ATP IV: Predicting Guideline Updates

Disclosures ATP IV: Predicting Guideline Updates Daniel M. Riche, Pharm.D., BCPS, CDE Speaker s Bureau Merck Janssen Boehringer-Ingelheim Learning Objectives Describe at least two evidence-based recommendations for dyslipidemia treatment that are different than what is currently recommended in the NCEP ATP III. Explain the proven patient demonstrated benefits of specific drug therapy options for the treatment of dyslipidemia. American Heart Association (AHA) Heart Disease and Stroke Statistics 2012 Update 82.6 Million Americans have Cardiovascular Disease Millions of Americans 80 60 40 20 0 76.4 75 44.1 * Total cholesterol 240 mg/dl 33.6 18.3 16.3 7.9 7 5.7 Circulation. 2012;125:e2-220. 1

Prevalence, Treatment, and Control of High Levels of LDL-Cholesterol CDC analysis based on NHANES data 71 million Americans with high LDL-C from 2005-2008 Population (%) 60 50 40 30 20 10 0 34.5 33.5 1999-2002 2005-2008 28.4 48.1 14.6 33.2 Prevalence Treatment# Control* # Self-reported currently taking cholesterol-lowering medication *LDL-C <100 mg/dl for high risk, <130 mg/dl for intermediate risk, or <160 mg/dl for low risk. MMWR. 2011;60:109. Lipid Treatment Assessment Project 2 (L-TAP2) 9955 patients on stable lipid-lowering therapy from 9 different countries 100 80 60 40 20 0 86 Low risk (<160) % Patients at LDL-C Goal 74 Moderate risk (<130) 67 High risk (<100) 30 Very high risk (<70) Circulation. 2009;120:28-34. Consensus Recommendations for Dyslipidemia Management 2001 - National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) 2004 - NCEP ATP III implications 2011 - AHA/ACC guidelines 2013 - ADA Standards of Medical Care in Diabetes. NCEP ATP IV (expected in 2013) ACC = American College of Cardiology; ADA = American Diabetes Association; AHA = American Heart Association; NHLBI = National Heart, Lung, and Blood Institute Targets of Treatment in Dyslipidemia Primary Target: LDL-C Secondary Target: Non-HDL-C (Only when LDL-C goal is met and if TG 200 mg/dl) EXCEPTION: Triglyceride lowering is an immediate target of therapy if 500 mg/dl Raising HDL-C is a tertiary target in certain patients Circulation. 2004; 110:227-39. Circulation. 2005; 112:2735-52. 2

NCEP ATP III: LDL-C Goal Values High Risk <100 mg/dl, <70 mg/dl is optional if Very High Risk CVD or Diabetes Yes No >20% High Risk <100 mg/dl 2 major CV risk factors* 10-year CHD risk: Framingham Score Yes No 10-20% <10% Moderately High Risk <130 mg/dl, <100 mg/dl is optional Moderate Risk <130 mg/dl Lower Risk <160 mg/dl *Major risk factors: Age ( 45yrs men, 55yrs women), hypertension, smoking, family history of premature CHD, HDL-C <40 mg/dl Circulation. 2004; 110:227-39. ATP III: Very High Risk Definition Presence of established CVD plus: 1) multiple major risk factors (esp. diabetes) 2) severe and poorly controlled risk factors (esp. continued cigarette smoking), 3) multiple metabolic syndrome risk factors (esp. triglycerides 200 mg/dl plus non-hdl-c 130 mg/dl with HDL-C < 40 mg/dl), and 4) patients with acute coronary syndromes Optional goal of <70 mg/dl does not apply to individuals who are not high risk Circulation. 2004; 110:227-39. ATP III: 30-40% Recommendation When LDL-lowering drug therapy is employed in high-risk or moderately high-risk intensity of therapy should be sufficient to achieve at least a 30-40% LDL-C reduction Standard Doses to Attain 30-40% LDL-C Reductions Drug Dose (mg/day) LDL-C reduction (%) Atorvastatin 10 39 Fluvastatin 40-80 25-35 Lovastatin 40 31 Pravastatin 40 34 Rosuvastatin 5-10 39-45 Simvastatin 20-40 35-41 Pitavastatin (not available in 2004) 1-2 mg/day attains 30-40% LDL-C reductions. Circulation. 2004; 110:227-39. Lipid-Lowering Therapies Statins (atorvastatin, fluvastatin, lovastatin, pravastatin, pitavastatin, rosuvastatin, simvastatin) Bile acid sequestrants (colesevelam, cholestyramine, colestipol) LDL-C HDL-C TG 18-63% 5-15% 7-30% 15-30% 3-5% 0 or Nicotinic acid 5-25% 15-35% 20-50% Fibric acid derivatives (gemfibrozil, fenofibrate) Cholesterol absorption inhibitor (ezetimibe) Omega-3 fatty acids (Rx strength) 5-20% or 10-20% 20-50% 18% 1% 7%? 9% 45% Executive summary of NCEP ATP III. JAMA. 2001; 285:2486-97; Crestor package insert. Astra-Zeneca, 2009; Zetia package insert. Merck/Schering-Plough Pharmaceuticals, 2009; Lovaza package insert. GlaxoSmithKline, 2009; Livalo package insert. Kowa Pharmaceuticals America, 2010. 3

