Upda Up date te on on tr triglyce iglycerides rides Brge rge - PowerPoint PPT Presentation

University of Copenh penhagen agen & Copenhagen University Hospital Upda Up date te on on tr triglyce iglycerides rides Børge rge G No Nordestga destgaard ard Pr Profes essor, sor, Ch Chief ef Ph Physici cian an, , MD, D, DMSc Co Confl flict ict of Interes terest t Di Discl closure ure: : th the e Da Danish h ta tax p x pay ayer er Consultancies or talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka Seiken, Amarin

 Remnants Chylo-  LDL microns  TG  TG Nordestgaard 2015  Pancreatitis  CVD  CVD (  CVD)

Lipids Lipoproteins HDL HDL cholesterol LDL LDL cholesterol Total choles- terol Remnants non-HDL Triglyce- cholesterol Remnant cholesterol rides (=TRL-cholesterol) or apoB Lp(a) Lp(a) total mass

Copenhagen General Population Study Nordestgaard, Nicholls, Langsted, Ray & Tybjærg-Hansen. Nat Rev Cardiol 2018 2018; 15: 261-272

Copenhagen General Population Study + Copenhagen City Heart Study 4 15 Plasma C-reactive protein, mg/dL N=115,734 3.5 10 3 Percent 2.5 5 2 Median 1.5 0 0 2 4 6 8 10 Plasma Triglycerides (mmol/L) 0 2 4 6 8 0 77 155 232 309 Signe Hansen, Madsen, Varbo, Nordestgaard. Clin Chem 2018; in press. Plasma low-density lipoprotein cholesterol

Intima Plasma LDL LDL Remnants Remnants LPL LPL FFA + Monoacylglycerol Macrophage Inflammation Chylomicron Cholesterol Anette Varbo MD PhD Triglycerides Foam cells Nordestgaard & Varbo, Lancet 2014; 384: 626-635

From triglyceride-rich lipoproteins to disease Lipoprotein lipase Triglycerides Free ee fatty ty acids ds Inflamma lammation tion Acut ute pancr ncrea eatis tis Remnant Cholesterol Foam cell Atherosclerosis Myocar cardial dial infar arction ction Nordestgaard 2018

HDL LDL Thrombosis Stable ApoB Remnants plaques containing lipoproteins Inflamed unstable Lp(a) plaques Nordestgaard 2018

Nonfasting Fasting LDL Chylomicron Chylomicron Remnant remnant cholesterol VLDL IDL Triglycerides Cholesterol Lipoprotein lipase Lipoprotein lipase Nordestgaard JACC 2017; 70: 1637-46

Copenhagen General Population Study R 2 = 12% Varbo, Freiberg, Nordestgaard Clin Chem 2018; 64: 219 – 230

Copenhagen City Heart Study and Copenhagen General Population Study Myocardial infarction N = 96,394 (Events = 3,287) 6 5 Hazard ratio (95%CI) 4 3 2 1 Nonfasting triglycerides 0 mmol/L 1 2 3 4 5 6 7 mg/dL 88 264 528 Nordestgaard & Varbo, Lancet 2014; 384: 626-635

Copenhagen City Heart Study and Copenhagen General Population Study Ischemic stroke N = 97,442 (Events = 2,994) 5 5 4 Hazard ratio (95%CI) 4 3 3 2 2 1 1 Nonfasting triglycerides 0 0 mmol/L 1 2 3 4 5 6 7 1 2 3 4 mg/dL 88 264 528 Nordestgaard & Varbo, Lancet 2014; 384: 626-635

Copenhagen City Heart Study and Copenhagen General Population Study All-cause mortality N = 98,515 (Events = 14,547) 5 Hazard ratio (95%CI) 4 3 2 1 Nonfasting triglycerides 0 mmol/L 1 2 3 4 5 6 7 mg/dL 88 264 528 Nordestgaard & Varbo, Lancet 2014; 384: 626-635

Copenha penhagen en City y Heart t St Study dy and d ol  Rem emnant nant choles ester terol Copenh penhagen en Ge Gener eral al Popula ulation tion Study dy Pl Plas asma: a: obser ervational tional 68,0 ,000 0 Indivi ividuals duals Gen eneti etic: : ca causa sal 12,0 ,000 0 IHD nant  / H DL-C  Rem emnant / HDL Pl Plas asma a Gen eneti etic ol  HDL DL cholester esterol Plas Pl asma ma Select ected genetic etic Gen eneti etic variants iants witho thout ut pleotr otropic opic effects ects terol  LDL DL choles ester Pl Plas asma ma Gen eneti etic Varbo et al. JACC 2013;61:427-436 1. 1.0 2.0 2. 4.0 4. Hazar ard ratio tio for ischemic hemic heart disea ease se per r 39 mg/dL dL = 1 mmol/L l/L chang ange

NEJM 2014 NEJM 2014 Other genetic studies with same conclusion: NEJM 2016 NEJM 2016 TG-rich remnants cause cardiovascular disease NEJM 2017 - independent of LDL-C and HDL-C 2017

