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Focus on triglycerides

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  • He who teaches does God's work!
    He who heals does too but medicine is not curing, it is taking pot luck dumb chances based on statistics made by vested interests of Pharma at patients' expense....So it the end it is doing the corporate devil's work?
    Nevertheless, he who shares slides that clear thinking and provide the power of clarification is an Angel of God!
    Thank you, Angel of God. My generation need not die as stupid as when we took our last Boards decades ago thanks to you, Angel!
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  • Lipoprotein classes and inflammation All the major lipoprotein classes impact in some way on the inflammatory process that leads to development of atherosclerosis. The triglyceride-rich lipoproteins—chylomicrons, very low density lipoprotein (VLDL), and their catabolic remnants—and low-density lipoprotein (LDL) are potentially proinflammatory, whereas high-density lipoprotein (HDL) is potentially anti-inflammatory. References: Doi H, Kugiyama K, Oka H, Sugiyama S, Ogata N, Koide SI, Nakamura SI, Yasue H. Remnant lipoproteins induce proatherothrombogenic molecules in endothelial cells through a redox-sensitive mechanism. Circulation 2000;102:670-676. Colome C, Martinez‑Gonzalez J, Vidal F, de Castellarnau C, Badimon L. Small oxidative changes in atherogenic LDL concentrations irreversibly regulate adhesiveness of human endothelial cells: effect of the lazaroid U74500A. Atherosclerosis 2000;149:295-302. Cockerill GW, Rye K-A, Gamble JR, Vadas MA, Barter PJ. High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.
  • Atherogenic particles Not only is LDL-C a risk factor for cardiovascular disease, but triglyceride-rich lipoproteins —very low density lipoprotein (VLDL), VLDL remnants, and intermediate-density lipoprotein (IDL)— may also increase the risk of heart disease. The NCEP ATP III uses non-HDL-C principally as a surrogate for these atherogenic particles.
  • Atherogenic particles Not only is LDL-C a risk factor for cardiovascular disease, but triglyceride-rich lipoproteins —very low density lipoprotein (VLDL), VLDL remnants, and intermediate-density lipoprotein (IDL)— may also increase the risk of heart disease. The NCEP ATP III uses non-HDL-C principally as a surrogate for these atherogenic particles.
  • Atherogenic particles Not only is LDL-C a risk factor for cardiovascular disease, but triglyceride-rich lipoproteins —very low density lipoprotein (VLDL), VLDL remnants, and intermediate-density lipoprotein (IDL)— may also increase the risk of heart disease. The NCEP ATP III uses non-HDL-C principally as a surrogate for these atherogenic particles.
  • Structure of LDL Of all of the plasma lipoproteins, LDL has been most investigated in terms of its role in inflammation. LDL consists of a surface monolayer of phospholipids and free cholesterol and a single molecule of apolipoprotein (apo) B, which encircles the lipoprotein. This surface monolayer surrounds a hydrophobic core of mainly cholesteryl esters but also some triglycerides. In itself, LDL is almost certainly not proinflammatory, but the particle can become modified in many ways. It is the modified LDL particle that is proinflammatory and proatherogenic. Reference: Murphy HC, Burns SP, White JJ, Bell JD, Iles RA. Investigation of human low-density lipoprotein by 1 H nuclear magnetic resonance spectroscopy: mobility of phosphatidylcholine and sphingomyelin headgroups characterizes the surface layer. Biochemistry 2000;39:9763-9770. Structure of HDL HDL has the same essential structure as LDL, with a surface monolayer of phospholipids and free cholesterol and a hydrophobic core consisting mainly of cholesteryl esters but also some triglyceride. However, HDL particles are smaller and contain different apolipoproteins, mainly apo A-I and apo A-II. Both these apolipoproteins have properties that protect the lipids against oxidative modification. In addition, some of the other proteins transported by HDL, such as paraoxonase, have antioxidant properties. Therefore, whereas LDL is very susceptible to oxidative modification, HDL is relatively resistant to it, and this is one of the reasons underlying the anti-inflammatory properties of HDL. Reference: Rye KA, Clay MA, Barter PJ. Remodelling of high density lipoproteins by plasma factors. Atherosclerosis 1999;145:227-238.
  • Fat in the diet consists of cholesterol as well as triglycerides. Dietary cholesterol is incorporated into micelles together with the biliary cholesterol that was already present. Dietary triglycerides are partially broken down by pancreatic lipases into fatty acids and monoglycerides, which are also incorporated into micellar particles.
  • Peripheral tissues produce within cells all the cholesterol needed for cellular homeostasis. However, the liver is the only organ that is capable of degrading cholesterol. Therefore, cholesterol must be transported through blood to the liver for processing, degradation, and secretion into bile. Because cholesterol is an insoluble molecule, it must be packaged and transported by special particles in the plasma called lipoproteins. High-density lipoproteins (HDL) are responsible for movement of most cholesterol from peripheral tissues through the blood back to the liver. Because the liver is the center of cholesterol homeostasis in the body, cholesterol that moves from peripheral tissues to the liver is considered to be moving in the reverse direction.
  • Molecular and histologic pathways for reverse cholesterol transport. To deliver peripheral cholesterol back to the liver or steroidogenic organs such as the adrenal glands, placenta, or ovaries, apoA-I and nascent discoidal HDL interact with cells such as macrophages and foam cells within blood vessel walls. The HDL undergoes a series of cell receptor–dependent and serum enzyme–dependent maturation and speciation reactions (HDL speciation). HDL can interact directly with a variety of hepatocyte surface receptors, including SR-BI. The cholesterol esters in HDL can also be transported back to the liver by an indirect pathway for reverse cholesterol transport that depends on CETP and the LDL and LDL-RRP receptors. ABCA1, ATP-binding membrane cassette transporter A1; apoA-I, apoprotein A-I; ApoE, apoprotein E; CE, cholesteryl ester; CETP, cholesterol ester transfer protein; GI, gastrointestinal; HDL, high-density lipoprotein; HL, hepatic lipase; IDL, intermediate-density lipoprotein; LCAT, lecithin:cholesterol acyltransferase; LDL, low-density lipoprotein; LDL-R, low-density lipoprotein receptor; LDL-RRP, low-density lipoprotein receptor–related protein; Lyso PC, lysophosphatidylcholine; PC, phosphatidylcholine; PGN, proteoglycan; PL, phospholipid; PLTP, phospholipid transfer protein; SR-BI, scavenger receptor BI; UC, unesterified cholesterol; VLDL, very low-density lipoprotein. (Reproduced with permission from Toth PP: High-density lipoprotein as a therapeutic target: Clinical evidence and treatment strategies. Am J Cardiol 96:50K-58K, 2005.)
  • Cellular cholesterol homeostasis in various tissues. A, Cholesterol homeostasis (hepatocytes). B, Cellular cholesterol efflux (peripheral cells). C, Selective uptake of cholesterol (adrenal cells, hepatocytes, endothelial cells). D, Adipocytes and E, macrophages foam cells. ABCA1 = ATP-binding cassette transporter A1; ABCG1 = ATP-binding cassette transporter G1; ACAT = acyl-coenzyme A:cholesterol acyltransferase; Apo = apolipoprotein; ASP = acylation-stimulating protein; CE = cholesterol esters; CETP = cholesteryl ester transfer protein; HDL = high-density lipoprotein; HMG CoA Red = hydroxymethylglutaryl coenzyme A reductase; HSL = hormone-sensitive lipase; IDL = intermediate-density lipoprotein; LCAT = lecithin cholesterol acyltransferase; LDL = low-density lipoprotein; LDL-R = low-density lipoprotein receptor; LRP = low-density lipoprotein receptor–related peptide; PLTP = phospholipid transfer protein; sER = smooth endoplasmic reticulum; SR-B1 = scavenger receptor B1; TG = triglycerides; VLDL = very-low-density lipoprotein; VLDL-R = very-low-density lipoprotein receptor.
