Metabolism, Atherogenic Properties and Agents to Reduce Triglyceride-Rich Lipoproteins (TRL) The Fifth IAS-OSLA Course on Lipid Metabolism and Cardiovascular Risk Muscat, Oman, February 8-11, 2019 Zuhier Awan, MD, PhD, FRCPC Associate Professor of Medicine, Biochemistry and Molecular Genetic Faculty of Medicine, King Abdulaziz University
OUTLINE 1 2 3 4 TRL Metabolism TRL Atherogenicity TRL Reducing Methods TRL in Guidelines
TRL Metabolism TRL Atherogenicity TRL Reducing Methods TRL in Guidelines TRL Metabolism
Lipid Profile TG Total Cholesterol: HDL LDL VLDL + IDL = TRL Triglycerides Total Cholesterol LDL-Cholesterol HDL-Cholesterol
>50% TG >50% CE >50% TG >50% CE TG Rich Lipoproteins (TRL) CE Rich Lipoproteins
Lipoprotein classified according to density and diameter.
Resembles all atherogenic particles Non-HDL ApoB Containing Non-HDL = Total chol. HDL chol.
Resembles the residual risk beyond LDL Chol. TG Rich Lipoproteins (TRL) ApoE Containing TRL = Total chol. HDL chol. LDL chol.
Genetics LPL is activated by ApoC-II and inhibited by ApoC-III
TG + CE + ApoB 100 MTTP Environment
Prevalence of Hypertriglyceridemia in Ethnic Populations
TRL Metabolism TRL Atherogenicity TRL Reducing Methods TRL in Guidelines TRL Atherogenicity
LPL activity is enhanced by variations in (APOC2, GPIHBP1, LMF1, APOA5) and suppressed by variations in (APOC3, ANGPTL3, ANGPTL4)
CM once in the bloodstream, much of the triglyceride is hydrolyzed into free fatty acid (FFA). The smaller, remnant particles are removed from the bloodstream by low-density lipoprotein receptor (LDLr) and lipid-rich plaque (LRP).
Here is where the TG cutoff came from
Emerging Risk Factors Collaboration JAMA 2009; 302: 1993-2000
Risk of IHD and MI for highest vs. lowest quintile of random non-fasting lipids, lipoproteins, and apolipoproteins in individuals in the general population. Børge G. Nordestgaard et al. Eur Heart J 2016 The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.
TG AND VASCULAR DISEASE Confounding Factors: HDL (inverse relationship; quality of HDL?) LDL (small, dense LDL is more atherogenic) Remnants = TC - HDL - LDL-C TG/HDL-C ratio: index of insulin resistance Insulin resistance (e.g. MetS, IFG, IGT, DM) Obesity (NAFLD and vascular risk) Coagulation (e.g. factor VI activation, PAI-1)
TG AND VASCULAR DISEASE Confounding Factors: Atherogenic Dyslipidaemia : 1. Low HDL-C level 2. High TG level 3. Increased small, dense LDL level
Rizzo M, Berneis K. Low-density-lipoproteins size and cardiovascular risk assessment QJM 2006; 99: 1-14
TRL 18 mg/dl TRL 50 mg/dl Otvos JD, et al. AmJ Cardiol. 2002
TRL 18 mg/dl TRL 50 mg/dl Otvos JD, et al. AmJ Cardiol. 2002
TRL Metabolism TRL Atherogenicity TRL Reducing method TRL in Guidelines TRL Reducing Methods
TRL Reducing Methods [1 st ] LIFESTYLE More effective than for cholesterol - Weight loss ( 0.015mmol/L per 1kg wt loss) - Regular exercise ( 10-20% with moderate to high intensity) - Alcohol cessation - Smoking cessation Treat underling disease Stop offending drugs Chapman et al. Eur Heart J. 2011 Jun;32(11):1345-61
Effects of Nutrition Practices on Triglyceride Lowering Grundy et al. Circulation. 2018
Liu et al. Am J Clin Nutr. 2001;73(3):560-566.
TREATMENT [1 st ] LIFESTYLE [2 nd ] LIPID LOWERING DRUGS Monotherapy Fibrates Nicotinic acid Fish oil Statins Ezetimibe Drug Combinations
% 20-50 Fibrates: Via PPARα, LPL & apoaii 20-50 Niacin: TG synthesis & apoai 30-40 Omega-3: Via SREBP-1c & PPARα 10-30 Statin: Ihb. HMG-CoA R, LDLR 8-15 PCSK9i: Neutralizing Ab, LDLR 5-10 Ezetimibe: Inh. NPC1L1, LDLR Miller et al. Circulation. May 24 2011;123(20):2292-2333. Chapman et al. Eur Heart J. 2011 Jun;32(11):1345-61
TRL Metabolism TRL Atherogenicity TRL Reducing Methods TRL in Guidelines TRL in Guidelines
TREATMENT FIBRATES In patients with high TG levels or atherogenic dyslipidaemia phenotype, fibrates were estimated to reduce cardiovascular risk by 28% or 30% Bruckert E, et al. Fibrates Effect on Cardiovascular Risk is Greater in Patients with High Triglyceride Levels or Atherogenic Dyslipidemia Profile: A Systematic Review and Metanalysis. J Cardiovasc Pharmacol. 2011; 57: 267-72 Specific patient group that benefits: - - With T2DM Subjects with Low HDL-C + high TG FIELD (fenofibrate) ACCORD (fenofibrate vs fenofibrate + simvastatin)
TREATMENT NICOTINIC ACID (+ laropiprant) Tolerability, glycaemia and urate? Very effective at raising HDL-C Now essentially a withdrawn drug
TREATMENT Fish Oils For high triglyceride levels Marine-derived omega-3 Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult - 2009 recommendations. Can J Cardiol 2009;25:567-79
TREATMENT STATINS Effect related to: 1] Baseline TG levels 2] Dose of statin (or LDL-C lowering efficacy)
Meta-Analysis: Ezetimibe Added to a Statin n = 5,039 LDL fall = 23.6% p< 0.0001 HDL increase = 1.7% p< 0.0001 TG fall = 10.7% p< 0.0001 Mikhailidis DP et al. Curr Med Res Opin 2007; 23: 2009-26
Simple Algorithm 150-200 CVD Risk Target LDL 200-500 CVD > Pancreatitis Target Non-HDL 500-1000 Pancreatitis > CVD Target TG then LDL ATP III Guidelines
FUTURE TREATMENT? LOMITAPIDE Is a microsomal triglyceride transfer protein (MTTP). Lomitapide is effective at TG lowering and may be useful for patients with genetic hypertriglyceridemia and recurrent acute pancreatitis who are refractory to traditional treatment. However, long term hepatic safety may be a concern and direct clinical trial-level data are lacking for this indication. Rizzo M, Perez-Martinez P, Nikolic D, Montalto G, Lopez-Miranda J. Novel approaches for the treatment of hypertriglyceridemia. Expert Opin Pharmacother 2013;14:1869-1873. - Selective antisense inhibition of apociii synthesis - Acyl-CoA:diacylglycerol acyltransferase-1 (DGAT-1) DGAT-1 intestine DGAT-2 liver - Apolipoprotein (apo) B-targeted antisense oligonucleotides (ASOs)
CONCLUSIONS TRL is an important but underestimated risk factor in the pathogenesis of atherosclerosis and must be treated. Lifestyle modification is the most important intervention. There are a number of agents able to reduce TRL.