1. Dyslipidemia: Managing a Key Cardiovascular Risk Factor AIMGP Clinic Seminar Updated by R. Cavalcanti Sep 2007

2. Outline Current Practice Guidelines Current Practice Guidelines Cases Cases Global Risk Assessment Global Risk Assessment Whom to Screen for Dyslipidemia? Whom to Screen for Dyslipidemia? Risk Categories & Lipid Targets Risk Categories & Lipid Targets Factors Influencing Risk Assessment Factors Influencing Risk Assessment Selected Studies Selected Studies Management Management Cases Revisited Cases Revisited

3. Current Practice Guidelines Canadian Guidelines Canadian Guidelines –“Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: summary of the 2003 update” CMAJ 169(9):921-4, 28 Oct 2003 –www.cmaj.ca/cgi/content/full/169/9/921/DC1 www.cmaj.ca/cgi/content/full/169/9/921/DC1 –CCS Position Statement on Dx and Rx dyslipidemia. Canadian Journal of Cardiology 2006;22(11):913-927

4. Current Practice Guidelines American Guidelines American Guidelines –“Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines” »Circulation 110:227-39, 13 July 2004 –“Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)” »JAMA 285(19):2486-97, 16 May 2001

5. Case 1 56 M 56 M –Acute MI 4 months ago –No current cardiovascular symptoms –Tested for DM post-MI »Negative –Non-smoker, no HTN Lipids measured while in hospital post-MI: Lipids measured while in hospital post-MI: –TC 4.2, LDL 2.5, HDL 1.3, TG normal (TC/HDL 3.2) What is his estimated risk of a cardiovascular event in the next 10 years? What is his estimated risk of a cardiovascular event in the next 10 years? How should you manage his lipids? How should you manage his lipids?

6. Case 2 45 F 45 F –‘Healthy’, BP 125/80 –Non-smoker, EtOH: 3 standard drinks/week –No cardiovascular symptoms Lipids measured at annual visit: Lipids measured at annual visit: –TC 6.5, LDL 4.1, HDL 1.4, TG normal (TC/HDL 4.6) What is her estimated risk of a cardiovascular event in the next 10 years? What is her estimated risk of a cardiovascular event in the next 10 years? How should you manage her lipids? How should you manage her lipids?

7. Case 3 55 F 55 F –DM Type 2 x 10 years (HbA1c 9.7%), HTN –post menopausal, BMI 33 –Non-smoker, EtOH: 4 standard drinks/day –No cardiovascular symptoms Lipids measured at annual visit: Lipids measured at annual visit: –TC 5.9, HDL 0.78, TG 9.8 (TC/HDL 7.6) What is her estimated risk of a cardiovascular event in the next 10 years? What is her estimated risk of a cardiovascular event in the next 10 years? How should you manage her lipids? How should you manage her lipids?

8. Current Challenges in Cardiovascular Risk Reduction Aging Population Aging Population –>20% Canadians will be >65 years old by 2011 –1,900,000 Canadians >80 years old by 2026 Obesity Obesity –31% of Canadians are obese –Especially if abdominal adiposity, associated with increased prevalence of metabolic syndrome features (DM, HTN, ↑TGs, ↓HDL, insulin resistance) –Associated with ↑inflammatory markers (CRP, IL-6) Diabetes Diabetes –60,000 new cases per year in Canada –3,000,000 Canadians with DM by 2010

9. Global Risk Assessment Hyperlipidemia is an important risk factor, and should be used to assess overall cardio- vascular risk Hyperlipidemia is an important risk factor, and should be used to assess overall cardio- vascular risk Global CV risk should be used to assess treatment goals and modalities Global CV risk should be used to assess treatment goals and modalities Cardiac endpoints: Cardiac endpoints: –non-fatal MI –death due to CAD

10. Global Risk Assessment Risk assessment model adapted from the Framingham Heart Study Risk assessment model adapted from the Framingham Heart Study This model only applies in: This model only applies in: –Patients without diabetes –Patients without clinically evident cardiovascular disease (prior CAD, ischemic stroke, PAD) or CRF

11. Global Risk Assessment Which patients are automatically considered high risk (>20% 10-year risk)? Which patients are automatically considered high risk (>20% 10-year risk)? All adult patients with: All adult patients with: –DM –History of CAD –Ischemic stroke –Peripheral arterial disease –CRF ( < 60 ml/min of GFR)