Landmark Statin-based Trials Statin Treatment LDL-C (mg/dl) Primary Endpoint/ CV Event Rate (%) Trial (mg/day) Baseline Statin Placebo Statin 4S Simvastatin 20-40 mg 188 122 28.0 19.4 LIPID Pravastatin 40 mg 150 112 15.0 12.3 CARE Pravastatin 40 mg 139 98 13.2 10.2 HPS Simvastatin 40 mg 132 93 24.4 19.9 PROSPER Pravastatin 40 mg 147 97 16.2 14.1 WOSCOPS Pravastatin 40 mg 192 159 7.5 5.3 AFCAPS Lovastatin 20-40 mg 150 115 5.5 3.5 ASCOT-LLA Atorvastatin 10 mg 133 90 3.0 1.9 CARDS Atorvastatin 10 mg 118 77 9.0 5.8 JUPITER Rosuvastatin 20 mg 108 55 2.8 1.6 Critical Analysis of Evidence that Questions ATP III Recommendations Jacobson TA et al. Arch Intern Med. 1998; 158:1977-89. Heart Protection Study Collaborative Group. Lancet. 2002; 360:7-22. Shepherd J et al. Lancet. 2002; 360:1623-30. Sever PS et al. Lancet. 2003; 361:1149-58. Colhoun HM et al. Lancet. 2004; 364:685-96. Ridker PM et al. N Engl J Med. 2008; 359:2195-207. Audience Question 1 A 72 year old woman who was hospitalized for acute coronary syndrome 6 weeks ago has been treated with atorvastatin 20 mg daily. Her LDL-C is 90 mg/dl, HDL-C is 40 mg/dl, TG are 200 mg/dl, non-hdl is 130 mg/dl. Which of the following would you recommend? 1. Continue atorvastatin 20 mg daily 2. Increase atorvastatin to 80 mg daily 3. Change atorvastatin to simvastatin 40 mg daily 4. Change atorvastatin to rosuvastatin 10 mg daily Treat to New Targets (TNT) Trial Sub-analysis of 1,501 patients with CHD and diabetes Randomized to atorvastatin 10 mg or 80 mg daily for 5 yrs Major CV event (%) 25 20 15 10 5 10 mg atorvastatin Mean LDL = 99 mg/dl 0 0 1 2 3 4 5 6 Time (years) 80 mg atorvastatin Mean LDL = 77 mg/dl 25% RR reduction p=0.026 Diabetes Care. 2006;29:1220-6. 4

