TRIGLYCERIDESD P Mikhailidis

BSc MSc MD FCPP FRSPH FFPM FRCP FRCPath

Dept. of Clinical Biochemistry Royal Free campus

University College London (UCL)

DECLARATION OF INTEREST

• Attended conferences and gave talks sponsored by MSD, AstraZeneca and Libytec

DECLARATION OF INTEREST

• Lead for Guidelines on the Management of Carotid Artery Stenosis (Eur Soc Vasc Surg)

• Chair European Expert Panel on Small Dense Low Density Lipoprotein

• Co-chair Expert Panel on Post-Prandial Lipaemia

DECLARATION OF INTEREST

Editor-in-Chief of several journals: • Curr Med Res Opin• Expert Opin Pharmacother• Angiology• Curr Vasc Pharmacol • Open Cardiovasc Med J • Clinical Lipidology

TRIGLYCERIDES ARE NOT TREATED WELL IN DAILY

CLINICAL PRACTICE: why?

TG recommendationNormal: <1.7 mmol/l (150 mg/dl)

Borderline High: 1.7 – 2.25 mmol/l (150 –199 mg/dl)

High: 2.25 – 5.6 mmol/l (200 – 499 mg/dl)

Very High: >5.6 mmol/l (>500 mg/dl)

NCEP ATP III 2004

TRIGLYCERIDES

Commercial Promotion?

TRIGLYCERIDES

FASTING or NON-FASTING?

Are we are in a constant postprandial state?

TRIGLYCERIDESFASTING or NON-FASTING?

Kolovou GD, Mikhailidis DP, Kovar J, Lairon D, Nordestgaard BG, Ooi TC, Perez-Martinez P, Bilianou H, Anagnostopoulou K, Panotopoulos G. Assessment and ClinicalRelevance of Non-fasting and Postprandial Triglycerides: An Expert Panel Statement.Curr Vasc Pharmacol 2011; 9: 258 - 70

Kolovou GD, Mikhailidis DP, Nordestgaard BG, Bilianou H, Panotopoulos G. Definitionof postprandial lipaemia. Curr Vasc Pharmacol 2011; 9: 292 - 301

Mihas C, Kolovou GD, Mikhailidis DP, Kovar J, Lairon D, Nordestgaard BG, Ooi TC,Perez-Martinez P, Bilianou H, Anagnostopoulou K, Panotopoulos G. Diagnostic value ofpostprandial triglyceride testing in healthy subjects: a meta-analysis. Curr VascPharmacol 2011; 9: 271 - 80

TRIGLYCERIDESFASTING or NON-FASTING?

For standardized postprandial testing, a single FTT meal canbe given after an 8 hfast and should consist of 75 g of fat, 25 g of carbohydrates and 10 g of protein.

A single TG measurement 4 h after a FTT meal provides a good evaluation of thepostprandial TG response.

TG LEVELS AND VASCULAR DISEASE

Ideal fasting levels: < 2.0 mmol/l (177 mg/dl)< 1.7 mmol/l (150 mg/dl)

Ideal non-fasting levels: <2.5 mmol/l (220 mg/dl)anytime after meals or oral fat tolerance test (oFTT). Will depend on fat load.

Primary hypertriglyceridaemiaLipid Disorder Molecular Defect Incidence Lipoprotein

AbnormalityLipid Profile Presentation

Familial Chylomicronemia Syndrome (FCS)

LPL deficiency,apo CII deficiency

Apo A-VLMF-1GPIHBP1

1 per 1,000,000 ↑↑ Chylomicrons, ↑↑ TG (>1000 mg/dL)

Early onset ↑↑ TG, eruptive xanthomas, recurrent pancreatitis

Familial Combined Dyslipidaemia

Unknown 1/200 ↑ VLDL, ↑ LDL ↑ TG↑ LDL-C, ↓HDL-C,↑ small dense LDL

Often seen with obesity, insulin resistance, hypertension

Familial Hypertriglyceridaemia

Unknown 1/500 ↑↑ VLDL ↑ TG (200-1000 mg/dL)

Family members usually affected

Dysbeta-lipoproteinaemia

Abnormal ApoE 1/5000 ↑ Chylomicrons,↑ VLDL remnants (IDL)

↑ TG (250-600 mg/dL)↑ Total cholesterol

Palmar and tuberoeruptivexanthomas

Primary hypertriglyceridaemiaGPIHBP1: glycosylphosphatidylinositol-anchored HDL-binding protein which helps anchor chylomicrons to the endothelial surface.

LMF1 factor 1: lipase maturation factor-1 is an endoplasmic reticulum chaperone protein required for post-translational activation of LPL.

Apo A-V: stabilizes the lipoprotein-enzyme complex.

Circulating inhibitors of the LPL enzyme.