  • The liver is a unique organ because it is capable of cholesterol catabolism and conversion of cholesterol into bile salts. The liver expresses an enzyme called cholesterol-7  -hydroxylase, which is the first and rate-limiting step of a complex enzymatic cascade in which the steroid nucleus of cholesterol is hydroxylated in two or three positions and the side chain of cholesterol is shortened and carboxylated. The end product is a molecule called a bile salt. One of the two bile salts produced in the livers of humans is called cholate, as shown on this slide. Although similar in appearance to cholesterol, cholate is quite a different molecule in its physical properties. Unlike cholesterol, which is highly insoluble in water, bile salts are highly soluble detergent-like molecules. Detergents are molecules that can aggregate to transport otherwise insoluble molecules, such as cholesterol, in an aqueous environment.
  • There are three main points of regulation for cholesterol absorption into the body. When the micellar particle comes in the proximity of an enterocyte, cholesterol is transported into the enterocyte through a channel recently identified as NPC1L1. A fraction of this cholesterol is pumped back out of the enterocyte into the intestinal lumen by the complex ABCG5/G8, and the remainder is esterified by the enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT) into cholesteryl esters. Reference: Altmann SW, Davis HR Jr, Zhu LJ, Yao X, Hoos LM, Tetzloff G, Iyer SP, Maguire M, Golovko A, Zeng M, Wang L, Murgolo N, Graziano MP. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science 2004;303:1201-1204.
  • Triglycerides are assimilated into the body by the separate absorption of fatty acids and monoglycerides, which are re-esterified by the enzyme acyl-coenzyme A:diglycerol acyltransferase (DGAT) to form triglycerides.
  • Triglycerides and cholesteryl esters are incorporated, together with apolipoprotein (apo) B-48, to form chylomicron particles, which are exocytosed into the lymph and then enter the circulation.
  • Intestinal cholesterol absorption Intestinal cholesterol absorption is an important origin of circulating LDL-C. Although dietary cholesterol does contribute, the majority (2/3 to 3/4) of cholesterol delivered to the intestine is derived from biliary cholesterol excretion. Intestinal cholesterol undergoes micellar adaptation by bile acids and is then absorbed into the intestinal cells. The ensuing free cholesterol may subsequently be "pumped" back into the intestine through adenosine triphosphate – binding cassette (ABC) transporters ABCG5 and ABCG8. Alternatively, intestinal free cholesterol may be esterified through acyl-coenzyme A:cholesterol acyltransferase (ACAT), and then packaged into chylomicrons (CMs) in the intestinal epithelial cell by microsomal triglyceride transfer protein (MTP). As CMs leave the intestine, their cholesterol is transported through the lymphatic system to the liver. Reference: Bays H, Dujovne C. Colesevelam HCl: a non-systemic lipid-altering drug. Expert Opin Pharmacother 2003;4:779-790. Bays H. Ezetimibe. Expert Opin Investig Drugs 2002;11:1587-1604.
  • HDL is assembled through the combination of cholesterol, phospholipids, and apo A I, produced in the liver and gut. Cholesterol is incorporated in part by the action of the adenosine triphosphate-binding cassette-1 and is then esterified by lecithin CE transfer protein (LCAT) allowing HDL to enlarge into spherical HDL3 and HDL2. VLDL is secreted by the liver and processed on the vascular endothelium by LPL. LPL is activated by apo C II and inhibited by apo C III. CMs are secreted by the gut. Phospholipids released by lipolysis of both CM and VLDL contribute to the formation of small dense pre |[beta]| or discoidal HDL and the VLDL remnant particle is either taken up directly by the liver through the lipoprotein-like receptor or is transformed into LDL by action of CE transfer protein, exchanging the CE-rich core of HDL with VLDL TGs. CM remnants are taken up by the liver. TG-rich HDL is then processed by HL into smaller dense HDL. Mature HDL2 either transfers CEs to the liver by interaction with the scavenger receptor B-1 or transfers its CE-rich core to VLDL remnants creating LDL. Small dense pre |[beta]| or discoidal HDL is subject to accelerated degradation in part by the kidney.
  • The exogenous, endogenous, and reverse cholesterol pathways. The exogenous pathway transports dietary fat from the small intestine as chylomicrons to the periphery and the liver. The endogenous pathway denotes the secretion of very low density lipoprotein (VLDL) from the liver and its catabolism to intermediate density lipoprotein (IDL) and low-density lipoprotein (LDL). Triglycerides are hydrolyzed from the VLDL particle by the action of lipoprotein lipase (LPL) in the vascular bed, yielding free fatty acids (FFAs) for utilization and storage in muscle and adipose tissue. High-density lipoprotein (HDL) metabolism is responsible for the transport of excess cholesterol from the peripheral tissues back to the liver for excretion in the bile. Nascent HDL-3 particles derived from the liver and small intestine are esterified to more mature HDL-2 particles by enzyme-mediated movement of chylomicron and VLDL into the HDL core, which is removed from the circulation by endocytosis.
  • Endogenous lipid metabolism. In the liver, triglycerides (TGs), cholesteryl esters (CEs), and apolipoprotein B100 are packaged as very low density lipoprotein (VLDL) particles. TG is hydrolyzed by lipoprotein lipase (LPL) to generate intermediate density lipoprotein (IDL), which is further metabolized to generate low density lipoprotein (LDL). This particle can be removed by the liver or by peripheral cells. Cholesterol derived from LDL regulates several processes and can be used for the synthesis of bile acids, steroid hormones, and cell membranes.
  • Pathways involved in chylomicron remnant metabolism. In sequestration, chylomicron remnants are trapped in the space of Disse, through proteoglycan binding mediated by apolipoprotein E (E). In processing, enzymes, including lipases, can continue processing the remnants to smaller particles. In uptake, receptors involved in the uptake of the remnants appear to include the low-density lipoprotein (LDL) receptor and the LDL receptor–related protein (LRP). Apo-E, apolipoprotein E; HL, hepatic lipase; HSPG, heparan sulfate proteoglycans; LPL, lipoprotein lipase.
  • Hypertriglyceridemia Increases CHD Risk in Patients with Low HDL-C Levels Prospective Cardiovascular Münster Study In the Prospective Cardiovascular Münster Study (PROCAM), 1 triglyceride levels  200 mg/dL doubled the coronary heart disease (CHD) risk in patients with elevated ratios (> 5.0) of low- to high-density lipoprotein cholesterol (LDL-C/HDL-C). Most patients with LDL-C/HDL-C values > 5.0 had HDL-C levels < 39 mg/dL. These data suggest that hypertriglyceridemic patients with reduced HDL-C levels are at particularly high risk of CHD. Reference: Assmann G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Münster study. Am J Cardiol. 1992;70:733–737.
  • Evidence from the 8-year Copenhagen Male Study involving 2906 men further substantiated that triglyceride levels were independently related to increased CHD risk. The relation between triglycerides and CHD risk was inspite of adjusting for HDL.
