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Hyperlipidemia 2014: New Guidelines, New Controversies

Hyperlipidemia 2014: New Guidelines, New Controversies. Patrick E. McBride, M.D., M.P.H. James H. Stein, M.D. Division of Cardiovascular Medicine Preventive Cardiology Program. Disclosures. McBride – no conflicts of interest. Outline. New lipid guidelines - McBride

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Hyperlipidemia 2014: New Guidelines, New Controversies

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  1. Hyperlipidemia 2014: New Guidelines, New Controversies Patrick E. McBride, M.D., M.P.H. James H. Stein, M.D. Division of Cardiovascular MedicinePreventive Cardiology Program

  2. Disclosures • McBride – no conflicts of interest

  3. Outline • New lipid guidelines - McBride • Overview of key points • Evidence/use of statins • CVD risk prediction • Myalgias • Misconceptions / misinterpretations

  4. Outline • Beyond the guidelines • Do HDL-C and TG matter? • When to use non-statin medications • The use of niacin!

  5. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults www.heart.org Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation, American Pharmacists Association, American Society for Preventive Cardiology, Association of Black Cardiologists, Preventive Cardiovascular Nurses Association, and Women Heart: The National Coalition for Women with Heart Disease

  6. New Guidelines Address 3 Critical Questions • What is the evidence for LDL-C levels and risk assessment for initiation of treatment? (who to treat) • Should we use LDL-C goals or targets for treatment? • What medications have evidence for use in the treatment of cholesterol? (include harm)

  7. Guideline Scope • Focus on treatment of blood cholesterol to reduce ASCVD risk in adults • Emphasize adherence to a heart healthy lifestyle - See lifestyle guidelines • Identify individuals most likely to benefit from cholesterol-lowering therapy: statin benefit groups • Identify safety issues

  8. “These guidelines are not a replacement for clinical judgment; they are meant to guide and inform decision-making.”

  9. Advances in the Guidelines • Focus is on treatment of LDL-C • Treatment is based on risk: not just on LDL-C • Risk assessment - evidence to support its use in identifying patients to treat • Treatment based on evidence and the intensity of treatment; no LDL targets

  10. New Perspective on LDL-C & non-HDL-C Goals • Lack of RCT evidence to support titration of drug therapy to specific LDL-C goals • Strong evidence that appropriate intensity of statin therapy should be used to reduce ASCVD risk in those most likely to benefit • Quantitative comparison of statin benefits with statin risk • Non-statin therapies: benefits/safety profiles not comparable to statins

  11. Why Not Continue to Treat to Target? Current RCT data do not indicate precise targets Unknown magnitude of additional ASCVD risk reduction with one target compared to another target Unknown rate of additional adverse effects from multidrug therapy used to achieve specific goals Unknown net benefit from treat-to-target approach

  12. No LDL Targets or Measurements? • No targets does not mean no measurements • Consider checking lipid panel to see if your therapy has put the patient in a reasonable range for risk • LDL-C <40 mg/dL is too low - lower statin dose • Consider adjusting therapy (lifestyle, other) if LDL-C not low enough for risk

  13. Primary Prevention: Global Risk Assessment • To estimate 10-year ASCVD risk • New Pooled Cohort Risk Equations • White and black, men and women • More accurately identifies higher risk individuals for statin therapy • Focuses statin therapy on those most likely to benefit • Consider not initiating statin therapy in high-risk groups not found to benefit from statins (advanced HF, hemodialysis)

  14. Statins Reduce CVD Risk • Cholesterol Treatment Trialists (CTT) Collaborators • Prospective meta-analysis of RCTs conducted from 1994 to 2009 • 129,526 subjects in 21 statin vs. control • 39,612 subjects in 5 more vs. less intensive • Median follow-up = 5.1 years Lancet 2010;376:1670

  15. CTT Collaborators • Improved CVD outcomes per 39 mg/dL reduction in LDL-C (all p<0.0001) • 10% reduction in all-cause mortality • 20% reduction in coronary mortality • 21% reduction in major CVD events • 26% reduction in MI or CHD death • 24% reduction in PCI/CABG • 15% reduction in stroke Lancet 2010;376:1670

