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TRIGLYCERIDESD P Mikhailidis
BSc MSc MD FCPP FRSPH FFPM FRCP FRCPath
Dept. of Clinical Biochemistry Royal Free campus
University College London (UCL)
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DECLARATION OF INTEREST
• Attended conferences and gave talks sponsored by MSD, AstraZeneca and Libytec
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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
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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
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TRIGLYCERIDES ARE NOT TREATED WELL IN DAILY
CLINICAL PRACTICE: why?
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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
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TRIGLYCERIDES
Commercial Promotion?
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TRIGLYCERIDES
FASTING or NON-FASTING?
Are we are in a constant postprandial state?
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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
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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.
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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.
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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
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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.
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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
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WHY TREAT ELEVATED TG LEVELS?
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WHY TREAT ELEVATED TG LEVELS?
1. Vascular disease
2. Acute pancreatitis
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WHY TREAT ELEVATED TG LEVELS?
1. Vascular disease
2. Acute pancreatitis
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NCEP ATP III -TRIGLYCERIDES
At 5.6 mmol/l (500 mg/dl),the priority is TG levels,not LDL levels
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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
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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.
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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
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WHY TREAT ELEVATED TG LEVELS?
1. Vascular disease
2. Acute pancreatitis
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Emerging Risk Factors Collaboration JAMA 2009; 302: 1993-2000
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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
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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)
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TG LEVELS AND VASCULAR DISEASE
“Atherogenic Dyslipidaemia”:
Low HDL-C level High TG level Increased small, dense LDL level/proportion
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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)
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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
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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.
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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
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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
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Metabolic SyndromeCLINICAL RELEVANCE?
• Risk of diabetes [X 5]• Risk of vascular events [X 2 - 3]• Non alcoholic fatty liver disease [NAFLD]
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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
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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
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BASICS OF TREATMENT
LEVEL 1• Lifestyle (more effective than for cholesterol)
LEVEL 2• Glycaemia (IFG, IGT, MetS, DM)
LEVEL 3• Drugs
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TREATMENT
[A] LIFESTYLE
[B] GLYCAEMIC CONTROL
[C] LIPID LOWERING DRUGS• FIBRATES• “Nicotinic acid”• STATINS • “OMACOR” (concentrated fish oil preparations)• “Ezetimibe”
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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
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TREATMENT
• LIFESTYLE
AlcoholObesity (waist circumference)GlycaemiaSmoking
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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
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TREATMENT
• FIBRATES
“Specific patient group” that benefits:
Low HDL-C + high TG
FIELD (fenofibrate)
ACCORD (fenofibrate vs fenofibrate + simvastatin)
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TREATMENT
STATINS
Effect related to:A] Baseline TG levelsB] Dose (or LDL-C lowering efficacy) of statin
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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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TREATMENT
NICOTINIC ACID (+ laropiprant)
Tolerability, glycaemia and urate? Very effective at raising HDL-C
Now essentially a withdrawn drug
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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
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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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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.
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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