Improving Complex Risk Assessment and Diagnosis of Patients with Severe Dyslipidemia
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1 Improving Complex Risk Assessment and Diagnosis of Patients with Severe Dyslipidemia April 3, 213 Anaheim, California Educational Partner:
2 Session 1: Improving Complex Risk Assessment and Diagnosis of Patients with Severe Dyslipidemia Learning Objectives 1. Implement strategies to improve patient adherence and compliance to lipid modifying therapies 2. Define treatment goals for patients with mixed dyslipidemia based on the latest guidelines for lipid management issued by the National Cholesterol Education Program (NCEP), National Lipid Association (NLA), and other relevant treatment recommendations 3. Review the potential role for diagnostic panels and important makers to improve CV risk assessment in complex patient populations 4. Utilize effective treatment strategies for the management of patients with multiple cardiometabolic risk factors 5. Improve the diagnosis and treatment of patients with homozygous or heterozygous familial hypercholesterolaemia (FH) Faculty Alan S. Brown, MD Interventional Cardiologist, Midwest Heart Specialists-Advocate Medical Group Medical Director, Midwest Heart Disease Prevention Center Naperville, Illinois Dr Alan Brown has been the director of the prevention center/lipid clinic for Midwest Heart Specialists, a group of 52 cardiologists located in Chicago's western suburbs, since its inception in He was appointed clinical associate professor of medicine and cardiology at Loyola University in Dr Brown is board certified in internal medicine, cardiology, echocardiography and clinical lipidology. Dr Brown has served as governor/president of the Illinois Chapter of the American College of Cardiology (ACC) and subsequently was elected chairman of the board of governors for the American College of Cardiology in 24. He is a fellow of the American College of Cardiology and also has been a member of the ACC's prevention of cardiovascular disease committee, the annual scientific program committee, and served as a member of the ACC board of trustees from 23 through 26. He is a fellow of the National Lipid Association and serves on the board of directors for the National Lipid Association. James M. Falko, MD Clinical Professor of Medicine Endocrinology/Lipid Clinic University of Colorado Hospital Aurora, Colorado Dr James Falko is the clinical professor of internal medicine, division of endocrinolgy, diabetes and metabolism at the University of Colorado, Denver. Previously he was professor in the division of endocrinology, diabetes, and metabolism at Ohio State University College of Medicine, Columbus; where he has also served as professor of molecular and cellular biochemistry. Dr Falko has been a practicing internist/endocrinologist/lipidologist since 1979 and has served as director of the lipid program both at Ohio State and the McConnell Heart Center at Ohio Health. Session 1
3 Faculty Financial Disclosure Statements The presenting faculty reports the following: Dr Brown reports serving as a speaker for Kowa Pharmaceuticals America, Inc. He is a consultant for Aegerion Pharmaceuticals and Kowa Pharmaceuticals America, Inc. Dr Falko reports serving on a speakers bureau for Kowa Pharmaceuticals America, Inc and Merck & Co, Inc. Education Partner Financial Disclosure Statement The content collaborators at the National Lipid Association report the following: Peter Jones, MD, reports serving on the advisory boards for Atherotech Diagnostics Lab, Merck & Co, Inc and Roche. Peter Toth, MD, PhD, reports serving on a speakers bureau for AbbVie, Amarin Pharma Inc, AstraZeneca, Genzyme Corporation, Kowa Pharmaceuticals America, Inc and Merck & Co, Inc. He is a consultant for Amgen Inc, Atherotech Diagnostics Lab, Genzyme Corporation, Kowa Pharmaceuticals America, Inc, LipoScience Inc and Merck & Co, Inc. Suggested Reading List Ballantyne C. Clinical Lipidology: A Companion to Braunwald s Heart Disease Expert Consult: Online and Print. 