Common secondary causes of hypertriglyceridaemia

• Alcohol (excessive intake)• Drugs: β-blockers, thiazides, estrogens, oral contraceptives, tamoxifen,

corticosteroids, retinoic acid derivatives, resins, interferon, protease inhibitors

• Renal disease (e.g. nephrotic syndrome)• Diabetes mellitus (IGT, IFG)• Metabolic syndrome• Obesity• Smoking• Hypothyroidism• Pregnancy• Liver disease• Systemic lupus erythematosus• Monoclonal gammopathy, multiple myeloma, lymphoma• Infections

WHY TREAT ELEVATED TG LEVELS?

WHY TREAT ELEVATED TG LEVELS?

1. Vascular disease

2. Acute pancreatitis

WHY TREAT ELEVATED TG LEVELS?

1. Vascular disease

2. Acute pancreatitis

NCEP ATP III -TRIGLYCERIDES

At 5.6 mmol/l (500 mg/dl),the priority is TG levels,not LDL levels

ACUTE PANCREATITIS ELEVATED TG LEVELS?

• Relatively poorly documented for obvious reasons• TG Levels:Compared with individuals with plasma TG < 89 mg/dl (< 1 mmol/l), HRs for acute pancreatitis were:1.6 (95% CI, 1.0-2.6; 4.3 events/10 000 person-years) for individuals with TG 89 - 176 mg/dl (1.00 - 1.99 mmol/l), 2.3 (95% CI, 1.3-4.0; 5.5 events/10 000 person-years) for 177 - 265 mg/dl (2.00 - 2.99 mmol/L), 2.9 (95% CI, 1.4-5.9; 6.3 events/10 000 person-years) for 366 - 353 mg/dl (3.00 - 3.99 mmol/l), 3.9(95% CI, 1.5-10.0; 7.5 events/10 000 person-years) for 354 - 442 mg/dl (4.00 -4.99 mmol/l) and 8.7 (95% CI, 3.7-20.0; 12 events/10 000 person-years) for individuals with TG levels ≥ 443 mg/dl (≥ 5.00 mmol/l) (trend, p = 6 × 10-8).

Copenhagen studies n = 116 550 individuals; Median follow-up = 6.7 years

ACUTE PANCREATITIS ELEVATED TG LEVELS?

• Pathophysiology: includes hydrolysis of TG by pancreatic lipase and excessive formation of free fatty acids (saturate albumin) with inflammatory changes and capillary injury. Hyperviscosity and ischaemia may play a role.

• Treatment: dietary modification, lipid lowering agents, insulin and/or heparin. Plasmapheresis.Prevention (TG control): seems to work.

ACUTE PANCREATITIS ELEVATED TG LEVELS?

References

• Pedersen SB, Langsted A, Nordestgaard BG. Nonfasting Mild-to-Moderate Hypertriglyceridemia and Risk of Acute Pancreatitis. JAMA Intern Med 2016; 176: 1834 - 42

• Valdivielso P, Ramírez-Bueno A, Ewald N. Current knowledge of hypertriglyceridemic pancreatitis. Eur J Intern Med 2014: 689 - 94

WHY TREAT ELEVATED TG LEVELS?

1. Vascular disease

2. Acute pancreatitis

Emerging Risk Factors Collaboration JAMA 2009; 302: 1993-2000

TG LEVELS AND VASCULAR DISEASE

Risk of vascular events was increased in a meta-analysis of 262,525 participants (10,158 events).

Increase in risk was 19 – 27% for every 1.0 mmol/l (88mg/dl) increase in TG levels from the baseline value after 4 – 12 years follow up.

N Sarwar et al. Circulation 2007; 115: 450 - 8

TG LEVELS AND VASCULAR DISEASE

Confounding factors: HDL (inverse relationship; quality of HDL?)LDL (small, dense LDL is more atherogenic)Remnants = TC - HDL - LDL-CTG/HDL-C ratio: an index of insulin resistanceInsulin resistance (e.g. MetS, IFG, IGT, DM)Obesity (NAFLD and vascular risk)Coagulation (e.g. factor VII activation, PAI-1)

TG LEVELS AND VASCULAR DISEASE

“Atherogenic Dyslipidaemia”:

Low HDL-C level High TG level Increased small, dense LDL level/proportion

TG LEVELS AND VASCULAR DISEASE

Non-HDL-C:

1] Total cholesterol – HDL-C2] Treatment target when TG levels are raised > 2.26

mmol/l (200 mg/dl)3] Target value: 0.8 mmol/l (30 mg/dl) higher

than LDL-C targets (1.8 -2.6 mmol/l; 70 -100 mg/dl)

Remnant cholesterol

Cholesterol content of the TG-rich lipoproteins composed of VLDLs and some IDLs in the fasting state and of these 2 lipoproteins together with chylomicron remnants in the non-fasting state.

Remnants = TC - HDL - LDL-C

Risk of ischaemic heart disease and myocardial infarction for highest vs. lowest quintile of random non-fasting lipids, lipoproteins, and apolipoproteins as part of standard and expanded

lipid profiles in individuals in the general population.

