„Residuales Risiko“: Wie wichtig sind High-Density-Lipoproteine und Triglyzeride?

Zusammenfassung

In klinischen Studien bewirkt die Senkung des LDL-Cholesterins (LDL-C) mit Statinen eine Verminderung der Inzidenz kardiovaskulärer Ereignisse um etwa ein Drittel. Das bedeutet aber umgekehrt, dass ein sogenanntes „residuales Risiko“ bestehen bleibt. Neben hohem Lipoprotein(a) gelten Störungen im Stoffwechsel der triglyzeridreichen Lipoproteine und der High Density Liproteine als Effektoren des residualen Risikos. Beide Lipoproteinparameter korrelieren umgekehrt miteinander. Die ätiologischen Beiträge von Triglyzeriden und / oder HDL zur Entwicklung von Herz-Kreislauf-Erkrankungen lassen sich daher weder aus Beobachtungsstudien noch aus Interventionsstudien abschätzen. Die bislang enttäuschenden Ergebnisse von Interventionsstudien mit Hemmstoffen des Cholesterinester-Transferproteins und insbesondere die Gesamtheit aller genetisch-epidemiologischen Untersuchungen sprechen dafür, dass in den letzten 10 Jahren die Bedeutung des HDL-Cholesterins überbewertet, die Bedeutung der Triglyzeride dagegen unterschätzt wurde. Hohe Triglyzeride wirken nicht immer atherogen, sondern vor allem dann, wenn sie mit der Akkumulation relativ cholesterinreicher, inkomplett katabolisierter remnants der Chylomikronen und Very Low Density Lipoproteine einher gehen (familiäre Typ III Hyperlipoproteinämie, metabolisches Syndrom, Diabetes mellitus). Die Normalisierung der Konzentration von Triglyzeriden und remnants durch Hemmung der Ausprägung von Apolipoprotein C3 ist ein neuer, aussichtsreicher therapeutischer Ansatzpunkt.

Abstract

In clinical trials, the reduction of LDL-cholesterol (LDL-C) with statins reduces the incidence rate of cardiovascular events by approximately one third. This means, that a sizeable “residual risk” remains. Besides high lipoprotein (a), disorders in the metabolism of triglyceride-rich lipoproteins and high density liproteins have been implicated as effectors of the residual risk. Both lipoprotein parameters correlate inversely with each other. Therefore, the etiological contributions of triglycerides and / or of HDL for developing cardiovascular disease can hardly be estimated from either observational studies or from intervention studies. The largely disappointing results of intervention studies with inhibitors of the cholesteryl ester transfer protein and in particular the available set of genetically-epidemiological studies suggest that in the last decade, the importance of HDL cholesterol has been overvalued, while the importance of triglycerides has been underestimated. High triglycerides not always atherogenic, but only if they are associated with the accumulation relatively cholesterol-enriched, incompletely catabolized remnants of chylomicrons and very low density lipoproteins (familial type III hyperlipidemia, metabolic syndrome, diabetes mellitus). The normalization of the concentration of triglycerides and remnants by inhibiting the expression of apolipoprotein C3 is hence a new, promising therapeutic target.

Schlüsselwörter

Cholesterin - Triglyzeride - Remnants - Lipoproteine hoher Dichte - Atherosklerose

Keywords

cholesterol - triglycerides - remnants - high density lipoproteins - atherosclerosis

