Metabolism, Atherogenic Properties and Agents to reduce Triglyceride-Rich Lipoproteins Manfredi Rizzo, MD, PhD

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1 Metabolism, Atherogenic Properties and Agents to reduce Triglyceride-Rich Lipoproteins Manfredi Rizzo, MD, PhD Associate Professor of Internal Medicine Faculty of Medicine, University of Palermo, Italy & Affiliate Associate Professor of Internal Medicine School of Medicine, University of South Carolina, USA

2 DISCLOSURE I have given talks, attended conferences and participated in advisory boards and trials sponsored by - Amgen - Astra Zeneca - Boehringer-Ingelheim - Lilly - Meda Pharma - Merck - Novo Nordisk - Roche - Servier

3 METABOLISM courtesy of Prof. Nevrez Koylan

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5 TG-rich Lipoproteins: Chylos, VLDL, IDL, remnants

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9 ATHEROGENIC PROPERTIES courtesy of Prof. D.P. Mikhailidis

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11 Emerging Risk Factors Collaboration JAMA 2009; 302:

12 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 (88 mg/dl) increase in TG levels from the baseline value after 4 12 years follow up.

13 Risk of ischaemic heart disease and myocardial infarction for highest vs. lowest quintile of random non-fasting lipids, lipoproteins, and apolipoproteins in individuals in the general population. Børge G. Nordestgaard et al. Eur Heart J 2016;eurheartj.ehw152 The Author Published by Oxford University Press on behalf of the European Society of Cardiology.

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

16 TG AND VASCULAR DISEASE Confounding factor: Atherogenic Dyslipidaemia : 1.Low HDL-C level 2.High TG level 3.Increased small, dense LDL level/proportion

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

18 AGENTS TO REDUCE TG-RICH LIPOPROTEINS courtesy of Prof. D.P. Mikhailidis

19 TREATMENT LIFESTYLE more effective than for cholesterol - use of the Mediterranean diet for MetS components (Obesity, Glycaemia, ) - Alcohol - Smoking

20 TREATMENT [A] LIFESTYLE [B] LIPID LOWERING DRUGS FIBRATES STATINS Fish oil preparations Ezetimibe (Nicotinic acid) Drug Combinations

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22 TREATMENT FIBRATES In 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 < ) 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:

23 TREATMENT FIBRATES 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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25 TREATMENT STATINS Effect related to: A] Baseline TG levels B] Dose (or LDL-C lowering efficacy) of statin

26 Canadian Cardiovascular Society position statement Fish oils for high triglyceride levels 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult recommendations. Can J Cardiol 2009;25:567-79

27 Meta-Analysis: Ezetimibe Added to a Statin n= 5,039 LDL fall = 23.6% p< HDL increase = 1.7% p< TG fall = 10.7% p< Mikhailidis DP et al. Curr Med Res Opin 2007; 23:

28 TREATMENT NICOTINIC ACID (+ laropiprant) Tolerability, glycaemia and urate? Very effective at raising HDL-C Now essentially a withdrawn drug

29 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: Selective antisense inhibition of apolipoprotein C3 synthesis - Acyl-CoA:diacylglycerol acyltransferase-1 (DGAT-1) DGAT-1 intestine DGAT-2 liver - Apolipoprotein (apo) B-targeted antisense oligonucleotides (ASOs)

30 CONCLUSIONS - Hypertriglyceridemia 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 TG-rich lipoproteins.