1 st ed. Philadelphia, Pennsylvania: Saunders Books; 29. Betteridge J. Case Studies in Lipid Management. 1 st ed. London, England: Informa Healthcare; 26. Davidson M, Maki K, Toth P. Therapeutic Lipidology. 1 st ed. Totowa, New Jersey: Humana Press Incorporated; 27. Tonkin A. Therapeutic Strategies in Lipid Disorders. 1 st ed. Oxford, England: Clinical Publishing; 29. Toth P, Sica D,. Clinical Challenges in Hypertension II. 1 st ed. Oxford, England: Clinical Publishing; 21. Toth P, Sica D. Clinical Challenges in Lipid Disorders. 1 st ed. Oxford, England: Clinical Publishing; 28. Session 1
4 SESSION 1 8:3 AM 1: AM Improving Complex Risk Assessment and Diagnosis of Patients with Severe Dyslipidemia SPEAKERS Alan S. Brown, MD James M. Falko, MD Presenter Disclosure Information The following relationships exist related to this presentation: Dr Brown reports serving as a speaker for Kowa Pharmaceuticals America, Inc. He is a consultant for Aegerion Pharmaceuticals and Kowa Pharmaceuticals America, Inc. Dr Falko reports serving on a speakers bureau for Kowa Pharmaceuticals America, Inc and Merck & Co, Inc. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Complex Risk Assessment Alan S. Brown, MD Interventional Cardiologist, Midwest Heart Specialists- Advocate Medical Group Medical Director, Midwest Heart Disease Prevention Center Naperville, IL Approximately how many patients do you see each week with Dyslipidemia 1. None 2. 1 to to to to to to 6 8. >6 Outcomes Question 1 In meta-analyses, a 4 mg/dl reduction in LDL-C decreases major CV events by: 1. 1% 2. 22% 3. 3% 4. 36% Outcomes Question 2 Based on recent clinical trial results, statin add-on therapy with niacin is reasonably indicated for: 1. Additional CV event reduction 2. Increasing HDL-C 3. Reducing severe triglyceride elevations 4. Sparing statin dose escalation 1
5 Outcomes Question 3 Chronic Kidney disease is: 1. Considered a CHD risk equivalent 2. Not associated with progression to dialysis 3. Defined as an estimate GRF > 6 ml/min/1.73m² ARS Question #1: All of the following are true about the Cholesterol Treatment Trialists (CTT) meta-analysis of statin trials except: 1. LDL-C reduction in women does not significantly reduce CHD risk 2. LDL-C reduction by 1 mmol/l reduces major CHD events regardless of baseline LDL-C 3. LDL-C reduction by 1 mmol/l reduces major CHD events in people with 1 yr FRS < 1% ARS Question #2: Statin therapy in CKD subjects results in: 1. Increased incidence of hemorrhagic stroke 2. Greater reduction in major CHD events for dialysis patients vs. nondialysis 3. A significant 17% reduction in major CHD events compared to placebo Chronic Kidney Disease (CKD) CKD is considered by many to be a CHD equivalent (observations from FHS, from T2DM in FIELD, and from JUPITER) Cardiovascular endpoints are complicated in these patients, and these may not be modifiable by reducing LDL-C In particular, ESRD dialysis patients have outcomes that are too complicated or advanced to be modifiable by lipid treatment (AURORA and 4D trials) Chronic Kidney Disease (CKD) Framingham Heart Study: CKD as Predictor of CVD Death Defined as an estimated GFR (determined by MDRD or CKD-Epi equation) <6 ml/min/1.73 m² Stage 3 CKD is GFR 3-59 ml/min Stage 4 CKD is GFR ml/min Renal failure (Stage 5) is GFR < 15 ml/min National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (K/DOQI) considers Stage 3-5 as CHD equivalent risk Arch Intern Med 27;167:1122; Arch Intern Med 27;167:1386 Am J transplant 24;(Suppl 7):13 53 Probability of CVD death Time (years) 3a CKD: GFR women, men 3b CKD: GFR 3-44 women, 3-5 men Am J Cardiol 28;12;47 No CKD/+CVD CKD3a/No CVD CKD3b/No CVD No CKD/No CVD 2
