1. The future of HDL raisingBy
Ashraf Reda M.D.
Minoufiya University
President of: WGLVR 1

2. Reverse cholesterol transport
Peripheral
Tissue
Blood
Excess cholesterol
Liver
Bile
HDL:
Reverse cholesterol transport 6
Ashraf Reda,M.D.

3. from liver or intestine
Reverse cholesterol transport and HDL metabolism
Bile FC
A-1
A-1 CE CE FC CE
ABC1
SR-B1
LCAT FC
Mature HDL
Nascent HDL
from liver or intestine
Macrophage
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 7
Ashraf Reda,M.D.

4. HDL Reverse cholesterol transport(Apo-A1—ABC-A1)
Inhibition of adhesion molecules
Antioxident
Vasotonic effect
Prevent LDL oxidation and deposition
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. 2
Ashraf Reda,M.D.

5. BP increase In 1.6% 1.6%++BP -------------------- 9 Ashraf Reda,M.D.
Title: Torcetrapib in Patients With Below-Average High-Density Lipoprotein Cholesterol Levels (Torcetrapib in Patients With Below-Average HDL-C Levels) Year Published 2006 Topic(s): General Cardiology Summary Posted: 11/1/2006 Writer: Ms. Sabina A. Murphy The goal of the trial was to evaluate the safety and efficacy of treatment with torcetrapib, a cholesteryl ester transfer protein inhibitor, in patients with below-average high-density lipoprotein cholesterol (HDL-C).
Drugs/Procedures Used Patients were randomized in a double-blind manner to treatment with torcetrapib 10 (n = 32), 30 (n = 31), 60 (n = 34), or 90 mg/day (n = 33) or placebo (n = 32). Lipid parameters were evaluated every 2 weeks for 8 weeks.
Principal Findings At baseline, HDL-C averaged from 37 to 40 mg/dl and low-density lipoprotein cholesterol (LDL-C) averaged from 117 to 128 mg/dl. At 8-week follow-up, the primary endpoint of percent change from baseline in HDL-C was greater in the torcetrapib groups compared with placebo (increase relative to placebo of 9.0%, 27.5%, 45.1%, and 54.5% for 10, 30, 60, and 90 mg/day, respectively; p < for all except 10 mg group). Absolute changes in HDL-C were +3 mg/dl in 10 mg group, +10 mg/dl in 30 mg group, +16 mg/dl in 60 mg group, and +21 mg/dl in 90 mg group. Percent reduction in LDL-C was significantly greater in the 90 mg group (16.5% relative to placebo, p < 0.01). Parameters of change in the ratio LDL-C/HDL-C, ratio apo B-100/apo A-I, and large HDL particles were also improved in the 30 mg and higher groups relative to placebo. There were not significant changes in total cholesterol or triglycerides. In the torcetrapib groups, 1.6% (2/129) had significant blood pressure increases; no patients permanently discontinued therapy due to blood pressure elevations. The average change in blood pressure using all follow-up measures during the study in the torcetrapib groups ranged from to mm Hg for systolic blood pressure and from -0.7 to mm Hg for diastolic blood pressure.
Interpretation Among patients with below-average HDL-C, treatment with torcetrapib, a cholesteryl ester transfer protein inhibitor, was associated with larger increases in HDL-C at 8 weeks compared with placebo in a dose-dependent manner. Statins have been shown to significantly reduce LDL-C among a variety of patients. However, therapies targeting increase in HDL-C are fewer and have shown limited success. Torcetrapib has been shown in small studies to increase HDL-C. However, larger trials evaluating the clinical effects of torcetrapib are still ongoing. Additionally, while the overall adverse event profile appears minimal, it should be noted that small blood pressure increases have been reported in recent trials with torcetrapib. The degree and impact of these changes require further monitoring to fully understand the efficacy and safety profile of torcetrapib. 9
Ashraf Reda,M.D.