  16. Primary Prevention: Statin Therapy • Thresholds for initiating statin therapy derived from RCTs • Before initiating statin therapy, engage in a discussion of the potential for ASCVD risk reduction benefits, potential for adverse effects, medication interactions, and patient preferences

  17. Statin Benefit Groups • Clinical ASCVD(includes stroke and PAD) • LDL-C ≥190 mg/dLw/out secondary cause • Primary prevention • Diabetes mellitus (DM) and 40-75 years old: LDL-C 70-189 mg/dL • Primary Prevention: No DM and age 40-75 years: LDL-C 70-189 mg/dL, if ASCVD risk ≥7.5% • Requires risk discussion – consider statin therapy after lifestyle trial

  18. Intensity of Statin Therapy • Use evidence-based therapy • High risk patients = high intensity Rx • 10 year ASCVD risk ≥7.5% (I, A) • Moderate risk = moderate intensity Rx • 10 year ASCVD risk ≥5%-7.5% (IIA, B) • Consider if LDL-C > 160 mg/dL, genetic dyslipidemia, family hx of premature heart disease, hsCRP> 2 mg/L, CAC >300 or 75th %tile, ABI ≤0.9, or high lifetime risk (IIB, C)

  19. Intensity of Statin Therapy *Individual responses to statin therapy varied in RCTs - expected to vary in clinical practice. ‡Simvastatin 80 mg was evaluated in RCTs but is not recommended by the FDA due to the risk of myopathy & rhabdomyolysis

  20. Safety • RCTs & meta-analyses used to identify important safety considerations • Allow estimation of net benefit from statins • Expert guidance on management of statin-associated adverse effects, including muscle symptoms • Advise use of additional information including pharmacists, manufacturers prescribing information, & drug information centers for complex cases

  21. Creatinine Kinase and ALT • Baseline/ongoing measures of CK and ALT not needed • Consider if underlying muscle or liver disease or patient at increased risk • Family or personal history • Concomitant meds that may interact • Clinical problems that predispose • Measure if patient is symptomatic

  22. Management of Mild-Moderate Statin-Associated Myalgias • Discontinue statin until sx are evaluated • Evaluate the patient for other conditions that might increase the risk for muscle symptoms* • Hypothyroidism, kidney/liver disease, rheumatologic disorders (PMR), steroid myopathy, low Vitamin D status, or primary muscle diseases • If after 2 months without statin Rx, muscle sx or elevated CK levels do not resolve completely, consider other causes of muscle sx

  23. Management of Severe Myalgia or Fatigue on Statin Therapy • Promptly discontinue the statin • Evaluate for rhabomyolysis • CK • Creatinine • Urine analysis for myoglobinuria

  24. New Lipid Guidelines Summary • These guidelines are a simpler approach to previous guidelines • Focus on ASCVD risk and statins • For primary prevention: “patient-centered” • Guidelines will change as high-quality data becomes available • Many gaps in the evidence • New medications on the horizon

  25. Beyond the Guidelines • Did not review evidence for treatment • Low HDL-C • Hypertriglyceridemia • Combined dyslipidemias • Lipoprotein evaluation/treatment • Limited information/recommendations • Biomarkers • Atherosclerosis imaging

  26. Residual CVD Risk on Statins 30 25 20 CV Event Rate (%) 15 10 5 0 TNT 4S CARE HPS PROVE-IT Control Statin

  27. HDL-C, mg/dL Low HDL-C Increases CHD Risk, Even if LDL-C is Low: Framingham Heart Study Patient 1 LDL-C 100 HDL-C 25 Patient 2 LDL-C 220 HDL-C 45 1 CHD Relative Risk 2 LDL-C, mg/dL Kwiterovich PO, Am J Cardiol 1998;82:19Q

  28. Residual CVD Event Rates on Statins are Predicted by HDL-C Levels • Post-hoc analysis, TNT • RCT of 9770 CHD patients on atorvastatin, 10 or 80 mg • Quintiles of HDL-C levels predicted CVD events (p=0.04) • Among subjects with LDL-C <70 mg/dL, HDL-C levels independently predicted CVD events (p=0.03) Barter PJ, et al. N Engl J Med 2007;357:1301