Cholesterol Treatment Trialists (CTT) Collaboration Meta-analysis of large (n>1000), randomized trials of 2 yrs duration More vs. Less intensive statin therapy: 5 trials (n=39,612), median 5 yr follow-up Trials were in patients with coronary heart disease Statin vs. control: 21 trials (n=129,526), median 4.8 yr follow-up CV event risk reductions per 1.0 mmol/l LDL-C reduction at 1 year were estimated Lancet. 2010; 376: 1670 81. CTT Collaboration: More vs. Less Statin Therapy Weighted mean further reduction in LDL-C was 0.51 mmol/l (~19 mg/dl) Further Event Reduction Major Vascular Events 15% (P<0.001) CHD Death or Non-Fatal MI 13% (P<0.001) Coronary Revascularization 19% (P<0.001) Ischemic Stroke 16% (P=0.005) CV event reductions proportionate to LDL-C reductions, even when baseline LDL-C was <2 mmol/l (77 mg/dl) Lancet. 2010; 376: 1670 81. LDL Goals of < 70 mg/dl ATP III recommendation: Therapeutic option for patients with established CV disease and additional risk factors or high risk comorbidities Evidence-based recommendation: Appropriate for all patients with coronary heart disease regardless of the presence of other comorbidities American Diabetes Association: Standards of Medical Care in Diabetes Dyslipidemia: Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels, for diabetic patients with overt CVD, or without CVD if >40 yrs with 1 other CVD risk factors If drug-treated patients do not reach targets on maximal tolerated statin therapy, a reduction in LDL-C of 30-40% from baseline is an alternative therapeutic goal Triglycerides <150 mg/dl and HDL-C >40 mg/dl in men and >50 mg/dl in women, are desirable. However, LDL-C targeted statin therapy remains the preferred strategy. If targets not reached on maximally tolerated doses of statins, combination therapy using statins and other lipid-lowering agents may be considered but has not been evaluated in outcome studies for either CVD outcomes or safety Diabetes Care. 2013; 36 (suppl 1):S11-66. 5

STATIN wors e Collaborative AtoRvastatin Diabetes Study (CARDS) Double-blind, randomized trial in 2838 primary prevention patients with type 2 diabetes randomized to placebo or atorvastatin 10 mg daily for 3.9 years Primary Endpoint: Major CV Event (%) Placebo (LDL-C ~ 118 mg/dl) 37% reduction p=0.001 Atorvastatin 10 mg/day (LDL-C ~ 77 mg/dl) The Heart Protection Study (HPS) High-risk patients, age 40-80 yr randomized, doubleblind, to placebo or simvastatin 40 mg daily for 5 yr Subgroup of 5963 had diabetes LDL-C decreased from 123 mg/dl to 89 mg/dl Vascular Events Simvastatin Risk ratio 40 mg daily Placebo STATIN better STATIN worse Diabetes at baseline 601 (20.2%) 748 (25.1%) 0.4 0.6 0.8 1.0 1.2 1.4 Reductions even when baseline was LDL-C < 116 mg/dl Lancet. 2004; 364:685-96. Lancet. 2003; 361: 2005 16 ADA and ACC Consensus Statement: Lipoprotein Management in Patients With Cardiometabolic Risk Highest Risk: CVD or DM with 1 major risk factor High Risk: No CVD, no DM with 2 major risk factors DM with no major risk factors Goal Values (mg/dl) LDL-C Non-HDL-C Apo B <70 <100 <80 <100 <130 <90 Other major risk factors (beyond dyslipidemia) include cigarette smoking, hypertension, and family history of premature coronary artery disease. Diabetes Care. 2008;31:811-22. LDL-C Reduction in Diabetes ATP III recommendation: Statin therapy if not at goal LDL value < 100 mg/dl for most Therapeutic option of < 70 mg/dl if established CVD Evidence-based recommendation: Nearly all patients (age >40 yrs) benefit from statin based therapy, regardless of LDL-C value 6

