Update on Dyslipidemia and Recent Data on Treating the Statin Intolerant Patient Steven E. Nissen MD Chairman, Department of Cardiovascular Medicine Cleveland Clinic Disclosure Consulting: Many pharmaceutical companies Clinical Trials: AbbVie, Amgen, AstraZeneca, Cerenis, Esperion, Eli Lilly, Novo Nordisk, The Medicines Company, Orexigen, and Pfizer. Companies are directed to pay any honoraria, speaking or consulting fees directly to charity so that neither income nor tax deduction is received.
Beyond Statins: Is LDL Reduction Enough? 700 CV Death/MI (Number of events) 600 500 400 300 200 34% reduction Placebo Treated 31% reduction 100 0 4S Trial WOSCOPS Trial 2 prevention trial with simvastatin 1 prevention trial with pravastatin
Potential Role of Triglycerides as a Source of Residual Risk
Total Cholesterol Distribution: CHD vs. Non-CHD Patients (Framingham) 40 30 Non-CAD (mean 219 mg/dl CAD (mean 244 mg/dl) Percent of Population 20 10 0 0 150 200 250 300 350 Level of Serum Cholesterol at Initial Exam (mg/dl) Castelli. Am J Med. 1984;76:4-12.
Women s Health Study, Nurses Health Study, and Health Professionals Follow-up Study Risk According to Lipoprotein Cholesterol Level Study LDL-C Non-HDL-C TG WHS (n = 27,673) 1.74 (1.40, 2.16) 2.52 (1.95, 3.25) 2.58 (1.95, 3.41) HPFS (n = 739) 2.07 (1.24, 3.45) 2.75 (1.62, 4.67) 2.12 (1.21, 3.70) Pooled NHS + HPFS (n = 1478) 1.79 (1.23, 2.64) 2.53 (1.72, 3.72) 2.17 (1.51, 3.11) Pischon T, et al. Circulation. 2005;112:3375-3383. Mora S, et al. Circulation. 2009;119:931-939. Mendivil CO, et al. Circulation. 2011;124:2065-2072.
High Triglycerides Contribute to Significant Residual Risk After Statin Treatment Insights from PROVE IT-TIMI-22 Post-Hoc Analysis 25 20 20.3% RR=0.64 (0.53 0.78) P=0.001 30-Day Risk of Death, MI, or Recurrent ACS (%) 15 10 5 13.5% 0 200 (n=603) <200 (n=2,796) On-Treatment Triglycerides (mg/dl) Miller M, et al. J Am Coll Cardiol. 2008;51:724 730.
Carriers Identified with Lower Triglycerides and Reduced Risk for Early-Onset MI R19X IVS2+1G>A 14 12 10 8 6 4 2 0 Cases Controls 20 18 16 14 12 10 8 6 4 2 0 Cases Controls OR = 0.18 ; P=0.03 OR = 0.65 ; P=0.26
ACCORD: Effect of Fenofibrate on Trigylcerides
ACCORD Primary Endpoint: MI. Stroke, Death Median 6% Increase in HDL-C (P<0.001) HR = 0.92 0.79 to 1.08 Accord Study Group. N Engl J Med 2010;362:1563-74 Triglycerides-162 mg/dl HDL-C - 38.1 mg/dl
Patients In Accord with TG 204 mg/dl and HDL 34 mg/dl Showed 31% Reduction in Risk Pre-specified subgroup analysis (baseline TG levels 204 mg/dl + HDL-C 34 mg/dl) suggested favorable risk reduction for MACE with fenofibrate (HR 0.69; 95%CI 0.49 0.97; p=0.032 within subgroup, p=0.06 for interaction). Adapted from ACCORD Study Group, N Engl J Med 2010 April 29; 362(17):1563-1574.
Meta-analysis: Fibrates and CHD Events According to Mean Baseline Triglycerides Mean Baseline TG No. of Trials Relative Risk (95% CI) P-value for heterogeneity <2.00 mmol/l (<177 mg/dl) 6 0.89 (0.82, 0.96) p = 0.03 2.00 mmol/l ( 177 mg/dl) 5 0.68 (0.53, 0.88) Jun M, et al. Lancet. 2010;375:1875-1884.