12. Global Risk Assessment What are the risk factors in Framingham risk calculator? What are the risk factors in Framingham risk calculator? –Age –Gender –Smoking history –Lipid profile (TC, HDL) –Systolic BP

13. If the calculated 10-year risk is: ≥20% - ‘High Risk’ 11-19% - ‘Moderate Risk’ ≤10% - ‘Low Risk’

14. Whom to Screen for Dyslipidemia? Influenced by cardiac risk factors: By age alone (Canadian Guidelines): By age alone (Canadian Guidelines): –Men over age 40 –Women over age 50 (or post-menopausal) Adults at any age if: Adults at any age if: –At least 2 risk factors »DM, HTN, Smoking, Abdominal Obesity »Family history of early cardiovascular disease –Physical signs of hyperlipidemia »Xanthomata, xanthelasmas, arcus corneae, etc –Evidence of existing atherosclerosis

15. Manifestations of Dyslipidemia ↑TGs Eruptive xanthomata on the forearm of a patient with severe ↑TGs ↑LDL (the patient at the bottom has heterozygous familial hyperchol- esterolemia) Xanthelasmas and tendon xanthomata in patients with severe ↑LDL (the patient at the bottom has heterozygous familial hyperchol- esterolemia)

16. Diagnosis of Asymptomatic Atherosclerosis To aid in risk stratification To aid in risk stratification Recommended: Recommended: –Physical examination –Ankle-Brachial Index Possibly useful in patients already known to be at ‘moderate risk’: Possibly useful in patients already known to be at ‘moderate risk’: –Carotid ultrasonography –EKG –Exercise stress testing in men >40 years old with established cardiovascular risk factors

17. Risk Categories & Lipid Targets More about LDL targets to come later – for high-risk patients, these are minimum targets – they should be lower if at all possible

18. Lipid Targets: Triglycerides No discrete triglyceride goal in each category, but the optimal level is TG <1.7 No discrete triglyceride goal in each category, but the optimal level is TG <1.7 TG >10 requires targeted treatment to prevent pancreatitis independent of cardiovascular risk TG >10 requires targeted treatment to prevent pancreatitis independent of cardiovascular risk –diet & lifestyle changes –fibrate or niacin, fish oil

19. Factors Influencing Risk Assessment Metabolic Syndrome Metabolic Syndrome Abdominal Obesity Abdominal Obesity Apolipoprotein B (apoB) Apolipoprotein B (apoB) Lipoprotein(a) Lipoprotein(a) Homocysteine Homocysteine C-Reactive Protein (CRP) C-Reactive Protein (CRP) Genetic Risk Genetic Risk

20. Factors Influencing Risk Assessment Presence of the Metabolic Syndrome: ↑ Risk Presence of the Metabolic Syndrome: ↑ Risk –A clustering of cardiovascular risk factors, including abdominal obesity, insulin resistance, and hypertension, as well as lipid abnormalities (↑TGs and ↓HDL) Presence of Abdominal Obesity: ↑ Risk Presence of Abdominal Obesity: ↑ Risk –with waist circumference as a useful estimate

21. Factors Influencing Risk Assessment Apolipoprotein B (apoB) Apolipoprotein B (apoB) –↑ApoB (for the same lipid levels) = smaller, denser, more atherogenic LDL particles –ApoB levels correlate better than LDL levels to clinical outcomes in statin trials –For ‘high risk’ patients, target apoB <0.9g/L Lipoprotein(a) (lp(a)) Lipoprotein(a) (lp(a)) –Appears to be an independent risk factor for premature atherosclerosis and CAD

22. Factors Influencing Risk Assessment Homocysteine Homocysteine –↑homocysteine levels predict adverse outcomes in patients with CAD –Fixed-dose folate & B12 supplementation trials so far have been negative –No evidence yet to screen for homocysteine

23. Factors Influencing Risk Assessment C-Reactive Protein (CRP) C-Reactive Protein (CRP) –↑CRP may add prognostic information to Framingham –↑CRP associated with abdominal obesity and the metabolic syndrome –May be useful in persons with a calculated 10- year risk of 11-19% (‘moderate risk’) »More aggressive Rx?