(TRL-C=remnant cholesterol) Vallejo-Vaz AJ…..Ray KK. Circulation 2018;138:770-781

Other clinical studies with similar data / conclusion: TG-rich remnants explain CV & mortality residual risk beyond statin therapy - independent of LDL-C and HDL-C Lawler PR et al. J Am Heart Assoc. 2017 6 e007402

All study participants 54% reduction in major CVD event per 1 mmol/L triglyceride reduction Odds Ratio for major CVD event Fibrate trials 1.0 ACCORD FIELD BIP 0.8 VA-HIT 0.7 HHS Carlson and Rosenhamer 0.5 0.2 0.4 0.6 0.8 1.0 Triglyceride reduction, mmol/L Nordestgaard & Varbo, Lancet 2014; 384: 626-635

New and ongoing trials Triglyceride-lowering therapy to reduce residual Major Atherosclerotic Cardiovascular Event risk after statin treatment. Using n-3 fatty acids: Icosapent Ethyl (EPA) REDUCE UCE-IT IT: N=8000 (results NEJM & AHA 2018) EPA+DHA STREN ST ENGTH: GTH: N=13,000 (fully recruited) Using a selective peroxisome proliferator alpha modulator (SPPARM - α ) - pemafibrate: PROM OMINENT INENT: : N=10,000 (50% recruited) Nordestgaard 2018

NEJM 2018 online

Low Dose Omega-3 Mixtures Show No Significant Cardiovascular Benefit No. of Events (%) Favors Favors Source Treatment Control Rate Ratios (CI) Treatment Control Coronary heart disease 0.97 (0.87 – 1.08) Nonfatal myocardial infarction 1121 (2.9) 1155 (3.0) 0.93 (0.83 – 1.03) Coronary heart disease 1301 (3.3) 1394 (3.6) 0.96 (0.90 – 1.01) Any 3085 (7.9) 3188 (8.2) P =.12 Stroke 1.03 (0.88 – 1.21) Ischemic 574 (1.9) 554 (1.8) 1.07 (0.76 – 1.51) Hemorrhagic 117 (0.4) 109 (0.4) 1.05 (0.77 – 1.43) Unclassified/other 142 (0.4) 135 (0.3) 1.03 (0.93 – 1.13) Any 870 (2.2) 843 (2.2) P =.60 Revascularization 1.00 (0.93 – 1.07) Coronary 3044 (9.3) 3040 (9.3) 0.92 (0.75 – 1.13) Noncoronary 305 (2.7) 330 (2.9) 0.99 (0.94 – 1.04) Any 3290 (10.0) 3313 (10.2) P =.60 0.97 (0.93 – 1.01) Any major vascular event 5930 (15.2) 6071 (15.6) P =.10 0.5 1.0 2.0 Rate Ratio Adapted with permission ǂ from Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: Meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol. 2018;3:225-234. [ ǂ https://creativecommons.org/licenses.org/by-nc/4.0/]

NE NEJM JM 20 2018 18 on onlin line

JELIS Suggests CV Risk Reduction with EPA in Japanese Hypercholesterolemic Patients Kaplan-Meier Estimates of Incidence of Coronary Events Total Population Primary Prevention Cohort Secondary Prevention Cohort 4 2.0 Major coronary events (%) 3 1.5 Control Control Control 8.0 EPA* EPA* 2 1.0 EPA* 4.0 1 0.5 Hazard ratio: 0.81 (0.69 – 0.95) Hazard ratio: 0.82 (0.63 – 1.06) Hazard ratio: 0.81 (0.657 – 0.998) p=0.011 p=0.132 p=0.048 0 0 0 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 Years Years Years Numbers at risk Control group 9319 8931 8671 8433 8192 7958 7478 7204 7103 6841 6678 6508 1841 1727 1658 1592 1514 1450 Treatment group 9326 8929 8658 8389 8153 7924 7503 7210 7020 6823 6649 6482 1823 1719 1638 1566 1504 1442 *1.8 g/day Adapted with permission from Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090-1098.

EPA and DHA Have Differing Effects on Cellular Membranes Reprinted with permission* from Sherratt SCR, Mason RP. Eicosapentaenoic acid and docosahexaenoic acid have distinct membrane locations and lipid interactions as determined by X-ray diffraction. Chem Phys Lipids . 2018;212:73-79. [*https://creativecommons.org/licenses.org/by-nc/4.0/]

Key Inclusion Criteria – REDUCE-IT Age ≥45 years with established CVD (Secondary Prevention 1. Cohort) or ≥50 years with diabetes with ≥1 additional risk factor for CVD (Primary Prevention Cohort) Fasting TG levels ≥150 mg/ dL and <500 mg/dL* 2. LDL-C >40 mg/dL and ≤100 mg/ dL and on stable statin therapy 3. ( ± ezetimibe) for ≥4 weeks prior to qualifying measurements for randomization Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018. Bhatt DL. AHA 2018, Chicago.

Key Exclusion Criteria 1. Severe (NYHA class IV) heart failure 2. Severe liver disease 3. History of pancreatitis 4. Hypersensitivity to fish and/or shellfish Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018. Bhatt DL. AHA 2018, Chicago.