ELEVATED TRIGLYCERIDES: RISK MARKER OR RISK FACTOR? Podcast - PowerPoint PPT Presentation

ELEVATED TRIGLYCERIDES: RISK MARKER OR RISK FACTOR?

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This program was developed by the Canadian Collaborative Research Network and is supported by an unrestricted educational grant received from HLS Therapeutics Inc.

Discussants Robert Hegele, MD, FRCPC, FACP, FAHA, FCAHS, FCCS Alan D. Bell, MD, CCFP, FCFP Jacob J. Wolfe Distinguished Medical Research Chair in Human Family Physician and Assistant Professor, Gene Function; Martha G. Blackburn Chair in Cardiovascular Department of Family and Community Medicine, University of Toronto, Research; Director, London Regional Genomics Centre; Scientist, Molecular Medicine, Robarts Research Institute; Toronto, ON Distinguished University Professor, Departments of Medicine (Division of Endocrinology) and Biochemistry, Western University London, ON

Disclosures Alan D. Bell Robert Hegele Relationships with financial interests: Relationships with financial interests: – Grants/ Research Support: Acasti, – Grants/ Research Support: Amgen, Sanofi, Amgen, Aegerion, HSFO, Bristol Myers Squibb, Janssen, CIHR, Regeneron, Akcea, Cerenis, AstraZeneca, Novartis, Pfizer, Bayer, The Medicines Co. Lilly, Boehringer Ingelheim, HLS Therapeutics, Spectrum – Honoraria: Amgen, Akcea, Sanofi, Therapeutics, Sanofi, Bausch Health Canadian Medical & Surgical – Honoraria: As above Knowledge Translation Research Group – Consulting Fees: As above – Consulting Fees: Aegerion, Amgen, – Clinical Trial Participation: Amgen, Sanofi, Akcea, Genzyme, Boehringer Ingelheim, AstraZeneca, Regeneron, Acasti Bristol Myers Squibb, Lilly, Sanofi, Akcea – Clinical Trial Participation: N/A – Patents: None – Patents: N/A – CME Development: See Honoraria – CME Development: N/A

Discussion topics: . 1. Management challenges for high-risk CV patients in primary care. - Residual risk - Advanced treatment options – who gets what? . 2. Are elevated TG associated with CV risk? . 3. What is the impact of TG lowering on CV risk? . 4. What is the effect of fish oil, Omega-3 FA and IPE on TG levels and CV outcomes? - REDUCE IT design and results

Relationship between LDL-C and CV event rate Rosenson RS. Exp Opin Emerg Drugs 2004;9(2):269-279, LaRosa JC et al. N Engl J Med 2005;352:1425-1435.

Substantial residual risk remains in many patients with high CV risk despite intense statin therapy *Death, myocardial infarction, unstable angina requiring hospitalization, revascularization (>30 days), stroke †Coronary heart disease death, non-procedure-related MI, resuscitation after cardiac arrest, stroke 1. Adapted from Cannon CP et al. N Engl J Med. 2004;350:1495-1504. 2. Adapted from LaRosa JC et al. 2. N Engl J Med. 2005;352:1425-1435.

Many factors contribute to CV risk LDL-C–related risk Statins reduction Residual CV risk TGs Oxidation Endothelial dysfunction Inflammation Membrane instability/cholesterol crystals Plaque instability CV=cardiovascular; LDL-C=low-density lipoprotein cholesterol; TG=triglyceride 7. Libby P. Eur Heart J . 2015;36:774-776. 8. Ganda OP et al. J Am Coll Cardiol . 2018;72:330-343. 9. Ference BA et al. JAMA . 2019;321(4):364-373.

Elevated TGs Predict Residual Risk Despite Achieving LDL-C <1.80 mmol/L with a High-Dose Statin (Results From PROVE-IT TIMI 22) 25 Risk of Death, MI, or Recurrent ACS 20.3% 20 (≥30 Days Post - ACS, %) 13.5% 15 Higher TG levels are associated with a 41% increase 10 in risks of coronary events* 5 ‡ P = .001 0 TG ≥ 1.70 mmol/L TG < 1.70 mmol/L† (n=603) (n=2796) ACS=acute coronary syndrome; CI=confidence interval; HR=hazard ratio; LDL-C=low-density lipoprotein cholesterol; mg/dL=milligrams/deciliter; MI=myocardial infarction; mmol/L=millimoles/liter; TG=triglyceride; *Death, myocardial infarction, or recurrent acute coronary syndrome; † From adjusted HR of TGs <200 mg/dL (95% CI, 0.60 (0.45%-0.81%)). 13. Miller M et al. J Am Coll Cardiol . 2008;51(7):724-730.

