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HDL: The Bad of the Good

HDL: The Bad of the Good. i.e. What Do We Really Know Jonathan Martin PGY1 June 1 st , 2011. Cardiac Risk Markers. Age LDL - high HDL – low Diabetes Family History Prior Events Etc . . . Table 1. Baseline Characteristics Analyzed for Development of TIMI Risk Score for UA/NSTEMI*.

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HDL: The Bad of the Good

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  1. HDL: The Bad of the Good i.e. What Do We Really Know Jonathan Martin PGY1 June 1st, 2011

  2. Cardiac Risk Markers • Age • LDL - high • HDL – low • Diabetes • Family History • Prior Events • Etc . . .

  3. Table 1. Baseline Characteristics Analyzed for Development of TIMI Risk Score for UA/NSTEMI*. Antman, E. M. et al. JAMA 2000;284:835-842

  4. Table 1. Baseline Characteristics Analyzed for Development of TIMI Risk Score for UA/NSTEMI*. Risk factors included family history of CAD, hypertension, hypercholesterolemia, diabetes, or being a current smoker Antman, E. M. et al. JAMA 2000;284:835-842

  5. Niacin (B3) • Coenzyme in lipid metabolism, tissue respiration, and glycogenolysis • Inhibits VLDL and LDL synthesis, altering lipid balance and therefore: • Effective at increasing HDL levels

  6. Niacin (B3) • Starting dose ~250mg, titrated up to 1-3G/day • Maximum dose 6G per day (or 4.5G/day) • Major Side Effect: Flushing / Pruritus • Also noted to cause severe hepatotoxicity • Have caution with Statins • Rare but severe rhabdomyolysis

  7. AIM HIGH TRIAL • Niacin Plus Statin to Prevent Vascular Events • 9/2005 – 9/2012 • National Heart, Lung, and Blood Institute (NIH) • With support of Abbott and Merck

  8. AIM HIGH: Primary Endpoints • Randomized, Double Blinded throughout • Composite of CHD Death, Nonfatal MI, Ischemic Stroke, Hospitalization for NSTEMI, or symptom-driven coronary or cerebral revascularization

  9. AIM HIGH: Secondary Endpoints • Composite of CHD Death, non-fatal MI, high-risk ACS, or ischemic stroke • Cardiovascular mortality

  10. AIM HIGH: Inclusion • Age > 45 • Vascular Disease • Documented CAD • Documented cerebrovascular or carotid disease • Documented PAD • Dyslipidemia • LDL less than 160 • Male HDL less than 40, Female HDL less than 50 • 150 < Total < 400

  11. AIM HIGH: Exclusion • CABG within 1 year • PCI within 4 weeks • Hospitalized with ACS within 4 weeks • Fasting Glucose > 180 or A1C > 9% • Non-compliant Diabetes monitoring • Use of certain P450 3A4 metabolizers

  12. AIM HIGH: Enrollment • 3,414 patients enrolled, followed over 32 months • Average age 64 years old • 92% with CAD • 81% with Metabolic Syndrome • 71% with HTN • 34% with Diabetes Mellitus • > 50% with prior MI

  13. AIM HIGH: Lead-In • During lead-in, patients were started on Simvastatin to achieve 40 < LDL < 80 • Simvastatin was dose-adjusted to max dose as needed to achieve LDL • If goal not reached, Ezetimibe 10mg qDay • Not declared what happened to patients who still did not reach goal levels

  14. AIM HIGH: Randomized • 1718 patients then received Niacin ER (Niaspan) 2000mg/day • (if Niacin not tolerated, reduced to 1500mg/day) • If still not tolerated, discontinued • 1696 patient received a placebo

  15. AIM HIGH: 32 month look in • No difference in primary end-point • “Significant increase in HDL” • These numbers have not yet been released • Niacin patients with small increase in strokes • 28 (1.6%) vs 12 (0.7%) • Of these, 9 stopped Niacin up to 4 yrs earlier

  16. AIM HIGH: Predecessors • The ACCORD Trial • Fenofibrate increased HDL and decreased Triglycerides, but no effect on cardiovascular events • The ILLUMINATE Trial • Pfizer drug Torcetrapib

  17. ILLUMINATE: Set up • 15,067 pts with CHD or DM 2 • Avg age 61 • Primary endpoint: composite of CHD death, non-fatal MI, stroke, hospitalization for ACS

  18. ILLUMINATE: Lead In • Lead-in: 10 weeks to achieve LDL < 100 • 10 weeks of lifestyle modification • Adjunct dose-adjusted Atorvastatin • Those that achieved target were randomized to Torcetrapib 60mg vs Placebo

  19. ILLUMINATE: 12 month look in • THE GOOD • 72.1% increase in HDL (p<0.001) • 24.9% decrease in LDL (p<0.001) • 9% decrease in Triglycerides (p<0.001)

  20. ILLUMINATE: 12 month look in • THE BAD • Increased All-Cause Mortality (p=0.006) • Increased Primary Endpoint Events • 464 events in Torcetrapib group • 373 events in statin only group • P = 0.001

  21. ILLUMINATE: Unintended Effects • Systolic Blood Pressure was significantly higher in the treatment group • 5.4mmHg v 0.9mmHg; p<0.001 • Deaths secondary to infection were significantly higher in the treatment group • 9 vs 0

  22. What have we learned? • Cardiac markers determined by studies of correlation, not necessarily causality • No signaling pathways are fully understood • Likely that the majority of signaling molecules are yet to be characterized • Medications often go to phase III with limited harm data • Medications should be used when needed, but limit their use beyond proven benefit

  23. Resources • http://jama.ama-assn.org/content/284/7/835.full • Clinical Trials Registry NCT00120289 • NIH.gov: AIM HIGH Stopped Early • The Failure of Torcetrapib: The Search for the Reason Why: ILLUMINATE: Study Results

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