                                                    or when combining a statin with an agent known to increase myotoxicity),
                                                                                                                                                                                 but this is not routinely necessary in other patients.”
                          0.0
                                20   25       30           35           40           45   50      55       60         65          70         3.                                  “It is not necessary to measure CK levels in asymptomatic patients during
                                                                     LDL-C Reduction (%)                                                                                         the course of statin therapy, because marked, clinically important CK
                            Note: the data for this analysis were derived from prescribing information,                                                                          elevations are rare and are usually related to physical exertion or other
                           summary basis of approvals, clinical trials, and other sources. Prospectively                                                                         causes.”
                         designed comparative clinical trials were not utilized in this analysis and results
                                                 should be interpreted with caution
Reprinted with permission from: Brewer HB, et al. Am J Cardiol. 2003;92(suppl):23K–29K.                                                                                                 McKenney JM, et al. Am J Cardiol. 2006;97(suppl):89C–94C.




                    NLA Recommendations to Health Care Professionals                                                                                                                NLA Recommendations to Health Care
                      Regarding Muscle Safety With Statin Use (Cont)                                                                                                             Professionals Regarding Muscle Safety With
        4.                “Patients receiving statin therapy should be counseled about the
                                                                                                                                                                                              Statin Use (Cont)
                          increased risk of muscle complaints, particularly if the initiation of                                                   7. “In patients who develop tolerable muscle complaints or
                          vigorous, sustained endurance exercise or a surgical operation is                                                           are asymptomatic with a CK 10 the ULN, statin therapy may
                          being contemplated; they should be advised to report such muscle                                                            be continued at the same or reduced doses and symptoms
                          symptoms to a health professional”                                                                                          may be used as the clinical guide to stop or continue
        5.                “CK measurements should be obtained in symptomatic patients to
                                                                                                                                                      therapy.”
                          help gauge the severity of muscle damage and facilitate a decision of
                          whether to continue therapy or alter doses.”                                                                             8. “In patients who develop rhabdomyolysis (a CK > 10,000
                                                                                                                                                      IU/L or a CK 10 times the ULN with an elevation in serum
        6.                “In patients who develop intolerable muscle symptoms with or without                                                        creatinine or requiring IV hydration therapy), statin therapy
                          a CK elevation and in whom other etiologies have been ruled out, the
                          statin should be discontinued. Once asymptomatic, the same or
                                                                                                                                                      should be stopped. IV hydration therapy in a hospital
                          different statin at the same or lower dose can be restarted to test the                                                     setting should be instituted if indicated for patients
                          reproducibility of symptoms. Recurrence of symptoms with multiple                                                           experiencing rhabdomyolysis. Once recovered, the risk vs
                          statins and doses requires initiation of other lipid-altering therapy.”                                                     benefit of statin therapy should be carefully reconsidered.”
                                                                                                                                             McKenney JM, et al. Am J Cardiol. 2006;97(suppl):89C–94C.
      McKenney JM, et al. Am J Cardiol. 2006;97(suppl):89C–94C




                                                                                                                                                                                             Occurrence of ALT Elevations Greater
                                                                                                                                                                                             Than 3x ULN as a Function of Percent
                                                                                                                                                                                                  Change in LDL-C and Dose
                                                                                                                                                                                                         Fluvastatin (20, 40, 80 mg)         Atorvastatin (10, 20, 40, 80 mg)
                                                                                                                                                                                                         Lovastatin (20, 40, 80 mg)          Rosuvastatin (10, 20, 40 mg)
                                                                                                                                                                                 3.0
                                                                                                                                             Occurrence of ALT >3x ULN (%) (%)




                                                                                                                                                                                                         Simvastatin (40, 80 mg)

                                                                                                                                                                                 2.5


                                       Hepatic-Related                                                                                                                           2.0

                                                                                                                                                                                 1.5
                                     Adverse-Event Profile                                                                                                                       1.0

                                         With Statins                                                                                                                            0.5

                                                                                                                                                                                 0.0
                                                                                                                                                                                       20    25     30        35        40             45   50        55         60             65   70
                                                                                                                                                                                                                        LDL-C Reduction (%)
                                                                                                                                                                    Note: the data for this analysis were derived from prescribing information,
                                                                                                                                                                   summary basis of approvals, clinical trials, and other sources. Prospectively
                                                                                                                                                                 designed comparative clinical trials were not utilized in this analysis and results
                                                                                                                                                                                         should be interpreted with caution
                                                                                                                                       Adapted from: Brewer HB. Am J Cardiol. 2003;92(suppl):23K–29K.
                                   NLA Recommendations to Health Care Professionals                                                                                        NLA Recommendations to Health Care Professionals
                                        Regarding Hepatic Safety With Statin Use                                                                                                Regarding Hepatic Safety With Statin Use
                                  1.   “During the routine general evaluation of patients being considered for statin and other lipid-
                                       lowering therapy, it is advisable to obtain liver transaminase levels. If these tests are found to                                 5. “Should the clinician identify objective evidence of significant liver
                                       be abnormal, further investigation should be performed to determine the etiology of the                                               injury in a patient receiving a statin, the statin should be discontinued.
                                       abnormal test results.”                                                                                                               The etiology should be sought and, if indicated, the patient referred to
                                                                                                                                                                             a gastroenterologist or hepatologist.”
                                  2.   “Until there is a change in the FDA-approved prescribing information for statins, it is appropriate
                                       to continue to measure transaminase levels before starting therapy, 12 weeks after initiating                                      6. “If an isolated asymptomatic transaminase level is found to be elevated
                                       therapy, after a dose increase, and periodically thereafter. However, routine monitoring of liver                                     1–3 times the ULN, there is no need to discontinue the statin.”
                                       function tests is not supported by the available evidence and the current recommendation for
                                       monitoring needs to be reconsidered by the FDA.”                                                                                   7. “If an isolated asymptomatic transaminase level is found to be > 3
                                                                                                                                                                             times the ULN during a routine evaluation of a patient administering a
                                  3.   “The clinician should be alert to patient reports of jaundice, malaise, fatigue, lethargy, and                                        statin, the test should be repeated and, if still elevated, other etiologies
                                       related symptoms in patients taking statin therapy as a signal of potential hepatotoxicity.                                           should be ruled out. Consideration should be given to continuing the
                                       Evidence for hepatotoxicity includes jaundice, hepatomegaly, increased indirect bilirubin level                                       statin, reducing its dose, or discontinuing it based on clinical
                                       and elevated prothrombin time (rather than simple elevations in liver transaminase levels).”                                          judgment.”
                                  4.   “The preferred biochemical test to ascertain significant liver injury is fractionated bilirubin, which,                            8. “According to the Expert Liver Panel, patients with chronic liver
                                       in the absence of biliary obstruction, is a more accurate prognosticator of liver injury than                                         disease, nonalcoholic fatty liver disease, or nonalcoholic
                                       isolated aminotransferase levels.”                                                                                                    steatohepatitis may safely receive statin therapy.”


                                 McKenney JM, et al. Am J Cardiol. 2006;97(suppl):89C–94C                                                                                      McKenney JM, et al. Am J Cardiol. 2006;97(suppl):89C–94C.




