Postprandial Hypertriglyceridemia and Cardiovascular Disease: Current and Future Therapies

Nordestgaard BG, Freiberg JJ. Clinical relevance of non-fasting and postprandial hypertriglyceridemia and remnant cholesterol. Curr Vasc Pharmacol. 2011;9:281–6. Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F, Boren J, Catapano AL, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J. 2011;32:1345–61. •• Miller M, Stine NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123:2292–333. This articlepaper reports the recent recommendations for the management of hypertriglyceridemia. Ford ES, Li CY, Zhao GX, Pearson WS, Mokdad AH. Hypertriglyceridemia and its pharmacologic treatment among US adults. Arch Intern Med. 2009;169:572–8. Despres JP, Moorjani S, Lupien PJ, Tremblay A, Nadeau A, Bouchard C. Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. Arterioscler Thromb Vasc Biol. 1990;10:497–511. Taskinen MR. Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia. 2003;46:733–49. Yen CL, Stone SJ, Koliwad S, Harris C, Farese Jr RV. DGAT enzymes and triacylglycerol biosynthesis. J Lipid Res. 2008;49:2283–301. Chan DC, Chen MM, Ooi EM, Watts GF. An ABC of apolipoprotein C-III: a clinically useful new cardiovascular risk factor? Int J Clin Pract. 2008;62:799–809. Adiels M, Olofsson SO, Taskinen MR, Boren J. Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008;28:1225–36. Patsch JR, Miesenbock G, Hopferwieser T, Muhlberger V, Knapp E, Dunn JK, et al. Relation of triglyceride metabolism and coronary artery disease. Studies in the postprandial state. Arterioscler Thromb Vasc Biol. 1992;12:1336–45. Weintraub MS, Grosskopf I, Rassin T, Miller H, Charach G, Rotmensch HH, et al. Clearance of chylomicron remnants in normolipidaemic patients with coronary artery disease: case control study over three years. BMJ. 1996;312:935–9. Hodis HN, Mack WJ. Triglyceride-rich lipoproteins and the progression of coronary artery disease. Curr Opin Lipidol. 1995;6:209–14. Watts GF, Mandalia S, Brunt JNH, Slavin BM, Coltart DJ, Lewis B. Independent associations between plasma lipoprotein subfraction levels and the course of coronary artery disease in the St. Thomas' Atherosclerosis Regression Study (STARS). Metabolism. 1993;42:1461–7. • Sarwar N, Sandhu MS, Ricketts SL, Butterworth AS, Di Angelantonio E, et al. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet. 2010;375:1634–9. This study provides new evidence supporting a link between TRLs and coronary disease. Nordestgaard BG, Stender S, Kjeldsen K. Reduced atherogenesis in cholesterol-fed diabetic rabbits. Giant lipoproteins do not enter the arterial wall. Arterioscler Thromb Vasc Biol. 1988;8:421–8. Rapp JH, Lespine A, Hamilton RL, Colyvas N, Chaumeton AH, Tweedie-Hardman J, et al. Triglyceride-rich lipoproteins isolated by selected-affinity anti-apolipoprotein B immunosorption from human atherosclerotic plaque. Arterioscler Thromb Vasc Biol. 1994;14:1767–74. Proctor SD, Mamo JC. Retention of fluorescent-labelled chylomicron remnants within the intima of the arterial wall – evidence that plaque cholesterol may be derived from post-prandial lipoproteins. Eur J Clin Investig. 