• Literatur

• 1 Nabel EG, Braunwald E. A tale of coronary artery disease and myocardial infarction. N Engl J Med 2012; 366: 54-63
• 2 Perk J, De Backer G, Gohlke H et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2012; 33: 1635-1701
• 3 Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003; 326: 1423
• 4 Bergeron N, Phan BA, Ding Y et al. Proprotein convertase subtilisin / kexin type 9 inhibition: a new therapeutic mechanism for reducing cardiovascular disease risk. Circulation 2015; 132: 1648-1666
• 5 Boekholdt SM, Hovingh GK, Mora S et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol 2014; 64: 485-94
• 6 Ference BA, Majeed F, Penumetcha R et al. Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 x 2 factorial Mendelian randomization study. J Am Coll Cardiol 2015; 65: 1552-1561
• 7 Emerging Risk Factors Collaboration, Di Angelantonio E, Sarwar N, Perry P. et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009; 302: 1993-2000
• 8 Boekholdt SM, Arsenault BJ, Hovingh GK et al. Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: a meta-analysis. Circulation 2013; 128: 1504-1512
• 9 van der Steeg WA, Holme I, Boekholdt SM et al. High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies. J Am Coll Cardiol 2008; 51: 634-642
• 10 Abbasi A, Corpeleijn E, Gansevoort RT et al. Role of HDL cholesterol and estimates of HDL particle composition in future development of type 2 diabetes in the general population: the PREVEND study. J Clin Endocrinol Metab 2013; 98: E1352-9
• 11 Mineo C, Yuhanna IS, Quon MJ, Shaul PW. High density lipoprotein-induced endothelial nitric-oxide synthase activation is mediated by Akt and MAP kinases. J Biol Chem 2003; 278: 9142-9149
• 12 Nofer JR, van der Giet M, Tolle M et al. HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J Clin Invest 2004; 113: 569-581
• 13 Davidson WS, Silva RA, Chantepie S et al. Proteomic analysis of defined HDL subpopulations reveals particle-specific protein clusters: relevance to antioxidative function. Arterioscler Thromb Vasc Biol 2009; 29: 870-876
• 14 Vickers KC, Palmisano BT, Shoucri BM et al. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol 2011; 13: 423-433
• 15 Besler C, Heinrich K, Rohrer L et al. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J Clin Invest 2011; 121: 2693-2708
• 16 Griffin JH, Kojima K, Banka CL et al. High-density lipoprotein enhancement of anticoagulant activities of plasma protein S and activated protein C. J Clin Invest 1999; 103: 219-227
• 17 von Eckardstein A, Widmann C. High-density lipoprotein, beta cells, and diabetes. Cardiovasc Res 2014; 103: 384-394
• 18 Zewinger S, Speer T, Kleber ME et al. HDL cholesterol is not associated with lower mortality in patients with kidney dysfunction. J Am Soc Nephrol 2014; 25: 1073-1082
• 19 Silbernagel G, Schöttker B, Appelbaum S et al.: High-density lipoprotein cholesterol, coronary artery disease, and cardiovascular mortality. Eur Heart J 2013; 34: 3563-3571
• 20 Weichhart T, Kopecky C, Kubicek M et al. Serum amyloid A in uremic HDL promotes inflammation. J Am Soc Nephrol 2012; 23: 934-947
• 21 Zewinger S, Drechsler C, Kleber ME et al. Serum amyloid A: high-density lipoproteins interaction and cardiovascular risk. Eur Heart J 2015; 36: 3007-3016
• 22 Rohatgi A, Khera A, Berry JD et al. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med 2014; 371: 2383-2393
• 23 Johannsen TH, Kamstrup PR, Andersen RV et al. Hepatic lipase, genetically elevated high-density lipoprotein, and risk of ischemic cardiovascular disease. J Clin Endocrinol Metab 2009; 94: 1264-1273
• 24 Haase CL, Tybjaerg-Hansen A, Qayyum AA et al. LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54, 500 individuals. J Clin Endocrinol Metab 2012; 97: E248-E256
• 25 Schwartz GG, Olsson AG, Abt M et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012; 367: 2089-2099
• 26 Group HTC, Landray MJ, Haynes R et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014; 371: 203-212
• 27 Bansal S, Buring JE, Rifai N et al. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007; 298: 309-316
• 28 Triglyceride Coronary Disease Genetics Consortium, Emerging Risk Factors Collaborattion, Sarwar N, Sandhu MS, Ricketts SL. et al. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet 2010; 375: 1634-1639
• 29 Burgess S, Harshfield E. Mendelian randomization to assess causal effects of blood lipids on coronary heart disease: lessons from the past and applications to the future. Curr Opin Endocrinol Diabetes Obes 2016; 23: 124-130
• 30 Hegele RA, Ginsberg HN, Chapman MJ et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol 2014; 2: 655-666
• 31 Verges B. Abnormal hepatic apolipoprotein B metabolism in type 2 diabetes. Atherosclerosis 2010; 211: 353-360
• 32 Murao K, Wada Y, Nakamura T et al. Effects of glucose and insulin on rat apolipoprotein A-I gene expression. J Biol Chem 1998; 273: 18959-18965