                                       Drug-Drug Interactions Resulting from                                                                                             Drug-Drug Interactions CYP Inhibition
                                       Impaired (Liver) Metabolism of Statins                                                                                                     (May include parent or active metabolites)
                                                                                                                                                                                                                   Cytochrome P450

                                   Atorvastatin                                                                                                                                   Statin                       3A4       2C8                       2C9
                                    Lovastatin                                                                                                                                    Pravastatin
                                   Simvastatin                                                                                                                                    Atorvastatin                 ( )
                                                                    CYP 450                                             Plasma                 Rhabdomyolysis
                                                                                                                         levels                 Reported With                     Fluvastatin                (minor)
                                  Ketoconazole                                                                             of                    Lovastatin &
                                                                       3A4                                                                                                        Simvastatin
                                  Erythromycin                                                                          Statins                  Simvastatin*
                                                                                                                                                                                  Lovastatin
                                    Diltiazem
                                  Itraconazole                                                                                                                                    Rosuvastatin                (minor)                               (minor)
                                    Grapefruit                       * 1. Lees RS et al. N Engl J Med 1995;333:664-665. 2. Ballantyne CM et                                       Gemfibrozil
                                                                     al. J Am Coll Cardiol 1992; 19:1315-21. 3. Corpier CL. JAMA
                                      Juice                          1988;260(2):239-241. 4. Ahmad S. Am Heart J 1993;126:1494-1495. 5.
                                      Others                         Meier C et al. Schweiz Med Wochen 1995;125:1342-1346. 6. Jacobson
                                                                                                                                                                         Adapted from Lenner näs and Fager. Clin Pharmacokinet. 1997;32:403.
                                                                     RH et al. JAMA 1997;277:296.      7. Jody DN. JAMA 1997;277:296-297.
                                                                     8. Segaert MF et al. Reactions 1996;622:10-11. 9. FDA report 1997.




                                   Effects of Itraconazole on Serum Concentrations of
                                                Simvastatin and Pravastatin                                                                                                    Other Lipid-lowering Medications
                                                                                                                                                                           Generic                  Trade®                        Recommended        Max daily
                                               Simvastatin                                                                                 Pravastatin                                                                             starting dose      dose
                                                                                         Pravastatin concentration (ng/ml)
Total simvastatin acid (ng/ml)




                                 200                                                                                                                                       Fibrates
                                                            with Itraconazole                                                200                   with Itraconazole       Gemfibrozil                Lopid                         1200 mg/day
                                 175                        with Placebo                                                     175                   with Placebo            Fenofibrate                Tricor (Others)                 160 mg         160 mg/day
                                 150                                                                                         150                                           Niacin
                                 125                                                                                         125                                           Immediate release          Niacor; Nicolar               1500 mg/day*         6 g/day
                                                                                                                                                                           Extended release           Niaspan                        375 mg/day          2 g/day
                                 100                                                                                         100                                           (750 mg capsules)
                                  75                                                                                          75                                           Resins
                                  50                                                                                          50                                           Cholestyramine             Questran;                       4-8 g/day          24 g/day
                                                                                                                                                                                                      Prevalite; LoCHOLEST
                                  25                                                                                          25
                                                                                                                                                                           Colestipol                 Colestid                       5-10 g/day        30 g/day
                                   0                                                                                           0                                           Colesevelam                WelChol                        6 tabs/day       7 tabs/day
                                       0   2      4     8     12    16    20     24                                                0   1   2   3    4   6   8 10 12 24     (625 mg tablets)

                                                      Time (hours)                                                                             Time (hours)                Other:
                                                                                                                                                                           Ezetimibe                   Zetia                        10mg tab/day       10mg/day
                                                   Itraconazole 200 mg or placebo given for 4 days,                                                                        ezetimibe+simva             Vytorin               10mg ezet+simva 10/20/40/80)
                                            then one dose of simvastatin or pravastatin 40 mg administered.                                                                * Titrated up over a 3-6 week period.
                                                                                              Neuvonen et al. Clin Pharmacol Ther 1998;63:332-41.
                        Fibrates                                                                                         Fibrates
                (Gemfibrozil, Fenofibrate)                                                                       (Gemfibrozil, Fenofibrate)
                                                                                       Adverse effects:
Actions:                                                                                  • Dyspepsia, abdominal pain, rash cholelithiasis, preexisting gallbladder
                                                                                            disease and diarrhea
  • Lowers Trigs (approx 25% for Gem, 30-50% for fenofibrate)
                                                                                       Comments
  • Moderately lowers total and LDL (0-4% for Gem, up to 20% for                          • Caution in patients also taking a "statin” gemfibrozil due to 2C8/9 inhibition
    fenofibrate*)                                                                           (+/- fenofibrate)
  • Raises HDL (approx. 8% for Gem, 1-34% for fenofibrate )                               • Caution with warfarin administration (--> incr. INR)
                                                                                          • Fenofibrate is a uricosuric in most patients
Dosing:                                                                                Studies:
  • Gemfibrozil: 600mg BID, 30 minutes before meals                                       • Helsinki Heart Disease Trial (gemfibrozil, 1o prev.) 34% reduction in CHD
                                                                                            (p<0.02) (Frick NEJM 1987;317:1237-45)
  • Fenofibrate: Multiple formulations: eg. 145mg/day with meals (avail as                • VA-HIT trial (NEJM 1999;341:410-418 ): Reduction in CVD death + NFMI (in
    48mg for use in renally impaired)                                                       men with normal LDL-C (<140) and low HDL-C (<40), TG <300 mg/dL
     • Dosage adjustment may be necessary with reduced renal function 5.3%                • FIELD¥ Fenofibrate group HR;0.89 (95%CI 0.75-1.05, p=0.16) for any CV event,
       increase in ALT/AST >3x ULN (vs. 1.1% PL)                                            NFMI HR;0.76, (95%CI 0.62-0.94, p=0.01) coronary heart disease mortality 1.19
                                                                                            (95% CI 0.9-1.57, p=0.22)
                                                                                             • Other findings, less albuminuria progression (p=0.002), retinopathy
 * Depending on initial LDL this may be as low as 20% or – ve (ie raising of LDL-C              needing laser Tx p=0.0003) sign, in crease in pancreatitis and PE
 say 14-45% if Trigs 300-500 or >500mg/dL)                                                   • Included n=9795 Type 2 DM patients some, with add-on statins
                                                                                      ¥ Keech,   Lancet 2005;366:1849-1861




  Gemfibrozil for the Secondary Prevention of                                                            VA-HIT Lipid Profile and
 Coronary Heart disease in Men with Low Levels                                       Gem                   End Point Results
                    of HDL-C                                                         significantly
                                                                                     reduced risk of
                                                                                     major CV                                                               P < 0.006
                    (VA-HIT)                                                         events in pts
                                                                                     with CAD
                           NEJM 1999;341:410-418                                     whose primary               10                                  8
                                                                                     lipid
                                                                                     abnormality
                                                                                                                  5                                         CHD Death/
                                                                                     was a low HDL                             TC           TG
   • Purpose: Gemfibrozil for secondary prevention: would                                                                             0                     Nonfatal MI
                                                                                     Thus the rate %
                                                                                                   of   Change    0
     raising HDL-C reduce coronary events?                                           cardiac events                                 LDL-C           HDL-C
                                                                                     is reduced by                -5           -3
   • Subjects: 2531 men (<74 yo, median 64 yo) with HDL-C                            raising HDL-C
                                                                                     and lowering
                                                                                                                 -10
     <40mg/dL, LDL < 140mg/dL and Trigs <300mg/dL (actual BL                         Trigs
                                                                                     independent of
                                                                                                                 -15
     LDL-C 111, HDL 32 and TG 160mg/dL)                                              LDL changes.