Børge G. Nordestgaard et al. Eur Heart J 2016;eurheartj.ehw152

© The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.

Metabolic SyndromeConsensus definition 2009

1. Waist circumference: according to ethnicity

2. HDL: men = 1.0 mmol/l (40 mg/dl) women = 1.3 mmol/l (50 mg/dl)

3. Fasting TG: > 1.7 mmol/l (150 mg/dl) or treatment

4. Fasting Glucose: ≥ 5.6 mmol/l (100 mg/dl), treatment or IGT

5. BP: >130/>85 mmHg or treatment

Circulation 2009: 120: 1640-45

Metabolic SyndromeConsensus definition 2009

Waist circumference (cm) by ethnicity:men women

Europid 94 or 102 80 or 88

Asian 90 80

Middle East, 94 80Mediterranean

Sub-Saharan 94 80Africa

Central or 90 80South America

Metabolic SyndromeCLINICAL RELEVANCE?

• Risk of diabetes [X 5]• Risk of vascular events [X 2 - 3]• Non alcoholic fatty liver disease [NAFLD]

Natural historyNAFLD

NASH

Fibrosis

Cirrhosis and complications

Hepatocellular carcinoma

?

The majority of patients have a good prognosis without disease progression or may experience disease regression

NAFLD• ALT > AST• Waist circumference• Liver ultrasound (also Fibroscan)• Insulin resistance• Biopsy is the only definitive diagnosis• New markers? • Risk formulas: NAFLD fibrosis score (NFS), fibrosis

4 calculator (FIB-4) and Enhanced Liver Fibrosis (ELF) or FibroTest

→NAFLD is a hepatic manifestation of Metabolic Syndrome→More NAFLD (NASH) patients will die from a vascular

cause than a hepatic cause

BASICS OF TREATMENT

LEVEL 1• Lifestyle (more effective than for cholesterol)

LEVEL 2• Glycaemia (IFG, IGT, MetS, DM)

LEVEL 3• Drugs

TREATMENT

[A] LIFESTYLE

[B] GLYCAEMIC CONTROL

[C] LIPID LOWERING DRUGS• FIBRATES• “Nicotinic acid”• STATINS • “OMACOR” (concentrated fish oil preparations)• “Ezetimibe”

TREATMENT• LIFESTYLEMediterranean diet on MetS components:

Waist circumference (- 0.4 cm, 95% CI: -0.8 to - 0.0) HDL-C (1.2 mg/dl, 95% CI: 0.4 to 2.0) TGs (- 6.1 mg/dl, 95% CI: -10.3 to -1.9) Systolic BP (- 2.3 mmHg, 95% CI: -3.5 to -1.2) Diastolic BP (- 1.6 mmHg, 95% CI: -2.0 to -1.1) Glucose (- 3.9 mg/dl, 95% CI:-5.8 to -1.9)

• Numbers rounded off

Kastorini CM, et al. J Am Coll Cardiol 2011;57:1299-313

TREATMENT

• LIFESTYLE

AlcoholObesity (waist circumference)GlycaemiaSmoking

TREATMENT

• FIBRATESIn patients with high TG levels or atherogenic dyslipidaemia Phenotype, fibrates were estimated to reduce cardiovascular risk by 28% (95%CI, 15 to 39%; p < 0.001) or 30% (95%CI,19 to 40%; p < 0.0001)

Bruckert E, et al. Fibrates Effect on Cardiovascular Risk isGreater in Patients with High Triglyceride Levels orAtherogenic Dyslipidemia Profile: A Systematic Review andMetanalysis. J Cardiovasc Pharmacol. 2011; 57: 267 - 72

TREATMENT

• FIBRATES

“Specific patient group” that benefits:

Low HDL-C + high TG

FIELD (fenofibrate)

ACCORD (fenofibrate vs fenofibrate + simvastatin)

TREATMENT

STATINS

Effect related to:A] Baseline TG levelsB] Dose (or LDL-C lowering efficacy) of statin

TREATMENT

NICOTINIC ACID (+ laropiprant)

Tolerability, glycaemia and urate? Very effective at raising HDL-C

Now essentially a withdrawn drug

TREATMENT

NICOTINIC ACID (+ laropiprant)

Tolerability, glycaemia and urate? Very effective at raising HDL-C

Now essentially a withdrawn drug

Canadian Cardiovascular Society position statement

Fish oils•For high triglyceride levels•Epidemiology

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

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

FUTURE TREATMENT?

Brahm AJ, Hegele RA. Lomitapide for the treatment of hypertriglyceridemia. Expert Opin Investig Drugs 2016;25:1457-63

• 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.

FUTURE TREATMENT?

Selective antisense inhibition of apolipoprotein C3 synthesis

Acyl-CoA:diacylglycerol acyltransferase-1 (DGAT-1)

Apolipoprotein (apo) B-targeted antisense oligonucleotides (ASOs)

DGAT-1 intestineDGAT-2 liver