  • In a prospective cohort study of 7587 women and 6394 men, aged 20 to 93 years, followed up from baseline (1976-1978) until 2004, the cumulative incidence of myocardial infarction, ischemic heart disease and total death increased with increasing levels of non-fasting triglycerides. Nordestgaard BG, Benn M, Schnohr P, et al . Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease and death in men and women. JAMA . 2007;298(3):299-308
  • In a prospective cohort study of 7587 women and 6394 men, aged 20 to 93 years, followed up from baseline (1976-1978) until 2004, the cumulative incidence of myocardial infarction, ischemic heart disease and total death increased with increasing levels of non-fasting triglycerides. Nordestgaard BG, Benn M, Schnohr P, et al . Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease and death in men and women. JAMA . 2007;298(3):299-308
  • Importantly, triglycerides are not just an independent risk factor for CHD, they also exhibit a synergistic relationship in terms of increased CHD risk, as shown by the PROCAM study. As seen in this slide, at any level of LDL, an elevated level of triglycerides further increases the risk of CHD. Eur Heart J 1998; 19 (Suppl M): M8-M14.
  • We have understood for decades the roles of ‘classical’ risk factors – elevated LDL-cholesterol, hypertension, elevated blood glucose and smoking – in the pathogenesis of cardiovascular disease. More recent research is continuing to define the contribution of emerging risk factors to the risk of developing type 2 diabetes and cardiovascular disease, particularly in the setting of insulin resistance. Abdominal obesity is associated with multiple cardiometabolic risk factors such as atherogenic elevated blood glucose (hypertriglyceridaemia and low HDL-cholesterol), elevated blood glucose and inflammation, which are major drivers of cardiovascular disease and type 2 diabetes. In addition, atherosclerosis is increasingly regarded as an inflammatory condition.
  • In addition to type 2 diabetes, insulin resistance is a pathogenic factor in the development of a broad spectrum of clinical conditions. These include hypertension, atherosclerosis, dyslipidaemia, decreased fibrinolytic activity, impaired glucose tolerance, acanthosis nigricans, hyperuricaemia, polycystic ovary disease, and obesity. American Diabetes Association. Consensus Development Conference on Insulin Resistance, 5–6 November 1997. Diabetes Care 1998;21(2):310–314.
  • Ethnic Variations in Lipid Parameters Insulin Resistance Atherosclerosis Study Small, dense low-density lipoprotein (LDL) particle size is now recognized as a risk factor for cardiovascular disease (CVD). LDL size was investigated as a possible explanation for differences in CVD rates among African-Americans, Hispanics, and non-Hispanic whites in the Insulin Resistance Atherosclerosis Study (IRAS). As this slide shows, LDL size differed significantly ( P < 0.001) by ethnic group, as did high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels. A comparison of the three ethnic groups revealed that reduced LDL size was associated with lower HDL-C levels and higher TG levels. African-Americans had higher HDL-C and lower TG levels than non-Hispanic whites. Hispanics had the opposite pattern, with lower HDL-C and higher TG levels than non-Hispanic whites. Reference: Haffner SM, D’Agostino R Jr, Goff D, et al. LDL size in African Americans, Hispanics, and non-Hispanic whites: the Insulin Resistance Atherosclerosis Study. Arterioscler Thromb Vasc Biol. 1999;19:2234–2240.
  • Plasma Insulin and Triglycerides Predict Ischemic Heart Disease: Quebec Cardiovascular Study In a nested case-control study within the Quebec Cardiovascular Study, the relationship between fasting insulin, which is a surrogate marker for insulin resistance, and CHD was examined in men who were principally nondiabetic. Subjects were stratified by low (<12 µU/ml), medium (12-15 µU/ml), and high (>15 µU/ml) insulin levels and by low (<150 mg/dL) and high (>150 mg/dL) triglycerides. The study found that high insulin levels predicted CHD both in men with low triglycerides and in men with high triglycerides. However, triglyceride level was not a significant predictor of CHD once one adjusted for insulin level. These results bring up an interesting but difficult area in cardiovascular epidemiology, which is whether triglyceride is a risk factor for CHD. Approximately 20 years ago, Stephen Hulley et al. suggested that triglyceride level was not a risk factor for CHD once adjustment was made for HDL. Although Hulley has been criticized for this view, few analyses that have looked at the possible relation between triglyceride and CHD have adjusted for whether people were diabetic. Because of the relation of triglyceride level to insulin level and possibly glucose level, most of the relation between triglyceride and CHD in observational studies may be due to confounding. To evaluate fully the effects of lowering triglyceride level on CHD, one has to look at clinical trial data as opposed to observational data. Among interventional studies, confounding may be less important in trials of behavioral interventions to lower triglyceride, because weight loss and increased physical activity not only lower triglyceride level but also improve insulin sensitivity and lower blood pressure. In contrast, if triglyceride is lowered by pharmacological means such as with a fibrate or a high-dose statin, there will be little effect on blood pressure or insulin sensitivity. References: Despres JP, Lamarche B, Mauriege P, Cantin B, Dagenais GR, Moorjani S, Lupien PJ. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996;334:952-957. Hulley SB, Rosenman RH, Bawol RD, Brand RJ. Epidemiology as a guide to clinical decisions. The association between triglyceride and coronary heart disease. N Engl J Med 1980;302:1383-1389.
  • Mechanisms Relating Insulin Resistance and Dyslipidemia (I) The pathophysiologic basis for diabetic dyslipidemia and its relation to insulin resistance is presented over the next four slides. In the first, we see that insulin-resistant fat cells undergo greater breakdown of their stored triglycerides and greater release of free fatty acids into the circulation. This is a common abnormality seen in both obese and nonobese insulin-resistant subjects and those with type 2 diabetes. Increased fatty acids in the plasma leads to increased fatty acid uptake by the liver; in the fed state and in the presence of adequate glycogen stores, which is the common situation in patients with type 2 diabetes that is reasonably well controlled and certainly the case in the insulin-resistant nondiabetic subject, the liver takes those fatty acids and synthesizes them into triglycerides.
  • Mechanisms Relating Insulin Resistance and Dyslipidemia (II) The presence of increased triglycerides stimulates the assembly and secretion of the apolipoprotein (apo) B and very low density lipoprotein. The result is an increased number of VLDL particles and increased level of triglycerides in the plasma, which leads to the rest of the diabetic dyslipidemic picture.
  • Mechanisms Relating Insulin Resistance and Dyslipidemia (III) In the presence of increased VLDL in the plasma and normal levels of activity of the plasma protein cholesteryl ester transfer protein (CETP), VLDL triglycerides can be exchanged for HDL cholesterol. That is, a VLDL particle will give up a molecule of triglyceride, donating it to the HDL, in return for one of the cholesteryl ester molecules from HDL. This leads to two outcomes: a cholesterol-rich VLDL remnant particle that is atherogenic, and a triglyceride-rich cholesterol-depleted HDL particle. The triglyceride-rich HDL particle can undergo further modification including hydrolysis of its tryglyceride, probably by hepatic lipase, which leads to the dissociation of the structurally important protein apo A-I. The free apo A-I in plasma is cleared more rapidly than apo A-I associated with HDL particles. One of the sites of clearance is the kidney. In this situation, HDL cholesterol is reduced, and the amount of circulating apo A-I and therefore the number of HDL particles is also reduced.
  • Mechanisms Relating Insulin Resistance and Dyslipidemia (IV) On the last slide in this series, we see a similar phenomena leading to small, dense LDL. Increased levels of VLDL triglyceride in the presence of CETP can promote the transfer of triglyceride into LDL in exchange for LDL cholesteryl ester. The triglyceride-rich LDL can undergo hydrolysis by hepatic lipase or lipoprotein lipase, which leads to a small, dense, cholesterol-depleted—and, in general, lipid-depleted—LDL particle.