6 egfr and Albuminuria as Predictors of CVD Events in T2DM: FIELD Trial A: egfr at baseline and yr 2 B. Albuminuria ( ACR) at baseline and yr 2 Diabetologia 21;54:32-43 ESC/EAS Guidelines for Managing Dyslipidemia Risk based approach (risk factors and SCORE) A. Very high risk: Documented CVD (invasive and noninvasive) MI, stroke, CABG, ACS, PAD, carotid plaque (US) Type 2 DM (CHD, CKD) Type 1 DM with microalbumin, end organ damage CKD SCORE 1% 1 yr risk for fatal CVD (3 X higher for fatal and nonfatal events) B. High risk: A. markedly elevated single RF (severe HTN, HeFH) B. Type DM at any age C. SCORE 5 and < 1% C. Moderate risk: SCORE 1 to < 5%; risk can be modified by FHx, HDL-C, Lp(a), apo B and MeS Atherosclerosis 211: 217: S1-S44 Eur Heart J 211: 32: Study of Heart and Renal Protection (SHARP): Eligibility History of chronic kidney disease not on dialysis: elevated creatinine on 2 occasions Men: 1.7 mg/dl (15 µmol/l) Women: 1.5 mg/dl (13 µmol/l) on dialysis: haemodialysis or peritoneal dialysis Age 4 years No history of myocardial infarction or coronary revascularization LDL-lowering treatment not definitely indicated or contraindicated Lancet 211;377: SHARP: Baseline characteristics Characteristic Mean (SD) or % Age 62 (12) Men 63% Systolic BP (mm Hg) 139 (22) Diastolic BP (mm Hg) 79 (13) Body mass index 27 (6) Current smoker 13% Vascular disease 15% Diabetes mellitus 23% Non-dialysis patients only (n=6247) egfr (ml/min/1.73m 2 ) 27 (13) Albuminuria 8% Lancet 211;377: SHARP: Major Atherosclerotic Events Event Eze/simv (n=465) Placebo (n=462) Major coronary event 213 (4.6%) 23 (5.%) Non haemorrhagic stroke 131 (2.8%) 174 (3.8%) Any revascularization 284 (6.1%) 352 (7.6%) Risk ratio & 95% CI Major atherosclerotic event 526 (11.3%) 619 (13.4%) 16.5% SE 5.4 reduction (p=.22) Other cardiac death 162 (3.5%) 182 (3.9%) Haemorrhaghic stroke 45 (1.%) 37 (.8%) Other major vascular events 27 (4.5%) 218 (4.7%) 5.4% SE 9.4 reduction (p=.57) Major vascular event 71 (15.1%) 814 (17.6%) 15.3% SE 4.7 reduction (p=.12) Lancet 211;377: Eze/simv Placebo better better SHARP: Major Atherosclerotic Events by renal status at randomization Eze/simv (n=465) Placebo (n=462) Non dialysis (n=6247) 296 (9.5%) 373 (11.9%) Dialysis (n=323) 23 (15.%) 246 (16.5%) Risk ratio & 95% CI Any patient 526 (11.3%) 619 (13.4%) 16.5% SE 5.4 reduction (p=.22) No significant heterogeneity between non-dialysis and dialysis patients (p=.25) Lancet 211;377: Eze/simv better Placebo better 3
7 CTT: Effect of LDL-C Change on Major CVE ARS Question #3: Proportional reduction in atherosclerotic event rate (95% CI) 3% 25% 2% 15% 1% More vs Less (5 trials) Statin vs control (21 trials) SHARP 17% risk reduction SHARP 5% 32 mg/dl difference % Incremental CHD risk reduction has been shown with which treatment added to maximal statin therapy 1. Extended release niacin 2. Ezetimibe 3. Cholestryl ester transfer protein inhibition 4. Fenofibrate 5. None of the above Mean LDL cholesterol difference between treatment groups (mg/dl) Is there incremental risk reduction from add-on therapy to optimal statin use Completed trials: ACCORD: T2DM; statin vs statin + fenofibrate AIM HIGH and HPS 2 THRIVE: statin vs ER niacin or ERN/laropiprant Trials in progress: IMPROVE IT: Post ACS; statin vs statin + ezetimibe CETPi + statin vs statin (REVEAL, ACCELERATE) EPA omega-3 + statin vs statin (REDUCE IT) Anti-PCSK9 + statin vs statin (ODYSSEY, FOURIER) Atherothrombosis Intervention in Metabolic Syndrome with low HDL/high trigylcerides: Impact on Global Health (AIM HIGH) Results 3414 subjects with CVD; mean age 64; 34% with T2DM and 71% with MeS; 94% had prior statin use Randomized to simvastatin ± ezetimibe to reduce LDL-C < 8 mg/dl, and then to niacin ER 2 gm (n = 1718) or PBO (n = 1696) NEJM 211;365; AIM HIGH: Baseline Lipids (mg/dl) AIM HIGH: HDL-C at Baseline & Follow-up On Statin Off Statin 55 Combination Therapy (n=3,196) (n=218) 5 Monotherapy LDL-C (mean) HDL-C (mean) Triglycerides (median) Non-HDL (mean) Apo-B (mean) mg/dl P <.1 * * * Baseline Year 1 Year 2 Year 3 4
