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1 1:45 2:45pm Lipid Management: A Primary Care Perspective Presenter Disclosure Information The following relationships exist related to this presentation: Richard F. Wright, MD, FACC, has no financial relationships to disclose. SPEAKER Richard F. Wright, MD, FACC 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. Learning Objectives Utilize evidence-based lipoprotein management strategies for non-ldl-c lipid targets Describe the risk factors, disease spectrum, and appropriate management of familial hypercholesterolemia 213 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce ASCVD in Adults Four statin benefit groups: 1. Patients with CVD (ACS, MI, angina, revascularization, stroke, TIA, PVD) but w/o class II-IV CHF (with LVEF<35%) or ESRD 2. LDL-C > 19 mg/dl 3. Patients age 4-75 with diabetes and LDL-C 7-19 w/o CVD 4. Patients w/o CVD or diabetes, age 4-75 with LDL 7-19 mg/dl and a 1 yr risk 7.5% No evidence to support use of LDL-C or nonhdl-c treatment targets; instead use appropriate statin intensity Stone NJ, et al. 213 ACC/AHA Blood Cholesterol Guideline. J Am Coll Cardiol Nov ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce ASCVD in Adults High-intensity statins (lower LDL > 5%): Group 1 and 2 Atorvastatin 4-8 mg Rosuvastatin 2-4 mg Moderate-intensity statins (lower LDL 3-5%): Group 3 & 4 Atorvastatin 1-2 mg Pravastatin 4 mg Rosuvastatin 1 mg Lovastatin 4 mg Simvastatin 2-4 mg Non-statin lipid drugs alone or in combination with statins: no data to make any recommendation No recommendation about primary prevention in patients with 1 yr risk < 7.5%; use clinical judgment and other factors: FHx, LDL-C > 16 mg/dl, hs-crp > 2 mg/l, CACS > 3, ABI <,9 or high lifetime risk. Stone NJ, et al. 213 ACC/AHA Blood Cholesterol Guideline. J Am Coll Cardiol Nov 213 Non-HDL Cholesterol and CVD Risk Non-HDL-C Calculation: Non-HDL-C = TC-HDLC Non-HDL-C Goal: 3 mg/dl above LDL-C goal Significance of Non-HDL-C Encompasses all known and potential atherogenic lipid particles (linearly proportional to Apo B) Has been shown to be a stronger predictor of cardiovascular death than LDL-C, especially in women Bittner V. Curr Opin Lipidol. 23;14: Cui Y, et al. Arch Intern Med. 21;161: Ridker PM. JAMA. 25; 294: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Circulation. 22;16:

2 LDL Particle Number Distribution in Type 2 Diabetes Subjects Percent of Subjects Percent of Subjects 5 th 2 th 5 th 8 th percentile 2 1% 24% 43% 21% 11% (n=19) (n=364) (n=631) (n=37) (n=163) (nmol/l) 2 16% 43% 3% 9% 2% (n=147) (n=377) (n=26) (n=76) (n=15) % Cromwell WC, Otvos JD. (nmol/l) AJC. 26;98: LDL-C 7-99 mg/dl (n=1,484) LDL-C < 7 mg/dl (n=871) History of Niacin Therapy for Raising HDL Coronary Drug Project (1975) men with previous MI and hypercholesterolemia Mean follow-up 6.2 years Total mortality similar in the two groups at 5 years (24.4% niacin vs 25.4% placebo, P=NS) Niacin did provide a significant reduction in recurrent nonfatal MI (27% reduction, P <.4) HDL-Atherosclerosis Treatment Study (HATS) (21) 2 3-year, randomized, double-blind trial 16 patients with coronary disease, low HDL-C, and normal LDL-C levels Simvastatin plus niacin resulted in significant regression of angiographic coronary atherosclerosis and reductions in clinical events rate 1. Coronary Drug Project. JAMA. 1975;231: Brown BG, et al. N Engl J Med. 21;345: AIM-HIGH: Niacin Plus Statin to Prevent Vascular Events ER niacin 5/1/15/2 mg and simvastatin 4 mg 4-8 week run-in with niacin dose increased each week Inclusion Criteria Age 45 History of vascular disease Atherogenic dyslipidemia LDL-C 16 mg/dl HDL-C 4 mg/dl men or 5 mg/dl women TG 15 mg/dl 4 mg/dl For patients entering the trial on a statin HDL-C 42 mg/dl men or 53 mg/dl women TG 125 mg/dl 4 mg/dl ER niacin 2 or 15 mg and simvastatin 2/4/8 mg* Simvastatin 2/4/8 mg* 3-5 years * dependent on LDL-C levels, ezetimibe 1 mg may be added Primary Endpoint Composite Endpoint for first event: CHD death nonfatal MI ischemic stroke hospitalization for high-risk non-stemi ACS Secondary Endpoint Composite of CHD death, nonfatal MI, or ischemic stroke out to common date AIM-HIGH Investigators. N Engl J Med. 211;365: AIM-HIGH Baseline Lipids (mg/dl) On Statin (n=3,196) Off Statin (n=218) LDL-C (mean) HDL-C (mean) Triglycerides (median) Non-HDL (mean) Apo-B (mean) AIM-HIGH Investigators. N Engl J Med. 211;365: AIM-HIGH Primary Outcome: First CV Event* AIM-HIGH: What Happened? Cumulative % with Primary Outcome Combination Therapy Monotherapy HR 1.2, 95% CI.87, 1,21 Log-rank P value=.79 Lipid Outcomes with Niacin: HDL-C from 35 to 42 mg/dl TG from 164 to 122 mg/dl LDL-C from 74 to 62 mg/dl 16.4% 16.2% ER niacin vs placebo + simvastatin/ezetimibe N at risk Time (years) *composite of death from CHD, nonfatal MI, ischemic stroke, hospitalization for ACS, or symptom-driven coronary or cerebral revascularization AIM-HIGH Investigators. N Engl J Med. 211;365: In this aggressively managed group of patients, was there no residual risk, hence no need for niacin? Prior studies done with Niacin IR. Perhaps niacin ER ineffective? effect? Niacin did not lower Apo B or LDL-P? Otvos JD. J Clin Lipidol. 211;5: HDL raising not effective if LDL-P or Apo B at goal? Perhaps raising HDL-C with no impact on HDL-P with low ApoB/LDL-P levels is not effective? The surprising AIM-HIGH results are not surprising when viewed through a particle lens (Otvos, 211)

3 HPS2-THRIVE Trial Randomized, placebo-controlled trial of ER niacin and laropiprant* 25,673 men and women with pre-existing cardiovascular disease Aged 5-8 years Prior history of: MI, ischaemic stroke or TIA, PAD, or diabetes with other CHD No contraindication to study treatments No significant liver, kidney or muscle disease * Laropiprant not FDA approved; suspended worldwide 213 HPS2-THRIVE Collaborative Group. Eur Heart J. 213;34: HPS2-THRIVE: Characteristics of Randomized Participants % or mean (SD) ERN/LRPT (12,838) (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%) HPS2-THRIVE Collaborative Group. Eur Heart J. 213;34: All ERN=extended release niacin LRPT=laropiprant HPS2-THRIVE: Baseline Lipids on Statin- Based Therapy 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 HPS2-THRIVE Collaborative Group. Eur Heart J. 213;34: HPS2-THRIVE: Reasons for Stopping Study Treatment ERN/LRPT (12,838) (12,835) Excess Any medical 16.4% 7.9% 8.5% Skin 5.4% 1.2% 4.2% Gastrointestinal 3.9% 1.7% 2.1% Musculoskeletal 1.8% 1.%.8% Diabetes-related.9%.4%.5% Liver.4%.3%.1% Other 4.1% 3.3%.8% Any non-medical 8.9% 8.7%.3% Any reason 25.4% 16.6% 8.7% 78% average compliance with active ERN/LRPT HPS2-THRIVE Collaborative Group. Eur Heart J. 213;34: LRPT=laropiprant ERN=extended release niacin HPS2-THRIVE: Effect of ERN/LRPT on Serious Adverse Events Diabetic complication New onset diabetes Infection Gastrointestinal Musculoskeletal Heart failure Bleeding Skin Excess p value 3.7% <.1 1.8% <.1 1.4% <.1 1.