  • Schematic summary relating insulin resistance (IR) to the characteristic dyslipidemia of type 2 diabetes mellitus. IR at the adipocyte results in increased free fatty acid (FFA) release. Increased FFA flux stimulates very-low-density lipoprotein (VLDL) secretion, causing hypertriglyceridemia (TG). VLDL stimulates a reciprocal exchange of TG to cholesteryl ester (CE) from both high-density lipoprotein (HDL) and low-density lipoprotein (LDL), catalyzed by CE transfer protein (CETP). TG-enriched HDL dissociates from ApoA-1, leaving less HDL for reverse cholesterol transport. TG-enriched LDL serves as a substrate for lipases that convert it to atherogenic small, dense LDL particles (SD LDL). (From Ginsberg HN. Insulin resistance and cardiovascular disease. J Clin Invest 2000;106:453-458.)
  • Insulin resistance and dyslipidemia. The suppression of lipoprotein lipase and very-low-density lipoprotein (VLDL) production by insulin is defective in insulin resistance, leading to increased free fatty acid (FFA) flux to the liver and increased VLDL production, which results in increased circulating triglyceride concentrations. The triglycerides are transferred to low-density lipoprotein (LDL) and high-density lipoprotein (HDL), and the VLDL particle gains cholesterol esters by the action of the cholesterol ester transfer protein (CETP). This leads to increased catabolism of HDL particles by the liver and loss of apolipoprotein (Apo) A, resulting in low HDL concentrations. The triglyceride-rich LDL particle is stripped of the triglycerides, resulting in the accumulation of atherogenic small, dense LDL particles.
  • Dyslipidemia in Diabetes As described in the preceding slides, high triglyceride and high VLDL levels lead to low HDL, fewer HDL particles, and small, dense LDL.
  • Small, Dense LDL and CHD: Potential Atherogenic Mechanisms Data from in vitro and in vivo studies suggest that small, dense LDL may be particularly atherogenic. In vitro, small, dense LDL appears to be more susceptible to oxidative modification. Because they are smaller, these particles appear to penetrate the endothelial layer of the arterial wall more easily. The apo B molecule in small, dense LDL undergoes a conformational change that leads to decreased affinity for the LDL receptor, therefore allowing this LDL particle to remain in the circulation longer and be more liable to oxidative modification and uptake into the vessel wall. Finally, in population studies and small clinical studies, small, dense LDL is associated with the insulin-resistance syndrome as well as with high triglycerides and low HDL cholesterol. Reference: Austin MA, Edwards KL. Small, dense low density lipoproteins, the insulin resistance syndrome and noninsulin-dependent diabetes. Curr Opin Lipidol 1996;7:167-171.
  • Hypertriglyceridemia and CHD Risk: Associated Abnormalities One should not focus extensively on the atherogenic potential of small, dense LDL to the exclusion of considering hypertriglyceridemia as a risk factor. There are a number of reasons to consider hypertriglyceridemia as at least a marker of increased atherogenic potential. First of all, hypertriglyceridemia is associated with the accumulation of chylomicron remnants, which we know can be atherogenic, and accumulation of VLDL remnants, which are also atherogenic. As previously discussed, hypertriglyceridemia generates small, dense LDL and is the basis for low HDL in the general population. Hypertriglyceridemia is also associated with increased coagulability and decreased fibrinolysis, as shown by its association with increased levels of plasminogen activator inhibitor 1 (PAI-1) and factor VII and its activation of prothrombin to thrombin.
  • Pharmacologic Agents for Treatment of Dyslipidemia In this slide, we can see a summary of the actions of the different classes of drugs available for treating the dyslipidemia of diabetes. The HMG-CoA reductase inhibitors, or statins, are very effective in lowering LDL cholesterol levels in patients with diabetes, have variable but often significant effects on triglyceride levels, and have a modest but potentially important ability to raise HDL cholesterol levels. The fibrates, of which gemfibrozil and fenofibrate are available in the United States, are very good at lowering triglycerides and raising HDL cholesterol levels. These effects of fibrates on triglycerides are usually better than those seen with statins. On the other hand, fibrates often have little effect on LDL cholesterol, and can even result in increased LDL levels in patients with more severe hypertriglyceridemia. Fenofibrate can lower LDL cholesterol significantly when used in patients with very high baseline LDL cholesterol levels. The bile acid–binding resins can achieve additional LDL cholesterol lowering when used with a statin, although GI side effects of the older resins may be particularly problematic in patients with diabetes. Newer, more potent bile acid sequestrants, such as colesevalem, may increase their efficacy in the diabetic population. Niacin is the best agent for raising HDL cholesterol and has significant effects on triglycerides and a modest ability to lower LDL cholesterol. Niacin appears to increase insulin resistance, however, and its use may require modification of the diabetic treatment regimen. Reference: American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care 2000;23(suppl 1):S57-S60.
  • Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults This slide presents the priorities for treating abnormalities of lipid metabolism set by the American Diabetes Association. LDL lowering is the first priority, based on the clinical trials showing marked reductions in morbidity when statins lower LDL cholesterol in the subgroups with diabetes. Raising HDL cholesterol is the second priority, followed by lowering triglycerides. ADA goals for all diabetics include an LDL cholesterol less than or equal to 100 mg/dL, an HDL cholesterol greater than 45 mg/dl (possibly even higher in women), and a triglyceride level less than 200 mg/dL. Reference: American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care 2000;23(suppl 1):S57-S60.
  • The molecular mechanisms by which statins act include inhibiting the rate of conversion of acetate molecules into cholesterol by the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting step in cholesterol biosynthesis. Because a precise amount of cholesterol is required in cells, inhibition of synthesis leads to a homeostatic response in which cells increase the density of LDL receptors on their surface. This increases the clearance rate of LDL particles from the plasma and reduces plasma LDL cholesterol secondarily.
  • Statins: mechanism of action As inhibitors of hepatic HMG-CoA reductase, the enzyme catalyzing the rate-limiting step in hepatic cholesterol synthesis, statins decrease synthesis of cholesterol by the liver, which results in two important effects: the up-regulation of LDL receptors by hepatocytes and consequent increased removal of apolipoprotein (apo) E – and B – containing lipoproteins from the circulation, and a reduction in the synthesis and secretion of lipoproteins from the liver. The net effect of statin therapy is to lower plasma concentrations of cholesterol-carrying lipoproteins, the most prominent of which is LDL. Importantly, however, statins also increase the removal and reduce the secretion of remnant particles, i.e., very low density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL). This means that in patients who have an elevation of both LDL-C and triglycerides (indicating increased levels of triglyceride-rich VLDL and IDL remnants as well as LDL), a statin is one of the therapies of choice because of its ability to effectively lower LDL-C and non – high-density lipoprotein cholesterol (non-HDL-C) levels.
  • Statins reduce TG levels in the range of 10% to 20%. Higher the baseline TG level, the greater the TG-lowering effect. AFCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study; ASCOT: Anglo Scandinavian Cardiac Outcome Trial; CARDS: Collaborative AtoRvastatin Diabetes Study; CARE: Cholesterol and Recurrent Events Study; HPS: Heart Protection Study; JUPITER: Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; LIPID: Long-Term Intervention with Pravastatin in Ischemic Disease; PROSPER: Prospective Study of Pravastatin in the Elderly at Risk; TG: triglyceride; 4s: Scandinavian Simvastatin Survival Study; WOSCOPS: West of Scotland Coronary Prevention Study. What Are the Effects of Statins on Triglycerides and What Are the Results of Major Outcomes Studies? Downloaded from http://cme.medscape.com
  • Rosuvastatin significantly decreased the levels of Low density cholesterol, Total cholesterol and triglycerides in both rosuvastatin naïve patients and patients switched over to rosuvastatin. In patients switched to rosuvastatin, achievement of target LDL-C levels improved from 29% to 72.9%. Tan AT , Low LP , Lim CH , et al . Effects of rosuvastatin on low-density lipoprotein cholesterol and plasma lipids in Asian patients with hypercholesterolemia. J Atheroscler Thromb . 2009;16(4):509-16.