1998;28:497–503. Pitas RE, Innerarity TL, Mahley RW. Foam cells in explants of atherosclerotic rabbit aortas have receptors for beta-very low density lipoproteins and modified low density lipoproteins. Arterioscler Thromb Vasc Biol. 1983;3:2–12. Zheng XY, Liu L. Remnant-like lipoprotein particles impair endothelial function: direct and indirect effects on nitric oxide synthase. J Lipid Res. 2007;48:1673–80. Alipour A, van Oostrom AJH, Izraeljan A, Verseyden C, Collins JM, Frayn KN, et al. Leukocyte activation by triglyceride-rich lipoproteins. Arterioscler Thromb Vasc Biol. 2008;28:792–7. Sambola A, Osende J, Hathcock J, Degen M, Nemerson Y, Fuster V, et al. Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity. Circulation. 2003;107:973–7. Moyer MP, Tracy RP, Tracy PB, van’t Veer C, Sparks CE, Mann KG. Plasma lipoproteins support prothrombinase and other procoagulant enzymatic complexes. Arterioscler Thromb Vasc Biol. 1998;18:458–65. Su JW, Nzekwu MM, Cabezas MC, Redgrave T, Proctor SD. Methods to assess impaired post-prandial metabolism and the impact for early detection of cardiovascular disease risk. Eur J Clin Investig. 2009;39:741–54. Smith D, Watts GF, Dane-Stewart C, Mamo JC. Post-prandial chylomicron response may be predicted by a single measurement of plasma apolipoprotein B48 in the fasting state. Eur J Clin Investig. 1999;29:204–9. Welty FK, Lichtenstein AH, Barrett PHR, Dolnikowski GG, Schaefer EJ. Human apolipoprotein B-48 and apoB-100 kinetics with stable isotopes. Arterioscler Thromb Vasc Biol. 1999;19:2966–74. Barrett PHR, Chan DC, Watts GF. Design and analysis of lipoprotein tracer kinetics studies in humans. J Lipid Res. 2006;47:1607–19. van Oostrom AJ, Alipour A, Sijmonsma TP, Verseyden C, Dallinga-Thie GM, Plokker HW, Cabezas MC. Comparison of different methods to investigate postprandial lipaemia. Neth J Med. 2009;67:13–20. Duez H, Lamarche B, Uffelman KD, Valero R, Cohn JS, Lewis GF. Hyperinsulinemia is associated with increased production rate of intestinal apolipoprotein B-48-containing lipoproteins in humans. Arterioscler Thromb Vasc Biol. 2006;26:1357–63. Blackburn P, Lamarche B, Couillard C, et al. Contribution of visceral adiposity to the exaggerated postprandial lipemia of men with impaired glucose tolerance. Diabetes Care. 2003;26:3303–9. Annuzzi G, de Natalev C, Iovine C, et al. Insulin resistance is independently associated with postprandial alterations of triglyceride-rich lipoproteins in type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol. 2004;24:2397–402. Hogue JC, Lamarche B, Tremblay AJ, Bergeron J, Gagné C, Couture P. Evidence of increased secretion of apolipoprotein B-48-containing lipoproteins in subjects with type 2 diabetes. J Lipid Res. 2007;48:1336–42. Johansen CT, Kathiresan S, Hegele RA. Genetic determinants of plasma triglycerides. J Lipid Res. 2011;52:189–206. •• Johansen CT, Kathiresan S, Hegele RA. The complex genetic basis of plasma triglycerides. Curr Atheroscler Rep. 2012;14:227–34. This is a good summary of the metabolic and genetic aspects of TRL metabolism. Stalenhoef AF, Malloy MJ, Kane JP, Havel RJ. Metabolism of apolipoproteins B-48 and B-100 of triglyceride-rich lipoproteins in normal and lipoprotein lipase-deficient humans. Proc Natl Acad Sci USA. 1984;81:1839–43. Stalenhoef AF, Malloy MJ, Kane JP, Havel RJ. Metabolism of apolipoproteins B-48 and B-100 of triglyceride-rich lipoproteins in patients with familial dysbetalipoproteinemia. J Clin Invest. 1986;78:722–8. Parrott CL, Alsayed N, Rebourcet R, Santamarina-Fojo S. ApoC-IIParis2: a premature termination mutation in the signal peptide of apoC-II resulting in the familial chylomicronemia syndrome. J Lipid Res. 1992;33:361–7. Pennacchio LA, Rubin EM. Apolipoprotein A5, a newly identified gene that affects plasma triglyceride levels in humans and mice. Arterioscler Thromb Vasc Biol. 2003;23:529–34. • Surendran RP, Visser ME, Heemelaar S, et al. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia. J Intern Med. 2012;272:185–96. This study identifies several rare genomic variants causing severe hypertriglyceridemia. Olano-Martin E, Abraham EC, Gill-Garrison R, et al. Influence of apoA-V gene variants on postprandial triglyceride metabolism: impact of gender. J Lipid Res. 2008;49:945–53. Couillard C, Vohl MC, Engert JC, et al. Effect of apoC-III gene polymorphisms on the lipoprotein-lipid profile of viscerally obese men. J Lipid Res. 2003;44:986–93. Waterworth DM, Ribalta J, Nicaud V, Dallongeville J, Humphries SE, Talmud P. ApoCIII gene variants modulate postprandial response to both glucose and fat tolerance tests. Circulation. 1999;99:1872–7. Kolovou GD, Mikhailidis DP, Kovar J, et al. Assessment and clinical relevance of non-fasting and postprandial triglycerides: an expert panel statement. Curr Vasc Pharmacol. 2011;9:258–70. Van Gaal LF, Wauters MA, De Leeuw IH. The beneficial effects of modest weight loss on cardiovascular risk factors. Int J Obes Relat Metab Disord. 1997;21 Suppl 1:S5–9. Chan DC, Watts GF, Ng TW, Yamahita S, Barrett PHR. Effect of weight loss on markers of triglyceride-rich lipoprotein metabolism in the metabolic syndrome. Eur J Clin Investig. 2008;38:743–51. Riches FM, Watts GF. HuaJ, Stewart GR, Naoumova RP, Barrett PHR. Reduction in visceral adipose tissue is associated with improvement in apolipoprotein B-100 metabolism in obese men. J Clin Endocrinol Metab. 1999;84:2854–61. Volek JS, Sharman MJ, Gómez AL, DiPasquale C, Roti M, Pumerantz A, Kraemer WJ. Comparison of a very low-carbohydrate and low-fat diet on fasting lipids, LDL subclasses, insulin resistance, and postprandial lipemic responses in overweight women. J Am Coll Nutr. 2004;23:177–84. Bassuk SS, Manson JE. Physical activity and the prevention of cardiovascular disease. Curr Atheroscler Rep. 2003;5:299–307. Mestek ML, Plaisance EP, Ratcliff LA, Taylor JK, Wee SO, Grandjean PW. Aerobic exercise and postprandial lipemia in men with the metabolic syndrome. Med Sci Sports Exerc. 2008;40:2105–11. Gill JM, Al-Mamari A, Ferrell WR, et al. Effects of prior moderate exercise on postprandial metabolism and vascular function in lean and centrally obese men. J Am Coll Cardiol. 2004;44:2375–82. Gill JM, Mees GP, Frayn KN, Hardman AE. Moderate exercise, postprandial lipaemia and triacylglycerol clearance. Eur J Clin Investig. 2001;31:201–7. Kolovou GD, Anagnostopoulou KK, Salpea KD, et al. The effect of statins on postprandial lipemia. Curr Drug Targets. 2007;8:551–60. Chan DC, Watts GF, Barrett PHR, et al. Effect of atorvastatin on chylomicron remnant metabolism in visceral obesity: a study employing a new stable isotope breath test. J Lipid Res. 2002;43:706–12. Hogue JC, Lamarche B, Deshaies Y, Tremblay AJ, Bergeron J, Gagne C, Couture P. Differential effect of fenofibrate and atorvastatin on in vivo kinetics of apolipoproteins B-100 and B-48 in subjects with type 2 diabetes mellitus with marked hypertriglyceridemia. Metabolism. 2008;57:246–54. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 1998;98:2088–93. Kolovou GD, Kostakou PM, Anagnostopoulou KK, Cokkinos DV. Therapeutic effects of fibrates in postprandial lipemia. Am J Cardiovasc Drugs. 2008;8:243–55. Watts GF, Barrett PH, Ji J, et al. Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome. Diabetes. 