• 33 Rachek LI. Free fatty acids and skeletal muscle insulin resistance. Prog Mol Biol Transl Sci 2014; 121: 267-292
• 34 Turner RC, Millns H, Neil HA et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ 1998; 316: 823-828
• 35 Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation 1979; 60: 473-485
• 36 Patsch JR, Miesenbock G, Hopferwieser T et al.: Relation of triglyceride metabolism and coronary artery disease. Studies in the postprandial state. Arterioscler Thromb 1992; 12: 1336-1345
• 37 Langsted A, Freiberg JJ, Nordestgaard BG. Fasting and nonfasting lipid levels: influence of normal food intake on lipids, lipoproteins, apolipoproteins, and cardiovascular risk prediction. Circulation 2008; 118: 2047-2056
• 38 Nordestgaard BG, Zilversmit DB. Large lipoproteins are excluded from the arterial wall in diabetic cholesterol-fed rabbits. J Lipid Res 1988; 29: 1491-1500
• 39 Nordestgaard BG, Tybjaerg-Hansen A, Lewis B. Influx in vivo of low density, intermediate density, and very low density lipoproteins into aortic intimas of genetically hyperlipidemic rabbits. Roles of plasma concentrations, extent of aortic lesion, and lipoprotein particle size as determinants. Arterioscler Thromb 1992; 12: 6-18
• 40 Feussner G, Feussner V, Hoffmann MM et al. Molecular basis of type III hyperlipoproteinemia in Germany. Hum Mutat 1998; 11: 417-423
• 41 Varbo A, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation. Circulation 2013; 128: 1298-1309
• 42 März W, Scharnagl H, Winkler K et al. Low-density lipoprotein triglycerides associated with low-grade systemic inflammation, adhesion molecules, and angiographic coronary artery disease: the Ludwigshafen Risk and Cardiovascular Health study. Circulation 2004; 110: 3068-3074
• 43 Grammer TB, Kleber ME, März W et al. Low-density lipoprotein particle diameter and mortality: the Ludwigshafen Risk and Cardiovascular Health Study. Eur Heart J 2015; 36: 31-38
• 44 TG and HDL Working Group of the Exome Sequencing Project. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014; 371: 22-31
• 45 Do R, Stitziel NO, Won HH et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 2015; 518: 102-106
• 46 Bernelot Moens SJ, van Capelleveen JC, Stroes ES. Inhibition of ApoCIII: the next PCSK9?. Curr Opin Lipidol 2014; 25: 418-422
• 47 Jun M, Foote C, Lv J et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010; 375: 1875-1884
• 48 Rajamani K, Colman PG, Li LP et al.: Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet 2009; 373: 1780-1788
• 49 Rubins HB, Robins SJ, Collins D et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999; 341: 410-418
• 50 ACCORD Study Group, Ginsberg HN, Elam MB. et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010; 362: 1563-1574
• 51 Lee M, Saver JL, Towfighi A et al. Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. Atherosclerosis 2011; 217: 492-498
• 52 Canner PL, Berge KG, Wenger NK et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986; 8: 1245-1255
• 53 AIM-HIGH Investigators, Boden WE, Probstfield JL. et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011; 365: 2255-2267
• 54 Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis 2010; 210: 353-361
• 55 Lavigne PM, Karas RH. The current state of niacin in cardiovascular disease prevention: a systematic review and meta-regression. J Am Coll Cardiol 2013; 61: 440-446
• 56 van der Steeg WA, Kuivenhoven JA, Klerkx AH et al. Role of CETP inhibitors in the treatment of dyslipidemia. Curr Opin Lipidol 2004; 15: 631-616
• 57 Borggreve SE, Hillege HL, Wolffenbüttel BH et al. An increased coronary risk is paradoxically associated with common cholesteryl ester transfer protein gene variations that relate to higher high-density lipoprotein cholesterol: a population-based study. J Clin Endocrinol Metab 2006; 91: 3382-3388
• 58 Barter PJ, Caulfield M, Eriksson M et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357: 2109-2122
• 59 Vergeer M, Bots ML, van Leuven SI et al. Cholesteryl ester transfer protein inhibitor torcetrapib and off-target toxicity: a pooled analysis of the rating atherosclerotic disease change by imaging with a new CETP inhibitor (RADIANCE) trials. Circulation 2008; 118: 2515-2522
• 60 Meyer P, Nigam A, Marcil M, Tardif JC. The therapeutic potential of high-density lipoprotein mimetic agents in coronary artery disease. Curr Atheroscler Rep 2009; 11: 329-333
• 61 Bailey D, Jahagirdar R, Gordon A et al. RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J Am Coll Cardiol 2010; 55: 2580-2589
• 62 Bodzioch M, Orso E, Klucken J et al. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 1999; 22: 347-351
• 63 Ritsch A, Scharnagl H, März W. HDL cholesterol efflux capacity and cardiovascular events. N Engl J Med 2015; 372: 1870-1871
• 64 HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin / laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013; 34: 1279-1791