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.
Figure 3-17. Structure of high-density lipoprotein (HDL). More than 50% of HDL weight is from apolipoproteins (apos), more than 90% of which are apos A-I and A-II. The core of HDL consists mostly of cholesteryl ester and small amounts of triglycerides, and the surface contains mostly phosphatidylcholine and unesterified cholesterol (seeFig. 3-6). Despite these common features, HDL is heterogenous in particle size or density, as well as apo composition. Not only is apo heterogeneity in the form of particles containing apo A-I (Lp A-I) and those containing both apos A-I and A-II (Lp A-I/A-II), but HDL also contains small amounts of the remainder of the exchangeable apos, apos C-I, C-II, C-III, E, and A-IV. These general features are schematically illustrated here. The relative size and density of HDL may be compared with other lipoproteins (seeFigure 3-19A); the presence of multiple subpopulations of HDL is also seen. A, The Lp A-I particle. Apo C-II, C-I, and C-III are likely to be associated predominantly with this particle. B, The Lp A-I/A-II particle is shown with apo A-II. (Adapted from Segrest et al..) References: . Segrest JP, Garber DW, Brouillette CG, et al. The amphipathic a helix: a multifunctional structural motif in plasma lipoproteins. Adv Protein Chem 1994 45 303-369
Cholesterol that is synthesized or deposited in peripheral tissues is returned to the liver in a process referred to as reverse cholesterol transport in which high-density lipoprotein (HDL) plays a central role.1 HDL may be secreted by the liver or intestine in the form of nascent particles consisting of phospholipid and apolipoprotein A-I (apoA-I). Nascent HDL interacts with peripheral cells, such as macrophages, to facilitate the removal of excess free cholesterol (FC), a process facilitated by the ATP-binding cassette protein 1 (ABC1) gene. FC is generated in part by the hydrolysis of intracellular cholesteryl ester (CE) stores. HDL is then converted into mature CE-rich HDL as a result of the plasma cholesterol-esterifying enzyme lecithin:cholesterol acyltransferase (LCAT), which is activated by apoA-I.2 CE may be removed by several different pathways, including selective uptake by the liver, ie, the removal of lipid without the uptake of HDL proteins (shown in this slide). Selective uptake appears to be mediated by the scavenger receptor class-B, type I (SR-BI), which is expressed in the liver and has been shown to be a receptor for HDL.3 CE derived from HDL contributes to the hepatic-cholesterol pool used for bile acid synthesis. Cholesterol is eventually excreted from the body either as bile acid or as free cholesterol in the bile.2 Acton S, Rigotti A, Landschulz KT, et al. Identification of scavenger receptor SR-BI as a high-density lipoprotein receptor. Science. 1996;271:518-520. Breslow JL. Familial disorders of high-density lipoprotein metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York: McGraw-Hill; 1995:2031-2052. Fielding CJ, Fielding PE. Molecular physiology of reverse cholesterol transport. J Lipid Res. 1995;36:211-228.
This slide shows the selective uptake of high-density lipoprotein (HDL) cholesteryl ester (CE), described in the previous slide, together with another important pathway of reverse cholesterol transport involving the action of plasma CE transfer protein (CETP). CE can be transferred from HDL to apolipoprotein (apo) B-containing proteins, such as very-low-density lipoproteins (VLDLs) and low-density lipoproteins (LDLs), by CETP.1,2 Through uptake of LDL by the liver via hepatic LDL receptors, cholesterol can then be returned to the liver,3 where it may eventually be excreted as bile.1 (This slide also illustrates the current belief that only modified apoB-containing proteins are taken up by macrophages. &quot;Oxidation&quot; is given as an example of modification.) Havel RJ, Kane JP. Introduction: structure and metabolism of plasma lipoproteins. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York: McGraw-Hill; 1995:1841-1851. Steinberg D. A docking receptor for HDL cholesterol esters. Science. 1996;271:460-461. Tall AR. Plasma cholesteryl ester transfer protein. J Lipid Res. 1993;34:1255-1274.