6. Mortality increase 10 Ashraf Reda,M.D.
On December 02, 2006, Pfizer informed the U.S. Food and Drug Administration (FDA) that it was suspending all clinical trials evaluating combination torcetrapib/atorvastatin therapy following data from the patient outcome study called ILLUSTRATE suggesting that mortality was significantly higher in patients who received this combination versus atorvastatin alone. (To read the FDA statement, click here). Torcetrapib is a potent and selective inhibitor of cholesteryl ester transfer protein (CETP).1 It is different from many other agents used for treating hyperlipidemia in that CETP inhibition increases the level of good cholesterol (HDL), while statins, for example, primarily reduce the level of bad cholesterol (low-density lipoprotein [LDL]).2 At ACC.07, three torcetrapib papers were presented as late-breaking clinical trials. Steven Nissen, MD, MACC, presented the results of the ILLUSTRATE trial based on those patients enrolled at the time the study was halted. (The data were published simultaneously in the New England Journal of Medicine.3). Dr. Nissen said reporting the available data might clarify the effects of torcetrapib and other CETP inhibitors on the atherosclerotic process. In the 910 patients available for 24-month IVUS follow-up, torcetrapib substantially increased HDL levels, but had serious negative effects, too. Torcetrapib 60 mg in combination with atorvastatin increased HDL by 61% and lowered LDL by 20% compared to atorvastatin monotherapy (Slide 1). However, torcetrapib also increased systolic blood pressure by an average of 4.6 mm Hg. Despite the improved lipid profile, combination therapy did not reduce the progression of coronary atherosclerosis (the primary efficacy endpoint) versus atorvastatin alone (Slide 2). Finally, adverse events showed a numerical excess in the torcetrapib group, but these differences did not reach statistical significance, although Dr. Nissen emphasized that the trial was not powered for outcomes. Also presented at ACC.07 were two imaging studies assessing the impact of torcetrapib/atorvastatin on atherosclerotic disease progression. The data, from the RADIANCE studies, were presented by John J. P. Kastelein, MD, PhD. The trials evaluated two different populations: patients with heterozygous familial hyperlipidemia (RADIANCE 1; n = 904) and patients with mixed hyperlipidemia (RADIANCE 2; n = 752). The study designs were similar: after a variable run-in period of atorvastatin alone, patients were randomized to continue on atorvastatin or to a combination of torcetrapib/atorvastatin. B-mode ultrasound was performed at baseline and every 6 months during and after 24 months of double-blind treatment.4 The results: For either population studied, the addition of torcetrapib to atorvastatin had no incremental benefit over atorvastatin alone. Indeed, if anything, there was a trend toward harm, with the combination therapy leading to disease progression and atorvastatin alone leading to disease regression based on mean common carotid intima-medial thickness (Slide 3). This was despite robust increases in HDL cholesterol and decreases in LDL. In his presentation, Dr. Nissen noted that in the 20 years since the introduction of statins, no new classes of anti-atherosclerotic drugs have been introduced. “We continue to believe that drugs to raise HDL cholesterol levels represent promising therapeutic targets,” he said, “(but) it remains uncertain whether the unfavorable torcetrapib results were due to the ‘molecule’ or the mechanism of action. Although discouraging, we do not think these results preclude the possibility that another CETP inhibitor will produce favorable effects, but they do ‘raise the bar.’” Interpretation According to Michael H. Davidson, MD, FACC, the mechanism of CETP inhibitors has been controversial. He said, “Our LDL/HDL levels are modulated by CETP, so it was thought to be an attractive target to try to raise HDL,” but instead of making new HDL, which is the approach used by apo- (apolipoprotein) AI, CETP inhibition “would actually make HDL bigger and slow down its clearance from the blood.” Interestingly, Dr. Davidson said, there are human examples of CETP deficiency in Japan. While these individuals have very high HDL levels ( mg/dL), their risk of heart disease is not necessarily lower. Admittedly, he said, few such patients have been studied, but “maybe CETP inhibition for raising HDL may not provide any benefit” and may, in fact, cause harm. There are at least two other CETP inhibitors in ongoing trials. Plus, there is a vaccine for CETP in human trials, and it is being reformulated to better inhibit CETP function. Also, there are studies underway of the previously mentioned apo-AI. Said Dr. Davidson, “Apo-AI is the primary protein that builds HDL, so apo-AI up-regulators that either directly increase the synthesis of the protein or increase the genes that produce the protein are two approaches.” A third approach, he said, produces a synthetic HDL by taking apo-AI out of the blood and combining it with a phospholipid shell, which is what investigators evaluated in the Effects of Reconstituted HDL on Atherosclerosis (ERASE) trial, the results of which were presented at ACC.07. The reconstituted HDL (CSL-111) chemically and biologically resembles native HDL and was administered as four weekly infusions. Intravascular ultrasound and coronary angiography were performed at baseline (for PCI) and follow-up, which occurred 2-3 weeks after the last study infusion. Among the 145 patients with evaluable examinations at baseline and follow-up, there was no significant difference between CSL-111 and placebo in the primary efficacy endpoint of percent change in coronary atheroma volume (-3.4% vs. -1.6%, respectively). However, in this proof-of-concept study, CSL-111 did lead to a significant difference in three secondary efficacy endpoints: change in atheroma volume versus baseline (-3.4% or -5.3 mm3), change in plaque characterization indexes, and change in coronary score on QCA. Dr. Davidson concluded, “The HDL story is not by any means over,” said Dr. Davidson. “It's going to continue to be a very exciting area of research. But, unfortunately, any new drug to modify HDL will not be available for the next 7 to 10 years.” Second Opinion Alfred A. Bove, MD, PhD, FACC:It was a rough week in New Orleans for those targeting HDL in an effort to reduce the progression of atherosclerosis. Certainly, lipids are a lot more complicated than many had hoped years ago when we first came to understand the distinction between “good” HDL and “bad” LDL. The latest data are indeed discouraging but, as Dr. Davidson said in concluding the symposium, “We are not giving up.” 10
Ashraf Reda,M.D.