  29. Why Do We Have HDL? • Reverse cholesterol transport – unlikely to be selected for until recent increase in CVD deaths • Anti-inflammatory effects • Host defense and immunity • Protection from endotoxin • Protection from trypanosomes

  30. HDL and Host Defense Courtesy of Dan Rader, MD

  31. HDL Atherosclerosis Treatment Study (HATS) • N = 160 CAD patients • HDL-C: women 40 mg/dL, men 35 mg/dL • Baseline lipids: TC 199, HDL-C 32, TG 203, LDL-C 127 mg/dL • Randomized, 2 x 2 factorial • Simvastatin and niacin • Antioxidants (C and E, -carotene, selenium) • Outcomes after 3 years Brown BG, et al. N Engl J Med. 2001;345:1583

  32. HATS: Clinical Endpoints -89% Placebo Simva + niacin 23.7 25 Antioxidants 21.4 S + N + AV 20 14.3 15 Composite Event Rate (%) 10 * 5 2.6 0 Coronary Death, MI, Stroke, or Revascularization * p=0.003 vs placebo Brown BG, et al. N Engl J Med. 2001;345:1583

  33. AIM-HIGH • N=3,414 men and women with • Atherosclerotic vascular disease • HDL-C ≤40 (men); ≤50 mg/dL (women) • TG 150-400 mg/dL • LDL-C ≤180 mg/dL • Randomized to simvastatin vs. simvastatin + ER niacin • 1 endpoint: CHD death, MI, stroke, high-risk ACS, or symptom-driven coronary or cerebral revascularization The AIM-HIGH Investigators. N Engl J Med 2011;365:2255

  34. AIM-HIGH • Power: 85% for 25% CVD event reduction with N=850 events • ER niacin: 500 mg/d, titrated to 2000 mg/d over 4 - 8 weeks (open-label run-in) • If tolerated 1500 mg/d randomized to maximally tolerated dose of ER niacin or a placebo “spiked” with 50 mg of IR niacin • Simvastatin adjusted during the first 6 months to a LDL-C target of 40 - 80 mg/dL • Ezetimibeadded to reach LDL-C goal The AIM-HIGH Investigators. N Engl J Med 2011;365:2255

  35. AIM-HIGH • After 1 year, ER niacin/statin vs. statin • HDL-C (mean 35 mg/dL)  by 23% vs. 9% • TG (mean 163 mg/dL)  by 28% vs. 5% • LDL-C (mean 74 mg/dL)  by 10% vs. 4% • Non-HDL-C from 108 to 90 mg/dL vs. 108 to 102 mg/dL • Stopped for futility after a mean of 3 years • Primary end point occurred in 282 patients in the niacin group (16.4%) and in 274 patients in the placebo group (16.2%) (HR 1.02; p=0.79) The AIM-HIGH Investigators. N Engl J Med 2011;365:2255

  36. AIM-HIGH The AIM-HIGH Investigators. N Engl J Med 2011;365:2255

  37. HPS2-THRIVE • Prospective RCT to determine if • Niacin + laropiprant prevents CVD events on a background of statin therapy • High-risk patients receiving intensive LDL-lowering tx • N=25,673, aged 50-80 years old • All had ASCVD • All on simvastatin 40 mg (+ ezetimibe10 mg/d, if needed to get TC <135 mg/dL) • Randomized to niacin 2 g/d + laropiprant 40 mg/d vs. placebo The HPS2-THRIVE Collaborative Group. N Engl J Med 2014;371:203

  38. HPS2-THRIVE • After a median of 4 years • HDL-C (mean 44 mg/dL)  by 6 mg/dL • TG (mean 125 mg/dL)  by 33 mg/dL • LDL-C (mean 63 mg/dl)  by 10 mg/dL • Niacin-laropiprant had no sig. effect on ASCVD (13.2% vs. 13.7%; RR 0.96; p=0.29) • Absolute 3.7% increase in serious side effects – esp. DM, infection, GI, and myalgia (in China: RR 5.2 vs 1.5 in Europe) The HPS2-THRIVE Collaborative Group. N Engl J Med 2014;371:203

