UPDATES IN LIPID 2017 Cardiovascular Symposium MANAGEMENT SUDHA RAVILLA, MD, DIPLOMATE, ABCL MEDICAL DIRECTOR CLINICAL LIPIDOLOGY TMHPP METABOLIC HEALTH CENTER
INTRODUCTION CVD is STILL the No. 1 cause of mortality world wide!
LIPOPROTEINS AND ASCVD RISK LDL-C?, HDL-C?, TG?
LDL-C: EVIDENCE FOR ASCVD RISK? Epidemiologic evidence: LDL-C Independent Risk Factor: FHS 1.5 times higher incidence of CHD if LDL-C > 160 vs LDL-C < 130 mg/dl. Genetic evidence: SNP mutations of PCSk9, ApoB, ApoE, LDLR genes modify CV risk +/- (Key point in genetics: Duration of exposure has >impact on CVRR: genes captures LT Risk!) Clinical trials: demonstrated NET CV benefits with LDL C Reduction: Prim Prevention trials: WOSCOPS, AFCAPS/TexCAPS, CARDS, MEGA, JUPITER, ASCOT-LLA Sec Prevention trials: 4S, CARE, LIPID, LIPIS, HPS, ALLIANCE More Intensive vs Less Intensive: PROVE-IT, TNT, IDEAL, A-Z, SEARCH
AFTER LDL-C REDUCTION. EVENTS STILL HAPPEN! RESIDUAL RISK?
RESIDUAL RISK: ATHEROGENIC DYSLIPIDEMIA: HIGH TG/LOW HDL/ HIGH NON-HDL-C RRRi (Scientists, Cardiologists, Endocrinologists) 2008 to address RR! Atherogenic Dyslipidemia is underdiagnosed and undertreated! Prevalent in pts with Dm, Met Sx, who typically have discordance between LDL-C and non-hdl- C/ApoB...So, we can t stop at LDL lowering! Multifactorial intervention needed : Lifestyle modification, Targeting ALL lipid goals, Optimal control of BP and Glycemia.
HDL-C: EVIDENCE FOR ASCVD RISK?
HDL-C: EVIDENCE FOR ASCVD RISK? Epidemiological data Strong for Inverse correlation of HDL-C with Heart Dx! Still a great Biomarker for Heart Dx Risk - Crucial RF in Risk Stratificn of pts! BUT recent Genetic studies and Clinical trial evidence have been disappointing! Functionality of HDL matters: The sheer cholesterol load of HDL particles does not reflect Efflux Capacity- Reverse Cholesterol transport. This indeed may be the missing piece to the puzzle?! Summary: HDL Hypothesis losing heat due to conflicting genetic studies, dismal outcomes in clinical trials..keep in mind there is no magic bullet to target HDL in a pure fashion to know for sure!
TRIGLYCERIDES: EVIDENCE FOR ASCVD RISK? IT S BACK!!! Genetic, Epidemiologic studies and Meta analyses indicate: TG strong and Independent CV risk predictor! Validity as a Biomarker of ASCVD, especially in combination with low HDL-C and Elevated LDL-C has been well established! Growing Genetic evidence for CAUSALITY now! TG levels maintain assn with CHD even after adjusting for HDL-C! Clinical trial evidence for TG lowering : Negative so far for Prim end points! (Caveat: In trials involving TG lowering agents (ACCORD, AIM-HIGH), subgroup analysis of pts with TG >~200 mg and HDL-C <~34mg/dl had lower events ~29 and 36% respectively!)
REMEMBER... REMNANT PARTICLES CAN BE ATHEROGENIC Am J Cardiol 2016; 118
PHARMACOTHERAPY
LDL FOCUSED PHARMACOTHERAPY WITH + OUTCOMES TRIAL EVIDENCE MECHANISM OF LDL LOWERING : LDL RECEPTOR UPREGULATION HMG CoA Reductase Inhibition (production/clearance) Statin (AFCAPS/TEXCAPS, CARE, LIPID,4S, HPS, TNT, SPARCL, JUPITER) NPC1L1 Protein (absorption) Ezetimibe (IMPROVE-IT: S+Z in recent ACS) and SHARP: S+Z in CKD) Bileacids Sequestration (disposal) BAS (LRC-CPPT: BAS vs Placebo, Monotherapy, Prim prevention trial) LDL receptor density PCSk9 ab (ODYSSEY outcomes: Alirocumab + Statin/Post-ACS 2018 and FOURIER: Evolocumab + Statin/CVD 2017)
LDL, LDL-R, PCSK9 and PCSK9 ANTIBODY DYNAMICS
OTHER LIPID ALTERING MECHANISMS.. Lower VLDL production, Fatty acid synthesis Nicotinic acid, Fibrates, Omega-3. (TRIALS: CDP, HATS, FATS, AIM-HIGH, HPS-THRIVE, ACCORD, FIELD, JELIS); REDUCE IT(EPA only) pending ApoB production (ASO to mrna for ApoB100) Mipomersen (HoFH) (No major CV morbidity and mortality data) Microsomal Triglyceride transfer Protein Lomitapide (HoFH) Remove LDL from circulation LDL Apheresis (Ho & Heterozygous FH) CETP: Riddled with negative trials so far Anacetrapib pending (REVEAL)
CANDIDATES FOR COMBINATION THERAPY MAKING THE CASE FOR S+NS THERAPY NLA Approach: High or Very High risk patients with less than desirable response to moderate or High Intensity Statin therapy. Recurrent events or progressive ASCVD despite High Intensity Statin Rx. FH patients + ASCVD or poorly controlled non-lipid RF & not at non-hdl and LDL-C goals. Recent ACS on at least moderate intensity Statin Rx. Intolerance to Statin Rx. *Prim Prevention popln: factor in CAC score (300 Agt), hs-crp (>2 mg/l), severe disturbance in a major ASCVD RF (Fam Hx/Tobacco), LDL> 160, Lp(a), CKD, ABI < 0.9, discordance between LDL-C & non-hdl, ApoB consider adding Rx!