24. Factors Influencing Risk Assessment C-Reactive Protein (CRP) C-Reactive Protein (CRP) –Do not measure during acute illness or in patients with chronic inflammatory disease –Measure 2x, two weeks apart, use the lower value –Low risk <1 mg/ml & high risk 3-10mg/ml –If >10mg/ml, look for infection/inflammation

25. Factors Influencing Risk Assessment Genetic Risk Genetic Risk –A confirmed, unambiguous family history of early onset CAD increases the risk for first-degree relatives (parents, siblings, children) »RRI 1.7-2.0 –Early onset is defined as <55 years old for men and <65 years old for women (this is the age of the index relative who had the cardiac event)

26. Selected Major Studies There are many, many, many trials of statins There are many, many, many trials of statins We will discuss: We will discuss: –MRC/HPS- largest trial of 2a. prevention (+ 1a. prevention in high risk pt) –ASCOT-LLA- largest trial of 1a. Prevention –INTERHEART: largest study of risk factors

27. Selected Major Trials MRC/BHF Heart Protection Study: MRC/BHF Heart Protection Study: –20,556 men & women aged 40-80 with TC >3.5 –All at ‘high risk’ of CAD »Known CAD/MI/PVD/CVS »DM, HTN, or both –RCT: Simvastatin 40mg vs. placebo –Decreased death rate by 13% at 5 years »Decreased combined cardiovascular end points by 24% »Benefits in all subgroups, including baseline LDL <2.6 –Very compelling, well done trial Lancet 360(9326):7-22, 6 July 2002

28. Selected Major Trials Anglo-Scandinavian Cardiac Outcomes Trial Anglo-Scandinavian Cardiac Outcomes Trial –9000 patients aged 40-79 with baseline TC <6.5 –All hypertensive »Had at least 3 risk factors for CAD »No pre-existing coronary disease –RCT: Atorvastatin 10mg vs. placebo for 5 years »↓ MI by 36% »↓ stroke rate by 27% »↓ all cardiovascular events and procedures by 21% »↓ total coronary events by 29% –Study was stopped after 3 years because of significant benefit in the treatment group Lancet 361(9364):1149-58, 5 April 2003

29. Selected Major Studies The INTERHEART study The INTERHEART study –Potentially modifiable risk factors associated with MI in 52 countries: –Case Control: 15,152 cases & 14,820 controls in 52 countries on every inhabited continent –Findings consistent between old/young, male/female, different countries –9 risk factors accounted for »>90% of the risk (in men) » >94% of the risk (in women) Lancet 364(9437):4999-5014, 4 Sept 2004

30. The INTERHEART study Increase risk Increase risk –↑ApoB/ApoA1 ratio »OR 3.25 –Smoking (current vs. never) »OR 2.87 –Psychosocial factors »OR 2.67 –DM »OR 2.37 –History of HTN »OR 1.91 –Abdominal Obesity »OR 1.12 1 st vs. 3 nd tertile »OR 1.62 2 nd vs. 3 rd tertile Protective: –eating fruits & vegetables daily »OR 0.70 –≥3 units/week of alcohol »OR 0.91 –moderate/strenuous physical activity »OR 0.86

31. Treatment

32. Treatment

33. Treatment In low or moderate risk patients In low or moderate risk patients –Start with lifestyle, progress to Rx based on targets In ‘high risk’ patients: In ‘high risk’ patients: –Start drug treatment immediately (statin), concurrently with diet and lifestyle modification –Priority is to get LDL <2.5 and TC/HDL <4 –If can’t reach LDL <2.5: »Cholesterol absorption inhibitors (ezetimibe) better tolerated »Bile acid sequestrants (cholestyramine, colestipol) »Either can decrease LDL by another 10-20% compared with statin alone »Limited evidence for CV benefit

34. 2004 ATP III Update

35. Lower LDL Targets In high risk patients mounting evidence supports lower LDL-C targets In high risk patients mounting evidence supports lower LDL-C targets Latest CCS guidelines (CJC 2006): Latest CCS guidelines (CJC 2006): –High risk patients: LDL-C < 2.0; TC:HDL <4.0 Revision NCEP (Circulation 2004): Revision NCEP (Circulation 2004): –Suggested targets for high risk patients –LDL-C <1.8