  • The primary mode of action of the fibrates is via activation of the nuclear transcription factor PPARα, predominantly expressed in tissues that metabolize fatty acids, such as the liver, kidney, heart and muscle. On activation, PPARα binds as heterodimers with RXR, which subsequently recognises and binds to specific PPARα response elements leading to modulation of expression of the target genes. The result is an increase in apo A-1, lipoprotein lipase and HDL levels and decrease in apo CIII, which promotes the clearance of circulating triglyceride-rich lipoproteins. In addition, fibrates promote a shift in the density of LDL particles towards larger, more buoyant particles that are less susceptible to oxidation and have increased affinity for the LDL receptor. Fibrates also exert pleiotropic effects in the artery wall. PPARα is involved in the control of the anti-inflammatory response, via inhibition of the transcription factor NFκB. Fibrates can also attenuate the production of pro-inflammatory stimuli such as interleukin 6 (IL-6) and various prostaglandins, as well as the acute phase proteins, including fibrinogen and C-reactive protein. Fibrates: Therapeutic Review: Mechanism of Action of Fibrates. Available from: http://www.medscape.com.
  • The primary mode of action of the fibrates is via activation of the nuclear transcription factor PPARα, predominantly expressed in tissues that metabolize fatty acids, such as the liver, kidney, heart and muscle. On activation, PPARα binds as heterodimers with RXR, which subsequently recognises and binds to specific PPARα response elements leading to modulation of expression of the target genes. The result is an increase in apo A-1, lipoprotein lipase and HDL levels and decrease in apo CIII, which promotes the clearance of circulating triglyceride-rich lipoproteins. In addition, fibrates promote a shift in the density of LDL particles towards larger, more buoyant particles that are less susceptible to oxidation and have increased affinity for the LDL receptor. Fibrates also exert pleiotropic effects in the artery wall. PPARα is involved in the control of the anti-inflammatory response, via inhibition of the transcription factor NFκB. Fibrates can also attenuate the production of pro-inflammatory stimuli such as interleukin 6 (IL-6) and various prostaglandins, as well as the acute phase proteins, including fibrinogen and C-reactive protein. Fibrates: Therapeutic Review: Mechanism of Action of Fibrates. Available from: http://www.medscape.com.
  • The primary mode of action of the fibrates is via activation of the nuclear transcription factor PPARα, predominantly expressed in tissues that metabolize fatty acids, such as the liver, kidney, heart and muscle. On activation, PPARα binds as heterodimers with RXR, which subsequently recognises and binds to specific PPARα response elements leading to modulation of expression of the target genes. The result is an increase in apo A-1, lipoprotein lipase and HDL levels and decrease in apo CIII, which promotes the clearance of circulating triglyceride-rich lipoproteins. In addition, fibrates promote a shift in the density of LDL particles towards larger, more buoyant particles that are less susceptible to oxidation and have increased affinity for the LDL receptor. Fibrates also exert pleiotropic effects in the artery wall. PPARα is involved in the control of the anti-inflammatory response, via inhibition of the transcription factor NFκB. Fibrates can also attenuate the production of pro-inflammatory stimuli such as interleukin 6 (IL-6) and various prostaglandins, as well as the acute phase proteins, including fibrinogen and C-reactive protein. Fibrates: Therapeutic Review: Mechanism of Action of Fibrates. Available from: http://www.medscape.com.
  • Nicotinic acid: mechanism of action The last of our LDL-C – lowering drugs is nicotinic acid, or niacin. Niacin appears to exert its effects by inhibiting lipoprotein synthesis and decreasing the production of VLDL particles by the liver. It inhibits the peripheral mobilization of free fatty acids, thus reducing hepatic synthesis of triglycerides and the secretion of VLDL. It also reduces apo B. The net result is a reduction in VLDL particles secreted by the liver and thus less substrate to make LDL particles. It increases the production of apo A-I and thereby HDL through mechanisms that are not clear.
  • Potential triglyceride-lowering mechanisms of omega-3 FA Feeding omega-3 FA has been shown to inhibit (–) lipogenesis and the activities of diacylglycerol acyltransferase (DGAT), phosphatidic acid (PA), and hormone-sensitive lipase and to stimulate (+) β-oxidation, phospholipid synthesis, and apo B degradation. The end result is a reduced rate of secretion of very low density lipoprotein (VLDL) triglyceride (TG). Additional abbreviations on slide: FA, fatty acid; CPT, carnitine phosphotransferase; DAG, diacylglycerol; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; PAP, phosphatidic acid phosphohydrolase; NEFA, serum nonesterified fatty acids; apo, apolipoprotein. Reference: Harris WS and Bulchandani D. Why do omega-3 fatty acids lower serum triglycerides? Curr Opin Lipidol 2006; 17:387-393.
  • Dyslipidemia treatment summary. *Exception: Immediate medication (gemfibrozil or niacin) for patients with TG >1000 mg/dL due to high risk of pancreatitis, or LDL-C >220 mg/dL due to genetic disorders and resistance to nonpharmacologic treatment after ruling out secondary causes. †Notes: (1) Goal LDL-C <100 mg/dL (70 mg/dL optional) with CHD/noncoronary atherosclerosis, diabetes mellitus, or 10-yr CHD-risk >20%; (2) Goal LDL-C <130 mg/dL if no known CHD or noncoronary atherosclerosis but high risk; (3) Goal LDL-C >160 mg/dL with ≥2 risk factors or LDL-C >190 mg/dL in isolation. ‡See text: Statins and fibrates and/or niacin may be used in combination with close monitoring for hepatitis or myositis (risk of interaction 2-6%). CHD, coronary heart disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LDL-C, LDL cholesterol; TG, triglyceride. Modified from McBride PE, Underbakke G, Stein DH: Dyslipidemias. In Taylor RB (ed): Family Medicine: Principles and Practice, 6th ed. New York, Springer-Verlag, 2003, pp 1019-1029.