How can we reduce residual risk in which high risk patients? Strategy Who +ve Who -ve Reversible Risk Everyone Unmotivated Factors PCSK9i LDL-C above target Needle averse, cost Extended DAPT Low bleed risk High bleed risk Dual Pathway Low bleed risk High bleed risk Antithrombotic Systolic BP < 120 SPRINT criteria Frailty IPE Elevated TG (> 1.7 Pill averse mmol/L), DM

Discussion topics: . 1. Management challenges for high-risk CV patients in primary care. - Residual risk - Advanced treatment options – who gets what? . 2. Are elevated TG associated with CV risk? . 3. What is the impact of TG lowering on CV risk? . 4. What is the effect of fish oil, Omega-3 FA and IPE on TG levels and CV outcomes? - REDUCE IT design and results

Triglyceride-rich particles Triglyceride: cholesterol content Triglyceride Cholesterol Chylomicron VLDL IDL LDL HDL TRL particles ApoB particles (non-HDL) ApoA

Secondary causes of hypertriglyceridemia Central Hypothyroidis Calorie Excess adiposity m Nephrotic Insulin Alcohol resistance/metabolic syndrome syndrome/prediabetes Physical Diabetes Medications inactivity mellitus

Copenhagen Studies: Observational association between raised TG, vascular risk and mortality Non-fasting triglyceride (mmol/L) TG, triglyceride Nordestgaard BG, Varbo A. Lancet. 2014;384:626-635.

Emerging Risk Factors Study: observational association between raised TG and vascular risk 5 Ischemic heart disease Ischemic stroke N=302,430 N=173,312 4 (events=12,785) (events=2,534) Hazard ratio (95% CI) 3 2 1 0 1 2 3 4 5 6 7 1 2 3 4 5 6 7 Non-fasting triglyceride (mmol/L) TG, triglyceride. Nordestgaard BG, Varbo A. Lancet. 2014;384:626-635.

Adjustments for HDL-C and non-HDL-C attenuate TG association with CVD 3 Adjusted for age and sex Hazard ratio (95% CI) 2 Further adjusted for non-lipid risk factors 1 Further adjusted for non–HDL-C and HDL-C 0 1.0 2.0 3.0 0 0.5 U s ual TG 1 co 1.5 ncentratio 2 n (m 2.5 m o /L ) 3 CVD, cardiovascular disease; HDL, high-density lipoprotein; TG, triglyceride. Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration. Lancet. 2010;375:1634-9; Emerging Risk Factors Collaboration. JAMA. 2009;302:1993-2000.

Do genetic variants that alter LDL-C, HDL-C, and TG Levels impact MI Risk? Do people with more LDL DL-raising alleles (1-SD  ) have highe her MI risk? 113% YES P=10 -10 Do people with more HDL DL-raising alleles (1-SD  ) have low ower er MI risk? No effect NO P=0.63 Do people with more TG-raising alleles (1-SD  ) have highe her MI risk? 54% YES P=10 -8 Change in MI risk HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; TG, triglyceride. Musunuru K, Kathiresan S. Circ Res. 2016;118:579-85.

Observational and causal genetic associations of raised remnant cholesterol and TG with outcomes MI, myocardial infarction; TG, triglyceride. Adapted from 1. Varbo A et al. J Am Coll Cardiol. 2013;61:427-436, 2. Jørgensen AB et al. Eur Heart J. 2013;34:1826-33, and 3. Thomsen M et al. Clin Chem. 2014;60:737-46.

Are triglycerides a causal risk factor? Cardiovascular By Bystande stander? ? benefit HDL-C Causal Cau sal r risk sk fact ctor or? Triglyceride-rich lipoproteins Adapted from Libby P. et al. Eur Heart J. 2015;36:774-6.

Discussion topics: . 1. Management challenges for high-risk CV patients in primary care. - Residual risk - Advanced treatment options – who gets what? . 2. Are elevated TG associated with CV risk? . 3. What is the impact of TG lowering on CV risk? . 4. What is the effect of fish oil, Omega-3 FA and IPE on TG levels and CV outcomes? - REDUCE IT design and results

Have we been studying the right patients? Subgroup with HIGH TG, Subgroup without HIGH TG, Low HDL-C Low HDL-C ACCORD ACCORD FIELD FIELD BIP BIP HHS HHS VA-HIT VA-HIT Summary Summary 0.125 0.25 0.5 1 0.125 0.25 0.5 1 Odds ratio (95% CI) Odds ratio (95% CI) Adapted from Sacks FM et al. N Engl J Med. 2010;363:692-4

Have we been studying the right patients? Subgroup with HIGH TG, Does triglyceride- Low HDL-C lowering therapy ACCORD FIELD confer CV benefit BIP in individuals with HHS elevated VA-HIT triglycerides? Summary 0.125 0.25 0.5 1 Odds ratio (95% CI) Adapted from Sacks FM et al. N Engl J Med. 2010;363:692-4

Post hoc analysis suggests that individuals with elevated TG and low HDL-C benefit from fibrates Study Duration (y) 5.0 5.1 6.2 5.0 4.7 4,081 2,531 3,090 9,795 5,518 N (High TG) (1,046) (788) (459) (2,517) (1,822) Baseline TG 1.99 1.82 1.64 1.74 1.83 (mmol/L) HDL-C, high-density lipoprotein cholesterol; TG, triglycerides. Manninen V et al. Circulation. 1992;85:37-45; Robins SJ et al. JAMA. 2001;285:1585-91; Bezafibrate Infarction Prevention (BIP) Study. Circulation. 2000;102:21-7; Scott R et al. Diabetes Care. 2009;32:493-8; ACCORD Study Group. N Engl J Med. 2010;362:1563-74.