metabolism, atherogenic properties and agents to reduce...
TRANSCRIPT
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Metabolism, Atherogenic Properties and Agents
to Reduce Triglyceride-Rich Lipoproteins (TRL)
Zuhier Awan, MD, PhD, FRCPC Associate Professor of Medicine, Biochemistry and Molecular Genetic
Faculty of Medicine, King Abdulaziz University
The Fifth IAS-OSLA Course on Lipid Metabolism and Cardiovascular Risk
Muscat, Oman, February 8-11, 2019
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TRL Metabolism TRL Atherogenicity TRL Reducing Methods TRL in Guidelines
OUTLINE
1 2 3 4
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TRL Metabolism
TRL Metabolism TRL Atherogenicity TRL Reducing Methods TRL in Guidelines
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•TG •Total Cholesterol:
•HDL •LDL •VLDL + IDL = TRL
Lipid Profile Triglycerides
LDL-Cholesterol HDL-Cholesterol
Total Cholesterol
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TG Rich Lipoproteins (TRL)
CE Rich Lipoproteins
>50% TG
>50% TG
>50% CE
>50% CE
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Lipoprotein classified according to density and diameter.
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Non-HDL = Total chol. – HDL chol.
Non-HDL
“ApoB Containing”
Resembles all atherogenic
particles
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TRL = Total chol. – HDL chol. – LDL chol.
TG Rich Lipoproteins (TRL)
“ApoE Containing”
Resembles the residual risk beyond
LDL Chol.
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“LPL” is activated by ApoC-II and
inhibited by ApoC-III
Genetics
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TG + CE + ApoB100 “MTTP”
Environment
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Prevalence of Hypertriglyceridemia in Ethnic Populations
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TRL Atherogenicity
TRL Metabolism TRL Atherogenicity TRL Reducing Methods TRL in Guidelines
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LPL activity is enhanced by variations in
(APOC2, GPIHBP1, LMF1, APOA5) and
suppressed by variations in
(APOC3, ANGPTL3, ANGPTL4)
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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).
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Here is where the TG cutoff
came from
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Emerging Risk Factors Collaboration
JAMA 2009; 302: 1993-2000
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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.
Risk of IHD and MI for highest vs. lowest quintile of random non-fasting lipids, lipoproteins, and
apolipoproteins in individuals in the general population.
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TG AND VASCULAR DISEASE
Confounding Factors:
HDL (inverse relationship; quality of HDL?)
LDL (small, dense LDL is more atherogenic)
Remnants = TC - HDL - LDL-C
Insulin resistance (e.g. MetS, IFG, IGT, DM)
Obesity (NAFLD and vascular risk)
Coagulation (e.g. factor VI activation, PAI-1)
TG/HDL-C ratio: index of insulin resistance
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TG AND VASCULAR DISEASE
“Atherogenic Dyslipidaemia”:
1. Low HDL-C level
2. High TG level
3. Increased small, dense LDL level
Confounding Factors:
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Rizzo M, Berneis K. Low-density-lipoproteins size and cardiovascular risk assessment QJM 2006; 99: 1-14
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Otvos JD, et al. AmJ Cardiol. 2002
TRL 18 mg/dL TRL 50 mg/dL
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Otvos JD, et al. AmJ Cardiol. 2002
TRL 18 mg/dL TRL 50 mg/dL
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TRL Reducing Methods
TRL Metabolism TRL Atherogenicity TRL Reducing method TRL in Guidelines
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TRL Reducing Methods
[1st ] LIFESTYLE
More effective than for cholesterol
- Regular exercise (↓10-20% with moderate to high intensity)
- Alcohol cessation
- Smoking cessation
Treat underling disease
Stop offending drugs
- Weight loss (↓0.015mmol/L per 1kg wt loss)
Chapman et al. Eur Heart J. 2011 Jun;32(11):1345-61
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Effects of Nutrition Practices on Triglyceride Lowering
Grundy et al. Circulation. 2018
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Liu et al. Am J Clin Nutr. 2001;73(3):560-566.
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TREATMENT
[1st ] LIFESTYLE
[2nd ] LIPID LOWERING DRUGS
Monotherapy
Fibrates
Nicotinic acid
Fish oil
Statins
Ezetimibe
Drug Combinations
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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
%
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TRL in Guidelines
TRL in Guidelines
TRL Metabolism TRL Atherogenicity TRL Reducing Methods
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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)
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TREATMENT
•NICOTINIC ACID (+ laropiprant)
Tolerability, glycaemia and urate?
Very effective at raising HDL-C
Now essentially a withdrawn drug
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•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
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TREATMENT
•STATINS
Effect related to:
1] Baseline TG levels
2] Dose of statin (or LDL-C lowering efficacy)
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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
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150-200
• CVD Risk
• Target LDL
200-500
• CVD > Pancreatitis
• Target Non-HDL
500-1000
• Pancreatitis > CVD
• Target TG then LDL
ATP III Guidelines
Simple Algorithm
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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)
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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.