Further elucidation of the molecular mechanisms involved in high-density lipoprotein (HDL) metabolism promises to help identify potential targets for decreasing the incidence and progression of atherosclerotic cardiovascular disease. Investigations of the genetic mechanisms involved in normal and defective HDL metabolism may lead to the development of novel therapies. Research is focusing on three areas: HDL-associated apolipoproteins; HDL-modifying plasma enzymes and transfer proteins (eg, lecithin:cholesterol acyltransferase [LCAT], cholesteryl ester transfer protein [CETP], and hepatic lipase); and cellular and cell-surface proteins involved in HDL metabolism (eg, ATP-binding cassette transporter 1[ABC1] and scavenger receptor class-B, type I [SR-BI]).1-4 Acton SL, Kozarsky KF, Rigotti A. The HDL receptor SR-BI: a new therapeutic target for atherosclerosis? Mol Med Today. 1999;5:518-524. Fruchart JC, Duriez P. High-density lipoproteins and coronary heart disease: future prospects in gene therapy. Biochimie. 1998;80:167-172. Rader DJ, Mauglais C. Genes influencing HDL metabolism: new perspectives and implications for atherosclerosis prevention and treatment. Mol Med Today. 2000; in press. Rader DJ. Gene therapy for atherosclerosis. Mol Ther. 1998;1:680-689.
Familial apolipoprotein A-I (apoA-I) defects may be caused by complete deficiency of the apoA-I gene or by mutations in the apoA-I gene (discussed in the following slide). Genetic deficiency of apoA-I may be due to the deletion of the gene or to nonsense mutations that prevent the synthesis of apoA-I protein, which results in an absence of plasma high-density lipoprotein (HDL).1-3 Patients with this disorder sometimes display cutaneous xanthomas. The risk of premature cardiovascular disease in patients with apoA-I deficiency may be increased, but the onset of symptoms varies from the third to the seventh decade.4 Breslow JL. Familial disorders of high-density lipoprotein metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York: McGraw-Hill; 1995:2031-2052. Ng D, Leiter L, Vezina C, et al. Apolipoprotein A-1 Q[-2]X causing isolated apolipoprotein A-1 deficiency in a family with analphalipoproteinemia. J Clin Invest. 1994;93:223-229. Norum RA, Lakier JB, Goldstein S, et al. Familial deficiency of apolipoproteins A-I and C-III and precocious coronary-artery disease. N Engl J Med. 1982;306:1513-1519. Schaefer EJ, Heaton WH, Wetzel MG, Brewer HB Jr. Plasma apolipoprotein A-1 absence associated with a marked reduction of high density lipoproteins and premature coronary artery disease. Arteriosclerosis. 1982;2:16-26. Mutations in the apolipoprotein A-I (apoA-I) gene may also lead to marked reductions in levels of high-density lipoprotein cholesterol (HDL-C) (usually 15-30 mg/dL) and apoA-I protein. The decrease in apoA-I levels among individuals with these structural mutations is the result of rapid catabolism of apoA-I.1 The first apoA-I mutation to be described was apoA-IMilano, 2,3 which results in an average 40% decrease in apoA-I and a 67% decrease in HDL-C.4 Subjects with structural apoA-I mutations do not appear to have clinical sequelae, although a mutation in the apoA-I gene at the amino-terminus has been described in association with systemic amyloidosis.5,6 ApoA-I structural mutations are only rarely associated with premature atherosclerotic disease.1 Franceschini G, Sirtori CR, Capurso A, Weisgraber KH, Mahley RW. A-IMilano apoprotein: decreased high-density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family. J Clin Invest. 1980;66:892-900. Nichols WC, Dwulet FE, Liepnieks J, et al. Variant apolipoprotein AI as a major constituent of a human hereditary amyloid. Biochem Biophys Res Commun. 