Potential Role of Omega-3 Based Therapies
Red Blood Cell Content of Omega-3 Associated with Reduced Risk of CV Death EPA+DHA Levels and CV Risk in Physician s Health Study 1.2 0.9 1.00 Odds Ratio 0.6 0.52 0.3 0.19 0.10 0.0 3.3 4.3 5.0 6.5 Mean Red Cell DHA+EPA by Quartile (%) Albert CM et al. N Engl J Med 2002:346:1113-1118.
Origin Trial: Omega 3 in Dysglycemic Patients Origin Trial Investigators. N Engl J Med 2012;367:309-18
Why Did Origin Fail? Wrong dosage! Patients received only 1 gram of omega-3 fatty acids Wrong control! The placebo was olive oil, which is not neutral. Wrong patients! Mean HDL-C 46 mg/dl and median triglycerides 141 mg/dl
Strength Trial Design Patients with hypertriglyceridemia (180-500 mg/dl) and low HDL (<42mg/dL men, 47mg/dL women) and high risk for CVD (Estimated N=13,000) Omega-3 CA s + statin (n=6500) Corn oil + statin (n=6500) 3-5 years follow up Primary endpoint: Major Adverse Cardiovascular Events (MACE): Composite of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, emergent/elective coronary revascularization, and hospitalization for unstable angina (UA)
Improved Omega-3 Formulation: Free Fatty Acids Rather than Ethyl Esters Free fatty acid the absorbable form of Omega-3 Novel formulation allows for distinct bioavailability advantages. Freely absorbed without need to be hydrolyzed by pancreatic lipase Coating delays absorption into the gut Once-daily dose that can be taken independent of meals
GAUSS3 Design: Two Double-Blind Phases Phase A 511 patients enrolled at 53 centers with a history of intolerance to multiple statins due to muscle-related adverse effects. 10 weeks Atorvastatin 20 mg Placebo 10 weeks Atorvastatin 20 mg Placebo Phase B Patients proceeded to Phase B only if they had intolerable muscle symptoms on atorvastatin, but not placebo, or CK 10 x ULN during prior statin treatment 2 1 24 weeks Monthly SC evolocumab 420 mg Daily oral ezetimibe 10 mg
Selected Baseline Characteristics Characteristic Phase A (n=491) Phase B (n=218) Ezetimibe (n=73) Evolocumab (n=145) Age (years) 61 59 59 Male Gender 50% 47% 54% Coronary Heart Disease 35% 29% 33% NCEP-ATP III High Risk 63% 52% 58% Intolerance to 3 statins 82% 82% 82% Total Cholesterol (mg/dl) 301 308 307 LDL-C (mg/dl) 212 222 219 HDL-C (mg/dl) 51 50 50
Phase A: Study Drug Discontinuation Events Intolerable Muscle Symptoms N = 491 On atorvastatin, but not placebo 209 (42.6%)* On placebo, but not atorvastatin 130 (26.5%) On both placebo and atorvastatin 48 (9.8%) No symptoms on either treatment 85 (17.3%) Did not complete Phase A 20/511 Bypassed Phase A due to CK elevation 10 x ULN 19 (3.9%)* *218 of these 228 eligible patients proceeded to Phase B
Percent Change in LDL-C (%) LDL-C Values Over Time During Phase B 0-10 -20-30 -40 Mean reduction 16.7% (LDL-C = 181 mg/dl) Ezetimibe Evolocumab -50-60 -70 Mean reduction 53.0% (LDL-C = 104 mg/dl) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Weeks Following Randomization in Phase B
Phase B: Adverse Effects and Drug Discontinuations Ezetimibe (n=73) Evolocumab (n=145) Total muscle-related events 21 (28.8%) 30 (20.7%) Myalgia, muscle pain or weakness 17 (23.3%) 25 (17.2%) Investigator reported CK Increase 1 (1.4%) 4 (2.8%) Discontinuation of Treatment for Any Reason Discontinuation of oral treatment 14 (19.2%) 23 (15.9%) Discontinued SC drug treatment 4 (5.5%) 7 (4.8%) Discontinuation of Treatment for Muscle Symptoms Discontinued oral drug treatment 5 (6.8%) 11 (7.6%) Discontinued SC drug treatment 0 (0%) 1 (0.7%)
The Glagov Study: Background and Scientific Rationale
Change in PAV (%) GLAGOV: Effect of Very Low LDL-C on Progression 2 1 0-1? -2 20 30 40 50 60 70 80 90 100 110 LDL-C during Treatment (mg/dl) Nicholls S. et al. JAMA. 2007;297:499-508.