HOW TO USE RX?: ORDER OF AGENTS FOR FURTHER LDL-C LOWERING PER NLA?? NLA Recs: 1. Ezetimibe 10 mg qday (Reduced ASCVD when added to Statin in a RCT) 2. Colesevelam 625 mg 6/day or 3.75 gms/day (Reduced ASCVD events as Monotherapy) 3. Niacin (ER) titrated to a max of 2 g/day (Reduced ASCVD when used as Monotherapy in the CDP trial, and MAY benefit pts not at goal with LDL/non-HDL). So, useful if used to lower LDL-C, not to raise HDL-C! NOT recommended in addn to Statin when LDL-C is less than 70 mg/dl (AIM-HIGH And HPS-THRIVE)! However, in AIM-HIGH, benefit seen in TG > 200 and HDL <32!
ACC ECDP 2016:CATEGORIES & SUBGROUPS THAT QUALIFY FOR ADDITION OF NS THERAPY ENDORSED BY THE NLA! Group I ASCVD WITHOUT Comorbidities: Zetia, 2 nd line : BAS/PCSK9 (LDL>100) ASCVD WITH Comorbidities: Zetia, 2 nd line : PCSK9 (LDL> 70) ASCVD + LDL > 190 mg/dl: Zetia or BAS, OR 1 st line: PCSk (LDL>70) Group II LDL > 190 With ASCVD: LDL >190 Without ASCVD: (LDL>100, >130, dep on addnal RF)
ACC ECDP 2016:CATEGORIES & SUBGROUPS THAT QUALIFY FOR NS THERAPY ENDORSED BY THE NLA! Group III *DM (<7.5% 10 yr risk): Zetia, BAS ; PCSK9 NO ROLE in Prim Prev! *DM (>7.5% 10 yr risk): (LDL threshold: >100 //non-hdl>130) Group IV *10 yr risk > 7.5%, NS limited role only if poor response + Truly Statin-intolerant pts or addnal High risk markers! (LDL threshold>100) *If 10 yr risk is 5-7.5%, NO NS! Presumption: All are on STATIN therapy!
SPECIAL POPULATIONS Heart Failure: Recs have changed for Sxatic Heart Failure (Ischemic HF) now reasonable to consider Statins/No data for NS-clinical Judgement needed/no PCSK9 ab! CKD: CKD HIGHER risk than counterparts for Prim and Secondary Prev! HD + ASCVD : Rx should be individualized clinical judgement/no PCSK9ab!
HOW TO APPLY ALL OF THIS INFORMATION? Some guidelines please?.to compare and contrast?
TWO DIFFERENT PREVENTION APPROACHES TWO DIFFERENT PERSPECTIVES
EVIDENCE BASE ACC/AHA Randomized controlled trials (RCT) of statin therapy Meta-analyses of RCT NLA RCT of statin therapy RCT of non-statin therapies Meta-analyses of RCT Selected post-hoc analyses of RCT Observational epidemiologic studies Genetic studies Metabolic studies Mechanistic studies
CRUX OF THE ACC/AHA GUIDELINES
CRUX OF THE NLA GUIDELINES
UNDERSTANDING NON-HDL-C
WHAT IS THE ADVANTAGE OF NON-HDL-C OVER LDL-C IN ASSESSING ASCVD RISK?
RISK CALCULATORS ACC/AHA Use Pooled Cohort Risk calculator in non-hispanic Whites and non-hispanic African Americans age 40-79 without ASCVD and not on statin therapy; may be considered in other populations Assessment of lifetime risk may be considered in those aged 20-59 with no ASCVD and not at high short-term risk NLA Count number of major risk factors and use other risk indicators for clinical decision-making Consider the use of either the 10-year FRS, ACC/AHA Pooled Cohort Risk calculator, or 30-year risk in those with 2 major ASCVD risk factors; re-classify to higher risk those with >10% 10-year FRS, >15% ACC/AHA risk, or >45% long-term risk
MANAGEMENT OF HYPERTRIGLYCERIDEMIA AND THE METABOLIC SYNDROME ACC/AHA Not specifically addressed except for those with TG >500 mg/dl, for whom reference is made to the 2011 AHA Scientific Statement on TG NLA Lifestyle therapy is major focus, with TG-lowering drug therapy reserved for non-responders or those with TG >500 mg/dl Focus on TG reduction if TG >500 mg/dl For TG 200-499 mg/dl, targets of therapy are non-hdl-c and LDL-C Metabolic syndrome identified as a multiplex risk factor for T2DM and ASCVD
MY PERSONAL APPROACH? HYBRIDIZE, FIND MIDDLE GROUND, KEEP THE PATIENT IN THE MIX AND TRY TO PRACTICE THE ART OF MEDICINE!