Dyslipidemia: Managing a Key Cardiovascular Risk Factor AIMGP Clinic Seminar Updated by R. Cavalcanti Sep 2006

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 Recent Trials Selected Recent Trials Management Management Cases Revisited Cases Revisited

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 –Full text of 2003 update is only online, at: –“Recommendations for the management and treatment of dyslipidemia” CMAJ 162(10):1441-7, 16 May 2000

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 –“Executive Summary of the 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): , 16 May 2001

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?

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?

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?

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

Global Risk Assessment Since hyperlipidemia is important as a risk factor, it should be used to assess overall cardiac risk, and that risk should in turn be used to assess treatment goals and modalities Since hyperlipidemia is important as a risk factor, it should be used to assess overall cardiac risk, and that risk should in turn be used to assess treatment goals and modalities Cardiac endpoints? Cardiac endpoints? –non-fatal MI –death due to CAD

Global Risk Assessment Risk assessment model adapted from the Framingham Heart Study Risk assessment model adapted from the Framingham Heart Study This model is only: This model is only: –For non-diabetic patients –For patients without clinically evident cardiovascular disease (including prior CAD, ischemic stroke, and/or peripheral arterial disease) or CRF

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: »DM »History of CAD »Ischemic stroke »Peripheral arterial disease »CRF

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

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

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

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)

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

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

Lipid Targets: Triglycerides There is no longer a discrete triglyceride goal in each category, but the optimal level is set at TG <1.7 There is no longer a discrete triglyceride goal in each category, but the optimal level is set at TG <1.7 If TG >10 it needs targeted treatment (diet & lifestyle changes, fibrate or niacin, fish oil) to prevent pancreatitis independent of cardiovascular risk If TG >10 it needs targeted treatment (diet & lifestyle changes, fibrate or niacin, fish oil) to prevent pancreatitis independent of cardiovascular risk

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 Hormone Replacement Therapy (HRT) Hormone Replacement Therapy (HRT)

Factors Influencing Risk Assessment Presence of the Metabolic Syndrome Presence of the Metabolic Syndrome –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 Presence of Abdominal Obesity –with waist circumference as a useful estimate

Factors Influencing Risk Assessment Apolipoprotein B (apoB) Apolipoprotein B (apoB) –There is 1 molecule of apoB in each atherogenic lipid particle (VLDL, IDL, LDL, lp(a))’ –↑apoB (for the same lipid levels) = smaller, denser, more atherogenic LDL particles –Better estimate than LDL of cardiovascular risk –ApoB levels correlate better than LDL levels to clinical outcomes in statin trials –For ‘high risk’ patients, target apoB <0.9g/L –Sample does not need to be fasting

Factors Influencing Risk Assessment Lipoprotein(a) (lp(a)) Lipoprotein(a) (lp(a)) –Appears to be an independent risk factor for premature atherosclerosis and CAD –Its atherogenicity seems to depend on the presence of other factors, and its utility as a risk factor seems to disappear if the LDL is markedly lowered –Monogenic and not responsive to diet –Lp(a) >30mg/dL in patients with TC/HDL ratio >5.5 or other major risk factors may indicate need for earlier and more intensive LDL-lowering therapy

Factors Influencing Risk Assessment Homocysteine Homocysteine –↑homocysteine levels predict adverse outcomes in patients with CAD –Fixed-dose folate & B12 trials looking at cardiovascular endpoints are ongoing –No ‘treat-to-target’ trial (to homocysteine <9μmol/L) –No evidence yet to screen for homocysteine

Factors Influencing Risk Assessment C-Reactive Protein (CRP) C-Reactive Protein (CRP) –↑CRP may add prognostic information to Framingham Study data –↑CRP associated with abdominal obesity and the metabolic syndrome –May be clinically useful in identifying people who are at higher risk than their Global Risk Assessment would indicate (especially for people with a calculated 10-year risk of 11-19%, so calculated to be at ‘moderate risk’)

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

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 –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)

Factors Influencing Risk Assessment Hormone Replacement Therapy (HRT): Hormone Replacement Therapy (HRT): –Should not be initiated for primary or secondary prevention of CAD –Unless otherwise necessary (e.g. for osteoporosis treatment or for severe menopausal symptoms) try to stop or taper HRT in women >55 years old who have been on it for >5 years –Consider stopping HRT in the setting of an acute cardiovascular event –Consider stopping HRT before an ACB, PCI, or other surgical procedure

Selected Major Trials MRC/BHF Heart Protection Study: MRC/BHF Heart Protection Study: –HPS: Lancet 360(9326):7-22, 6 July 2002 –20,556 men & women aged 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% »Decreased combined cardiovascular end points by 24% –Benefits in all subgroups, including baseline LDL <2.6 –Very compelling, well done trial –Ultimate LDL target still unclear, other studies now looking at LDL targets of <1.8

Selected Major Trials Anglo-Scandinavian Cardiac Outcomes Trial Anglo-Scandinavian Cardiac Outcomes Trial –ASCOT: Lancet 361(9364): , 5 April 2003 –9000 patients aged 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 »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

Selected Major Trials The INTERHEART study The INTERHEART study –Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries: Lancet 364(9437): , 4 Sept 2004 –Case Control: 15,152 cases & 14,820 controls in 52 countries on every inhabited continent –Findings consistent between old/young, male/female, different countries with different standards of living –9 risk factors accounted for >90% (in men) and >94% (in women) of the population attributable risk (PAR) of acute MI

Selected Major Trials The INTERHEART study: The INTERHEART study: –The 9 risk factors: »Smoking (OR 2.87 current vs. never, p<0.0001) »↑ApoB/ApoA1 ratio (OR st vs. 5 th quintile, p<0.0001) »History of HTN (OR 1.91, p<0.0001) »DM (OR 2.37, p<0.0001) »Abdominal Obesity (OR st vs. 3 nd tertile & OR nd vs. 3 rd tertile, p<0.0001) »psychosocial factors (OR 2.67, p<0.0001) »eating fruits & vegetables daily (OR 0.70, p<0.0001) »≥3 units/week of alcohol (OR 0.91, p=0.03) »moderate/strenuous physical activity (OR 0.86, p<0.0001)

Treatment

Treatment

Treatment In ‘high risk’ patients: In ‘high risk’ patients: –Start drug treatment immediately, concurrently with diet and lifestyle modification –Priority is to get LDL <2.5 and TC/HDL <4 –Given HPS data: »Treat with Simvastatin 40mg or equivalent statin »LDL target of 2.5 at most –If can’t reach LDL <2.5: »Bile acid sequestrants (cholestyramine, colestipol) »Cholesterol absorption inhibitors (ezetimibe) better tolerated »Either can decrease LDL by another 10-20% compared with statin alone

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

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

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

Treatment Combination Drug Therapy: Combination Drug Therapy: –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) »lowest possible doses of each »very close follow-up watching for hepatotoxicity and myositis »if no CRF

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

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

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 / CK: AST / ALT / CK: –Get baseline –Repeat whenever you test lipids: »6 weeks after a dose increase »Every 6-12 months –Check more frequently: »If on maximum doses »If on combination therapy (especially a statin plus a fibrate) –Check if symptomatic

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?

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?

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?