8 AIM HIGH: LDL-C at Baseline & Follow-up mg/dl * P <.1 Baseline Year 1 Year 2 Year 3 Combination Therapy Monotherapy AIM HIGH: Primary Outcome Cumulative % with Primary Outcome HR 1.2, 95% CI.87, 1,21 Log-rank P value=.79 Combination Therapy Monotherapy 16.4% 16.2% N at risk Time (years) Monotherapy Combination Therapy HPS2-THRIVE: Randomized placebo-controlled trial of ER niacin and laropiprant in 25,673 patients with pre-existing cardiovascular disease Eligibility: Men and women Aged 5-8 years Prior history of: myocardial infarction; ischaemic stroke or TIA; peripheral arterial disease; or diabetes with other CHD No contra-indication to study treatments No significant liver, kidney or muscle disease Characteristics of randomized participants % or mean (SD) ERN/LRPT (12,838) Placebo (12,835) Men 83% 83% 21,229 (83%) Age (years) (7.5) Prior disease Coronary 78% 78% 2,137 (78%) Cerebrovascular 32% 32% 817 (32%) Peripheral arterial 13% 12% 3214 (13%) Diabetes 32% 32% 8299 (32%) All Baseline LIPIDS on statin-based therapy Effects of ER niacin/laropiprant on lipids Mean (SD) baseline mg/dl mmol/l Total cholesterol 128 (22) 3.32 (.57) Direct-LDL 63 (17) 1.64 (.44) HDL 44 (11) 1.14 (.29) Triglycerides* 125 (74) 1.43 (.84) *64% fasted for >8 hours Year of FU LDL-C (mg/dl) HDL-C (mg/dl) Triglycerides (mg/dl) STUDY AVERAGE (mmol/l) (-.25) (.16) -.37 Based on previous observational studies and randomized trials, it was anticipated such lipid differences might translate into a 1-15% reduction in vascular events Eur Heart Journal 213 5
9 Effect of ERN/LRPT on MAJOR VASCULAR EVENTS Patients suffering events (%) Risk ratio.96 (95% CI.9 1.3) Logrank P= Years of follow-up 15.% 14.5% Placebo ERN/LRPT MAJOR VASCULAR EVENTS by low HDL/high triglycerides and prior statin use Low HDL-C, high triglycerides Randomized allocation ERN/LRPT Placebo Risk ratio & 95% CI (12838) (12835) Het or trend χ² (uncorrected p value) Yes 333 (15.1%) 334 (15.5%). No 1363 (12.8%) 1424 (13.3%) (p=.95) Prior statin use (years) None 522 (16.9%) 52 (16.8%) 2.88 > <3 478 (11.7%) 467 (11.5%) (p=.9) 3 <6 291 (1.9%) 316 (11.8%) 6 45 (13.5%) 455 (15.2%) All 1696 (13.2%) 1758 (13.7%) 3.5% SE 3.3 reduction ERN/LRPT better Placebo better Effect of ERN/LRPT on serious adverse events (median follow-up 3.9 years) Diabetic complication New onset diabetes Infection Gastrointestinal Musculoskeletal Heart failure Bleeding Skin Active ERN/LRPT Placebo Percentage of patients Excess p value 3.7% <.1 1.8% <.1 1.4% <.1 1.% <.1.7%.8.4%.5.7%.2.3%.26 How do you use niacin, or not, for lipid treatment Not for routine add-on therapy to maximal statin dosing with LDL-C < 7 and apo B < 8 Not as a HDL-C only raising therapy Can be useful for: Severe hypertg Persistent apo B/nonHDL-C elevation on statin High Lp(a) May be a viable monotherapy in statinintolerant patients (JACC 212; Dec online meta-analysis of niacin in CV prevention found 34% decrease in CV events) DEFINE: Changes in Lipid/apoproteins in the Anacetrapib-Treated Patients Variable Baseline Week 24 Week 76 LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Non-HDL cholesterol (mg/dl) Apolipoprotein B (mg/dl) Apolipoprotein A1 (mg/dl) Total cholesterol (mg/dl) Lipoprotein(a) (mmol/l) % 15% -2% 42% -4% Evacetrapib + Statin: Percent Change From Placebo Percent Change * * * * * * Atorvastatin, 2 mg/d Simvastatin, 4 mg/d Rosuvastatin, 1 mg/d LDL-C HDL-C Triglycerides CRP * P <.5 Cannon CP, Shah S, Dansky HM et al. N Engl J Med. 21. Epub. J Am Med Assoc. 211;36(19):
