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).

Here is where the TG cutoff

came from

Emerging Risk Factors Collaboration

JAMA 2009; 302: 1993-2000

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.

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

TG AND VASCULAR DISEASE

“Atherogenic Dyslipidaemia”:

1. Low HDL-C level

2. High TG level

3. Increased small, dense LDL level

Confounding Factors:

Rizzo M, Berneis K. Low-density-lipoproteins size and cardiovascular risk assessment QJM 2006; 99: 1-14

Otvos JD, et al. AmJ Cardiol. 2002

TRL 18 mg/dL TRL 50 mg/dL

Otvos JD, et al. AmJ Cardiol. 2002

TRL 18 mg/dL TRL 50 mg/dL

TRL Reducing Methods

TRL Metabolism TRL Atherogenicity TRL Reducing method TRL in Guidelines

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

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

[1st ] LIFESTYLE

[2nd ] 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 in Guidelines

TRL in Guidelines

TRL Metabolism TRL Atherogenicity TRL Reducing Methods

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

•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

- 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.