7. ILLUMINATE / ILLUSTRATE: Torcetrapib increases CV end points
Failure of HDL theory????
Failure of CETP inhibition???? OR
Recently, the first large-scale morbidity and mortality trial (ILLUMINATE) to evaluate the cardiovascular end points of a CETP inhibitor ( torcetrapib) has been prematurely stopped because the mortality was significantly increased in the treated group. Why torcetrapib caused excess death is not known. Based on the fact that HDL interacts with endothelial nitric oxyde synthase (eNOS) and nitric oxide (NO) secretion, which partly controlled blood pressure and that torcetrapib could increase blood pressure among some patients, we hypothesize that CETP inhibition could have significantly inhibit eNOS. CETP inhibition would have enlarged HDL size resulting in a deficit in the interaction between HDL and the Scavenger Receptor class B type I (SR-BI), which is an important link between HDL and eNOS activation. We suggest that the deficit in NO secretion would have been sufficient among all patients to induce a destabilization of the plaques of atheroma, but could have induced a pathogenic increase in blood pressure only in patients whose eNOS activity was naturally weak due to genetic polymorphisms of this enzyme. We also hypothesize that the increase in HDL levels, induced by CETP inhibition, coupled with the capacity of HDL to induce endothelin-1 secretion would have aggravated the cardiovascular risks under this CETP inhibitor treatment. 3
Ashraf Reda,M.D.

8. 1 + 1 = 1 HDL interacts with eNOS & NO secretion
Torcetrapib increases BP +
There must be a change in HDL function with Torcetrapib

9. Inhibition of CETP will increase HDL availability and reduce LDL
Apo-A-1
Apo-B CE
CETP CE
Mature HDL
VLDL/LDL
Idea:
Inhibition of CETP will
increase HDL availability and reduce LDL 5
Ashraf Reda,M.D.

10. from liver or intestine
Reverse cholesterol transport and HDL metabolism
Bile FC
A-1
A-1 CE CE FC CE
ABC1
SR-B1
LCAT FC
Mature HDL
Nascent HDL
from liver or intestine
Macrophage
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 7
Ashraf Reda,M.D.

11. HDL metabolism: Reverse cholesterol transport and the role of CETP
Bile FC
A-1
A-1 CE CE FC FC
ABC1
LCAT
SR-B1 CE
Nascent HDL
from liver or intestine
Mature HDL
Macrophage
CETP
LDL
receptor
SR-A B
Oxidation CE
VLDL/LDL 8
Ashraf Reda,M.D.