36. Treatment If TC/HDL ratio is still high: If TC/HDL ratio is still high: –Lifestyle modification –Increasing Statin Dose (with LDL at target) –Combination Drug Therapy

37. Treatment Lifestyle modification: Lifestyle modification: –For ↑TGs: »weight loss »restriction of refined carbohydrates »no alcohol, increased exercise –For ↓HDL: »weight loss »increased monounsaturated fats »moderate alcohol (if TGs normal) »increased aerobic exercise

38. Treatment Increasing Statin Dose (with LDL at target): Increasing Statin Dose (with LDL at target): –For ↓HDL and/or mild ↑TGs (TGs <5), may achieve target TC/HDL ratio by increasing the statin dose even if the target LDL has been reached

39. Treatment Combination Drug Therapy (Limited if any evidence) : Combination Drug Therapy (Limited if any evidence) : –Moderate ↑TGs -> add salmon oil (1-3g tid) to statin –↓HDL -> combine statin with niacin. –Caution: »1) niacin can cause increased insulin resistance »2) niacin-statin combination increases risk of hepatotoxicity –If intolerant to niacin: »consider statin-fibrate combination (simvastatin or pravastatin with fenofibrate, NOT gemfibrozil) (simvastatin or pravastatin with fenofibrate, NOT gemfibrozil) »lowest possible doses of each »very close follow-up watching for hepatotoxicity and myositis »if no CRF

40. Treatment If ↑TGs: If ↑TGs: –Ideal target <1.7 »1 st line: lifestyle modification »Treatments aimed at lowering the TC/HDL ratio usually also help lower TGs –If TGs >6 despite lifestyle changes, need drug treatment even if the TC/HDL ratio is acceptable »Treatment is needed to avoid pancreatitis »Options: Fibrate Fibrate Niacin Niacin Salmon oil Salmon oil

41. Follow-Up Which blood work should be ordered in follow-up? How frequently?

42. Follow-Up Lipids: Lipids: –6 weeks after start / change of dose (levels reach steady state within 6 weeks of start/change of medication) –Long-term follow-up every 6-12 months AST / ALT (0.5 –3% incidence): AST / ALT (0.5 –3% incidence): –Get baseline –Use with caution if AST/ALT > 3 x normal –At 12 weeks after initiation or change in dose (FDA) CK (< 0.5% incidence): CK (< 0.5% incidence): –Get baseline –Check only if symptomatic with myalgias (ATP III guideline)

43. Case 1 Revisited 56 M 56 M –Acute MI 4 months ago –No current cardiovascular symptoms –Tested for DM post-MI »Negative –Non-smoker, no HTN Lipids measured while in hospital post-MI: Lipids measured while in hospital post-MI: –TC 4.2, LDL 2.5, HDL 1.3, TG normal (TC/HDL 3.2) What is his estimated risk of a cardiovascular event in the next 10 years? What is his estimated risk of a cardiovascular event in the next 10 years? –Assumed to be ≥20% How should you manage his lipids? How should you manage his lipids?

44. Case 2 Revisited 45 F 45 F –‘Healthy’, BP 125/80 –Non-smoker, 3 units EtOH/week –No cardiovascular symptoms Lipids measured at annual visit: Lipids measured at annual visit: –TC 6.5, LDL 4.1, HDL 1.4, TG normal (TC/HDL 4.6) What is her estimated risk of a cardiovascular event in the next 10 years? What is her estimated risk of a cardiovascular event in the next 10 years? –Calculated to be 1% How should you manage her lipids? How should you manage her lipids?

45. Case 3 Revisited 55 F 55 F –DM Type 2 x 10 years (HbA1c 9.7%), HTN –post menopausal, BMI 33 –Non-smoker, 4 units EtOH/day –No cardiovascular symptoms Lipids measured at annual visit: Lipids measured at annual visit: –TC 5.9, HDL 0.78, TG 9.8 (TC/HDL 7.6) What is her estimated risk of a cardiovascular event in the next 10 years? What is her estimated risk of a cardiovascular event in the next 10 years? –Assumed to be ≥20% How should you manage her lipids? How should you manage her lipids?