10 Outcomes Trials With Statin + CETPi Trial Therapy Endpoint dal- OUTCOMES HPS 3- REVEAL Statin ± Dalcetrapib 6 mg Atorvastatin ± Anacetrapib 1 mg ACCELERATE Statin ± Evacetrapib 1 mg N Patients Dates CVD 18, Post ACS Stopped 212; No benefit CVD 3, 2 prevention 11-'15 (4 yrs) CVD 12, 2º prevention Summary Strong evidence that statin-induced reduction in LDL-C in high risk people results in lower CVD events Chronic kidney disease (not requiring dialysis) is a powerful marker of high CV risk and should be an indication for intensive preventive treatments Incremental CV risk benefit of lipid drug treatment beyond maximal statin doses is limited if baseline LDL-C is low. Studies in progress will address whether further apo B lipoprotein reductions ± HDL- C raising can provide cost effective additional risk benefit dal-outcomes NEJM 212; online 11/5 HPS 3 -REVEAL: revealtrial.org FAMILIAL HYPERCHOLESTEROLEMIA: Case Finding, Clinical Assessment, and Treatment Approaches James M. Falko, MD Clinical Professor of Medicine Endocrinology/Lipid Clinic University of Colorado Hospital Aurora, CO ARS Question #1: Which of the following treatments is not currently indicated for the treatment of homozygous familial hypercholesterolemia 1.Mipomersen 2.PCSK9 monoclonal antibody therapy 3.Lomitapide 4.Apheresis 5.Statins Prevalence 1. Heterozygotes occur with a frequency of about 1 in 3 to 5 patients. 2. Heterozygous FH is one of the most commonly occurring congenital metabolic disorders. Serum total cholesterol is elevated in the range of 3-55 mg/dl. 3. Since patients have one normal LDL-R gene, their hepatocytes take up LDL-C at approximately one-half the rate of unaffected patients. Prevalence 1. Homozygotes occur with a frequency of approximately 1 in 1 million. 2. Serum cholesterol ranges from 65-1 mg/dl. Homozygotes have near total or total loss of LDL-R functionality. 3. Homozygotes can inherit two copies of the same mutant allele, or may be classified as compound homozygotes due to the inheritance of two different mutant alleles. 7
11 Genetics 1. Defined as an autosomal dominant trait with complete penetrance causing congenitally elevated levels of LDL cholesterol. 2. There is a gene dosage effect with homozygotes having significantly greater elevations of LDL-C and earlier cardiovascular disease onset than subjects who are heterozygotes. Genetics 1. Affected subjects are at increased risk for all forms of atherosclerotic disease and premature death secondary to lifelong pathogenic elevations in serum LDL-C. 2. The gene for LDLR resides on the short arm of chromosome 19 (19p ). 3. The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff lists 1614 mutations in the LDL receptor gene. Non-fatal CAD in FH (Utah) vs. General US Population Cumulative Probability of Clinical CAD Non-FH Men FH Men Age Hopkins PN, et al. Am J Cardiol 21; 87:547 and unpublished observations Non-FH Women FH Women Age Genetics Other etiologies for the FH phenotype include: 1. Autosomal dominant hypercholesterolemia attributable to gain of function mutations in PCSK9 2. Deficiency of 7-alpha hydroxylase 3. Autosomal recessive hypercholesterolemia (due to reduced expression of an adaptor protein that facilitates the association of LDLR with clathrin in cell surface coated pits). 4. Mutations in the gene for apo B can also give rise to FH (familial defective apo B). Physical Findings Yellow-orange cutaneous xanthomas Tendon xanthomas Xanthalasma Corneal arcus Heart murmur stemming from aortic or mitral valve stenosis Can develop aortic outflow tract stenosis Arterial bruits (carotid, femoral) arising from diffuse, systemic atherosclerosis Polyarthritis Tendinitis Heterozygous Familial Hypercholesterolemia: Corneal arcus Non-Specific signs Xanthelasma Courtesy of Dr. Jean Davignon, University of Montreal 8