1988;156:762-768. Rader DJ. Lipid disorders. In: Topol EJ, ed. Textbook of Cardiovascular Medicine. Philadelphia: Lippincott-Raven; 1998:59-90. Soutar AK, Hawkins PN, Vigushin DM, et al. Apolipoprotein AI mutation Arg-60 causes autosomal dominant amyloidosis. Proc Natl Acad Sci U S A. 1992;89:7389-7393. Tall AR, Dammerman M, Breslow JL. Disorders of lipoprotein metabolism. In: Chien KR, ed. Molecular Basis of Cardiovascular Disease: A Companion to Braunwald's Heart Disease. Philadelphia: W.B. Saunders; 1999:413-427. Weisgraber KH, Bersot TP, Mahley RW, Franceschini G, Sirtori CR. A-IMilano apoprotein: isolation and characterization of a cysteine-containing variant of the A-I apoprotein from human high-density lipoproteins. J Clin Invest. 1980;66:901-907. Two forms of lecithin:cholesterol acyltransferase (LCAT) deficiency have been described: complete deficiency and partial deficiency; the latter is referred to as fish-eye disease.1 Both types of LCAT deficiency result in markedly reduced levels of high-density lipoprotein cholesterol (HDL-C) (< 10 mg/dL) and apolipoprotein (apo) A-I; variable hypertriglyceridemia; and corneal opacities. Despite very low levels of HDL-C and apoA-I, these conditions rarely lead to premature atherosclerotic disease. Complete LCAT deficiency, but not fish-eye disease, is characterized by progressive proteinuria and renal insufficiency.1 The following slide describes the effect of LCAT deficiency on HDL metabolism. Glomset JA, Assmann G, Gjone E, Norum KR. Lecithin:cholesterol acyltransferase deficiency and fish-eye disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York: McGraw-Hill; 1995:1933-1951. High-density lipoprotein (HDL) facilitates the removal of unesterified cholesterol from cells; the cholesterol is then esterified by the action of the lipoprotein-associated enzyme lecithin:cholesterol acyltransferase (LCAT).1 Familial LCAT deficiencies therefore lead to: 1) a relative absence of apolipoprotein A-I, and 2) rapid catabolism of HDL, resulting in plasma HDL-cholesterol levels of < 10 mg/dL.2 Fielding CJ, Fielding PE. Molecular physiology of reverse cholesterol transport. J Lipid Res. 1995;36:211-228. Glomset JA, Assmann G, Gjone E, Norum KR. Lecithin:cholesterol acyltransferase deficiency and fish-eye disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York: McGraw-Hill; 1995:1933-1951. Tangier disease is a very rare autosomal codominant condition due to mutations in both alleles of the ATP-binding cassette protein 1 (ABC1) gene.1 Patients with Tangier disease have high-density lipoprotein cholesterol (HDL-C) levels < 5 mg/dL and extremely low levels of apolipoprotein A-I (apoA-I) due to markedly accelerated catabolism of apoA-I and apoA-II. Cholesterol accumulation in the reticuloendothelial system results in enlarged orange tonsils and hepatosplenomegaly.2 Intermittent peripheral neuropathy can also be seen due to cholesterol accumulation in Schwann cells.2 Assmann G, von Eckardstein A, Brewer HB Jr. Familial high-density lipoprotein deficiency: Tangier disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill; 1995:2053-2072. Lawn RM, Wade DP, Garvin MR, et al. The Tangier disease gene ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway. J Clin Invest. 1999;104:R25-31. Tangier disease is probably associated with some increased risk of premature atherosclerotic vascular disease, but this risk does not seem to be proportional to the markedly decreased high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels. Patients with Tangier disease have a pathologic accumulation of cholesterol in macrophages as well as in cells of the reticuloendothelial system.1 Heterozygotes have moderately reduced HDL-C and apoA-I levels and an increased risk of premature atherosclerotic vascular disease, but they show no evidence of cholesterol accumulation (eg, tonsillar enlargement or hepatosplenomegaly).1 Assmann G, von Eckardstein A, Brewer HB Jr. Familial high-density lipoprotein deficiency: Tangier disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill; 1995:2053-2072.
HDL-C also exerts other positive effects in the body, including inhibition of adhesion molecules and anti-oxidative effects on LDL-C. Dr. Francis indicated that raising HDL-C levels should therefore be beneficial to patients, although this is difficult to quantify, as there are no agents that act solely to increase HDL-C levels.