LDL-C Change from Baseline (mg/dl) Change in LDL-Cholesterol During Treatment 20 10 0-10 -20-30 -40 Mean LDL-C 93.0 mg/dl Change from baseline 3.9% 90 mg/dl -50-60 -70-80 Mean LDL-C 36.6 mg/dl Change from baseline -59.8% 29 mg/dl 0 8 16 24 32 40 48 56 64 72 80 88 Study Week
Primary and Key Secondary Efficacy Parameters Change in PAV (%) Change in TAV (mm 3 ) Primary: Percent Atheroma Volume Secondary: Total Atheroma Volume 0.2 0 0.05 P = NS 0-1 -0.9 P = NS -0.2-2 -0.4 P < 0.0001-3 P < 0.0001-0.6-4 -0.8-1 -0.95 P <0.0001-5 -6-5.8 P <0.0001-1.2 Statin monotherapy -7 Statin monotherapy Statinevolocumab Statinevolocumab
LDL-C Change from Baseline (mg/dl) Exploratory Subgroup: Baseline LDL-C <70 mg/dl 30 20 10 0-10 -20-30 -40-50 -60-70 -80-90 Mean LDL-C 70.6 mg/dl Change from baseline 16.4% 65.5 mg/dl Mean LDL-C 24.0 mg/dl Change from baseline -58.3% 15.0 mg/dl 0 8 16 24 32 40 48 56 64 72 80 88 Study Week
Change in PAV (%) Percentage Regressing (%) Exploratory Subgroup: Baseline LDL-C <70 mg/dl Percent Atheroma Volume Fraction Showing Regression 0 100% -0.3-0.6-0.35 P = NS 80% 81.2% -0.9-1.2 P < 0.0001 60% 48.0% -1.5 40% -1.8-2.1-1.97 P <0.0001 20% -2.4 Statin monotherapy 0% Statin monotherapy Statinevolocumab Statinevolocumab
Change Percent Atheroma Volume (%) Mean On-Treatment LDL-C vs. Change in PAV Locally Weighted Polynomial Regression (LOESS) Plot with 95% confidence limits On-Treatment LDL-C (mg/dl)
Adverse Clinical Events and Safety Findings Event Placebo (N=484) Evolocumab (N=484) Death 0.8% 0.6% Nonfatal MI 2.9% 2.1% Nonfatal Stroke 0.6% 0.4% Hosp. for Unstable Angina 0.8% 0.6% Coronary Revascularization 13.6% 10.3% First Major Cardiovascular Event 15.3% 12.2% Injection site reactions 0% 0.4% Anti-evolocumab binding antibody NA 0.2% Neutralizing antibodies NA 0% Neurocognitive events 1.2% 1.4% New onset diabetes 3.7% 3.6% Myalgia 5.8% 7.0%
SJ Nicholls and coauthors Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial Published online November 15, 2016 Available at jama.com and mobile.jamanetwork.com jamanetwork.com
Some Final Thoughts LDL is now universally accepted as the major driver of atherosclerosis, however, the question of how far to reduce lipid levels has remained a moving target. In medical school, we were taught that a normal total cholesterol was any value <300 mg/dl. Over 4 decades, evidence has accumulated suggesting that optimal LDL-C levels for patients with coronary disease may be much lower than commonly achieved. While we await large outcome trials for PCSK9 inhibitors, the GLAGOV Trial provides intriguing evidence that clinical benefits may extend to LDL-C levels as low as 20 mg/dl.