12 Homozygous Familial Hypercholesterolemia: Screening 5-year old 17-year old 21-year old DAVIGNON 26 Universal screening for elevated serum cholesterol is recommended. FH should be suspected when untreated fasting LDL-c or non-hdl-c levels are at or above the following: Adults ( 2 years): LDL-C 19 mg/dl or non-hdl-c 22 mg/dl; Children, adolescents and young adults (<2 years): LDL-C 16 mg/dl or non- HDL-C 19 mg/dl. Screening For all individuals with these levels, a family history of high cholesterol and heart disease in first-degree relatives should be collected. The likelihood of FH is higher in individuals with a positive family history of hypercholesterolemia or of premature CHD (onset in men before age 55 years and women before age 65 years). Cholesterol screening should be considered beginning at age 2 for children with a family history of premature cardiovascular disease or elevated cholesterol. All individuals should be screened by age 2. Screening Cascade screening involves testing lipid levels in all first-degree relatives of diagnosed FH patients. As cascade screening proceeds, newly identified FH cases provide additional relatives who should be considered for screening. Cascade screening is the most cost-effective means of finding previously undiagnosed FH patients and is also cost-effective in terms of cost per year of life saved. Diagnosis These LDL cholesterol levels should prompt the clinician to strongly consider a diagnosis of FH and obtain further family information: LDL-C 25 mg/dl in a patient aged 3 or more; LDL-C 22 mg/dl for patients aged 2 to 29; LDL-C 19 mg/dl in patients under age 2. Treat All FH Patients Very high lifetime risk of coronary heart disease (CHD) Very high risk of premature onset CHD. Early treatment is highly beneficial. Long term drug therapy of patients with FH removes the excess lifetime risk of CHD due to the genetic disorder, with a goal of reducing CHD risk to a level similar to that of the general population. FH requires lifelong treatment and regular follow-up. Reference for this and subsequent slides unless otherwise noted: Robinson JG, Goldberg A. J Clin Lipidol May 211 9
13 Treat All FH Patients Untreated FH Mean onset CVD Men early 4 s Women in early 5 s 24 times higher risk of MI before age 4 Long-term statin treatment largely ameliorates excess CVD risk due to FH Risk of long-term statin treated FH patients = Risk of general population Versmissen J, et al BMJ 28; 337: a2423 Drug Therapy Efficacy in FH Patients Extensive RCT evidence statins reduce CVD and overall mortality Severely hypercholesterolemic individuals Other populations (CVD, diabetes, men & women, multiple risk factors, low LDL-C) High dose statins reduce CVD risk more than moderate dose statins Cholesterol Treatment Trialists (14 trials). Lancet 25; 366: Cholesterol Treatment Trialists (Diabetes). Lancet 28; 371: Cholesterol Treatment Trialists. (26 trials). Lancet 21; 376: Intensify Drug Treatment in Highest Risk FH Patients Consider more aggressive treatment goals for highest risk FH patients LDL cholesterol <1 mg/dl Non-HDL cholesterol <13 mg/dl FH patients at highest risk Clinically evident CHD or other atherosclerotic CVD Diabetes Family history of very early CHD Men <45 years of age or women <55 years of age Current smoking >2 CVD risk factors Intensification of Therapy in FH Patients Consider in FH patients without any high risk characteristics After the initial 5% reduction in LDL-C, LDL cholesterol 16 mg/dl OR Non-HDL cholesterol 19 mg/dl High lipoprotein (a) 5 mg/dl using an isoform insensitive assay Ezetimibe, niacin, and bile acid sequestrants, are options for intensification of therapy, or for those intolerant of statins. Weigh potential benefit of multidrug regimens against potential for adverse effects, incrased cost, and decreasing adherence New Approaches to LDL Lowering 1. ApoB mrna Antisense Oligonucleotides 2. Microsomal Triglyceride Transfer Protein Inhibitors 3. Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors MIPOMERSEN 1