% <.1 Active ERN/LRPT.7%.4%.8.5.7%.2 Median follow-up: 3.9 years.3% LRPT=laropiprant Percentage of patients ERN=extended release niacin HPS2-THRIVE Collaborative Group. Eur Heart J. 213;34: ERN/LRPT: GI, Muscle & Skin SAEs Serious Adverse Event Risk ratio (95% CI) ERN/LRPT (12,838) (12,835) Gastrointestinal GI bleeding.8%.6% 1.53 ( ) Peptic ulcer/upper GI 1.9% 1.4% 1.37 ( ) Lower GI.9%.7% 1.39 ( ) Other GI 1.% 1.%.99 ( ) Any gastrointestinal SAE 62 (4.8%) 491 (3.8%) 1.28 ( ) Musculoskeletal Myopathy.6%.1% 4.43 ( ) Gout.3%.2% 1.91 ( ) Other 2.9% 2.7% 1.8 ( ) Any musculoskeletal SAE 481 (3.7%) 385 (3.%) 1.26 ( ) Skin Rash.4%.3% 1.63 ( ) Ulcer.2%.1% 1.61 ( ) Other.1%.% 2.59 ( ) Any skin SAE 86 (.7%) 51 (.4%) 1.67 ( ) HPS2-THRIVE Collaborative Group. Eur Heart J. 213;34:

4 Effect of ERN/LRPT on Infection and Bleeding Serious Adverse Event ERN/LRPT Risk ratio (95% CI) (12,838) (12,835) Infection Lower respiratory 4.3% 3.7% 1.17 ( ) Urinary tract.9%.8% 1.7 ( ) Abdominal/gastrointestinal.6%.5% 1.26 ( ) Skin.5%.3% 1.66 ( ) Other 2.4% 1.7% 1.38 ( ) Any infection SAE (8.%) (6.6%) 1.22 ( ) Bleeding Gastrointestinal.8%.6% 1.53 ( ) Intracranial 1.1%.9% 1.17 ( ) Other.6%.4% 1.66 ( ) Any bleeding SAE 326 (2.5%) HPS2-THRIVE Collaborative Group. Eur Heart J. 213;34: (1.9%) 1.38 ( ) Effects of ER Niacin/Laropiprant on Lipids Year of Follow-Up 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 HPS2-THRIVE Collaborative Group. Eur Heart J. 213;34: HPS2-THRIVE: Summary No significant benefit of ER niacin/laropiprant on the primary outcome of major vascular events when added to effective statin-based LDL-lowering therapy Significant excesses of serious adverse events (SAEs) due to known and unrecognised side-effects of niacin. Over 4 years, ER niacin/laropiprant led to SAEs in ~3 patients per 1 No clear evidence of differences in efficacy or safety in different types of patients (except for an excess of statin-related myopathy in Chinese patients) Findings are consistent with previous niacin trials The role of ER niacin for the treatment and prevention of cardiovascular disease needs to be reconsidered Fibric Acid Derivative Trials Helsinki Heart Study VA-HIT FIELD ACCORD HPS2-THRIVE Collaborative Group. Eur Heart J. 213;34: Helsinki Heart Study 4,81 men aged 4-55 years with non-hdl-c 2 mg/dl, initially free of coronary disease LDL-C 11%, HDL-C +11% 34% reduction in CHD endpoints Greatest benefits when triglyceride high or HDL-C low LDL-C/HDL-C >5. and triglycerides >2 mg/dl: risk was reduced by 71% Cumulative MIs+CV Deaths 1 1 % Gemfibrozil Years Veterans Affairs HDL Intervention Trial (VA-HIT) Gemfibrozil 6 mg bid 2,531 men with CAD HDL-C 4 (mean 32) LDL-C 14 (mean 111) Triglycerides 3 (mean 161) 25% diabetic 57% hypertensive BMI 29 kg/m 2 Followed for MI or coronary death over 5 years Frick MH, et al. N Engl J Med. 1987;317: Rubins HB, et al. N Engl J Med. 1999;341:

