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“S3-13: Lipids: Looking Forward to 2018” Hegele@Robarts.Ca “S3-13: Lipids: Looking forward to 2018” Heart and Stroke Clinical Update 1010-1140 9 Dec 2017 Robert Hegele MD, FRCPC, FACP Distinguished University Professor Endocrinologist, University Hospital Western University, London ON [email protected] Faculty/Presenter Disclosure • Faculty: Rob Hegele • Relationships with commercial interests: – Grants/Research Support: Amgen, ISIS, Pfizer, Lilly, Aegerion – Speakers Bureau/Honoraria: Valeant, Amgen, Aegerion. – Consulting Fees: Amgen, Sanofi, Valeant, Aegerion, Lilly – Other: N/A Question 1 1. What is the current Canadian lipid target for high-risk patients? A) LDL-C < 2.0 mmol/L B) non-HDL-C < 2.6 mmol/L C) apo B < 0.8 g/L D) all of the above 3 Question 2 2. What is the main mechanism of statin benefit? A) LDL-C reduction B) anti-inflammatory C) anti-thrombotic D) endothelial relaxation E) all of the above 4 Question 3 3. What is/are the current indication(s) for PCSK9 inhibition in Canada? A) familial hypercholesterolemia B) atherosclerotic cardiovascular disease, not controlled C) statin intolerance D) A and B only E) A, B and C 5 Objectives 1. To review current Canadian Lipid Guidelines 2. To appreciate the role of established treatments 3. To evaluate the potential of recently approved lipid treatments 7 Issues in the 2016 guidelines • keep LDL-C targets < 2.0 mmol/L • lower is better • non-fasting lipids to screen • non-HDL-C and apo B are alternate targets • Framingham or cardiovascular age • statins remain foundational Rx • non-statins: ezetimibe OK; niacin, fibrates less so • PCSK9-inhibitors Anderson et al. Can J Cardiol 2016; 32:1263-1282. 2016 Lipid Guidelines Anderson et al. Can J Cardiol 2016; 32:1263-1282. 2012 CCS Dyslipidemia Guidelines Update Table 7. Expected Benefit of Health Behaviour Changes Intervention (minimal dose for effect) Expected Outcome Dietary cholesterol intake98 ↓ LDL-C < 300 mg/day (NCEP step I diet) 10-12% < 200 mg/day (NCEP step II diet) 12-16% Saturated fats < 7% of daily caloric intake107 ↓ LDL-C 5-10%; ↓ CVD mortality 14% Phytosterols 1-2 g/day100 ↓ LDL-C 5-8% Soy proteins with isoflavones 25g/day101 ↓ LDL-C 3-5% Viscous fibre 10 g/day102 ↓ LDL-C 3-5% Nuts 30-67 g/day103 ↓ LDL-C 5-7%, ↓ TG 5-10% Portfolio type diet104 ↓ LDL-C 8-14% Mediterranean type diet105 ↓ LDL-C 5-10%; ↓ CVD mortality DASH (Dietary Approaches to Stop ↓ CVD mortality in those with hypertension 106 Hypertension) diet Anderson TJ, Gregoire J et al., Can J Cardiol 2013 Feb;29(2): 151-167 14/12/2017 Copyright © 2013, Canadian Cardiovascular Society 10 2012 CCS Dyslipidemia Guidelines Update Table 7. Expected Benefit of Health Behaviour Changes Intervention (minimal dose effect) Expected Outcome Moderated Alcohol intake 1-2 drinks/day ↑ HDL 5-10%, ↓ CVD events Weight loss and reduction of abdominal obesity42 ↓ LDL-C, ↑ HDL, ↓ TG, 5-10% of body weight loss ↓cardiometabolic risk Omega -3 - 2-4 g of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA)/day ↓ TG 25-30% in pts. with ↑ TG Exercise109,110 30-60 min/day moderate to vigorous intensity ↑ HDL 5-10%, ↓ CVD events Smoking cessation ↑ HDL, ↓ CVD events Anderson TJ, Gregoire J et al., Can J Cardiol 2013 Feb;29(2): 151-167 14/12/2017 Copyright © 2013, Canadian Cardiovascular Society 11 2016 Lipid Guidelines Treatment Targets: Statin Indicated Conditions • LDL-C consistently <2.0 mmol/L or (those who will benefit the most): >50% reduction • Clinical atherosclerosis* • Consider <1.8 mmol/L in patients with • Abdominal aortic aneurysm clinical atherosclerosis • Most diabetes mellitus • Apo B ≤0.80 g/L or non-HDL-C ≤2.6 • CKD (age >50 years) mmol/L be considered as alternative • LDL-C ≥5.0 mmol/L treatment targets *Clinical atherosclerosis, i.e. previous MI, or coronary revascularization by PCI or CABG surgery, other arterial revascularization procedures, angina pectoris, cerebrovascular disease including TIA, or peripheral arterial disease (claudication and/or ABI <0.9) . Anderson et al. Can J Cardiol 2016; 32:1263-1282. Non-fasting lipids Langsted et al. Circulation 2008;118:2047-2056 13 Non-HDL-C as an alternate target non-HDL-C = TC – HDL-C 14/12/2017 14 Here's your personalized Heart & Stroke Risk Assessment. Having trouble viewingRisk our email? View it online . assessment Your Personalized Risk http://www.heartage.me/ Assessment Report https://ehealth.heartandstroke.ca/ Your life expectancy* is: *Based on specific lifestyle risk factors. Read more. years 88 0 100 A Canadian male your age lives an average of 82 years. Your life expectancy is higher than other people of your age group and gender. You can still make positive changes to improve your cardiac health and protect what matters. The Heart and Stroke Foundation is here to support you and your family, every step of the way. Risk factors you cannot control Non-controllable