                                                                                                                 -20
   • Design: Double-blind PL-controlled for 5.1 years gemfibrozil
                                                                                                                 -25                                          -22
     1200mg/d vs PL                                                                                                                         -25
                                                                                                          -30
   • Primary end point: CHD death/nonfatal MI                                                Baseline (mg/dL)                 175    111    161       32




                                                                                     Effects of Long-term Fenofibrate Therapy on CV
  Gemfibrozil for the Secondary Prevention of                                             Events in 9795 People with Type 2 DM
 Coronary Heart disease in Men with Low Levels                                                      (The FIELD Study)
                    of HDL-C                                                                                           Lancet 2005;366:1849-1861)
                    (VA-HIT)
                           NEJM 1999;341:410-418                                     • Purpose: Fenofibrate for primary prevention in T2DM
   • Conclusions:                                                                    • Subjects: 9795 men and women (50-75 yo) not taking statins
                                                                                       at entry and total-C/HDL-C ratio of >4.0 or TG of 87-443mg/dL
        • For CHD patients whose primary lipid abnormality is low
                                                                                       (Only 38% had TG>150 and HDL <40/50mg/dL for men/women)
          HDL-C, therapy that increases HDL-C, reduces risk of
          major CV events                                                            • Design: Randomized, controlled study for 5 years of either
                                                                                       fenofibrate 200mg/d vs PL
        • The magnitude of coronary risk reduction approximates
          that of large statin trials in patient with elevated LDL-C                 • Primary end point: CHD death/nonfatal MI
  Effects of Long-term Fenofibrate Therapy on CV
       Events in 9795 People with Type 2 DM                                                                                                   Nicotinic Acid
                 (The FIELD Study)
                                                     Lancet 2005;366:1849-1861)
  •               Results: Fenofibrate was associated with the following:                                                  Agents
                             •   HR;0.89 (95%CI 0.75-1.05, p=0.16) for any coronary event (primary outcome)                 - Niacin (OTC -generic), niacin SR, niacin extended
                             •   HR;0.76, (95%CI 0.62-0.94, p=0.01) for NFMI                                                release
                             •   HR;1.19 (95% CI 0.9-1.57, p=0.22) in coronary heart disease mortality
                             •   HR;0.89 (95% CI 0.8-0.99, p=0.035) total CV disease events (included coronary
                                                                                                                           MOA
                                 revascularization)                                                                         - inhibits lipolysis, decreases hepatic esterfication
                                   • Less progression to abuminuria (p=0.002)
                                   • Less retinopathy needing laser treatment (p=0.0003)
                                                                                                                            of trigs reduced production of Apo B
                                   • Fewer patients who commenced statins (8% vs 17%, p<0.0001)                            Actions
  •               Interpretation:
                             • Fenofibrate did not significantly reduce primary outcome
                                                                                                                            - Lowers total, LDL (up to 17%) and TRG (up to
                             • Higher rate of statin use in PL group may have masked a treatment benefit                    35%)
                               (adjustment for new lipid-lowering therapy indicated fenofibrate reduced the                 - Raises HDL (substantially, up to 26% cf. statins)
                               risk of CHD by 19% (p=0.01) and total CVD events by 15% (p=0.04))




                                                       Nicotinic Acid                                                                            Nicotinic Acid
                                                                                                                      Comments:
 Dosing                                                                                                                  • Hepatic toxicity mostly related to SR products however experience with
                                                                                                                            extended release formulation (Niaspan® ) challenges this point
               • Start low ( eg. Immediate release 50 mg TID) and titrate upward (Sustained
                 release usually bid, extended release Niaspan ® qd)                                                     • Alcohol and hot drinks may increase
               • Maximum 6 grams / day (Niaspan® max 2g/d)                                                                dose related side effects (flushing etc.)
                                                                                                                         • HDL raising qualities may be beneficial for those who have maximized
               • Niaspan ® :begin with 4 weeks @500/day, then up to 1000mg/d for another 4
                                                                                                                            exercise (“three E’s)
                 weeks (taken before bed), usually up to 2 g/day
                                                                                                                      Studies:
 Adverse effects:                                                                                                        • CDP (niacin 2o prev.) non sign. Reduction in recurrent MI at 6 yrs, but 15
               • Mostly dose related, pruritis, GI intolerance (caution with PUD history) may                               year follow up 11% reduction over placebo in all cause mortality (p<0.001)
                 take ASA 30” before dose-may help to reduce flushing,                                                      )(Canner JACC1986;8:1245-55)
               • Hyperglycemia, (caution in diabetics) and hyperuracemia                                                 • Stockholm Ischemic Heart Disease 2o prev. Trials niacin + clofibrate
                                                                                                                            reduced total mortality vs. placebo (p<0.05) if baseline TG>133mg/dL
               • Liver toxicity (monitor as with statins, esp sustained release)
                                                                                                                      Role: Elevations in HDL-C, Reductions in Trigs with modest needs for lowering
               • Cautiously combined with statins for (Trig and HDL-C effects)                                          LDL-C or combination with statins if high trigs (>400mg/dL),




                                            Eg. Niacin (as Niaspan®) Efficacy
                                           (Goldberg Am J Cardiol 1998;82:35U-38U)
                                 30
                                                                                                              HDL-C
                                                                                             30%      29%
                                 20
                                                                                 24%
                                                                      21%
      Change from Baseline




                                 10                        16%
                                                 10%
                                   0
                                                 -3%
                                                            -8%
                                                                      -13%
                                 -10
                                               -5%          -12%                  -16%
                                                                        -17%                 -22%     -21%
                                 -20                      -14%                                                LDL-C

                                                                     -21%                                     Lp(a)
                                 -30
                                                                                  -25%
                                                                                                       -26%
                                                                                               -30%

 Forced                          -40                                            -32%
tritration
of N=131
                                                                                            -39%              TG
                                 -50
                                                                                                      -44%
                                            500 mg      1000        1500       2000        2500       3000
                    Omega-3 Fatty Acids
                                                                                                                 Omega-3 Fatty Acids
•   Omega-3 ethyl esters are indicated for use as an adjunct to diet for
    reducing very high levels of triglycerides (≥500 mg/dL) in adult patients
    (alpha-linolenic acid eicosapentaenoic acid [EPA] and docosahexaenoic                         • Proposed mechanism of action
    acid [DHA])                                                                                      • Increased intracellular degradation of Apo B-100 inhibits
     • In patients with type IV (high VLDL) dyslipidemia in monotherapy                                the secretion and synthesis of VLDL-C but enhanced
     • In patients with type IIb/III (high LDL-C and T-Chol) dyslipidemia in                           conversion of VLDL-C to LDL-C
       combination with statins when control of TG is not sufficient
                                                                                                  • Potential adverse effects
•   In patients with hypertriglyceridemia (≥500 mg/dL), omega-3 fatty acids
    have been shown to…                                                                              • Increased levels of LDL-C and potentially increased
     • Decrease TG levels by 45%                                                                       oxidizability of LDL-C
     • Decrease VLDL levels by 50%                                                                   • Increased bleeding time due to interference with platelet
     • Increase HDL-C levels by 9%                                                                     function
     • Increase LDL-C levels by up to 45%, but non-HDL tends to be lowered and
       particle size/buoyancy changes favorably                                                      • Common AEs; eructation, flu-like syndrome, dyspepsia,
                                                                                                       fishy taste
•   Dose: EPA+DHA of 2-4g/day (as single or divided dose)                                            • Monitor ALT and LDL-C levels
                        Stone NJ, Blum CB. Management of Lipids in Clinical Practice. 5th ed.         McKenney, Sica Pharmacotehrapy 2007;27:715-728
                                  Omacor [package insert]. Liberty Corner, NJ: Reliant; 2005.         Jacobson Clin Ther 2007;29:763-777




