Comprehensive Lipid Update: ATP Guidelines, Therapies & Future Trends

1. Lipid Update 2009 Thomas Rhyne White MD Cherryville Primary Care Carolinas Health Care Cherryville, North Carolina Board Certified- Family Practice, Clinical Lipidology TRWhiteMD@mac.com

3. ??? LDL-C 177 LDL-C 68

4. “It is not good to settle into a set of opinions ...” Tsunemoto, 1716

5. “ ... man is most uniquely human when he turns obstacles into opportunities.”- Hoffer

6. “ ... man is most uniquely human when he turns obstacles into opportunities.”- Hoffer

7. “ ... man is most uniquely human when he turns obstacles into opportunities.”- Hoffer

8. “ ... man is most uniquely human when he turns obstacles into opportunities.”- Hoffer

9. “ ... man is most uniquely human when he turns obstacles into opportunities.”- Hoffer

10. “ ... man is most uniquely human when he turns obstacles into opportunities.”- Hoffer

11. What I plan to cover ATP-III 2001 ATP-III Update 2004 What’s new? Lifestyle,Goals,Therapy ATP-IV 2010: What can we expect?

12. ATP-III www.nhlbi.nih.gov/guidelines/cholesterol

13. ATP-IIIMajor Risk Factors: Modify LDL Goals • Cigarette smoking • Hypertension (BP >140/90 mmHg or on Rx) • Low HDL cholesterol (<40 mg/dL) • Family history of premature CHD • CHD in male first degree relative <55 yrs • CHD in female first degree relative <65 yrs • Age (men >45 years; women >55 years)

14. ATP-IIITherapeutic Lifestyle Changes • Major Features • TLC Diet • Reduced intake of cholesterol-raising nutrients • Saturated fats <7% of total calories • Dietary cholesterol <200 mg per day • LDL-lowering therapeutic options • Plant stanols/sterols (2 g per day) • Viscous (soluble) fiber (10–25 g per day) • Weight reduction • Increased physical activity

15. ATP-IIILDL Cholesterol Goals and Cutpoints

16. HDL-C 46 TG 52 LDL-C 177 mg/dl

17. ATP-III The Metabolic Syndrome • General Features of the Metabolic Syndrome • Abdominal obesity (>40♂ >35♀) • Atherogenic dyslipidemia • Elevated triglycerides (>150) • Small LDL particles • Low HDL cholesterol (<40♂ <50♀) • Raised blood pressure (>130/>85) • Elevated glucose (Fasting >100) • Increased CV risk: Prothrombotic, Proinflammatory 3+/5

18. Additional ATP-III Recommendations • If TG’s> 500 mg/dl, treat to prevent pancreatitis. • If TG’s 200-499, calculate “nonHDL-C.” (TC-HDL) Treat to LDL-C & nonHDL-C goal (LDL-C goal + 30). ie, if LDL-C goal <100, nonHDL-C goal is <130 • If HDL-C <40 mg/dl, treat LDL-C ( nonHDL-C) to goal. “ATP-III does not specify a goal for HDL-C raising.” Consider niacin or fibrate if CHD or equivalent.

19. Additional ATP-III Recommendations • “Some persons will require combination drug therapy to reach ATP-III treatment goals ...” • “Although it seems desirable ... major randomized controlled trials have not been carried out.” • “ ... several smaller trials and angiographic trials have provided evidence of positive benefit for combined therapy.”

20. Additional ATP-III Recommendations • hsCRP: Most reliable marker of inflammation. • Routine measurement not recommended. • If elevated, consider more aggressive LDL lowering. • Lp(a): Highly genetic, atherosclerotic LDL particle. • Contribution beyond major risk factors uncertain. • Measurement issues. (“normal” <70) • Resistant to lowering. • Subclinical vascular testing – CIMT, CCS • Not recommended for routine testing. • May be considered as adjunct in risk assessment.

21. ATP-III Update Circulation 2004; 110:227-239 5 Major Clinical Trials HPS Simvastatin and high risk patients. PROSPER Pravastatin for ages 70-82. ALLHAT Pravastatin and HTN. ASCOT-LLA Atorvastatin and multiple risk factors. PROVE-IT Intensive vs moderate for ACS pts.

22. ATP-III Update Circulation 2004; 110:227-239 • Diabetics confirmed as a high risk group. • Elderly benefit from LDL-C lowering. • Lowering LDL-C <70 optional for very hi risk pts. • Lowering LDL-C <100 optional if moderately hi risk. • If high or moderately hi risk, lower LDL-C 30-40%. • Consider adding fibrate or niacin to LDL lowering therapy if high risk and low HDL-C and elevated TGs.

23. ATP-IIILDL Cholesterol Goals and Cutpoints (optional goal <70 10-20% optional goal <100 < 10%

24. Limitations of ATP • Focus on short-term (10 year) risk. • Recommendations represent consensus opinion. • Effort to keep the bar “achievable.” • Underestimation of risk imparted by Met-syn. • Lag between updates. • Tends to foster complacency and inertia.

25. Anticipated: Spring 2010 ATP-IV JNC-8 Obesity Guidelines

26. What’s New ? Lifestyle really matters ... Lipid profiles are changing. New goals of therapy are emerging. Aggressive treatment can be effective. Drugs may offer unexpected benefits.

27. Lifestyle

28. The INTERHEART StudyYusef et al, The Lancet, 9/04What are the risk factors for one’s 1st MI? Adverse Factors Protective Factors Dyslipidemia Fruits / Vegetables Smoking Exercise Stress Alcohol Diabetes Hypertension Obesity 7 cigs/d or 21 hrs/week exposure doubles CV risk The Lancet 2006

29. The INTERHEART StudyYusef et al, The Lancet, 9/04What are the risk factors for one’s 1st MI? Adverse Factors Protective Factors Dyslipidemia Fruits / Vegetables Smoking Exercise Stress Alcohol Diabetes Hypertension Obesity 29 METABOLIC SYNDROME !!!