5 VA-HIT: Gemfibrozil vs. in Patients with Low HDL-C Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study Design % change * P =.6 ** P <.1 No change -31% 6% -22%* -24%** LDL-C TG HDL-C Nonfatal Strokedeath MI or CHD Death 5-year study against a background of usual care, including the option to add other lipid-lowering therapies 9795 Type 2 Diabetes Patients No clear indication for lipidlowering therapy at baseline Fenofibrate 2 mg/day, n = Other lipid-lowering therapies, n = 49 +Other lipid-lowering therapies 5 Years or 5 CHD Events Rubins HB, et al. N Engl J Med. 1999;341: FIELD Study Investigators. Cardiovasc Diabetol. 24;3:9-24. FIELD: Baseline Characteristics Characteristic (n = 49) Fenofibrate (n = 4895) Male, % No Prior CVD, % Lipid parameters, mg/dl TC LDL-C HDL-C TG Dyslipidemic*, % *TG >15 mg/dl and HDL-C <4 mg/dl for men or <5 mg/dl for women FIELD: Primary and Secondary Endpoints Event Rate, % Fenofibrate 11% Reduction P =.16 24% Reduction 5.9 P = % Increase 4.2 P = % Reduction P =.35 CHD events* Nonfatal MI CHD Death Total CVD Coronary Events** Revascularization * Nonfatal MI and CHD death ** CHD events, stroke, CVD death, revascularizations % Reduction P = Keech A, et al. Lancet. 25;366: Keech A, et al. Lancet. 25;366: FIELD: Total CVD Events in Patient Subgroups ARR = 2.1% NNT = 48 14% Reduction P = Fenofibrate *<4 mg/dl (men) and <5 mg/dl (women) at baseline Triglycerides 15 mg/dl and low HDL-C at baseline Event Rate, % Patients With Low HDL-C* Patients With Dyslipidemia Keech A, et al. Lancet. 25;366: Event Rate, % 14% Reduction P = Fenofibrate ARR = 2.3% NNT = 44 Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Comparison of statin plus a fibrate vs statin monotherapy for reduction of CVD in diabetics at high CVD risk 5518 Type 2 Diabetes Patients Simvastatin + Fenofibrate Simvastatin + ACCORD Study Group. N Engl J Med. 21;362: Primary outcome : nonfatal MI, nonfatal stroke, or death from CV causes Follow-Up 4.7 Years

6 ACCORD Study Results Simvastatin + Fenofibrate ACCORD Study Group. N Engl J Med. 21;362: Simvastatin + Primary outcome 2.2% 2.4% NS (annual rate) Annual death rate 1.5% 1.6% NS Prespecified subgroup analysis suggested heterogeneity in treatment according to sex, with benefit for men and possible harm for women (P=.1 for interaction) P Possible benefit in fenofibrate group if baseline TG high >24 mg/dl and HDL-C <34 mg/dl. Primary outcome rate:12.4% fenofibrate vs. 17.3% placebo (P=.57 for interaction) ACCORD: Primary Outcome By Treatment Group and Baseline Subgroups Overall Fenofibrate % Events (# in group) 1.5% (2765) % Events (# in group) 11.3% (2753) Hazard Ratio Feno:Plac Interactio np Value Triglycerides & HDL.567 TG 24 mg/dl & HDL 34 mg/dl 12.4% (485) 17.3% (456) All others 1.X% (2264) 1.1% (2284) 1 2 Fenofibrate therapy better ACCORD Study Group. N Engl J Med. 21;362: therapy better Heart Protection Study (HPS): Major Vascular Events by Prior Disease Previous MI Other CHD (not MI) No prior CHD CVD PVD SIMVASTATIN PLACEBO (1269) (1267) 999 (23.5%) 125 (29.4%) 46 (18.9%) 591 (24.2%) 172 (18.7%) 212 (23.6%) Rate ratio & 95% CI STATIN better PLACEBO better 327 (24.7%) 42 (3.5%) Diabetes 276 (13.8%) 367 (18.6%) 24% SE 3 ALL PATIENTS 233 (19.8%) 2585 (25.2%) Heart Protection Study Collaborative Group. Lancet. 22;36:7-22. reduction (2P <.1) Treating to New Targets (TNT): Study Design Randomized, double-blind, placebo-controlled trial over 5 years 1,1 patients with: clinically evident CHD and LDL-C <13 mg/dl while on atorvastatin 1 mg daily LaRosa JC, et al. N Engl J Med. 25;352: Atorvastatin 8 mg Atorvastatin 1 mg Primary Endpoint: time to first major CV event* *CHD death, nonprocedural MI, resuscitation after cardiac arrest, or stroke TNT: Low LDL-C Benefits Patients With Diabetes and CHD Post hoc analysis: 15 subjects with diabetes, CHD, and