LDL - How low can you go? Terry Jacobsen, MD Director, Office of Health Promotion and Disease Prevention Emory University Atlanta, GA Anthony Gotto, MD Dean, Cornell University Medical College New York City, NY

LDL-How low can you go? Is lower really better? "The Lower the Better" in Hypercholesterolemia Therapy: A Reliable Clinical Guideline? 0:52.3 Jacobson TA. Ann Intern Med 2000 ; 133:549-554

LDL-How low can you go? Epidemiology Studies show curvilinear relationship PROCAM: Prospective Cardiovascular Munster Study MRFIT: Multiple Risk Factor Intervention Trial The mean lipid level for a CHD survivor is between 120 and 140 mg/dL. A “diminishing returns model” of benefit as lipid levels are lowered. 2:25

LDL-How low can you go? Secondary prevention trials CARE: Cholesterol and Recurrent Events trial No cardioprotective benefit in reducing LDL from 124 mg/dL to 71 mg/dL LIPID: Long-Term Intervention with Pravastatin in Ischaemic Disease study Showed only a 16% relative risk reduction in patients with LDL below 135 mg/dL 4:25

LDL-How low can you go? 4S trial Reductions in relative risk were independent of baseline LDL cholesterol levels: -35% in patients with LDL <169 mg/dL -36% in patients with LDL >206 mg/dL 6:30.5

LDL-How low can you go? Post-CABG trial Patients with saphenous vein grafts randomized to: moderate therapy (LDL <130) aggressive therapy (LDL <100) 4 year results: no significant difference in non-fatal MI or cardiovascular death 7:11.0

LDL-How low can you go? Primary prevention WOSCOPS AFCAPS/TexCAPS (West Of Scotland COronary Prevention Study) AFCAPS/TexCAPS (Air Force/Texas Coronary Atherosclerosis Prevention Study) No evidence that the higher dose led to greater reduction of events. 7:11.0

LDL-How low can you go? More isn’t better “The pharmacoeconomics also mitigate that maybe we can’t afford to get patients as low as possible. That maybe we need to focus in on other risk factors after we do drive LDL levels to goal.” Terry Jacobsen, MD Director, Office of Health Promotion and Disease Prevention Emory University Atlanta, GA 8:19.5

LDL-How low can you go? “2 to 1” The Lipid Research Clinic (LRC) trial established the “2 to 1” relation between cholesterol reduction and risk reduction. AFCAPS/TexCAPS (Air Force/Texas Coronary Atherosclerosis Prevention Study) did not show a linear relationship, but also did not show a threshold. 9:38.5

LDL-How low can you go? Hazards of subgroup analyses Subgroup analyses are hypothesis generating, not conclusive. What is the real premise of the trial? Who benefited from therapy? AFCAPS/TexCAPS: LDL>130 w/HDL<50 CARE: LDL >160 w/established CAD 9:38.5

LDL-How low can you go? Two questions If you start at LDL >120 or 200, should you be more aggressive? 2) With LDL 100-130, are you getting benefit by being more aggressive? Must wait for TNT, SEARCH, OXFORD trials 9:38.5

LDL-How low can you go? Goals aren’t everything LRC study showed no incremental reduction after 30% LDL reduction. Many trials didn’t reach NCEP goals, but did show benefit. Goals are important for populations, but advocating beyond them is premature. 9:38.5

LDL-How low can you go? Other factors Are there adverse consequences of a large LDL reduction? Are there dangers of hemorrhagic stroke? Are there other properties of statin therapy? Need to look at other risk factors as aggressively. 9:38.5

LDL-How low can you go? Treating to target Some patients’ LDL simply can’t be lowered to an acceptable target level. You can see benefit without reaching target, but would you see more if LDL were lower? We may never be able to completely answer the question. 9:38.5