ACTIVATE: ACAT inhibitor fails to reduce the progression of atherosclerotic coronary disease Nov 15, 2005 Michael O'Riordan Dallas, TX - An intravascular ultrasound (IVUS) study with the novel acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor pactimibe (Sankyo) has shown that the new agent failed to reduce atherosclerotic disease progression over 18 months when compared with usual care for patients with symptomatic CAD. Dr Steven Nissen Presenting the results of the ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE) study during the late-breaking clinical-trials session at the American Heart Association Scientific Sessions 2005 , lead investigator Dr Steven Nissen (Cleveland Clinic, OH) reported that not only did pactimibe not result in a change in percent atheroma volume, but changes in total atheroma volume and changes in atheroma volume in the most diseased segment showed unfavorable proatherogenic effects with the drug. Yet despite these negative results, Nissen sees a silver lining. &quot;We consider this trial a successful failure,&quot; said Nissen. &quot;Although the strategy of ACAT inhibition failed to reduce the progression of atherosclerosis, the quest for new therapeutic agents to limit coronary heart disease continues at a rapid pace. The ability of intravascular ultrasound to discriminate between effective and ineffective therapies will accelerate the process of selecting the most prominent approaches to treatment of atherosclerotic coronary disease.&quot; Patients with angiographically documented CAD During a morning press conference announcing the results, Nissen said that two forms of ACAT have been identified. ACAT1 is found predominantly in macrophages, and ACAT2 is present in the liver and in the intestinal mucosa. Inhibition of ACAT1 is intended to make more free cholesterol available for reverse cholesterol transport, which, theoretically, could reduce lipid accumulation within atherosclerotic lesions, explained Nissen. Previous animal models have shown that ACAT inhibition was capable of reducing atheroma volume, presumably by preventing the accumulation of cholesterol within macrophages and thereby inhibiting foam-cell formation, said Nissen. The purpose of the ACTIVATE study was to test this approach to limiting atherosclerosis in human subjects. In the ACTIVATE trial, investigators enrolled 534 patients with symptomatic coronary artery disease as documented by coronary angiography (>20% stenosis). Baseline characteristics between the two study arms were similar. Patients were well treated with background therapy, with a majority of patients taking statins. The average baseline LDL cholesterol levels were 95 mg/dL in both treatment arms. IVUS was performed using a 40-MHz transducer and a motorized pullback at 0.5 mm/sec through a target segment >30 mm in length. Patients were randomized to pactimibe 100 mg or placebo for 18 months of treatment. Approximately 60 patients in each study arm did not return for repeat IVUS of the target vessel. Regarding the primary efficacy parameter—change in percent atheroma volume—both treatment groups showed a statistically significant progression, although the increase in percent atheroma volume was slightly greater in the pactimibe group compared with placebo (p=0.77). When investigators looked at the two secondary IVUS efficacy parameters—change in atheroma volume in the total artery and then in most diseased segment—there were statistically significant differences favoring placebo. For total atheroma volume, the placebo-treated group showed significant regression while pactimibe treatment attenuated these benefits, eliminating the regression (p=0.04 between group). Similar results were observed in the 10-mm subsegment with the greatest plaque volume. Again, there was more pronounced regression in the placebo group than the pactimibe group (p=0.01 between groups). &quot;Pactimibe exhibited unfavorable effects, reducing the benefits of usual-care background therapies that included statins in nearly all patients,&quot; said Nissen. Asked why the drug failed to slow the progression of disease and might have even promoted it, Nissen said some researchers have suggested that increased levels of free cholesterol within the macrophage might cause apoptosis, possibly creating necrosis within the lesion. Specific inhibition of ACAT1 might also be atherogenic, as has been hinted at by other researchers, said Nissen. Using IVUS