                                                                                                  Summary of AHA Recommendations for
                   Omega-3 Fatty Acids                                                                   Omega-3 Fatty Acids
• Select Studies:                                                                                   Kris-Etherton et al Circulation 2002;106:2747-57
    • GISSI-Prevenzione: (Lancet 1999;354:447-55, Erratum Lancet                                Patient Population           Recommendations
      2001;357:642)
       • 11,323 post MI randomized to 850mg (EPA+DHA) vs. placebo.                              No CHD                       Eat a variety of fatty fish > twice/wk
       • After 3.5 yrs observed a 20% reduction in combined death, NFMI, stroke                                              Include Oils and other foods rich in
         (driven by 45% reduction in SCD)
    • Meta-analysis by Bucher Am J Med 2002;112:298-304 included 7951
                                                                                                                             alpha-linolenic acid (flaxseed, canola
      intervention subjects (receiving omega-3 FAs) and 7855 controls over                                                   and soybean oils; walnuts)
      more than 1 year follow-up                                                                CHD present                  1 g/day of EPA + DHA, preferably from
    • HR 0.8 (95% CI 0.5-1.2, p=0.16) for NFMI                                                                               fatty fish; use supplements after
    • HR 0.7 (95% CI 0.6-0.8, p=0.001) for sudden death                                                                      consulting a physician
    • HR 0.8 (95% CI 0.7-0.9, p=0.001) for total mortality
                                                                                                High triglyceride            2-4 g/day of EPA + DHA under
    • Risk reduction may arise from antiarrhythmic effect added to
      antiatherosclerotic effect                                                                levels                       physician’s care

       McKenney, Sica Pharmacotehrapy 2007;27:715-728
       Jacobson Clin Ther 2007;29:763-777




                                                                                                     Goals and Recommendations for Clinical
               Anti-hyperlipidemic Drug                                                            Management of Metabolic Syndrome : Non Drug
                     Combinations                                                                                Considerations
•   Statin+ Fibrate (gemfibrozil, fenofibrate)                                                                     (Grundy Circulation 2005;112:2735-2752)
    - increased likelihood of LFT increases, myopathy
•   Statin+ Ezetimibe                                                                               Lifestyle Risk Factors:
    - augmented LDL, HDL and TG response with no need to increase                                      • Abdominal Obesity
    monitoring (above statin rec.)                                                                         • Reduce body weight by 7-10% during year 1 of therapy. Continue to
•   Statin+ Niacin                                                                                           extent possible to achieve desirable wt (BMI<25kg/m2)
•   - augmented LDL, HDL and TG response with some need to increase                                        • How? Consistently encourage wt. maintenance/reduction -> balance
    monitoring (diabetics, SEs)                                                                              physical activity, caloric intake, and behavioral modification programs to
                                                                                                             achieve/maintain waist circumference of <40”(M) and <35” (F)
•   Statin+ omega-3 FAs
                                                                                                       • Atherogenic Diet
     • augmented TG lowering, non-HDL-C lowering and HDL-C raising
                                                                                                           • Reduce intake of saturated fat, trans fat, cholesterol
•   Statin+ resin (various)
    - augmented LDL, modest HDL and indifferent or worse TG response)                                      • How? Recommend: saturated fat <7% of total calories, reduce trans fat:
    - no need to increase monitoring                                                                         dietary cholesterol <200mg/d: total fat 25% to 35% of total calories, most
                                                                                                             fat should be unsaturated, simple sugars should be limited
  Goals and Recommendations for Clinical
Management of Metabolic Syndrome : Non Drug                                                                     Summary
              Considerations                                                           • Pharmacologic management of secondary targets such
             (Grundy Circulation 2005;112:2735-2752)                                     as the metabolic syndrome and non-HDL-C were
                                                                                         reviewed
Lifestyle Risk Factors:
                                                                                       • Major drug therapy for TG lowering and HDL-C raising
  • Physical Inactivity
                                                                                         may involve niacin, fibrates and omega-3 FAs
     • Regular moderate-intensity physical activity; at least 30” (preferably 60”)
       continuous or intermittent 5 d/wk, but preferably daily                         • These goals should be achieved in light of the weight of
     • How?                                                                              evidence supporting their proven outcomes (relative to
                                                                                         LDL-C and statins)
     • With CVD, assess risk to guide exercise advice, encourage 30-60”
       activity (walking to gardening) and some resistance training 2d/wk)             • Non-drug therapy to manage components of the
                                                                                         metabolic syndrome are offered
                                                                                       • Emphasis remains on LDL-C first, but clinicians must go
                                                                                         beyond LDL-C to include non-HDL, TG and HDL-C, and
                                                                                         other components of the metabolic syndrome




          Bile Acid Sequestrants                                                                  Bile Acid Sequestrants
 Agents
                                                                                         Actions
    1. Cholestyramine - Questran®, Questran Light®,
    Prevalite®                                                                             - Lowers total and LDL-C (little effect on HDL)
    2. Colestipol - Colestid®                                                              - Raises trigs (problem for those with high Trigs)
    3. Colesevlam HCl- Welchol ®                                                         Dosing
 MOA                                                                                       - Cholestyramine: initial 4 grams BID
    - Bind with bile acids forming an insoluble                                            - Colestipol: initial 5 grams BID
      complex which is excreted in the stool
                                                                                         Titrate upwards according to desired effect
    - Increased loss of bile acids causes increased
    oxidation of cholesterol into bile acids                                               - Colesevlam: 3 tabs bid or 6-7 tabs qd




                                                                                                            Colesevlam HCL
            Bile Acid Sequestrants                                                                          Welchol® Tablets
                                                                                     *Non-absorbed lipid lowering resin agent
 Adverse effects                                                                     *Indication: Alone or in combination with HMG-CoA inhibitors to
                                                                                           lower LDL-C
   - Mostly GI                                                                       *Dose: 6 tabs (3 bid) with food or fluids or 6 tabs qd. (max 7)
 Comments                                                                            *Available: 625mg Tablets
    • Drug and vitamin interactions (binding) (available data suggests               *Role: Like other resins:
      this is not a problem for a limited number of incident drugs
      (digoxin, etc.)                                                                      1)For patients intolerant or unable
    • Safe for children and in very effective if combined with statins
                                                                                           to take statins (eg. pregnancy,children, liver problems)
                                                                                           2)Combination with other agents
    • Poor compliance (gritty, GI issues, cost)
                                                                                     Unlike other resins:
                                                                                           1)Apparently no binding to limited drugs tested to date
            Ezetimibe (Zetia®) and Statins —                                                                                                                              ZETIATM (ezetimibe) —
                                                                                                                                                                            Drug Interactions
             Complementary Mechanisms                                                                                             • No clinically significant pharmacokinetic interactions with
                                                                                                                                         • statins (including atorvastatin, simvastatin, pravastatin, lovastatin, and
                                                                                                                                           fluvastatin)
         • ZETIA reduces the delivery of cholesterol to the liver
                                                                                                                                         • Warfarin, digoxin, ethinyl estradiol, levonorgestrel, glipizide, tolbutamide
           (acts at brush border of sm. Intestine and inhibits
           chol. Absorption decr. Delivery of chol. To liver and                                                                  • ZETIA is neither an inhibitor nor an inducer of these CYP1A2, 2D6,
           reduction of hepatic chol. Stores incr. Clearance                                                                        2C8/9, and 3A4 isozymes
           from blood)                                                                                                            • Cholestyramine: decreased the mean AUC of total ezetimibe ~55%. The
                                                                                                                                      incremental LDL-C reduction due to adding ezetimibe to cholestyramine
         • The distinct mechanism of ZETIA is complementary to                                                                        may be reduced by this interaction
           that of statins which reduce cholesterol synthesis in
                                                                                                                                  • Fibrates: co-administration of ZETIA with fibrates is not recommended -
           the liver1                                                                                                                 co-admin with fenofibrate or gemfibrozil                           1.5 to 1.7 fold increase in
         • The effects of ZETIA, either alone or in addition to a                                                                     ezetimibe
           statin, on cardiovascular morbidity or mortality have                                                                  • Cyclosporine: ZETIA increased 12-fold in 1 renal transplant patient
           not been established                                                                                                       receiving multiple medications, including cyclosporine
                                                                                                                                         • Patients who take both ZETIA and cyclosporine should be carefully
    1. Knopp RH. N Engl J Med. 1999;341:498–511.                                                                                           monitored