  • Transcript

    • 1. Focus on TriglyceridesFocus on TriglyceridesDr. Sachin Verma MD, FICM, FCCS, ICFCDr. Sachin Verma MD, FICM, FCCS, ICFCFellowship in Intensive Care MedicineFellowship in Intensive Care MedicineInfection Control Fellows CourseInfection Control Fellows CourseConsultant Internal Medicine and Critical CareConsultant Internal Medicine and Critical CareIvy Hospital Sector 71 MohaliIvy Hospital Sector 71 MohaliWeb:-Web:- http://www.medicinedoctorinchandigarh.comhttp://www.medicinedoctorinchandigarh.comMob:- +91-7508677495Mob:- +91-7508677495
    • 2. Lipoprotein Classes and InflammationLipoprotein Classes and InflammationDoi H, et al. Circulation. 2000;102:670-676; Colome C, et al. Atherosclerosis. 2000;49:295-302; Cockerill GW, et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994.HDLHDLLDLLDLChylomicrons, VLDL, andChylomicrons, VLDL, andtheir catabolic remnantstheir catabolic remnants> 30 nm> 30 nm 20–22 nm20–22 nmPotentially proinflammatoryPotentially proinflammatory9–15 nm9–15 nmPotentially anti-Potentially anti-inflammatoryinflammatory
    • 3. Classification of Lipids and LipoproteinsClassification of Lipids and Lipoproteins
    • 4. Chacteristics of LipoproteinsChacteristics of Lipoproteins
    • 5. Triglyceride rich LipoproteinsTriglyceride rich Lipoproteins
    • 6. Structure of LDL and HDLStructure of LDL and HDLHydrophobic CoreHydrophobic Coreof Triglyceride and Cholesterylof Triglyceride and CholesterylEstersEstersLDLHydrophobic Core of TriglycerideHydrophobic Core of Triglycerideand Cholesteryl Estersand Cholesteryl EstersSurface Monolayer of Phospholipids andSurface Monolayer of Phospholipids andFree CholesterolFree CholesterolApo A-IIApo A-IIApo A-IApo A-ISurface Monolayer of Phospholipids andSurface Monolayer of Phospholipids andFree CholesterolFree CholesterolHDL
    • 7. Digestion and Metabolism of Dietary FatDigestion and Metabolism of Dietary Fat
    • 8. Digestion and Metabolism of Dietary FatDigestion and Metabolism of Dietary Fat
    • 9. Reverse Cholesterol TransportReverse Cholesterol TransportBloodBloodPeripheralPeripheralTissuesTissuesLiverLiverBileBileExcessExcessCholesterolCholesterol
    • 10. Reverse Cholesterol TransportReverse Cholesterol Transport
    • 11. Reverse Cholesterol TransportReverse Cholesterol Transport
    • 12. Cholesterol Catabolism into Bile SaltsCholesterol Catabolism into Bile SaltsCholateCholateCholesterolCholesterolCholesterolCholesterol77αα-hydroxylase-hydroxylaseHOHOHOHOOHOHCOO -COO -OHOHBile salts are the breakdown products of cholesterol. Their function is to transportcholesterol in the digestive system
    • 13. LymphLymph EnterocyteEnterocyte IntestinalIntestinalLumenLumenCholesterol AbsorptionCholesterol AbsorptionCholesterolNPC1L1CholesterylEsterABCG5/G8ACAT
    • 14. LymphLymph EnterocyteEnterocyte IntestinalIntestinalLumenLumenTriglyceride AbsorptionTriglyceride Absorption2 Fatty Acid+MonoglycerideDGATTriglyceride
    • 15. LymphLymph EnterocyteEnterocyte IntestinalIntestinalLumenLumenChylomicron FormationChylomicron FormationCholesterylEsterCMapoB48Triglyceride
    • 16. Intestinal Cholesterol AbsorptionIntestinal Cholesterol AbsorptionIntestinalIntestinalepithelial cellepithelial cellLuminalLuminalcholesterolcholesterolMicellarMicellarcholesterolcholesterolBileBileacidaciduptakeuptakeABCG5ABCG8Cholesteryl estersACATMTPCM(esterification)excretionFreecholesterolCholesterolCholesterolTransporterTransporterDietaryDietarycholesterolcholesterolDietaryDietarycholesterolcholesterolBiliaryBiliarycholesterolcholesterolThroughThroughlymphaticlymphaticsystemsystemto theto theliverliver
    • 17. Lipoprotein MetabolismLipoprotein MetabolismHDL is assembled through the combination ofcholesterol, phospholipids, and apo A I, producedin the liver and gut. Cholesterol is incorporated inpart by the action of the adenosine triphosphate-binding cassette-1 and is then esterified by lecithinCE transfer protein (LCAT) allowing HDL toenlarge into spherical HDL3 and HDL2. VLDL issecreted by the liver and processed on the vascularendothelium by LPL. LPL is activated by apo C IIand inhibited by apo C III. CMs are secreted by thegut. Phospholipids released by lipolysis of bothCM and VLDL contribute to the formation of smalldense pre |[beta]| or discoidal HDL and theVLDL remnant particle is either taken up directlyby the liver through the lipoprotein-like receptoror is transformed into LDL by action of CE transferprotein, exchanging the CE-rich core of HDL withVLDL TGs. CM remnants are taken up by theliver. TG-rich HDL is then processed by HL intosmaller dense HDL. Mature HDL2 either transfersCEs to the liver by interaction with the scavengerreceptor B-1 or transfers its CE-rich core to VLDLremnants creating LDL. Small dense pre |[beta]|or discoidal HDL is subject to accelerateddegradation in part by the kidney.
    • 18. The exogenous, endogenous, and reverseThe exogenous, endogenous, and reversecholesterol pathways.cholesterol pathways.The exogenous pathway transports dietary fatfrom the small intestine as chylomicrons to theperiphery and the liver. The endogenous pathwaydenotes the secretion of very low densitylipoprotein (VLDL) from the liver and itscatabolism to intermediate density lipoprotein(IDL) and low-density lipoprotein (LDL).Triglycerides are hydrolyzed from the VLDLparticle by the action of lipoprotein lipase (LPL) inthe vascular bed, yielding free fatty acids (FFAs)for utilization and storage in muscle and adiposetissue. High-density lipoprotein (HDL) metabolismis responsible for the transport of excesscholesterol from the peripheral tissues back to theliver for excretion in the bile. Nascent HDL-3particles derived from the liver and small intestineare esterified to more mature HDL-2 particles byenzyme-mediated movement of chylomicron andVLDL into the HDL core, which is removed fromthe circulation by endocytosis.
    • 19. Endogenous Lipid MetabolismEndogenous Lipid Metabolism• In the liver, triglycerides (TGs),cholesteryl esters (CEs), andapolipoprotein B100 are packaged asvery low density lipoprotein (VLDL)particles.• TG is hydrolyzed by lipoprotein lipase(LPL) to generate intermediate densitylipoprotein (IDL), which is furthermetabolized to generate low densitylipoprotein (LDL).• This particle can be removed by theliver or by peripheral cells. Cholesterolderived from LDL regulates severalprocesses and can be used for thesynthesis of bile acids, steroidhormones, and cell membranes.
    • 20. Chylomicron Remnant MetabolismChylomicron Remnant Metabolism
    • 21. Atherogenicity of TG-rich particlesAtherogenicity of TG-rich particles
    • 22. Atherogenicity of TG-rich particlesAtherogenicity of TG-rich particles
    • 23. Modulation of VLDLModulation of VLDL
    • 24. Specific Dyslipidemias: Elevated TriglyceridesSpecific Dyslipidemias: Elevated TriglyceridesClassification of SerumClassification of SerumTriglyceridesTriglycerides NormalNormal <150 mg/dL<150 mg/dL Borderline highBorderline high 150–199150–199mg/dLmg/dL HighHigh 200–499200–499mg/dLmg/dL
    • 25. Causes of Elevated TriglyceridesCauses of Elevated Triglycerides Obesity and overweightObesity and overweight Physical inactivityPhysical inactivity Cigarette smokingCigarette smoking Excess alcohol intakeExcess alcohol intake High carbohydrate diets (>60% of energy intake)High carbohydrate diets (>60% of energy intake) Several diseases (type 2 diabetes, chronic renal failure, nephroticSeveral diseases (type 2 diabetes, chronic renal failure, nephroticsyndrome)syndrome) Certain drugs (corticosteroids, estrogens, retinoids, higher doses ofCertain drugs (corticosteroids, estrogens, retinoids, higher doses ofbeta-blockers)beta-blockers) Various genetic dyslipidemiasVarious genetic dyslipidemias
    • 26. Hypertriglyceridemia Increases CHD Risk inHypertriglyceridemia Increases CHD Risk inPatients with Low HDL-C LevelsPatients with Low HDL-C Levels* Bar represents 5% of subjects in which 25% of CHD events occurred. Assmann G, Schulte H. Am J Cardiol 1992;70:733–737.24 31116245050100150200250≤ 5.0 > 5.0*LDL-C/HDL-C ratioIncidenceper1,000(in6years)TG < 200 mg/dLTG ≥ 200 mg/dL
    • 27. Triglycerides as a risk factor for CHDTriglycerides as a risk factor for CHDCopenhagen Male StudyCopenhagen Male Study4.6%7.7%11.5%0246810121439-97mg/dl (n=982) 98-140 (n=973) >140 (n=951)Am J Cardiol 1999; 83: 13F-16FTriglyceride level(mg/dL)CumulativeincidenceofCHDandall-causemortalityN=2906; 8years
    • 28. Triglycerides as a risk factor for CHDTriglycerides as a risk factor for CHDCumulative Incidence of MICumulative Incidence of IHD
    • 29. Triglycerides as a risk factor for CHDTriglycerides as a risk factor for CHDCumulative Incidence of Total Death
    • 30. <130LDL-C3002502001501005001843384756112 107255Elevated triglycerides: A synergistic risk factorElevated triglycerides: A synergistic risk factorTG < 200 mg/dlTG > 200 mg/dl130-159 160-189 >190CHDcases/1000in8yearsPROCAM Study: Incidence of coronary heart disease events according to serum LDL-C and triglyceride concentration
    • 31. Global Cardiometabolic RiskGlobal Cardiometabolic Risk
    • 32. ↓↓↓↓↓↓↓↓↓↓↓↓↓↓TG and Metabolic SyndromeTG and Metabolic SyndromeInsulinInsulinResistanceResistanceHyper-Hyper-insulinaemiainsulinaemia↔↔HypertensionMicroalbuminuriaCentralobesity↑ Triglycerides↓ HDLcholesterol↑ Small dense LDLHyperuricemiaProthrombotic state(↑fibrinogen,↑Factor VIIa,↑fibrinolytic activity)↔↔↓↓Impaired Glucose ToleranceType 2 DiabetesDiabetes Care 1998;21(2):310–314. Williams G, Pickup JC.Handbook of Diabetes. 2nd Edition, Blackwell Science. 1999.