to look at specific targets Speaking with heart wire , Nissen said that it is difficult to determine whether the failure of the ACAT inhibitor is specific to the drug or the class in general. He said that other drugs in the class must be sufficiently different from pactimibe to justify future clinical trials, and while the results of the trial don't necessarily put an end to studying this class of drugs, the results are disappointing. Moreover, the safety of the drug class will have to be closely scrutinized, as there is now at least one drug in the class that at least looks proatherogenic, he said. Nissen pointed out that there were no differences in clinical outcomes between the pactimibe- and placebo-treated patients but stressed the study was not sufficiently powered to address clinical end points. One of the strengths of IVUS, he added, is that clinicians can study the effects of certain drugs quickly and effectively and without a large mortality trial. &quot;I think what you're going to see over the next five years is that, using methods like IVUS, we're going to be able to look at one target after another and tell you very quickly, we hope, which of them we ought to move forward with and which of them we should put on the back burner.&quot; Commenting on the study during the late-breaking clinical-trials session, Dr Valentin Fuster (Mount Sinai School of Medicine, New York, NY) directly addressed the IVUS technology and its role in future clinical trials. As to whether or not IVUS is an appropriate surrogate measure to decide about the fate of a compound, Fuster said it is a good &quot;contributor.&quot; He noted that there was good correlation between IVUS imaging and LDL-lowering therapy in the REVERSAL study, antihypertensive therapy in CAMELOT trial, and with the HDL-modifying therapy in the apolipoprotein (Apo) A-1 Milano study. Outside of the limitations of the ACTIVATE trial, including the lack of statistical power for clinical-outcome measures, Fuster told the assembled audience that the data do not look good for pactimibe. Based on the primary efficacy parameter, the agent doesn't hold the promise that was observed in earlier animal studies. He was cautious about overinterpreting secondary end points, however, particularly when the magnitude of change is small. The major question, said Fuster, is why pactimibe failed to provide benefit. One possibility is that pactimibe interfered with the body's reverse-cholesterol-transport process. &quot;Within the context of reasonably stable atherosclerotic plaque, as I assume is the case in such selected stable patients, with very low LDL levels and a low risk-factor profile at baseline, it is the scientific belief that the monocytes and foam cells act favorably in the reverse-cholesterol-transport process and require the ACAT enzyme to esterify free cholesterol for the activation of HDL to remove any excess of lipid deposits in the arteries,&quot; said Fuster. &quot;Therefore, we can reasonably speculate that such a defense mechanism of ACAT1 was inhibited by pactimibe, and thus the compound became ineffective or unfavorable.&quot;
Secondary causes of increased high-density lipoprotein cholesterol (HDL-C) levels include vigorous sustained aerobic exercise (eg, long-distance running),1 a very-high-fat diet,2 regular substantial alcohol intake,3 treatment with estrogens,4 and treatment with certain drugs (eg, phenytoin).5 Goerdt C, Keith M, Rubins HB. Effects of phenytoin on plasma high-density lipoprotein cholesterol levels in men with low levels of high-density lipoprotein cholesterol. J Clin Pharmacol. 1995;35:767-775. Kokkinos PF, Holland JC, Naravan P, et al. Miles run per week and high-density lipoprotein cholesterol levels in healthy, middle-aged men: a dose-response relationship. Arch Intern Med. 1995;155:415-420. Savolainen MJ. How does alcohol raise HDL-cholesterol concentration? Ann Med. 1990;22:141-142. Editorial. Walsh BW, Schiff I, Rosner B, et al. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med. 1991;325:1196-1204. West CF, Sullivan DR, Katan MB, Halferkamps IL, van der Torre HW. Boys from populations with high carbohydrate intake have higher fasting triglyceride levels than boys from populations with high fat intake. Am J Epidemiol. 1990;131:271-282.