                                                                                                                                     Plasma Cholesterol Comes Continuously From
               Pathways Affecting Cholesterol                                                                                              Both Production and Absorption
                Dietary Biliary
                               Balance*                                                                                    Endogenous cholesterol
                                                                                                                           production
                                                                                                                                                                                                                                        Intestinal cholesterol
                                                                                                                                                                                                                                        absorption
                  Cholesterol                   Cholesterol                     Intestinal Epithelial Cell                 (VLDL, IDL, LDL)                                                                                             (chylomicron, TG,
                                                                                                                                                                                                                                        plant sterols)


                       (Intake)

                                                                                                             CM                                                                                                                     •       Intestinal
                                                                  (Excretion)          Cholesterol Esters                                                                                                                                   cholesterol
                                    Luminal
                                                                                                                                                                                                                                            comes from
                                   Cholesterol                                                          ACAT                                                                                                                                bile (~75%)
                             Bile                                        ABCG5                         (Esterification)                                                                                                                     and the diet
     (Bile Acids)           Acids                                        ABCG8                                                                                                                                                              (~25%)1

                                    Micellar
                                   Cholesterol                                                                              •      Approximately
            (Micellar                                             Cholesterol
                                                                                                                                   50% is
           Cholesterol)                                           Transporter
                                                                                                                                   absorbed
                                                                                              Cholesterol                          into the
                                                              (Uptake)                                                             plasma2

                                                                                                                                                                                                                 VLDL = very low-density lipoprotein.
                                                                                                                          1. Shepherd J. Eur Heart J Supplements. 2001:3(suppl E):E2–E5.                         IDL = intermediate-density lipoprotein.
                                                                                                                          2. Homan R et al. Curr Pharm Design. 1997;3:29–44.                                     TG = triglyceride.
*Please see corresponding speaker notes for references.




                                                                                                                                       ZETIATM (ezetimibe) — Provided Additional
        Clinical Studies for ZETIATM (ezetimibe)                                                                                          Reduction in LDL-C When Added to
                      Monotherapy                                                                                                               Ongoing Statin Therapy
         Pooled Results From 2 Multicenter, Double-Blind, Placebo-Controlled, 12-Week                                                                                                 Statin + Placebo             Statin + ZETIA
                 Studies in 1,719 Patients With Primary Hypercholesterolemia                                                                                                               (n=390)                    (n=379)

                                                     LDL-C           TG (median)                HDL-C
                                                                                                                                                                           0%
                                  5%               1%                    0%                           1%*
                                  0%                                                                                                          Mean %
          Mean %                                                                                                                                                                                 –4%
                                                                                                                                              Change
          Change    –5%                                                                       –2%                                            in LDL-C                  –10%
           From                                                                                                                            From Treated
         Untreated –10%                                                         –8%*                                                         Baseline
         Baseline
                             –15%
                                                                                                                                                                       –20%
                             –20%                         –18%*                   Placebo (n=431)
                                                                                  ZETIA 10 mg (n=1,288)                                                                                                              –25%*
                                                                                                                                                                       –30%                      Mean LDL-C
     ♦ Experience in non-Caucasians is limited and does not permit a precise estimate of the                                    Statin Monotherapy 1                                 139 mg/dL                138 mg/dL
       magnitude of the effects of ZETIA                                                                                        After Adding Placebo or ZETIA                        133 mg/dL                102 mg/dL
       *P≤0.01 vs placebo.                                                                                                      *P<0.001 for ZETIA + statin vs placebo + statin.
                                                                                                                                1. Gagné C et al. Am J Cardiol. 2002;90:1084–1091.
     ZETIATM (ezetimibe) Added to Ongoing Statin —                                                                                          ZETIATM (ezetimibe) — Added LDL-C
           Triglycerides and HDL-C Results                                                                                                 Reduction With Any Atorvastatin Dose
                                                            Triglycerides (median)          HDL-C (mean)
                                                                                                                                                                                        ZETIA +                    ZETIA +               ZETIA +               ZETIA +
                                                                                                                                                                                 Atorva Atorva           Atorva    Atorva     Atorva     Atorva     Atorva     Atorva
                                                                                                        †                                                                        10 mg 10 mg             20 mg     20 mg      40 mg      40 mg      80 mg      80 mg
                                                      5%                                             3%                                                                          (n=60) (n=65)           (n=60)    (n=62)     (n=66)     (n=65)     (n=62)     (n=63)
                                                                                             1%                                                                           0%
                                                      0%
          %                                                                                                                                                              –10%
       Change                                     –5%            –3%                                                                      Mean %
        From                                                                                                                              Change                         –20%
                                                  –10%                                                                                   in LDL-C
       Treated                                                                                                                                                           –30%
       Baseline                                                                                                                            From
                                                  –15%                   –14%*                                                           Untreated                       –40%    –37%
                                                  –20%                                                                                   Baseline
                                                                                                                                                                         –50%                               –42%
                                                                                                                                                                                                                               –45%
                                                  –25%                                     Statin + Placebo                                                                                –53%*                   –54%*                            –54%
                                                                                                                                                                         –60%                                                            –56%*
                                                  –30%                                     Statin + ZETIA                                                                                                                                                      –61%*
                                                                                                                                                                         –70%
                                                                                                                                                                                                                             Atorvastatin        ZETIA + Statin
     *P<0.001 for ZETIA + statin vs statin alone.
     †
       P<0.05 for ZETIA + statin vs statin alone.                                                                                           *P<0.01 for ZETIA + statin vs statin alone.