    • 33. Ethnic Variations in Lipid ParametersEthnic Variations in Lipid ParametersAfrican-African- Non-HispanicNon-HispanicAmericansAmericans HispanicsHispanics WhitesWhites PP valuevalueN=N= 462 (27%)462 (27%) 546 (34%)546 (34%) 612 (38%)612 (38%) < 0.001< 0.001Total-C (mg/dL)Total-C (mg/dL) 212.5212.5 211.1211.1 213.2213.2 0.7820.782LDL-C (mg/dL)LDL-C (mg/dL) 143.8143.8 139.4139.4 140.7140.7 0.4100.410HDL-C (mg/dL)HDL-C (mg/dL) 47.047.0 42.342.3 44.044.0 < 0.001< 0.001TG (mg/dL)TG (mg/dL) 102.1102.1 147.7147.7 134.0134.0 < 0.001< 0.001LDL size (Å)LDL size (Å) 262.1262.1 257.6257.6 259.2259.2 < 0.001< 0.001Haffner SM et al. Arterioscler Thromb Vasc Biol 1999;19:2234–2240.
    • 34. Plasma Insulin and Triglycerides PredictPlasma Insulin and Triglycerides PredictIschemic Heart DiseaseIschemic Heart DiseaseDespres JP, et al. N Engl J Med. 1996;334:952-957.>150 mg/dlTriglycerides0.02.04.06.08.0OddsRatio<12 12-15 >15F-Insulin (µU/ml)4.6p=0.005<150 mg/dl1.01.55.3p=0.001p<0.0016.75.4p=0.002
    • 35. Mechanisms Relating Insulin Resistance andMechanisms Relating Insulin Resistance andDyslipidemiaDyslipidemiaFat CellsFat Cells LiverLiverInsulinInsulinIRIR XXFFAFFA
    • 36. Mechanisms Relating Insulin Resistance andMechanisms Relating Insulin Resistance andDyslipidemiaDyslipidemiaFat CellsFat Cells LiverLiverInsulinInsulinIRIR XX TGTG Apo BApo B VLDLVLDLVLDLVLDLFFAFFA
    • 37. (hepatic(hepaticlipase)lipase)Mechanisms Relating Insulin Resistance andMechanisms Relating Insulin Resistance andDyslipidemiaDyslipidemiaFat CellsFat Cells LiverLiverKidneyKidneyInsulinInsulinIRIR XX(CETP)(CETP)CECE TGTG Apo BApo B VLDLVLDLHDLHDLTGTGApo A-1Apo A-1FFAFFAVLDLVLDL
    • 38. (hepatic(hepaticlipase)lipase)Mechanisms Relating Insulin Resistance andMechanisms Relating Insulin Resistance andDyslipidemiaDyslipidemiaFat CellsFat Cells LiverLiverKidneyKidneyInsulinInsulinIRIR XX(CETP)(CETP)CECE TGTG Apo BApo B VLDLVLDL(CETP)(CETP)HDLHDL(lipoprotein or hepatic lipase)(lipoprotein or hepatic lipase)SDSDLDLLDLLDLLDLTGTGApo A-1Apo A-1TGTGCECEFFAFFAVLDLVLDL
    • 39. Schematic SummarySchematic SummarySchematic summary relating insulin resistance (IR) to the characteristic dyslipidemia of type 2 diabetes mellitus.
    • 40. Schematic SummarySchematic SummaryThe suppression of lipoprotein lipase andvery-low-density lipoprotein (VLDL)production by insulin is defective ininsulin resistance, leading to increasedfree fatty acid (FFA) flux to the liver andincreased VLDL production, whichresults in increased circulatingtriglyceride concentrations. Thetriglycerides are transferred to low-density lipoprotein (LDL) and high-density lipoprotein (HDL), and theVLDL particle gains cholesterol esters bythe action of the cholesterol ester transferprotein (CETP). This leads to increasedcatabolism of HDL particles by the liverand loss of apolipoprotein (Apo) A,resulting in low HDL concentrations.The triglyceride-rich LDL particle isstripped of the triglycerides, resulting inthe accumulation of atherogenic small,dense LDL particles.
    • 41. IncreasedIncreasedDyslipidemia in DiabetesDyslipidemia in DiabetesDecreasedDecreased Triglycerides VLDL LDL and smalldense LDL Apo B HDL Apo A-I
    • 42.  Increased susceptibility to oxidation Increased vascular permeability Conformational change in apo B Decreased affinity for LDL receptor Association with insulin resistance syndrome Association with high TG and low HDLSmall Dense LDL and CHD:Small Dense LDL and CHD:Potential Atherogenic MechanismsPotential Atherogenic MechanismsAustin MA et al. Curr Opin Lipidol 1996;7:167-171.