Dr. Francis indicated that there were no absolute targets for HDL-C but each of the guidelines on dyslipidemia mentions HDL-C levels. Although there are no reliable methods for increasing HDL-C, Dr. Francis gave several examples of strategies that might contribute to higher HDL-C levels: better diabetes control; PPAR agonists and metformin treatment; exercise; fibrate treatment; niacin treatment; use of statins; CETP inhibitors
HDL-Cholesterol By Ashraf Reda MD Professor of Cardiology Head of Cardiology Department Menofia University
Structure of HDL Rye KA et al. Atherosclerosis 1999;145:227-238. Hydrophobic Core of Triglyceride and Cholesteryl Esters apoA-II Surface Monolayer of Phospholipids and Free Cholesterol apoA-I -----
Bile Reverse cholesterol transport Peripheral Tissue Liver Blood Excess cholesterol
CE FC Macrophage ABC1 Nascent HDL from liver or intestine FC A-1 LCAT A-1 Mature HDL CE SR-B1 CE FC Bile CE= cholesterol ester; FC= free cholesterol; A-1= apolipoproteinA-1; ABC1= ATP-binding cassettte protein-1; LCAT= Lecithin:cholesterol acyl transeferase; SR-B1=scavenger receptor class B1 Reverse cholesterol transport and HDL metabolism
CE FC Macrophage ABC1 Nascent HDL from liver or intestine FC A-1 LCAT A-1 Mature HDL CE SR-B1 CE FC Bile VLDL/LDL B CETP CE LDL receptor HDL metabolism: Reverse cholesterol transport and the role of CETP Oxidation SR-A
Genes involved in HDL metabolism <ul><li>HDL assosciated Apos.: </li></ul><ul><li>Apo-A1 </li></ul><ul><li>Apo-E </li></ul><ul><li>Apo-IV </li></ul><ul><li>Modifying plasma enzymes and transfer protein </li></ul><ul><li>LCAT- CETP- PLTP </li></ul><ul><li>LPL- HL- Endoth. lipase </li></ul><ul><li>Cellular and cell surface protein </li></ul><ul><li>ABC1 </li></ul><ul><li>SR-B1 </li></ul>
Primary (genetic) causes of low HDL <ul><li>Apo-A1: </li></ul><ul><li>Complete Deficiency </li></ul><ul><li>Mutation (Milano Apo-A1) </li></ul><ul><li>LCAT </li></ul><ul><li>Complete deficiency </li></ul><ul><li>Partial (fish eye disease) </li></ul><ul><li>ABC-1 </li></ul><ul><li>Tangier disease (homo- or hetero- zygos) </li></ul><ul><li>Familial hypo alpha lipoproteinemia </li></ul><ul><li>Unknown genetic A/E </li></ul><ul><li>Metabolic syndrome </li></ul><ul><li>FCH with low HDL </li></ul><ul><li>Hypoalphalipoproteinemia </li></ul>HDL A-1 Mature HDL A-1 CE FC FC ABC-1 Macrophage
HDL <ul><li>Reverse cholesterol transport(Apo-A1—ABC-A1) </li></ul><ul><li>Inhibition of adhesion molecules </li></ul><ul><li>Antioxident </li></ul><ul><li>Vasotonic effect </li></ul><ul><li>Prevent LDL oxidation and deposition </li></ul>
HDL-raising effect of exercise the Health, Risk Factors, Exercise Training, and Genetics ( HERITAGE ) Family Study 1.5% 0.4% isolated low HDL <0.05 4.9% 4.9% low HDL/high TG P value Increase in apoA-I Increase in HDL Group
VA-HIT LRIAL Gemfibrozil 1200mg HDL 6% TG 31% No LDL change Risk reduction MI+CHD death +Stroke 24% P<0.001
Blocking the over-activated endocannbinoid system CB1 blockade Central CB1 Blockade Perepheral CB1 blockade (Adipose tissue) Exess abdominal fat Adeponectin Insulin Resistence Alter the atherogenic lipid profile CRP Food intake
HDL cholesterol and triglyceride parameters in the rimonabant- and placebo-treated groups Scheen A. American Diabetes Association 2005 Scientific Sessions; June 10-14, 2005; San Diego, CA. <0.001 16.4 3.6 -31.2 Change in triglycerides (mg/dL) <0.001 8.4 2.7 6.6 Change in HDL cholesterol (mg/dL) p Percent difference (compared with placebo) Placebo (n=348) Rimonabant 20 mg (n=339) End point
RIO-LIPIDS: Changes from baseline for the end points in the intention-to-treat population Després JP et al. N Engl J Med 2005; 353: 2121-2134. *last-observation-carried-forward analysis <0.001 +19.1 0.025 +14.2 +11.0 HDL (%) <0.001 -12.6 NS +1.2 -0.2 Triglycerides (%) <0.001 -7.1 0.029 -3.5 -2.4 Waist circumference (cm) <0.001 -6.9 <0.001 -3.1 -1.5 Weight (kg) p 20-mg rimonabant group p 5-mg rimonabant group Placebo group End point*
--- --- Adiponectin TNF-a Muscle Adipose tissue ---- ---- FA oxidation FFA clearance Glucose uptake Insulin sensetivity + + CB1 Lipoprotein lipase activity Fat accumulation in adipose T Adeponectin
PROactive subgroup analysis: Outcomes in patients with type 2 diabetes and previous MI Erdmann E. American Heart Association Scientific Sessions 2005; Nov 13-16, 2005; Dallas, TX. TG 11% HDL 18% 0.035 0.63 (0.41-0.97) 54 35 Time to ACS 0.045 0.72 (0.52-0.99) 88 65 Time to fatal/ nonfatal MI p Hazard ratio (95% CI) Placebo (n=1215), n Pioglitazone (n=1230), n End point
Statins are still the first line and LDL less than 70-100 mg/dl is the primary target