Audience Question 2 A 60 year old man with coronary artery disease and diabetes is treated with atorvastatin 40 mg daily. He will not consider a higher dose or another statin due to cost and perceived risks. His LDL-C is 90 mg/dl, HDL-C is 35 mg/dl, TG are 250 mg/dl, non-hdl is 140 mg/dl. Which of the following would you recommend? 1. Add fenofibrate 2. Add ezetimibe 3. Add niacin 4. Continue present therapy Clinical Scenarios Goal Monotherapy Combination Therapy LDL-C Lowering Non-HDL-C Lowering Triglyceride Lowering Statin Niacin Bile Acid Sequestrant Ezetimibe Statin (high-dose) Niacin Fibrate Omega-3 Fatty Acids Niacin Statin + Bile Acid Sequestrant Statin + Ezetimibe Statin + Niacin Others Statin + Fibrate Statin + Niacin Statin + Omega-3 Fatty Acids Others Fibrate + Omega-3 Fatty Acids Fibrate + Niacin Niacin + Omega-3 Fatty Acids ACCORD Study: Combination Lipid Therapy 5518 patients with type 2 diabetes treated with open-label simvastatin randomized to fenofibrate or placebo for 4.7 years Primary outcome: nonfatal MI, nonfatal stroke, or CV death End of Study Baseline Fenofibrate Placebo LDL-C (mg/dl) 100.6 81.1 80.0 HDL-C (mg/dl) 38.1 41.2 40.5 Triglycerides (mg/dl) 162 122 144 N Engl J Med. 2010; 362:1563-74. Annual Rate of Primary Endpoint (%) 4 3 2 1 0 ACCORD Study: Results Placebo P=0.32 Fenofibrate Subgroup analyses: Possible benefit for men and possible harm for women Possible benefit in patients with both high baseline triglycerides ( 204) and a low baseline HDL-C ( 34) P=0.057 for interaction N Engl J Med. 2010; 362:1563-74. 7

Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) Double-blind trial in 3414 patients with a history of CVD treated with statin therapy to an LDL-C of 40-80 mg/dl Randomized to placebo or extendedrelease niacin (1500-2000 mg daily) Primary endpoint: Composite CV events Clinical trial was stopped at 3 years, 18 months earlier than planned N Engl J Med. 2011;365:2255-67. AIM-HIGH: Results At Year 3 Baseline Niacin Placebo LDL-C (mg/dl) 75.8 65.2 68.3 HDL-C (mg/dl) 35.3 44.1 39.1 Triglycerides (mg/dl) 162 120 152 Incidence of Primary Endpoint Statin plus placebo: 16.2% Statin plus niacin: 16.4% p=0.80 N Engl J Med. 2011;365:2255-67. Combination Lipid Lowering Therapy ATP III recommendation: If high triglycerides or low HDL-C, consideration can be given to combining a fibrate or nicotinic acid with an LDL-lowering drug Evidence-based recommendation: The addition of a fibrate or nicotinic acid to statin-based LDL-lowering drug therapy does not reduce CV events Audience Question 3 A 65 year old woman has a history of hypertension, diabetes, and chronic kidney disease requiring hemodialysis. She is on no lipid lowering therapy but her LDL-C is 130 mg/dl, HDL-C is 45 mg/dl and TG are 150 mg/dl. Which of the following would you lipid lowering regimens would you recommend? 1. Lifestyle modifications alone 2. Lifestyle modifications + simvastatin 10 mg daily 3. Lifestyle modifications + atorvastatin 10 mg daily 4. Lifestyle modifications + colesevelam 3.75 g daily 8

Lipid-Lowering Therapy in Patients with End-Stage Renal Disease (ESRD) Requiring Hemodialysis Trial 4D Study: Atorvastatin 20 mg daily vs placebo for 4 yr AURORA Study: Rosuvastatin 10 mg daily vs placebo for 3.8 yr Population Type 2 diabetes plus long-term hemodialysis (n=1255) Long-term hemodialysis (n=2776) Primary Endpoint CV death, nonfatal MI, fatal/nonfatal stroke CV death, nonfatal MI, nonfatal stroke Relative Risk (95% CI) 0.92 (0.77 1.10) 0.96 (0.84 1.11) Pharmacotherapy. 2010;30:823-9. N Engl J Med. 2005; 353:238-48. N Engl J Med. 2009; 360:1395-407. Study of Heart and Renal Protection (SHARP) Patients with chronic kidney disease SCr 1.7 mg/dl in men, or 1.5 mg/dl in women Age 40 yrs., without prior MI Primary endpoint was major atherosclerotic events 4.9 yr. median follow-up Ezetimibe/ Simvastatin 10/20 mg (n=4193) Ezetimibe/ Simvastatin 10/20 mg (n=4650) Randomized (n=9438) Simvastatin 10 mg (n=1054) Re-randomized at 1 yr (n=886) Placebo (n=4191) Placebo (n=4620) Lancet. 2011; 377: 2181-92. Event SHARP: Results Ezetimibe/ Simvastatin (n=4650) Placebo (n=4620) Major atherosclerotic event 526 (11.3%) 619 (13.4%) Non-dialysis (n=6247) 296 (9.5%) 373 (11.9%) Dialysis (n=3023) 230 (15.0%) 246 (16.5%) Note: No significant heterogeneity between non-dialysis and dialysis patients (p=0.25) Risk ratio & 95% CI 0.6 0.8 1.0 1.2 1.4 Ezetimibe/ Simvatatin better Placebo better Lipid Lowering Therapy in CKD ATP III recommendation: Patients with chronic kidney disease, including those requiring hemodialysis, should be treated according to standard recommendations Evidence-based recommendation: Treating patients that have chronic kidney disease with statin-based therapy results in CV event lowering, but not in patients that require hemodialysis Lancet. 2011; 377: 2181-92. 9

