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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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
TRL Metabolism TRL Atherogenicity TRL Reducing Methods TRL in Guidelines
OUTLINE
1 2 3 4
TRL Metabolism
TRL Metabolism TRL Atherogenicity TRL Reducing Methods TRL in Guidelines
•TG •Total Cholesterol:
•HDL •LDL •VLDL + IDL = TRL
Lipid Profile Triglycerides
LDL-Cholesterol HDL-Cholesterol
Total Cholesterol
TG Rich Lipoproteins (TRL)
CE Rich Lipoproteins
>50% TG
>50% TG
>50% CE
>50% CE
Lipoprotein classified according to density and diameter.
Non-HDL = Total chol. – HDL chol.
Non-HDL
“ApoB Containing”
Resembles all atherogenic
particles
TRL = Total chol. – HDL chol. – LDL chol.
TG Rich Lipoproteins (TRL)
“ApoE Containing”
Resembles the residual risk beyond
LDL Chol.
“LPL” is activated by ApoC-II and
inhibited by ApoC-III
Genetics
TG + CE + ApoB100 “MTTP”
Environment
Prevalence of Hypertriglyceridemia in Ethnic Populations
TRL Atherogenicity
TRL Metabolism TRL Atherogenicity TRL Reducing Methods TRL in Guidelines
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).
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
•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
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
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
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