12. ILLUMINATE / ILLUSTRATE: Why do endpoints increased with Torcetrapib?
Interaction with e-NOS lead to BP rise
Enlarged HDL with impaired interaction with SR-B1 of the liver
Induction of Endothelin-1 secretion
Interfere with the reverse cholesterol transport
Recently, the first large-scale morbidity and mortality trial (ILLUMINATE) to evaluate the cardiovascular end points of a CETP inhibitor ( torcetrapib) has been prematurely stopped because the mortality was significantly increased in the treated group. Why torcetrapib caused excess death is not known. Based on the fact that HDL interacts with endothelial nitric oxyde synthase (eNOS) and nitric oxide (NO) secretion, which partly controlled blood pressure and that torcetrapib could increase blood pressure among some patients, we hypothesize that CETP inhibition could have significantly inhibit eNOS. CETP inhibition would have enlarged HDL size resulting in a deficit in the interaction between HDL and the Scavenger Receptor class B type I (SR-BI), which is an important link between HDL and eNOS activation. We suggest that the deficit in NO secretion would have been sufficient among all patients to induce a destabilization of the plaques of atheroma, but could have induced a pathogenic increase in blood pressure only in patients whose eNOS activity was naturally weak due to genetic polymorphisms of this enzyme. We also hypothesize that the increase in HDL levels, induced by CETP inhibition, coupled with the capacity of HDL to induce endothelin-1 secretion would have aggravated the cardiovascular risks under this CETP inhibitor treatment. 11
Ashraf Reda,M.D.

13. CETP inhibition to raise HDL: is it the correct way to go?NO 4
Ashraf Reda,M.D.

14. There are many way to skin a fish
&
We also have many way to raise HDL 12
Ashraf Reda,M.D.

15. Primary (genetic) causes of low HDL
Apo-A1:
Complete Deficiency
Mutation (Milano Apo-A1)
LCAT
Complete deficiency
Partial (fish eye disease)
ABC-1
Tangier disease (homo- or hetero- zygos)
Familial hypo alpha lipoproteinemia
Unknown genetic A/E
Metabolic syndrome
FCH with low HDL
Hypoalphalipoproteinemia CE
Mature HDL
A-1 FC
ABC-1 FC
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:
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:
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:
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 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:
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:
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:
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:
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:
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:
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:
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:
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
Macrophage 14
Ashraf Reda,M.D.

16. While there are a lot of unknowns, many believe that the best way to raise HDL-cholesterol levels is to produce more apoA-1, which is the precursor of new HDL cholesterol. ApoA-1 constitutes 70% of the HDL protein and is present on nearly all HDL particles. For this reason, said Rader, the upregulation of endogenous apoA-1 expression is considered one of the most promising approaches to the development of new therapies targeted to HDL cholesterol.
"In terms of pathways, I would say that the holy grail is promotion of apoA-1 gene transcription or apoA-1 production by liver, intestine, or both," Rader said. "If, somehow, a small molecule could be found that turned on the transcription of the apoA-1 gene, I really do think that would be very good, based on everything we know from preclinical models. There is no reason to think that would cause harm, unless there was some off-target effect, but we have every reason to think it would be a good thing."
Shah and his group at Cedars-Sinai Medical Center have performed proof-of-concept gene-therapy studies in mouse models with apoA-1 Milano, a variant of apoA-1, and have shown that it is possible to exploit the benefits of HDL cholesterol in this way. The method, however, is not yet being tested in human clinical trials, although Shah is optimistic that as gene therapy improves and more effective and safe vectors are available, this concept will be brought closer to human testing. 16
Ashraf Reda,M.D.