         VYTORIN™ (ezetimibe/simvastatin) Lowered
             LDL-C by 52% at the Starting Dose                                                                                                                                  Anti-hyperlipidemic Drug
                                                        Starting Dose                                                                                                                 Combinations
                                                           10/20 mg            10/40 mg            10/80 mg
                                                            (n=156)             (n=147)             (n=154)
                                              0                                                                                                        • Statin+ Fibrate (gemfibrozil, fenofibrate)
               From Untreated Baseline, %




                                                                                                                                                         - increased likelihood of LFT increases, myopathy
                Mean Decrease in LDL-C




                                                                                                                  VYTORIN 10/20 mg
                                                                                                                   Mean Baseline LDL-C
                                                                                                                       176 mg/dL                       • Statin+ Ezetimibe
                                            –25                                                                   Mean End Point LDL-C
                                                                                                                                                         - augmented LDL, HDL and TG response with no need
                                                                                                                        84 mg/dL

                                                                                                                  VYTORIN 10/80 mg                       to increase monitoring (above statin rec.)
                                                                                                                   Mean Baseline LDL-C
                                                                                                                       178 mg/dL
                                                                                                                  Mean End Point LDL-C
                                                                                                                                                       • Statin+ Niacin (Advicor as single entity)
                                            –50                                                                         70 mg/dL                         - augmented LDL, HDL and TG response with some
                                                           –52%*,†
                                                                                 –55%*,†                                                                 need to increase monitoring (diabetics, SEs))
                                                                                                    –60%*                                              • Statin+ resin (Welcol or others)
                                                  •   VYTORIN lowered LDL-C more than simvastatin across the dosage range.
                                                                                                                                                         - augmented LDL, modest HDL and indifferent or
                                                  •   Simvastatin lowered LDL-C by 34% at the 20-mg dose, 41% at the 40-mg dose,
                                                      and 49% at the 80-mg dose.
                                                                                                                                                         worse TG response)
Comparison with simvastatin.
                                                                                                                                                         - no need to increase monitoring
*P<0.001 for VYTORIN vs each corresponding dose of simvastatin.
†
  P<0.001 for VYTORIN vs next highest dose of simvastatin monotherapy.                         Bays ACC 2004




                                                                                                                                              Phase III Combination Therapy:
                         Combination Drug Therapy for                                                                                       Ezetimibe Plus Simvastatin—Efficacy
                            Hypercholesterolemia
                                                                                                                                                                                         LDL-C                           HDL-C                         TG
                                                                                                                                                                          20
                                                                                                                                             % Reduction from baseline




           • Useful for mixed dyslipidemias                                                                                                                                                                                         *
                                                                                                                                                                                                                                   9.3
                                                                                                                                                                          10                                             5.1 6.9
                                                                                                                                                                                                                   0.9                        2.4
           • Optimizes effects on relevant lipid fractions of                                                                                                               0
             interest                                                                                                                                                     -10
                                                                                                                                                                                 -1.3
                                                                                                                                                     at wk 12




                                                                                                                                                                                                                                                    -8.3
           • Selection may be complex based on                                                                                                                            -20           -18.1                                                          -16.6

             tolerance, drug interactions and cost                                                                                                                        -30
                                                                                                                                                                                                                                                               -24.1
                                                                                                                                                                                                                                                                *
           • Unknown outcome as of yet                                                                                                                                    -40               -36.1
                                                                                                                                                                                                                           Placebo (n=70)
                                                                                                                                                                          -50                                              Ezetimibe 10 mg (n=61)
           • Experience with some combinations are                                                                                                                                                  -49.9
                                                                                                                                                                                                                           Simvastatin (pooled, n=263)
             limited                                                                                                                                                      -60                        *                     Ezetimibe 10 mg
                                                                                                                                                                                                                           + simvastatin (pooled, n=274)
                                                                                                                                         *P<0.03 vs simvastatin.
                                                                                                                                          Davidson et al. J Am Coll Cardiol. 2002;39(suppl A):Abstract 1084-90.
               WelChol: Concomitant & Separate                                                                                                                              Advicor (Niaspan+Lovastatin)
                                                                                                                                                                                                         Long-Term Study
                   Dosing with Lovastatin                                                                                                                                   HDL                       TG                         LDL                   Lp(a)*

                                                                                                                                                                    50
                                                      LDL-C                    Total-C                        HDL-C                   TG                                                                                                                             41
                                       20                                                                                                                           40
                                                                                                                                                                                                                          30
                                                                                                                                                                                                            26
                                                                                                               5    4                                               30
% Change from baseline




                                                  0                            1                          1               2       1   0                                                         18




                                                                                                                                                         % Change
                                       0                                                                                                                            20
                                                                                                                                                                                   11
                                                                                                                                          -1 -2                     10
                                                                                                                                                                     0                   -2
                                                                                   -14
                                 -20                                                                                                                                                               -10
                                                                                         -21 -21                                                                    -10
                                                      -22                                                            * p < 0.05 vs placebo                                              -16                      -16
                                                                                                                                                                    -20                         -27
                                                                  -32          Placebo                                                                                                                                         -25                                     -25
                                 -40                        -34                                                                                                     -30              -25                     -34
                                                                               Lovastatin 10/d
                                                                               WelChol 2.3 g/d + Lovastatin 10 mg/d - together at dinner                                                       -34                          -41
                                                                                                                                                                    -40                                                                                               -42
                                                                               WelChol 2.3 g/d + Lovastatin 10 mg/d - 4 hrs apart                                                                          -41                -47                                     -45
                                                                                                                                                                    -50
                                 -60                                                                                                                                      Week       4         8            12            16                                            52
                                                                                                                                                                                  500/10 1000/20          1500/30       2000/40                                     2000/40
                                                                                                                                                                                 (n = 753) (n = 706)     (n = 676)     (n = 655)                                   (n = 226)
                                                                                   LDL-C and Total-C values are expressed as mean, whereas
                                                                                                                                                                                                                                     *N~200; point at Week 16 is
                                                                                             HDL-C and TG values are expressed as median.
                                                                                                                      Data on file, Sankyo Pharma Inc.                                                                               extrapolated




                                                                                                                                                                  Clinical Event Trials
                                                                                                                                                         Secondary   Using Statins Primary
                                                                                                                                                         4S                                                                      WOSCOPS
                                                                                                                                                         Simvastatin                                                             Pravastatin
                                                                                                                                                         LDL-C: 188 to 117 mg/dL                                                 >2 RF
                                                                                                                                                         HDL-C: 45.3 to 48.9 (8%)                                                LDL-C: 192 to 142 mg/dL
                                                                                                                                                         CHD Events: 25.5 to 16.4%                                               HDL-C: 44 to 46.2 (5%)
                                                                                                                                                                                                                                 CHD Events: 7.9 to 5.5%
                                                                                                                                                         LIPID
                                                                                                                                                         Pravastatin                                                             AFCAPS/TexCAPS
                                                                                                                                                         LDL-C: 150 to 112 mg/dL                                                 Lovastatin
                                                                                                                                                         HDL-C: 36 to 37.8 (6%)                                                  <2 RF
                                                                                                                                                         CHD Events: 15.7 to 12.3%                                               LDL-C: 156 to 115 mg/dL
                                                                                                                                                                                                                                 HDL-C: 38 to 39 (6%)
                                                                                                                                                         CARE                                                                    CHD Events: 5.6 to 3.3%
                                                                                                                                                         Pravastatin
                                                                                                                                                         LDL-C: 139 to 98 mg/dL
                                                                                                                                                         HDL-C: 36 to 39 (6%)                                          CHD events = nonfatal MI + CHD death.
                                                                                                                                                         CHD Events: 13.2 to 10.2%




                                                      Selected Major Trials of
                                                              Statins                                                                                                Key Studies and Therapeutic
                                                               Effects on Cardiac Events                                                                                       Options
                                        30               Rx
                                                         Placebo                                                                  25.5                   • Key (older landmark) Studies:
                   CV events Percent