14 ApoB anti-sense therapy: Mipomersen A 2-mer phosphorothioate antisense oligonucleotide complementary in sequence to segment of Apo B mrna 1,2 2 MOE 2 Deoxy (Supports RNase H Activity) G C C T C A G T C T G C T T C G C A C C Phosphorothioate Backbone 2 -O-(2-methoxyethyl)-modified ends provide high biological stability and binding affinity to mrna. 2 Mipomersen has significant distribution to the liver, where Apo B-1 is synthesized 3 1. Kastelein JJ, et al. Circulation. 26;114: Crooke ST, ed. Antisense Drug Technology: Principles, Strategies and Applications. 2nd ed. 28: Yu R, et al. Drug Metab Dispos. 27;35: MOE Mipomersen: Mechanism of Action 2 deoxy Mipomersen (apob) 2 MOE (supports RNase H activity) 2 MOE antisense strand 1,2 G C C T C A G T C T G C T T C G C A C C Phosphorothioate backbone Hepatocyte cell membrane apob mrna mrna antisense duplex RNase H recognizes duplex Cytoplasm DNA Nucleus 1. Kastelein JJ et al. Circulation 26;114: Crooke ST, ed. Antisense Drug Technology: Principles, Strategies and Applications. 2nd edn. 28:61 3. Yu R et al. Drug Metab Dispos 27;35:46 RNA is cleaved Mipomersen crosses the hepatocyte and nuclear membranes to target apob mrna 1,2 Mechanism of Action RNase H-mediated Degradation of Target mrna mrna Antisense Drug (Oligonucleotide) mrna-dna Duplex mrna-h Recognizes Duplex Mipomersen: Targeting Apo B at Point of Synthesis and Secretion Cholesterol Mipomersen VLDL 2 MOE Human Apo B mrna 2 Deoxy (Supports RNase H Activity) 2 MOE RNase H Apo-B Triglyceride A G T C T G C T T C G11 Phosphorothioate backbone Target Protein X VLDL IDL LDL1 LDL2 LDL3 Lp(a) Apo(a) Phase 2: Hypercholesterolemia, Monotherapy Dose-dependent Reduction of LDL-C LDL-C % change from baseline, Mean (SE) Once Weekly Dosing Placebo 5 mg 1 mg 2 mg 3 mg 4 mg (n = 1) (n = 8) (n = 8) (n = 8) (n = 8) (n = 8) Treatment period Summary of mipomersen efficacy on top of maximally-tolerated LLT Percentage change from baseline in LDL-C, apob, Lp(a), TG and HDL-C in patients treated with mipomersen Patient population Baseline Baseline LDL-C (mmol/l) (mg/dl) LDL-C Mean % change from baseline ApoB Mean Lp(a) Median TG Median HDL-C Mean HoFH % 27% 32% 18% 19% Severe HC % 36% 39% 15% 6% HeFH with CAD 4. 28% 26% 21% 14% 3% HC at high risk for CAD % 38% 26% 26% 2% Akdim F et al Eur Heart J. 211; 32: Day Raal FJ et al. Lancet 21;375:998 McGowan MP et al. PLoS One 212;7(11):e496 Stein EA et al. Circulation 212;126:2283 Cromwell W et al. J Am Coll Cardiol 211;57:Poster
15 HoFH Study: Effects of Mipomersen on LDL-C, Apo B and Lp(a) Mipomersin Phase 3 Trials: Safety On Treatment Adverse Events and Clinical Findings Apo B, LDL-C, and Lp(a) reductions Mean (95% Cl) % Change from Baseline in Apo B, LDL-C, and Lp(a) (Baseline represents maximum tolerated LLT) Wk 3% Apo B 3% LDL 8% Lp(a) 27% Apo B 25% LDL 32% Lp(a) Adverse Events Most common: mild-to-mod. inject. site reactions & flu-like symptoms 5% discontinued due to ISRs and 2.7% discontinued due to FLS Clinical Findings Transaminase increases 8.4% on mipomersen ALT 3x ULN on 2 occasions 7 days apart No effect on total bilirubin, albumin, PT Modest increase in hepatic fat; reversible after cessation of dosing No significant drug-drug interactions with statins, ezetimibe or warfarin No CYP45 induction or inhibition No P-glycoprotein inhibition No protein binding interaction No QTc changes in ECG study Raal FJ et al Lancet 21;375: Assembly and secretion of apob-1- containing lipoproteins in the liver LOMITAPIDE Cytoplasm ER lumen apob signal peptide apob MTP + Lipid (CE, TG) VLDL Degradation pathway Secretion pathway ER, endoplasmic reticulum; CE, cholesterol ester; MTP, microsomal triglyceride transfer protein; TG, triglyceride Adapted from Cuchel M et al. N Engl Med 27;356:148 Efficacy and safety of lomitapide in HoFH: single-arm, open-label phase III study Mean percent changes in LDL-C, TC and ALT and AST levels and percentage of apob