Primary objective: First major CV event JUPITER Trial Patients randomized to rosuvastatin 20 mg daily or placebo (planned for 3.5 yr) Patient profile (n=17,802) Primary prevention Men 50 yr, women 60 yr LDL-C <130 mg/dl with hscrp >2 mg/l JUPITER Results Stopped early after a mean of 1.9 years Median LDL (interquartile range) at 12 mo: Placebo 110 mg/dl (94-125) Rosuvastatin 55 mg/dl (44-72) P<0.001 25% (> 4000 patients) had LDL-C values < 44 mg/dl, with no undue harm demonstrated Primary Endpoint (events per 100 pt-years): Placebo 1.36 Rosuvastatin 0.77 HR=0.56 (0.46-0.69) P<0.00001 hscrp = high-sensitivity C-reactive protein N Engl J Med. 2008;359:2195-207. N Engl J Med. 2008;359:2195-207. JUPITER Results: Subgroups Subgroup Sex Male Female Age 65 yr >65 yr Race or Ethnic Group White Non-white # of Patients 11,001 6,801 8,541 9,261 12,683 5,117 Hazard Ratio (95% CI) p-value for Interaction 0.80 0.32 0.57 0.25 0.50 1.00 2.00 4.00 Rosuvastatin Placebo Better Better Cumulative Incidence of Primary Endpoint JUPITER Results in Older Patients: 5695 Patients Age 70 yrs N Engl J Med. 2008;359:2195-207. Ann Intern Med. 2010;152:488-96. 10

Lower Risk Patients and Very Low LDL-C ATP III recommendation: Primary prevention patients: treat to LDL goals of <160, <130, or <100 mg/dl based on CV risk very low LDL levels remote possibility of side effects from LDL lowering per se Evidence-based recommendation: Statin therapy reduces CV events if hs-crp is elevated in some primary prevention patients No harm seen in statin treated patients with very low LDL-C levels http://www.nhlbi.nih.gov/guidelines/indevelop.htm#status Predictions for the ATP IV Conversion of optional LDL goal of < 70 to a standard for patients with CVD Conversion of optional LDL goal of <100 to a standard for patients without CVD but with multiple CV risk factors Support for LDL-C targeted therapy, but further emphasis on non-hdl and apob Continued emphasis on statin based therapy Predictions for the ATP IV Tempered recommendations for combination lipid-lowering drug therapy Specific recommendations on certain subpopulations (CKD) Support of treatment in the very elderly Revised monitoring recommendations for statin therapy 11

Controversial Topics Role of advanced lipid testing in the management of dyslipidemia Replacement of specific lipid targets with percent reduction targets Reserved use of nicotinic acid and fibrates for patients with hypertriglyceridemia (triglycerides 500 mg/dl) Others. New Drugs Anacetrapib CETP inhibitor (stops HDL from transferring into VLDL or LDL) 100 mg/day DEFINE LDL 36% lipoprotein(a) 36.4% HDL 138% No SBP or CVD (unlike torcetrapib) REVEAL ongoing (2017) New Drugs Questions Homozygous Familial Hypercholesterolemia Kynamro (mipomersin) Once weekly injection apolipoprotein B-100 synthesis inhibitor Cost: $176,000 per year Juxtaped (lomitapide) 5-60 mg PO daily microsomal triglyceride transfer protein inhibitor Cost: $235,000-295,000 per year 12