  39. HPS2-THRIVE The HPS2-THRIVE Collaborative Group. N Engl J Med 2014;371:203-212

  40. HDL and Niacin • Niacin • AIM-HIGH: Niacin as add-on to effective statin tx does not reduce events • HPS-THRIVE: Supports AIM-HIGH, though risks may be due to laropiprant or niacin • Main effect may be LDL-lowering: main use as 2nd line for residual high LDL-C • HDL-C as a marker not a mediator – Mendelian randomization studies do not strongly support causal role Voight BF, et al. Lancet 2012; 380: 572 Holmes, MH. Eur Heart J 2014: doi:10.1093/eurheartj/eht571

  41. Triglycerides • Controversial as a marker as a cause of CVD risk, because of associations with • Obesity • Diabetes mellitus • Adverse lifestyle habits • Inflammation • Low HDL-C • Small LDL • LDL particle excess • Mendelian randomization studies do support causal role; weaker than for LDL-C Miller M, et al. Circulation 2011:123;2292 Holmes, MH. Eur Heart J 2014: doi:10.1093/eurheartj/eht571 Go D, Nature Genetics 2013:45; 1345

  42. Action to Control CVD Risk in Diabetes (ACCORD) Study • N = 5518 w/type II diabetes mellitus • Open-label simvastatin • RCT fenofibrate 160 mg vs. placebo • 1° outcomes = CVD death, non-fatal MI, non-fatal stroke • Mean duration 4.7 years • Baseline lipids: TC 175, HDL-C 38, TG 162, LDL-C 100 mg/dL N Engl J Med 2010; 362:1563

  43. ACCORD – Lipid Changes N Engl J Med 2010; 362:1563

  44. ACCORD – CVD Outcomes + revasc, hosp. CHF N Engl J Med 2010; 362:1563

  45. ACCORD - Subgroups N Engl J Med 2010; 362:1563

  46. AIM-HIGH • In a subset of patients with the highest TGs (≥198 mg/dL) and lowest HDL-C (<33 mg/dl), ER niacin showed a trend toward benefit (HR 0.74, p = 0.073) Guyton JR, et al. J Am CollCardiol2013;62:1580

  47. Japan EPA Lipid Intervention Study (JELIS) • RCT of 18,645 subjects with TC >253 • Pravastatin/simvastatin + EPA 1800 mg vs. statin alone (open-label) • 1° endpoint: SCD, fatal and non-fatal MI, unstable angina, PCI/CABG • Mean follow-up 4.6 years • Baseline lipids: HDL-C 59, TG 154,LDL-C 183 mg/dL Lancet 2007; 369:1090

  48. JELIS • LDL-C  25% in both arms; TG  9 vs 4% (p<0.001) all primary secondary • 1° endpoint: 262 (2.8%) EPA vs. 324 (3.5%) controls = 19% RRR; 0.7% ARR (p=0.011) • In those with CAD: 158 (8.7%) EPA vs. 197 (10.7%) controls = 19% RRR; 2% ARR (p=0.048) Lancet 2007; 369:1090

  49. Use of Non-Statin Lipid Therapies • If TGs >500 mg/dL • Fibrates (or niacin or fish oil) • Prevent pancreatitis and hepatic steatosis(non-guideline) • Use the max tolerated intensity of statin • Consider addition of a non-statin medication • Statin intolerance • Persistent, less than therapeutic response • Assure compliance with meds and lifestyle • High-intensity: if LDL <50% or >100 mg/dL • Moderate intensity: <30% decrease

  50. Use of Non-Statin Lipid Therapies • Risk-reduction benefits should outweigh potential for adverse effects • Focus on: • Clinical ASCVD <75 years of age • Baseline LDL-C ≥190 mg/dL (genetic) • Diabetes mellitus, 40-75 years of age • Prefer non-statin cholesterol-lowering medication that reduced ASCVD events in RCTs

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