    • 43.  Accumulation of chylomicron remnants Accumulation of VLDL remnants Generation of small, dense LDL-C Association with low HDL-C Increased coagulability-  plasminogen activator inhibitor (PAI-1)-  factor VIIc- Activation of prothrombin to thrombinHypertriglyceridemia and CHD Risk:Hypertriglyceridemia and CHD Risk:Associated AbnormalitiesAssociated Abnormalities
    • 44. ATP III Lipid and Lipoprotein ClassificationATP III Lipid and Lipoprotein ClassificationLDL Cholesterol (mg/dl) HDL Cholesterol (mg/dl)LDL Cholesterol (mg/dl) HDL Cholesterol (mg/dl)<100<100 OptimalOptimal < 40 Low< 40 Low100-129 Near/Above Optimal100-129 Near/Above Optimal >> 60 High60 High(Desirable)(Desirable)130-159 Borderline High130-159 Borderline High160-189 High160-189 High>>190190 Very HighVery HighCategories of Risk that Modify LDL GoalsCategories of Risk that Modify LDL GoalsCHD and CHD risk equivalentsCHD and CHD risk equivalents <100<100Multiple (2+) risk factorsMultiple (2+) risk factors <130<130Zero to one risk factorZero to one risk factor <160<160
    • 45. Treating Elevated TriglyceridesTreating Elevated TriglyceridesNon-HDL Cholesterol: Secondary TargetNon-HDL Cholesterol: Secondary Target Primary target of therapy: LDL cholesterolPrimary target of therapy: LDL cholesterol Achieve LDL goal before treating non-HDL cholesterolAchieve LDL goal before treating non-HDL cholesterol Therapeutic approaches to elevated non-HDL cholesterolTherapeutic approaches to elevated non-HDL cholesterol– Intensify therapeutic lifestyle changesIntensify therapeutic lifestyle changes– Intensify LDL-lowering drug therapyIntensify LDL-lowering drug therapy– Nicotinic acid or fibrate therapy to lower VLDLNicotinic acid or fibrate therapy to lower VLDL
    • 46. Management of dyslipidemiaManagement of dyslipidemia Primary aim is to achieve LDL goalPrimary aim is to achieve LDL goal For high TG (200-499 mg/dl), non-HDL is theFor high TG (200-499 mg/dl), non-HDL is thesecondary target of therapysecondary target of therapy– Increase statin doseIncrease statin doseOROR– Add fibrates/nicotinic acidAdd fibrates/nicotinic acid For HDL < 40 mg/dl drugs such as nicotinic acid orFor HDL < 40 mg/dl drugs such as nicotinic acid orfibrates have to be consideredfibrates have to be consideredNCEP guidelines, May 2001
    • 47. Managing Very High Triglycerides (≥500 mg/dL)Managing Very High Triglycerides (≥500 mg/dL) Goal of therapy: prevent acute pancreatitisGoal of therapy: prevent acute pancreatitis Very low fat diets (Very low fat diets (≤≤15% of caloric intake)15% of caloric intake) Triglyceride-lowering drug usually required (statins, fibrate orTriglyceride-lowering drug usually required (statins, fibrate ornicotinic acid)nicotinic acid) Reduce triglyceridesReduce triglycerides beforebefore LDL loweringLDL lowering
    • 48. First-line agentsFirst-line agents HMG CoA reductase inhibitorHMG CoA reductase inhibitor Fibric acid derivativeFibric acid derivativeSecond-line agentsSecond-line agents Bile acid binding resinsBile acid binding resins Nicotinic acidNicotinic acidPharmacologic Agents for Treatment ofPharmacologic Agents for Treatment ofDyslipidemiaDyslipidemiaAmerican Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60.In diabetic patients, nicotinic acid should be restricted to <2g/day. Short-acting nicotinic acid is preferred.Effect on lipoproteinLDL HDL Triglyceride
    • 49.  LDL cholesterol lowering*LDL cholesterol lowering* First choice: HMG CoA reductase inhibitor (statin) Second choice: Bile acid binding resin or fenofibrate HDL cholesterol raisingHDL cholesterol raising Behavior interventions such as weight loss, increased physicalactivity and smoking cessation Glycemic control Difficult except with nicotinic acid, which is relativelycontraindicated or fibrates Triglyceride loweringTriglyceride lowering Glycemic control first priority Fibric acid derivative (gemfibrozil, fenofibrate) Statins are moderately effective at high dose inhypertriglyceridemic subjects who also have high LDL cholesterol* Decision for treatment of high LDL before elevated triglyceride is based on clinical trial data indicating safety as well asefficacy of the available agents.Order of Priorities for Treatment of DiabeticOrder of Priorities for Treatment of DiabeticDyslipidemia in Adults*Dyslipidemia in Adults*
    • 50. LDLLDLReceptorReceptorStatins: Mechanism of ActionStatins: Mechanism of ActionAcetateLDLLDLHMG-CoAReductaseCholesterolStatins
    • 51. Statins: Mechanism of ActionStatins: Mechanism of ActionLDL receptor–mediated hepatic uptakeLDL receptor–mediated hepatic uptakeof LDL and VLDL remnantsof LDL and VLDL remnantsSerum VLDL remnantsSerum VLDL remnantsSerum LDL-CSerum LDL-CCholesterolCholesterolsynthesissynthesisLDL receptorLDL receptor(B–E receptor)(B–E receptor)synthesissynthesisIntracellular CholesterolIntracellular CholesterolApo BApo BApo EApo EApo BApo BSystemic CirculationSystemic CirculationHepatocyteHepatocyteReduce hepatic cholesterol synthesis, lowering intracellular cholesterol, which stimulates upregulation of LDL receptor andReduce hepatic cholesterol synthesis, lowering intracellular cholesterol, which stimulates upregulation of LDL receptor andincreases the uptake of non-HDL particles from the systemic circulation.increases the uptake of non-HDL particles from the systemic circulation.LDLLDLSerum IDLSerum IDLVLDLVLDLRRVLDLVLDLRRVLDLVLDL
    • 52. Statins: Beyond LDLStatins: Beyond LDLTrial Statin dose (mg) Triglyceride Lowering Effect4s Simvastatin 10-40 10%WOSCOPS Pravastatin 40 12%CARE Pravastatin 40 14%LIPID Pravastatin 40 11%PROSPER Pravastatin 40 13%AFCAPS Lovastatin 20-40 13%ASCOT Atorvastatin 10 14%CARDS Atorvastatin 10 19%HPS Simvastatin 40 14%JUPITER Rosuvastatin 20 17%Statins reduce TG levels in the range of 10% to 20%
    • 53. Rosuvastatin: The Switch Over AdvantageRosuvastatin: The Switch Over Advantage010203040PercentagereductionLipid ParametersRosuvastatin Naïve 39.9 28.8 9.2Switch Over toRosuvastatin24.5 16.6 3.8LDL-C TC TG Reduction in LDL-C, TC andTG in both rosuvastatinnaïve and switch overpatients. Improvement in LDL-Ctargets from 29% to 72.9% inswitch over group.
    • 54. Fibric Acid derivates: Mechanism of ActionFibric Acid derivates: Mechanism of ActionInteraction of FibratesInteraction of Fibrateswith PPARwith PPAR αα
    • 55. Fibric Acid derivates: Mechanism of ActionFibric Acid derivates: Mechanism of ActionFibrates lower small dense LDLFibrates lower small dense LDL
    • 56. Fibric Acid derivates: Mechanism of ActionFibric Acid derivates: Mechanism of ActionPPARPPAR αα activated by fibrates negativelyactivated by fibrates negativelyregulates fibrinogen- β expressionregulates fibrinogen- β expression
    • 57. Nicotinic Acid: Mechanism of ActionNicotinic Acid: Mechanism of ActionLiverLiver CirculationCirculationHDLHDLSerum VLDL results inSerum VLDL results inreduced lipolysis to LDLreduced lipolysis to LDLSerum LDLSerum LDLVLDLDecreases hepatic production of VLDL and of apo BDecreases hepatic production of VLDL and of apo BVLDL secretionVLDL secretionApo BApo BHepatocyteHepatocyte Systemic CirculationSystemic CirculationMobilization of FFAMobilization of FFATG synthesisTG synthesisVLDLLDL
    • 58. Acyl-CoAsynthaseFA UptakeFAGlycerol-3-P Lyso PA PADAGDGATTGPhospholipidsAcyl-CoA Acetyl CoAGlucoseUptakeLipogenesisAcetyl-CoAcarboxylaseFA synthaseVLDLApo B-100NEFAHormone-Sensitive LipaseAdipose TGDegradationPAPCell membraneTriglyceride-Lowering Mechanisms of Omega-3 FATriglyceride-Lowering Mechanisms of Omega-3 FAMitochondriaCPT-I, -IIAcyl-CoAdehydrogenasePeroxisomeAcyl-CoA oxidase(rodents only?)++++Β-oxidation–––––В-oxidationHarris WS and Bulchandani D. Curr Opin Lipidol 2006; 17:387-393.
    • 59. Dyslipidemia Treatment SummaryDyslipidemia Treatment Summary

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