LDL <13 mg/dl Atorvastatin 8 mg: 25% fewer CV events than in the 1-mg group Atorvastatin 1 mg: LDL=99 mg/dl Atorvastatin 8 mg: LDL=77 mg/dl Musculoskeletal safety profile comparable between 2 groups Lowering LDL levels below suggested guidelines continues to benefit high-risk patients Shepherd J, et al. Diabetes Care. 26 Jun;29(6): HPS: Vascular Events by LDL-C Baseline feature LDL-C < 1(2.6 mmol/l) < (3.4 mmol/l) STATIN PLACEBO Risk ratio & 95% CI (1269) (1267) STATIN better STATIN worse ALL PATIENTS (19.9%) (25.4%) Heart Protection Study Collaborative Group. Lancet. 22;36:7-22. Het c2 =.8 24% SE 2.6 reduction (2P<.1)

7 Case Study: Pat 62-year-old woman with family history of maternal uncle having MI at age 39 Physical exam normal except thickening of Achilles tendons bilaterally Labs Patient is euthyroid Chemistries: normal Total cholesterol: 35 mg/dl HDL-C: 5 mg/dl LDL-C: 21 mg/dl Triglycerides:175 mg/dl Genetic Etiologies for Very High LDL Familial Hypercholesterolemia (FH) LDL receptor mutation (heterozygous, homozygous, compound homozygous) Mutations in the gene for apo B can also give rise to FH (familial defective apo B). Deficiency of 7-alpha hydroxylase (cyp7a1mutation) Autosomal recessive hypercholesterolemia (due to reduced expression of adaptor protein that facilitates association of LDLR with clathrin in cell surface coated pits). Autosomal dominant hypercholesterolemia attributable to gain of function mutations in PCSK9 FH Prevalence Genetics Heterozygotes Frequency 1 in 3-5 One of most common congenital metabolic disorders Serum cholesterol: 3-55 mg/dl Since patients have one normal LDL-R gene, their hepatocytes take up LDL- C at approximately onehalf the rate of unaffected patients. Homozygotes Frequency 1 in 1 million Serum cholesterol: 65-1 mg/dl Have near total or total loss of LDL-R functionality Can inherit 2 copies of same mutant allele, or may be classified as compound homozygotes due to inheritance of 2 different mutant alleles Affected subjects are at increased risk for all forms of atherosclerotic disease and premature death secondary to lifelong pathogenic elevations in serum LDL-C. The gene for LDLR resides on the short arm of chromosome 19 (19p ). The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff lists 1614 mutations in the LDL receptor gene. Goldberg AC, et al. J Clin Lipidol Jun;5(3 Suppl):S1-S8. Goldberg AC, et al. J Clin Lipidol Jun;5(3 Suppl):S1-S8. Physical Findings in Familial Hypercholesterolemia Yellow-orange cutaneous xanthomas Tendon xanthomas Xanthelasma Corneal arcus Heart murmur stemming from aortic stenosis Can develop supravalvular stenosis of the aorta Arterial bruits (carotid, femoral) arising from diffuse, systemic atherosclerosis Polyarthritis Tendinitis Screening for FH Adults ( 2 years) Children, adolescents and young adults (<2 years) Screening Recommendations LDL cholesterol 19 mg/dl or non-hdl cholesterol 22 mg/dl LDL cholesterol 16 mg/dl or non- HDL cholesterol 19 mg/dl. Ask about family history of high cholesterol and heart disease in first-degree relatives Higher likelihood of FH with positive family history of hypercholesterolemia or CHD onset < 55 years (men), < 65 years women Consider cholesterol screening starting at age 2 for children with a family history of premature CHD or elevated cholesterol All individuals should be screened by age 2 Goldberg AC, et al. J Clin Lipidol Jun;5(3 Suppl):S1-S8.