risk factors for heart disease and stroke include your age, gender, ethnicity and family history. While our researchers find ways to stop heart disease and stroke before they happen, we've uncovered realistic ways so you can minimize your risks. FAMILY HISTORY See how your family history is affecting your life today, and how to take action with powerful steps that help break the cycle of heart disease and stroke. READ MORE Anderson et al. Can J Cardiol 2016; 32:1263-1282. Reduced all-cause mortality with statins LDL 4.4 mmol/L LDL-C 3.1 mmol/L 4S Investigators Lancet 2004; 364:771-7. Reduced all-cause mortality with statins HR 0.80 (0.67 to 0.97, P=0.02) LDL-C 2.8 LDLmmol/L-C 1.8 mmol/L 20 mg N Engl J Med 2008; 359: 2195-207 HOPE-3 LDL-C 3.2 mmol/L LDL-C 2.4 mmol/L 10 mg N Engl J Med 2016; 374:2021-31 Reduced all-cause mortality with statins Collins et al. Lancet. 2016 Sep 8. pii: S0140-6736(16)31357 Reduced major vascular events with statins CTTC 2016; 25 RCTs of statins; >170,000 patients Lancet 2016 Sep 8; doi 10.1016/S0140-6737(16)31357-5. LDL-C and CHD risk Benefits vs risks of lowering LDL-C with statins 10,000 patients receiving effective statin therapy for 5 years and lowered LDL-C by 2 mmol/L would result in: Major Rhabdomyolysis vascular Muscle Myopathy New- (if statin not Haemorrhagic events pain or (symptoms + onset stopped upon stroke weakness CK > 10xULN) diabetes prevented myopathy) 1,000 50-100 ~ 5 ~ 1 ~ 50 ~ 5 (secondary prevention patients) Based on CTT Collaboration meta-analyses of RCTs. Includes 22 trials (135,000 patients) comparing routine statin therapy to no routine statin therapy and 5 trials (40,000 patients) comparing more versus less intensive statin therapy. Collins R et al (2016) Lancet pii: S0140-6736(16)31357-5. doi: 10.1016/S0140-6736(16)31357-5. [Epub ahead of print] Cholesterol Treatment Trialists’ Collaboration (2016) https://www.cttcollaboration.org/ CLINICAL ATHEROSCLEROSIS Myocardial infarction, acute coronary syndromes Stable angina, documented coronary disease by angiography (>10% stenosis) Stroke, TIA, documented carotid disease Peripheral artery disease, claudication and/or ABI <0.9 ABDOMINAL AORTIC ANEURYSM Abdominal aorta >3.0 cm or Statin Previous aneurysm surgery DIABETES MELLITUS indicated ≥40 years of age or >15 years duration and age ≥30 years or conditions Microvascular complications CHRONIC KIDNEY DISEASE >3 months duration and ACR >3.0 mg/mmol or eGFR <60 ml/min/1.73m2 LDL-C ≥5.0 MMOL/L LDL-C ≥5.0 mmol/L or Documented familial hypercholesterolemia Excluded 2nd causes Canadian Journal of Cardiology DOI: (10.1016/j.cjca.2016.07.510) Anderson et al. Can J Cardiol 2016; 32:1263-1282. Statin doses and efficacy Am J Cardiol 2003; 92:152-60. Statin discontinuation = reduced survival • Side effects are the most common reason patients discontinue statins 1 • Survival is reduced in patients who discontinue, even compared to those on non-daily statin doses 2 Statin continued/daily dose Survival (%) Survival Statin continued/non-daily dose Statin discontinued Years 1. Cohen et al. J Clin Lipidol 2012;6:208–215. 2. Mampuya et al. Am Heart J 2013;166:597–603. Statin intolerance 1) statins not withheld on the basis of a potential, small risk of new-onset DM (Strong/Very Low). 2) evaluate purported statin-associated symptoms systematically, observe during cessation, re- initiation (same or switch), altered dosing frequency to find a tolerated, statin-based therapy. (Strong/Very Low). 3) we do not recommend vitamins, minerals or supplements for symptoms of myalgia perceived to be statin-associated. (Strong/Very Low). Approach to the statin intolerant patient 1. Rechallenge with another statin - better tolerated: fluva, prava 2. Alternating day statin - most efficacious: rosuva 3. Use a different lipid-lowering class - CAI: ezetimibe - resin: cholestyramine, colesevalam - fibrate? 4. Coenzyme Q10: 60 – 120 mg daily 5. Vitamin D (1000 IU daily) Joy TR, Hegele RA. Ann Intern Med 2009; 150:85827-68 Think twice about statins limited life expectancy limited QOL elderly/frail low CV risk end-stage renal disease end-stage CHF polypharmacy 28 Statins: summary - proven, evidence-based, life-saving - 30+ years real-world experience - first line Rx to reach targets - 5 statin-eligible conditions + intermediate risk - benefits >>> risks in properly selected patients - encourage compliance 29 IMPROVE-IT: Primary Endpoint Intention-To-Treat Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization (≥30 days), or stroke Hazard Ratio, 0.936 Simvastatin: 34.7% - 2742 events (95% CI, 0.89-0.99) Mean LDL-C = 1.8 mmol/L p=0.016 NNT*= 50 Simvastatin/Ezetimibe: 32.7% - 2572 events Mean LDL-C = 1.4 mmol/L Event Rate (%) Rate Event 7-year event rates * NNT = Number Needed to Treat Time since randomization (years) Cannon CP et al, N Engl J Med 2015;372:2387-2397.
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