                                        25
                                        20                                                                                                                          • Historically, 4S, CARE, LIPID and WOSCOPS,
                                                                                                                               16.4
                                                                                                                        15.7                                          AFCAPS
                                        15                                                            13.2     12.3
                                                                                                   10.2                                                             • Additional Studies: Heart Protection Study (HPS)
                                        10                               7.9
                                                         5.6       5.5                                                                                                (2002), PROSPER (2002), ASCOT-LLA (2003),
                                            5      3.3                                                                                                                ALLHAT (2003) PROVE-IT (2004)
                                            0
                                                 Tex/AFCAPS       WOSCOPS                           CARE            LIPID        4S
                                                                                                                                          LDL-C
                                                 115 156           142 192                         98 139          112 150     117 188    levels
                                                                                                                                          (mg/dL)
                                                Primary prevention                                   Secondary prevention
     Five Major (Newer) Trials With Clinical End Points
                                                                                                                             Advances Which Have Taken Place in
     • Heart Protection Study (HPS)                                                                                                  Recent Literature
     • Prospective Study of Pravastatin in the Elderly                                                              1) Evidence for aggressive optional targets
       at Risk (PROSPER)                                                                                                • HPS suggestive that treatment with statins in patients
                                                                                                                          with LDL <100mg/dL       outcome benefits
     • Antihypertensive and Lipid-Lowering                                                                              • PROVE-IT confirms LDL<70mg/dL in ACS patients
                                                                                                                          outcome benefits (vs. LDL=100mg/dL)
       Treatment to Prevent Heart Attack Trial
                                                                                                                        • TNT extends above findings to patients with chronic CAD
       (ALLHAT)
                                                                                                                        • Safety of statin therapy to these lower targets appears
     • Anglo-Scandinavian Cardiac Outcomes Trial                                                                          acceptable
       (ASCOT-LLA)                                                                                                  2) Statins are effective among special populations:
                                                                                                                        • ASCOT LLT- moderate to high risk- low dose statin
     • Pravastatin or Atorvastatin Evaluation and                                                                       • CARDS- diabetic specific trial –low dose statin
       Infection Trial (PROVE-IT)                                                                                   3) Other agents –combinations of agents are another means
                                                                                                                       for attaining these aggressive goals




                 The Heart Protection Study (HPS)                                                                                  Heart Protection Study Results:
                                                                                                                                           Risk Reduction
                          • Randomized, PL-controlled of effects of simvastatin and                                                                                                           Risk ratio (95% CI)
     Design                 antioxidant vitamins on morbidity and mortality                                                                                                           Statin better        Statin worse
                                                                                                                    Baseline feature         Statin (n=10,269)   Placebo (n=10,267)

                                                                                                                    Prior MI or other CHD        617 (16.8%)           840 (22.5%)
                                                                                                                    (7414)
                          • >20,536 men and women 40–80 yr at incr. risk of CHD due to
    Patients                prior disease with total-C >135 mg/dL*                                                  Any CHD or Risk             1459 (21.8%)          1841 (27.5%)
                                                                                                                    Equivalent

                                                                                                                    No prior CHD
                          • ≥5 yr Simvastatin (40 mg/d) vs placebo
   Treatment                                                                                                          CVD (1820)                 172 (18.7%)           212 (23.6%)
                          • ≥5 yr Vitamins (600 mg E, 250 mg C, 20 mg beta-carotene) vs                               PVD (2701)                 327 (24.7%)           420 (30.5%)
                            placebo                                                                                   Diabetes (3982)            276 (16.1%)           367 (18.6%)                              ↓24%
                                                                                                                                                                                                               (p<0.0001)
     Primary              • The effect of simvastatin on total and cause- specific mortality,                       All patients                2033 (19.8%)          2585 (25.2%)

                            secondary-cause specific morbidity and mortality                                                                                                          0.4   0.6   0.8   1.0   1.2   1.4
                                                                                                                      LDL-C 131 mg/dL (baseline) to
   *Increased risk of CHD due to prior disease defined as MI or prior CHD, occlusive disease of noncoronary           89 mg/dL (end of study)
    arteries, diabetes, or treated hypertension.                                                                      Average: 42 mg/dL (32%)
    HPS Collaborative Group. Lancet. 2002;360:7-22.                                                                 HPS Collaborative Group. Lancet. 2002;360:7-22.




        Heart Protection Study Results: Lipids                                                                                               HPS: Main Conclusions
                                                                                                                         • After allowance for non-compliance, 40mg daily
                                                                                                                           simvastatin safely reduces the risk of heart attack, of
                                                                                      Risk Ratio (95% CI)
 Baseline                       Statin                 Placebo
                                                                                                                           stroke, and of revascularization by about one-third
                                                                               Statin Better         Statin Worse
 LDL-C (mg/dL)                (n=10,269)              (n=10,267)

 <100                          282 (16.4%)             358 (21.0%)
                                                                                                                         •    5 years of statin treatment typically prevents these “major
                                                                                                                             vascular events” in about:
 100–129                       668 (18.9%)             871 (24.7%)
                                                                                                                                    100 of every 1000 people with previous MI
 ≥130                         1083 (21.6%)            1356 (26.9%)
                                                                                                                                     80       "      "       "       other CHD
                                                                                                                                     70       "      "       "       cerebrovascular disease
 All patients                 2033 (19.8%)            2585 (25.2%)                                   ↓24%                            70       "      "       "       other arterial disease
                                                                                                     (p<0.0001)                      70       "      "       "       diabetes (age 40+)
                                                                                                                                   irrespective of cholesterol level (or age, or sex, or other
                                                                         0.4    0.6    0.8     1.0     1.2    1.4                  treatments)



HPS Collaborative Group. Lancet. 2002;360:7-22.
        Comparison of Intensive and Moderate Lipid                                                                                     PROVE-IT
        Lowering with Statins after Acute Coronary                                                                                Death or Major CV Event
             Syndromes (PROVE-IT TIMI-22)                                                                          ARM                Lipid Changes
                        (Cannon et al NEJM:2004;350 1495-1504)                                                                                                      Pravastatin 40 mg                   16%
                                                                                                              30
                                                                                                                   Atorvastatin       106 to 62 (-42%)
                                                                                                                                                                                                        Red’n




                                                                                         Death or Major CV
        Background: Optimal level of LDL-C is unknown                                                         25   Pravastatin        106 to 95 (-10%)
                                                                                                                                                                                                          P = 0.005
        Methods: Enrolled 4162 hospitalized for ACS within 10                                                                                                             Atorvastatin 80 mg




                                                                                             event (%)
                                                                                                              20
          days; 40mg Prava vs. 80mg Atorvastatin (Median
                                                                                                                                                    Time            RR         Atorvastatin        Pravastatin
          baseline: LDL=106, HDL=39, TG=154, 78% males)                                                       15
                                                                                                                                                    30 days         17%             1.9%                2.2%
        Endpoint: composite of death from any cause, MI, UA                                                   10                                    90 days         18%             6.3%                7.7%
          requiring re-hospitalization, PCI within 30 days and                                                                                      180 days        14%             12.2%               14.1%
          stroke                                                                                               5
                                                                                                                                                    End             16%             22.4%               26.3%
        Design: to establish non-inferiority of Pravastatin vs.                                                0
          Atorvastatin follow-up mean 24 months                                                                    0     3        6     9     12      15       18         21       24         27     30
                                                                                                                                       Months of follow-up
                                                                                                                                            Cannon CP et al. N Engl J Med. 2004;350:1495-1504.