8 Treat All FH Patients Very high lifetime risk of coronary heart disease Very high risk of premature onset CHD Early and long term treatment is highly beneficial Long term drug therapy in patients with FH removes 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 LDL apheresis: LDL>2 mg/dl; 13 mg/dl with Lp(a) >5-6 mg/dl 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 Goldberg AC, et al. J Clin Lipidol Jun;5(3 Suppl):S1-S8. Versmissen J, et al. BMJ. 28; 337: a2423 Aggressive Approaches to LDL Lowering and Novel agents ApoB (LDL-C, Non-HDL-C) Lowering LDL apheresis ApoB mrna antisense oligonucleotides (indicated for HoFH) Microsomal triglyceride transfer protein (MTP) inhibitors (indicated for HoFH) Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors Current Statins Maximize or optimize Ezetimibe Bile acid sequestrants Niacin Fibrates Future? ApoB formation inhibitors PCSK9 inhibitors MTP inhibitors HoFH=homozygous familial hypercholesterolemia Antisense Mechanism of Action An antisense oligonucleotide (ASO) blocks the mrna translation into protein, therefore blocking protein synthesis ApoB-1 as a target Essential for the synthesis and transport of VLDL and LDL-C Plays a crucial role in lipid management Reductions in LDL-C and Lp(a) Levels in Ho- FH (n=51) with Mipomersen Mean % change from baseline in LDL-C Mean (95% CI) % change from baseline in Lp(a) Reduction in LDL-C over 28 weeks Mipomersen 2 mg Reduction in Lp(a) over 28 weeks % 25% 8% 31% Raal FJ, et al. Lancet. 21:375(9719)

9 Mipomersen Safety Injection site reactions (84%), flu-like symptoms (3%), nausea, headache 8.4% of mipomersen-treated patients had ALT > 3x ULN on two consecutive measures 7 days apart (vs % for placebo) Reversible, median increase in hepatic fat with no effects noted on liver synthetic function (total bilirubin, PT, albumin) Hepatic steatosis is a risk factor for progressive liver disease Human Monoclonal Antibody to PCSK9* Changes in Apo B, Non-HDL-C, and Lipoprotein(a) from Baseline to Week 12 by Treatment Group Intervention % Change Apo B % Change Non-HDL-C % Change Lipoprotein(a) Alirocumab* 5 mg/2 weeks -27.3* -33.6* -13.3** Alirocumab 1 mg/2 weeks -48.1* -55.6* -26.1* Alirocumab 15 mg/2 weeks -56.1* -62.5* -28.6* Alirocumab 2 mg/4 weeks -28.7* -37.4* -6.7** Alirocumab 3 mg/4 weeks -33.1* -4.7* -7.9** * P<.1 for % change Alirocumab vs. placebo ** P =.5 for % change Alirocumab vs. placebo *Alirocumab is an investigational drug McKenney JM, et al. J Am Coll Cardiol. 212;59: Microsomal Transfer Protein Inhibitors Key Clinical Take Home Points Dose-escalation study in 6 patients with homozygous familial hypercholesterolemia Lomitapide,* 1 mg/kg daily, decreased LDL-C by 5.9% and Apo B by 55.6% from baseline Markedly reduces Apo-B production Adverse effects were elevated aminotransferase levels and hepatic fat accumulation in 1-4% of patients at the 1. mg/kg dose range *Lomitapide is only approved for use in patients with homozygous familial hypercholesterolemia. LDL-C remains the principle target of therapy for patients at risk for CAD. (Evidence Level A) The evidence for HDL-C raising/tg lowering providing additional benefit on top of statins to reduce CHD risk is disappointing. (FIELD, AIM HIGH, ACCORD) Non-HDL-C and ApoB are better predictors of CHD risk than LDL-C in patients with elevated TG. (Evidence Level A) We still need a trial of patients with high non-hdl-c who are at LDL-C targets to prove treatment benefit. Cuchel M, et al. N Engl J Med. 27;356: Getting Non-HDL to Target in Mixed Dyslipidemia Consider the patient: age, finances, side effects Intensify LDL-C lowering or use combination therapy to adjust HDL-C/TG TG level > 2 with LDL-C/HDL-C ratio >5? This patient will likely benefit from niacin or fibrate Follow NCEP guidelines, until trial evidence suggests differently! Conclusions: LDL, HDL, TG, non-hdl Benefit of adding niacin or fenofibrate to statin to raise HDL-C in patients with T2DM, mixed dyslipidemia and CAD? Clinical benefits of novel therapies to increase HDL-C? Last 2 decades focused on LDL lowering. Current evidence is lacking. Jury remains out. Next decade will likely focus on HDL-C, TG, non-hdl-c, Apo B, FBS, BP and obesity. In order to adequately reduce residual risk we will need to be more aggressive at treating all the risk factors for CHD and to develop systems to provide better treatment to large numbers of patients.

10 Conclusions: Familial Hypercholesterolemia FH is a common genetic disorder Diagnosis is critical not only for the patient but also for family members Cascade screening is mandatory Aggressive treatment of LDL is necessary Several new therapeutic agents are under development that will likely be effective for treatment of FH and statin-intolerant patients Questions?