from baseline to Week 26 (n=23) hepatic fat in the liver 1 LDL-C 9 ALT 2 TC 8 AST ApoB B Study week Study week Mean ( SD) 5 Baseline Week 26 Week 56 Week 78 Mean (98% CI) LDL-C 5%, apob 15%, TG 45% Mean hepatic fat measure by NMRS (n=2) increased from 1% at baseline to 8.6% at Week 26, 5/8% at Week 56 and 8.3% at Week 78 Cuchel M et al. Lancet 212:dx.doi.org/1.116/S (12) Change from baseline (%) Transaminases IU/l) Hepatic fat (%) Clinical profile of lomitapide Requirements for administration Requires adherence to <1% fat diet Titration indices: elevation in ALT and GI AEs Need for supplementation (fat-soluble vitamin malabsorption) Adverse events 3 of 23 (13%) discontinuation due to GI AEs Weight loss in normal weight/bmi subjects in Phase III study Can cause fatty liver CYP3A4 interactions and requirement for simvastatin and warfarin dose adjustment Phase III study allowed changes in baseline treatment, and medication dose to reduce elevations in AST/ALT Cuchel M et al. N Engl J Med 27;356:148 Cuchel M et al. Lancet 212:dx.doi.org/1.116/S (12)
16 MTP inhibition: Mechanism of Action B-1 VLDL CIII E B-1 IDL E LPL CIII HL LDL-receptors B-1 LDL Extra-hepatic tissue PCSK9 MONOCLONAL ANTIBODY THERAPY MTP inhibitors Triglycerides ApoB-1 Acetyl-CoA CE HMG-CoA Mevalonic acid Cholesterol Lomitapide acts on both liver and intestine, and can inhibit apob-48 secretion Modified from: Ito MK et al. Ann Pharmacother 27;41:1669 Proprotein convertase subtilisin/kexin type 9 9 th member of family of secretory serine proteases; involved specifically in degradation of LDL Receptor Loss of function mutations are associated with lifelong low LDL-C levels and decreased risk of cardiovascular disease Gain of function mutations are associated with lifelong high LDL-C levels and increased risk of cardiovascular disease PCSK9 monoclonal antibody REGN727/ SAR236553: LDL-C reduction LDL-C mean ( SE) % change from baseline Baseline Week 2 Week 4 Week 6 Week 8 Week 1 Week % 39.6% 43.2% 47.7% % % -8 Placebo SAR mg Q2W SAR mg Q2W SAR mg Q4W SAR mg Q4W SAR mg Q2W Injections of 1 ml Mean percentage change in calculated LDL-C from baseline to Weeks 2, 4, 6, 8, 1 and 12 in the mitt population, by treatment group. Week 12 estimation using LOCF method LOCF, last observation carried forward McKenney JM et al. J Am Coll Cardiol 212;59:2344 Conclusions Conclusions 1. FH is associated with significantly elevated LDL-C and increased risk for CAD. 2. There are multiple etiologies for the phenotype of FH, the most common being a mutation in the gene for the LDL receptor. 3. FH is associated with multiple physical findings (xanthomas, xanthelasmas, etc) that increase the likelihood of the diagnosis of FH. 4. Universal screening for elevated serum cholesterol is recommended. 1. In the setting of HoFH lipid lowering with statins, ezetimibe, bile aid binding resins, and niacin frequently provide inadequate LDL-C reduction 2. LDL-C apheresis is an important treatment option where available 3. Two newly approved therapies for HoFH include mipomersen and lomitapide 4. PCSK9 monoclonal antibody therapy is an exciting, emerging new therapy that can also provide substantial reductions in atherogenic lipoproteins in patients with heterozygous FH 13
17 Outcomes Question 1 In meta-analyses, a 4 mg/dl reduction in LDL-C decreases major CV events by: 1. 1% 2. 22% 3. 3% 4. 36% Outcomes Question 2 Based on recent clinical trial results, statin add-on therapy with niacin is reasonably indicated for: 1. Additional CV event reduction 2. Increasing HDL-C 3. Reducing severe triglyceride elevations 4. Sparing statin dose escalation Outcomes Question 3 Chronic Kidney disease is: 1. Considered a CHD risk equivalent 2. Not associated with progression to dialysis 3. Defined as an estimate GRF > 6 ml/min/1.73m² Question & Answer 14
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