        Comparison of Intensive and Moderate Lipid
        Lowering with Statins after Acute Coronary                                                           Intensive Lipid Lowering with Atorvastatin in
             Syndromes (PROVE-IT TIMI-22)                                                                       Patients with Stable Coronary Disease
                        (Cannon et al NEJM:2004;350 1495-1505)                                                           (TNT) Study Design
    Results:
      - Median LDL-C was 95mg/dL for Pravastain vs. 62mg/dL for
      Atorvastatin (P<0.01)
                                                                                          Patient population
      - Estimates primary endpoint were 26.3% fro P vs. 22.4% for                                                                                                                  Atorvastatin 10 mg
      A (16% reduction, p=0.005;95%CI5-26%)                                                     250 centers                            Atorvastatin 10 mg
      - met the criteria for superiority of atorvastatin                                        in 14 countries                                                                    Atorvastatin 80 mg
                                                                                                (N = 10,001)
    Conclusions: Patients with recent ACS, intensive lipid lowering
                                                                                                Stable CHD
      statin provides greater protection. Substantial lowering of                                                                            8 weeks                                        4.9 years
                                                                                                LDL 130–250 mg/dL
      LDL-C
                                                                                                TG <600 mg/dL
    Comments: Safety-elevations in AST were 1.1% pravastatin vs.
      3.3% for atorvastatin (P<0.001), myalgias or muscle aches or
      elevations in CK were 2.7 vs. 3.3% for P vs. A (NS)                                   LaRosa, JC et al. NEJM 2005;352:1425-1435




                TNT: Results- Outcomes                                                                                                 TNT
                                                                                                                                   Results: Safety
                                Outcome                            RR             P
         160                    First major CV event              -22%         <0.001
                 152 mg/dL      CHD death or nonfatal MI          -20%          0.002                                                          Atorvastatin 10mg                  Atorvastatin 80mg
         140                    Fatal or nonfatal stroke          -25%          0.02                                                               (n=5006)                           (n=4995)
LDL-C
         120                                                                               Treatment-related AEs (%)                                  289 (5.8)                            406 (8.1)
                                        Atorvastatin 10 mg
         100
                                                                               24%         Treatment-related myalgia (%)                              234 (4.7)                            241 (4.8)
                                                             101 mg/dL
          80                                                                reduction
                                                               77 mg/dL                    Rhabdomyolysis* (%)                                           3 (0.06)                           2 (0.04)
          60                            Atorvastatin 80 mg
                                                                                           AST/ALT elevated >3x ULN (%)                                  9 (0.2)                            60 (1.2)
                                                                                                  *No cases were considered by the investigator with direct responsibility for the patient
           0                                                                                      to be causally related to atorvastatin, and none met ACC/AHA/NHLBI criteria for rhabdomyolysis
               0 mon    3 mon                                      60 mon
                                             Time
                                                                                        LaRosa, JC et al. NEJM 2005;352:1425-1435
LaRosa, JC et al. NEJM 2005;352:1425-1435
                                                                     TNT: Conclusion

  • Intensive lipid-lowering therapy with 80mg/d of atorvastatin
    in patients with stable CHD provides significant reduction in
    first major CV event beyond that afforded by treatment with
    10mg of atorvastatin per day
  • This outcome is achieved at the expense of increased LFT’s
    and no overall change in all-cause mortality




LaRosa, JC et al. NEJM 2005;352:1425-1435




                    High-Sensitivity C-reactive Protein
                         (hs-CRP) and CVD Risk                                                                                                    When to Measure hs-CRP
  • Acute-phase reactant produced by the liver in                                                                                   • Measure hs-CRP when it influences decision to use
    response to interleukin-6 and other cytokines                                                                                     lipid-lowering treatment:
                                                                                                                                        • Primary prevention with moderate risk
  • Epidemiologic studies suggest hs-CRP is a strong                                                                                      (10%-20% 10-y CHD risk)
    independent risk for myocardial infarction (MI),
                                                                                                                                        • Primary prevention in young individuals with strong family
    stroke, and PVD in CHD and CHD-free subjects                                                                                          history
  • Strongly associated with increased CHD events in                                                                                    • Secondary prevention with LDL-C <100 mg/dL,
    patients with unstable angina, stable angina, and                                                                                     non-HDL-C <130 mg/dL
    history of MI                                                                                                                   • No need to measure in:
                                                                                                                                        • Secondary prevention and type 2 diabetes with
  • Levels >0.38 mg/dL independently predictive of                                                                                        LDL-C >100 mg/dL or non-HDL-C >130 mg/dL
    vascular risk
  Ridker PM. Circulation. 2001;103:1813-1818.
  Jones PH et al. Am J Cardiol. 2003;92:152-160.                                                                                    Jones PH et al. Am J Cardiol. 2003;92:152-160.




                                                               CV Event-Free Survival
                                                       Quintiles of CRP                                Quintiles of LDL                          Cut points of risk for hs-CRP
                                                                                        1.00
                                            1.00
      CVD Event-Free Survival Probability




                                                                                1                                                                      Risk level                    hs-CRP (mg/L)
                                                                                        0.99
                                            0.99




                                                                                                                                1
                                                                                    2                                                                  Low                           <1
                                                                                                                                2
                                                                                        0.98
                                            0.98




                                                                                    3
                                                                                                                                3                      Average                       1.0 - 3.0
                                                                                4                                                                      High                          >3.0
                                                                                                                                4
                                                                                        0.97
                                            0.97




                                                                                                                                5
                                                                                5
                                                                                        0.96
                                            0.96




                                                   0   2         4        6     8              0   2          4       6     8
                                                           Years of Follow-Up                          Years of Follow-Up
                                                                                                                                         Pearson TA et al. Circulation 2003; 107:499-511.
 Ridker PM, et al. N Engl J Med. 2002;347:1557-1565.
 CV Event-Free Survival Using Combined CRP and LDL-
                   C Measurements                                                                                       CRP and Risk Assessment – 2003
                  Nonusers of Hormone-Replacement Therapy
                                                              1.00
                                                                                                                   • hs-CRP adds prognostic information to the Framingham
                         Probability of Event-free Survival


                                                                                              Low CRP-low LDL        Risk Score
                                                              0.99                                                 • As hs-CRP and LDL-C tend to detect somewhat different
                                                                                                                     high-risk groups, a combined screening approach using
                                                                                              Low CRP-high LDL       both bio-markers is superior to the use of either alone
                                                              0.98

                                                                                              High CRP-low LDL     • In primary prevention, high-hs-CRP/low-LDL-C
                                                                                                                     individuals are at higher absolute risk than low-hs-
                                                              0.97
                                                                                                                     CRP/high-LDL-C individuals, yet only the latter group is
                                                                                                                     currently recommended for statin therapy
                                                                                               High CRP-high LDL
                                                              0.96                                                 • However, modulating hs-CRP has not yet been shown to
                                                                                                                     affect cardiovascular risk
                                                              0.00
                                                                     0    2    4    6    8
                                                                         Years of Follow-up                        Jones PH et al. Am J Cardiol. 2003;92:152-160.
Ridker PM, et al. N Engl J Med. 2002;347:1557-1565.




                                                                                                                                        Questions?
                                                                         Summary
    • NCEP ATP III guides us to address LDL-C first, then
      issues of HDL-C, TG, non-HDL and the metabolic
      syndrome
    • New studies re-affirm role of statins in elderly, women,
      diabetics and possibly those with CHD regardless of
      starting cholesterol values (?)- they also suggest lower
      optional targets for select patients
    • New agents open door for further consideration of novel
      combinations with statins for those not tolerating high
      dose statins

				
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