30. The INTERHEART StudyYusef et al, The Lancet, 9/04What are the risk factors for one’s 1st MI? Adverse Factors Protective Factors Dyslipidemia Fruits / Vegetables Smoking Exercise Stress Alcohol Diabetes Hypertension Obesity 30 “Western diet” contributing world-wide ... The Lancet, 2008

31. Vitamin D - Why the Hype? • Classically associated with bone health. • Exploding evidence concerning its ubiquitous role. • “Normal” 25-OH D level: 32-100 ng/ml • “Deficient”:<20 “Insufficient”:20-30 “Ideal”: 40-60 • 40-80% of US adults are deficient / insufficient.

32. Groups at High Risk for Vitamin D deficiency Latitude > 35 degrees DM / Met-syn “Health conscious” Chronic renal failure Sedentary African-Americans Obese Hispanics

33. Vitamin D and CV Disease Dobnig et al, Arch Int Med 2008; 168(12): 1340-1349 3528 pts referred for coronary angiography Followed for 7.7 years

34. Vitamin D deficiency has been associated with ... • Increase in all CV events(F’ham Offspring,Wang, Circ 08) • Increase in MIs (Health Profs F/U Study, Giovannuci, AIM 08) • Increase stroke risk (LURIC, Pitz, Stroke 08) • Increased blood pressure (Foreman, HTN 07) • Increased PVD by ABI (NHANES data, ATVB, 08) • Increased CIMT (Targhan, Clin Endo 06)

35. Vitamin D and CV Protection:What is the Link? • Current thinking: Vitamin D modulates Renin. Renin activation → D binds to VDR → ↓renin D def→↑ renin→↑ang II →↑BP + inflammation • D deficiency:↑’s CRP, IL-6, adhesion molecules, MMPs. • Treatment reduces BP, Insulin Resistance. (Holick,NEJM 7/07)

36. Statin Myalgia and D deficiency Duell and Conner, Oregon AHA 11/08, Abstract #3701 99 lipid clinic patients Myalgia pts: 20.5 vs 30.1 81% myalgia pts <30 vs 52% 33% statin-tolerant with D Ahmed et al, Cincinnati Trans Res, 1/09;153:11-16 621 lipid clinic patients Myalgia pts: 28.6 vs 34.2 64% myalgia pts <32 vs 43% 92% statin-tolerant with D

37. Goals of Therapy

38. Is LDL-C adequate? PROVE-IT TNT

39. The INTERHEART StudyYusef et al, The Lancet, 9/04What are the risk factors for one’s 1st MI? Adverse Factors Protective Factors Dyslipidemia Fruits / Vegetables Smoking Exercise Stress Alcohol Diabetes Hypertension Obesity 39 apoB / apoA1 outpredicts other lipid parameters ... The Lancet 2008

40. Total Chol = (LDL-C) + ( HDL-C) + (VLDL-C) LDL-C = Total Chol – (HDL-C) – (TG/5) apoB apoB 90%=LDL apoB apoA1

41. When met-syndrome/DM present (HDL-C <40, TG >130), apoB / LDL-P # will be ↑↑↑, even when LDL-C is <70..

42. HDL-C 35 TG 235 LDL-C 68 apoB / LDL-P# likely very high

43. “Is LDL-C Passed Its Prime?”Michael Davidson MD, ATVB 2008 35+ studies now support apoB or LDL-P as superior to LDL-C for risk prediction. Sniderman SELA August 2008 “As new national guidelines are proposed based on evolving clinicaltrial data, an expanded focus beyond LDL-C appears warranted.”

44. Concensus Statement from the ADA & ACC:Brunzell et al, Diabetes Care 31:4 April 2008 1. “ apoB ... should be used to guide ... therapy.” 2. “ LDL particle # ...equally informative as apoB.” 3. nonHDL-C superior to LDL-C Very hi risk: LDL-C<70 nonHDL-C<100 apoB<80 High risk: LDL-C<100 nonHDL-C<130apoB<90 (LDL-P<850 (LDL-P<1000

45. A Practical, “Doable” Approach • Calculate nonHDL-C (Total Chol - HDL). • Treat to <100 mg/dl for high risk pts. • More predictive than LDL at any TG level.

46. Recent Clinical Studies

47. Volume 356:1503-1516 April 12,2007 Number:15 • 2287 stable predominantly male CAD patients • Randomized to optimal medical therapy +/- PCI LDL-C 71 at 5 yrs; 93% on statin; 95% asa • Primary end point: Death + nonfatal MI • 19% PCI group vs 18.5% optimal medical therapy • No statistical difference observed. Optimal Medical Therapy with or without PCI for Stable Coronary Disease William E. Boden, M.D et al , for the COURAGE Trial Research Group

48. JUPITER (Justification for the Use of statins in primary Prevention: an Intervention Trial Evaluating Rosuvastatin) No CVD; ♂>50, ♀>60 LDL<130, hsCRP>2 Rosuva 20mg vs placebo Treatment: LDL-C to 54 Time to first occurrence of a CV death, stroke, MI, hospitalization for unstable angina or arterial revascularization 44% Ridker et al, NEJM 12/08

49. Ridker et al, The Lancet, April 4 2009 When LDL-C <70 and hsCRP <1, events reduced by 76%.

50. What does JUPITER teach us? • Consistent with previous studies ...1% LDL-C = 1% events • A “metabolic syndrome” study? • 42% met criteria for met-syn • HDL-C 49 (40-60) • TG 118 (85-169) • HTN common BMI 28.3 Ridker et al, Circulation 2003