17. Other therapeutic Approaches
Milano type-apo A1 acutely increase HDL
Over expression of LCAT
ABCA1 activators
ETC-216: Recombinant Apo-A1 Milano
ETC-588:Phospholipid liposome (Cholesterol sponge)
Liver-X-receptors (LXR) agonists
Endothelial Lipase inhibitors to prevent Apo-A1 catabolism
While there are a lot of unknowns, many believe that the best way to raise HDL-cholesterol levels is to produce more apoA-1, which is the precursor of new HDL cholesterol. ApoA-1 constitutes 70% of the HDL protein and is present on nearly all HDL particles. For this reason, said Rader, the upregulation of endogenous apoA-1 expression is considered one of the most promising approaches to the development of new therapies targeted to HDL cholesterol.
"In terms of pathways, I would say that the holy grail is promotion of apoA-1 gene transcription or apoA-1 production by liver, intestine, or both," Rader said. "If, somehow, a small molecule could be found that turned on the transcription of the apoA-1 gene, I really do think that would be very good, based on everything we know from preclinical models. There is no reason to think that would cause harm, unless there was some off-target effect, but we have every reason to think it would be a good thing."
Shah and his group at Cedars-Sinai Medical Center have performed proof-of-concept gene-therapy studies in mouse models with apoA-1 Milano, a variant of apoA-1, and have shown that it is possible to exploit the benefits of HDL cholesterol in this way. The method, however, is not yet being tested in human clinical trials, although Shah is optimistic that as gene therapy improves and more effective and safe vectors are available, this concept will be brought closer to human testing. 15
Ashraf Reda,M.D.

18. The current evidence
Raising HDL is at least as important as reducing LDL in reducing coronary events and slowing atherosclerosis progression.
A strong statin +Niacin is the most effective strategy.
Meta-analysis showed >60% RR with combination therapy compared with + 25% with statin alone
This review of epidemiologic, arteriographic, and clinical trial evidence supports the idea that raising HDL-C is at least as important as a comparable percentage reduction of LDL-C. Indeed, the lipid response variable (%ΔHDL-C − %ΔLDL-C) is very strongly associated with slowing of coronary stenosis progression and reduction of clinical coronary events. This observation appears to apply to all U.S. Food and Drug Administration–approved pharmaceutical agents analyzed. Given these observations, a strong LDL-C–lowering agent, such as a statin, in combination with niacin—presently the most effective approved HDL-C–raising drug—would appear to provide the greatest potential for cardiovascular disease prevention. Current expert opinion holds that HDL-C–raising agents have not been proven beyond doubt to reduce cardiovascular risk either as monotherapy or when added to LDL-C–lowering agents. However, the evidence, as presented here, strongly supports this hypothesis in its straightforward logic and its fit with epidemiologic and with clinical trial data. If the relationships emerging from this analysis are proven true, risk reductions in the range of 60% to 75% would be achievable using currently available drug combinations, a major advance over the 25-35% risk reduction expected with statin monotherapy. Two trials are presently ongoing to examine this possibility. ACCORD will compare fenofibrate plus any statin with statin monotherapy in 9750 patients with type 2 diabetes. AIM-HIGH will compare simvastatin plus Niaspan with simvastatin monotherapy in 3300 patients with cardiovascular disease, low HDL-C, and high triglycerides. Both trials are due to complete in the 2009 to 2011 time frame. 18
Ashraf Reda,M.D.