2003;52:803–11. Chapman MJ. How does nicotinic acid modify the lipid profile? Eur Heart J Suppl. 2006;8:F54–9. King J, Crouse J, Terry J, Morgan T, Spray B, Miller N. Evaluation of effects of unmodified niacin on fasting and postprandial plasma lipids in normolipidemic men with hypoalphalipoproteinemia. Am J Med. 1994;97:323–31. Lamon-Fava S, Diffenderfer MR, Barrett PHR, et al. Extended-release niacin alters the metabolism of plasma apolipoprotein (apo) A-I and apoB-containing lipoproteins. Arterioscler Thromb Vasc Biol. 2008;28:1672–8. Plaisance EP, Mestek ML, Mahurin AJ, Taylor JK, Moncada-Jimenez J, Grandjean PW. Postprandial triglyceride responses to aerobic exercise and extended-release niacin. Am J Clin Nutr. 2008;88:30–7. Angerer P, von Schacky C. n-3 polyunsaturated fatty acids and the cardiovascular system. Curr Opin Lipidol. 2000;11:57–63. Harris WS, Isley WL. Clinical trial evidence for the cardioprotective effects of omega-3-fatty acids. Curr Atheroscler Rep. 2001;3:174–9. Slivkoff-Clark KM, James AP, Mamo J. The chronic effects of fish oil with exercise on postprandial lipaemia and chylomicron homeostasis in insulin resistant viscerally obese men. Nutr Metab. 2012;9:9. Tinker LF, Parks EJ, Behr SR, Schneeman BO, Davi PA. (n-3) fatty acid supplementation in moderately hypertriglyceridemic adults changes postprandial lipid and apolipoprotein B responses to a standardized test meal. J Nutr. 1999;129:1126–34. Park YS, Harris WS. Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance. J Lipid Res. 2003;44:455–63. Ooi EMM, Lichtenstein AH, Millar JS, et al. Effects of therapeutic lifestyle change diets high and low in dietary fish-derived FAs on lipoprotein metabolism in middle-aged and elderly subjects. J Lipid Res. 2012;53:1958–67. Nutescu EA, Shapiro NL. Zetimibe: a selective cholesterol absorption inhibitor. Pharmacotherapy. 2003;23:1463–74. Pandor A, Ara RM, Tumur I, et al. Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta-analysis of randomized controlled trials. J Intern Med. 2009;265:568–80. Bozzetto L, Annuzzi G, Corte GD, et al. Ezetimibe beneficially influences fasting and postprandial triglyceride-rich lipoproteins in type 2 diabetes. Atherosclerosis. 2011;217:142–8. Masuda D, Nakagawa-Toyama Y, Nakatani K, et al. Ezetimibe improves postprandial hyperlipidaemia in patients with type IIb hyperlipidaemia. Eur J Clin Investig. 2009;39:689–98. Hajer GR, Dallinga-Thie GM, van Vark-van der Zee LC, Visseren FL. The effect of statin alone or in combination with ezetimibe on postprandial lipoprotein composition in obese metabolic syndrome patients. Atherosclerosis. 2009;202:216–24. Naples M, Baler C, Lino M, Iqbal J, Hussain MM, Adeli K. Ezetimibe ameliorates intestinal chylomicron overproduction and improves glucose tolerance in a diet-induced hamster model of insulin resistance. Am J Physiol Gastrointest Liver Physiol. 2012;302:1043–52. Tremblay AJ, Lamarche B, Hogue JC, Couture P. Effects of ezetimibe and simvastatin on apolipoprotein B metabolism in males with mixed hyperlipidemia. J Lipid Res. 2009;50:1463–71. Adiels M, Taskinen MR, Packard C, et al. Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia. 2006;49:755–65. Chan DC, Watts GF, Gan SK, Ooi EMM, Barrett PRR. Effect of ezetimibe on hepatic fat, inflammatory markers, and apolipoprotein B-100 kinetics in insulin-resistant obese subjects on a weight loss diet. Diabetes Care. 2010;33:1134–9. Kim W, Egan JM. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol Rev. 2008;60:470–512. Schwartz EA, Koska J, Mullin MP, Syoufi I, Schwenke DC, Reaven PD. Exenatide suppresses postprandial elevations in lipids and lipoproteins in individuals with impaired glucose tolerance and recent onset type 2 diabetes mellitus. Atherosclerosis. 2010;212:217–22. Meier JJ, Gethmann A, Gotze O, Gallwitz B, Holst JJ, Schmidt WE, Nauck MA. Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans. Diabetologia. 2006;49:452–8. Farr S, Adeli K. Incretin-based therapies for treatment of postprandial dyslipidemia in insulin-resistant states. Curr Opin Lipidol. 2012;23:56–61. This is an excellent review of the use of incretin-based therapies in the treatment of postprandial dyslipidemias. Xiao CT, Bandsma RHJ, Dash S, Szeto L, Lewis GF. Exenatide, a glucagon-like peptide-1 receptor agonist, acutely inhibits intestinal lipoprotein production in healthy humans. Arterioscler Thromb Vasc Biol. 2012;32:1513–9. Qin XF, Shen H, Liu M, et al. GLP-1 reduces intestinal lymph flow, triglyceride absorption, and apolipoprotein production in rats. Am J Physiol Gastrointest Liver Physiol. 2005;288:943–9. Murata M, Hara K, Ide T. Alteration by diacylglycerols of the transport and fatty acid composition of lymph chylomicrons in rats. Biosci Biotechnol Biochem. 1994;58:1416–9. Tomonobu K, Hase T, Tokimitsu I. Dietary diacylglycerol in a typical meal suppresses postprandial increases in serum lipid levels compared with dietary triacylglycerol. Nutrition. 2006;22:128–35. Tada N, Shoji K, Takeshita M, et al. Effects of diacylglycerol ingestion on postprandial hyperlipedemia in diabetes. Clin Chim Acta. 2005;3536:87–94. Birch AM, Buckett LK, Turnbull AV. DGAT1 inhibitors as anti-obesity and anti-diabetic agents. Curr Opin Drug Discov Dev. 2010;13:489–96. Meyers C, Gaudet D, Tremblay K, Amer A, Chen J, Aimin F. The DGAT1 inhibitor LCQ908 decreases triglyceride levels in patients with the familial chylomicronemia syndrome. J Clin Lipidol. 2012;6:266–7. Cariou B, Zaïr Y, Staels B, Bruckert E. Effects of the new dual PPARα/δ agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care. 2011;34:2008–14. Risérus U, Sprecher D, Johnson T, et al. Activation of peroxisome proliferator–activated receptor (PPAR)δ promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men. Diabetes. 2008;57:332–9. Cuchel M, Meagher EA, du Toit TH, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2013;381:40–6. Visser ME, Witztum JL, Stroes ESG, Kastelein JJP. Antisense oligonucleotides for the treatment of dyslipidaemia. Eur Heart J. 2012;33:1451–8. This is an excellent review of the use of ASOs in the treatment of dyslipidemias. Akdim F, Stroes ES, Sijbrands EJ, et al. Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects receiving stable statin therapy. J Am Coll Cardiol. 2010;55:1611–8. Furtado JD, Wedel MK, Sacks FM. Antisense inhibition of apoB synthesis with mipomersen reduces plasma apoC-III and apoC-III-containing lipoproteins. J Lipid Res. 2012;53:784–91. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375:998–1006. Stein EA, Dufour R, Gagne C, et al. Apolipoprotein B synthesis inhibition With mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation. 2012;126:2283–92. Alexander V, Novak T, Viney N, Su J, Burkey, Singleton W, Geary R. Isis Pharmaceuticals. An antisense inhibitor of apolipoprotein C-III lowers fasting plasma apolipoprotein C-III and triglyceride concentrations in healthy volunteers. J Am Coll Cardiol. 2012;59:1685–5.