Selecting Successful Lipid-Lowering TreatmentsJames M. McKenney, Pharm.D.Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.Treatment Categories, LDL-C Goals and CutpointsRisk CategoryLDL-C GoalConsider Drug TherapyCHD or CHD risk equivalent250250Lova 20 mg1%9%32%Prava 10 mg6%11%22%Simva 10 mg1%20%28%*Nonfatal MI or CHD death; *ischemic events Downs JR et al. JAMA 1998;279:1615-1622. | Shepherd J et al. N Engl J Med 1999;333:1301-1307. | Scandinavian Simvastatin Study Group. Lancet 1994;344:1383-1389. | Sacks FM et al. N Engl J Med 1996;335:1001-1009. | LIPID Study Group. N Engl J Med 1998;339:1349-1357. | Schwartz GG et al. JAMA 2001;285:1711-1718. | Pitt B et al. N Engl J Med 1999;341:70-76.Endpoint Trials with the StatinsTrial DrugCHD Risk Reduction Primary PreventionAFCAPS/TexCAPS Lovastatin40%*WOSCOPS Pravastatin31%* Secondary Prevention4S Simvastatin34%*CARE Pravastatin24%*LIPID Pravastatin24%* IschemiaMIRACL Atorvastatin26%*AVERT Atorvastatin36%*CHD Risk Reduction with Statin TherapyLa Rosa JC et al. JAMA 1999;282:2340-2346. | Crouse JR III et al. Arch Intern Med 1997;157:1305-1310. | Pedersen TR et al. Am J Cardiol 1998;81:333-335.EndpointsEndpoints+203530250 5 101520Relative Risk Reduction (%)Relative Risk Reduction (%)404550Major coronary eventsCoronary deathsCardiovascular deathsNoncardiovascular eventsTotal mortalityStrokesIntermittent claudicationAnginaPotential Time Course of Statin Effects* Time course establishedDaysDaysYearsYearsLDL-C LDL-C lowered*lowered*InflammationInflammation reducedreducedVulnerableVulnerable plaquesplaques stabilizedstabilizedEndothelialEndothelial functionfunction restoredrestoredIschemicIschemic episodesepisodes reducedreducedCardiacCardiac eventsevents reduced*reduced*Statin Adverse EventsnCommon side effectsnHeadache Myalgia FatiguenGI intolerance Flu-like symptomsnIncrease in liver enzymesnOccurs in 0.5 to 2.5% of cases in dose-dependent mannernSerious liver problems are exceedingly rarenManage by reducing statin dose or discontinue until levels return to normalnMyopathynOccurs in 0.2 to 0.4% of patientsnRare cases of rhabdomyolysisnReduce bynCautiously using statins in patients with impaired renal functionnUsing the lowest effective dosenCautiously combining statins with fibratesnAvoiding drug interactionsnCareful monitoring of symptomsnPresence of muscle toxicity requires the discontinuation of the statinBile Acid Resins: Mechanism of ActionNet Effect: Net Effect: LDL-CLDL-CGall BladderGall Bladder LDL ReceptorsLDL Receptors VLDL and LDL removal VLDL and LDL removal Cholesterol 7-Cholesterol 7- hydroxylase hydroxylase Conversion of cholesterol to BA Conversion of cholesterol to BA BA SecretionBA SecretionLiverLiver BA ExcretionBA ExcretionTerminal IleumTerminal IleumBile AcidBile AcidEnterohepaticEnterohepatic Recirculation RecirculationReabsorptionReabsorption of of bile acidsbile acidsEffect of Colesevelam on LDL-CDavidson MH et al. Expert Opin Investig Drugs 2000;9:2663-2671. Reprinted with permission from Ashley Publications.Change in LDL-CChange in LDL-CPlaceboPlacebo3.8 g/d3.8 g/d4.5 g/d4.5 g/d(N=494 patients with baseline LDL-C of 130220 mg/(N=494 patients with baseline LDL-C of 130220 mg/dLdL and TG 0.10 Brown WV et al. Arteriosclerosis 1986;6:670-678. 1999 Lippincott Williams 317:1237-1245. | Manninen V et al. Circulation 1992;85:37-45. | BIP Study Group. Circulation 2000;102:21-27. | Rubins HB et al. N Engl J Med 1999;341:410-418.* Post hoc analysis of subgroup with TG 200 mg/dL and HDL-C 10 times the upper limit of normaland CK is 10 times the upper limit of normalGuidelines that arent implemented dont work