19. 2009-2011: What Are We Waiting For?
ACCORD: Fenofib+statin Vs Statin in 9750 pts with DM2
AIM-HIGH Simva +Niacepam Vs Simva in 3300 Pts (Metabolic syndrome) with CVD, low HDL and high TAG
Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE)
This review of epidemiologic, arteriographic, and clinical trial evidence supports the idea that raising HDL-C is at least as important as a comparable percentage reduction of LDL-C. Indeed, the lipid response variable (%ΔHDL-C − %ΔLDL-C) is very strongly associated with slowing of coronary stenosis progression and reduction of clinical coronary events. This observation appears to apply to all U.S. Food and Drug Administration–approved pharmaceutical agents analyzed. Given these observations, a strong LDL-C–lowering agent, such as a statin, in combination with niacin—presently the most effective approved HDL-C–raising drug—would appear to provide the greatest potential for cardiovascular disease prevention. Current expert opinion holds that HDL-C–raising agents have not been proven beyond doubt to reduce cardiovascular risk either as monotherapy or when added to LDL-C–lowering agents. However, the evidence, as presented here, strongly supports this hypothesis in its straightforward logic and its fit with epidemiologic and with clinical trial data. If the relationships emerging from this analysis are proven true, risk reductions in the range of 60% to 75% would be achievable using currently available drug combinations, a major advance over the 25-35% risk reduction expected with statin monotherapy. Two trials are presently ongoing to examine this possibility. ACCORD will compare fenofibrate plus any statin with statin monotherapy in 9750 patients with type 2 diabetes. AIM-HIGH will compare simvastatin plus Niaspan with simvastatin monotherapy in 3300 patients with cardiovascular disease, low HDL-C, and high triglycerides. Both trials are due to complete in the 2009 to 2011 time frame. While niacin can raise HDL cholesterol by 30%, it has been given a bad rap, mainly because as many as 20% to 30% of those who take it have side effects, such as itching and flushing. Still, niacin is making a comeback, especially since recent research has helped shed light on the cause of flushing, with selective agonists in development to alleviate these symptoms. In the Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), for example, a new combination tablet containing extended-release niacin and a specific blocker of prostaglandin D2 to prevent flushing is being tested in 20 000 patients, with the hope of reducing MI, stroke, or revascularization procedures in patients with existing vascular disease. The 3300-patient US National Institutes of Health (NIH) Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-C/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study will compare the incidence of major cardiovascular events in patients randomized to extended-release niacin plus simvastatin or simvastatin alone.
"If AIM-HIGH comes out negative, I'm throwing in the towel. I'm giving up. I'm retiring," joked Miller. 19
Ashraf Reda,M.D.

20. Conclusions CETP inhibition is a harmful strategy
Epidemiological studies and arterio-graphic data support HDL benefit
Niacin and combination therapy are effective and proven therapy for HDL raising
Apo-A1 targeting appear to be the most promising strategy to enhance reverse cholesterol transport
While niacin can raise HDL cholesterol by 30%, it has been given a bad rap, mainly because as many as 20% to 30% of those who take it have side effects, such as itching and flushing. Still, niacin is making a comeback, especially since recent research has helped shed light on the cause of flushing, with selective agonists in development to alleviate these symptoms. In the Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), for example, a new combination tablet containing extended-release niacin and a specific blocker of prostaglandin D2 to prevent flushing is being tested in 20 000 patients, with the hope of reducing MI, stroke, or revascularization procedures in patients with existing vascular disease. The 3300-patient US National Institutes of Health (NIH) Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-C/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study will compare the incidence of major cardiovascular events in patients randomized to extended-release niacin plus simvastatin or simvastatin alone.
"If AIM-HIGH comes out negative, I'm throwing in the towel. I'm giving up. I'm retiring," joked Miller. 20
Ashraf Reda,M.D.

21. Thank you 22
Ashraf Reda,M.D.

22. CardioLipid 2007
14-16 November

23. Aerobic exercise LSM Smoking cessation Combination therapy
Conclusions
A specific HDL raising agents may need further 5-10
years to show in the market
Don’t forget
Aerobic exercise
LSM
Smoking cessation
Combination therapy 21
Ashraf Reda,M.D.

24. It’s complex: Genes involved in HDL metabolism
HDL assosciated Apos.:
Apo-A1
Apo-E
Apo-IV
Modifying plasma enzymes and transfer protein
LCAT- CETP- PLTP
LPL- HL- Endoth. lipase
Cellular and cell surface protein
ABC1
SR-B1
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:
Fruchart JC, Duriez P. High-density lipoproteins and coronary heart disease: future prospects in gene therapy. Biochimie. 1998;80:
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: 13
Ashraf Reda,M.D.

25. Studies of HDL/apoA-1 infusion
Agent
Model
Main effects
Recombinant apoA-1 Milano
Humans
Stimulation of fecal cholesterol excretion
Plasma-derived human HDL
Stimulation of reverse cholesterol transport
Hyperlipidemic humans
Improved endothelial function
Recombinant apoA-1 Milano (ETC-216)
Acute coronary syndrome patients
Coronary atheroma regression in 5 weeks 17
Shah PK. Future Lipidol 2006; 1:55-64.
Ashraf Reda,M.D.