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Latest revision as of 21:13, 31 March 2015

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayokunle Olubaniyi, M.B,B.S [2]

Overview

There is an association between the concentration of circulating LDL cholesterol (LDL-c) and the risk of cardiovascular disease. There is an unmet need for more effective and tolerable therapies for the reduction of LDL-c. Ongoing studies are evaluating novel lipid-lowering therapeutic strategies, including anti-sense oligonucleotides (ASOs) to apolipoprotein B (apo B), proprotein convertase subtilisin/kexin type 9 (PCSK9), microsomal triglyceride transfer protein (MTP), thyromimetics, squalene synthase, adenosine triphosphate-citrate lyase, AMP-activated protein kinase, and sterol regulatory element binding proteins.

The Unmet Need Driving Research Towards a Lower LDL Cholesterol Goal

Although the relative rate of death attributable to cardiovascular disease has declined by 32.7% in the past decade, the disease burden remains high. Cardiovascular disease (CVD) accounts for 1 out of every 3 deaths in the United States,^[1] with direct medical costs due to CVD estimated to triple by 2030.^[2] LDL cholesterol is a major determinant of atherosclerotic CVD and has been an important target for improving cardiovascular outcomes.^[3] The abundance of data on statins (HMG CoA reductase inhibitors) for the primary and secondary prevention of CVD has contributed to their universal adoption as first-line therapies for LDL-C reduction. However, approximately 40% and 80% of individuals with high- and very-high cardiovascular risk, respectively, do not achieve their LDL-C goals with optimal doses of statins. ^[4] With data demonstrating that a lower limit for LDL-C reduction may not be applicable (particularly that values lower than those achieved with statins alone are associated with a further reduction in cardiovascular events^[5]), and given the 5-10% rate of statin-associated myalgia that has been linked to higher doses, as well as more potent statins, there seems to be a growing need for new therapeutics that effectively and safely reduce LDL cholesterol, and are associated with a reduction in cardiovascular events. ^[6]

Investigational Therapies

PCSK9 Inhibitiors

The function of PCSK9 was first described in 2003 when a gain-of-function mutation of PCSK9 gene (leading to increased activity) was associated with familial hypercholesterolemia in 4 french families.^[7] The association was further clarified in 2005 after the discovery of loss-of-function mutations of PCSK9 in patients with low LDL-C. This loss-of-function was linked to a 40% reduction in plasma levels of LDL-C in the studied population.^[8] PCSK9 has a major role in the metabolism of hepatic cholesterol. It is a serine protease that binds to the epidermal growth factor-like repeat A (EGF-A) domain of the low-density lipoprotein receptor (LDLR), inducing LDLR degradation in the lysosomes. Reduced LDL receptor levels result in decreased metabolism of low density lipoprotein (LDL), which could lead to hypercholesterolemia.^[9] The sterol regulatory element-binding protein-2 (SREBP-2), which is activated in the presence of low intracellular levels of cholesterol, also induces the expression of PCSK9, thereby increasing the amount of circulating LDL-cholesterol.^[10] Several drugs have been investigated for the inhibition of PCSK9, and have demonstrated a more potent lowering of LDL cholesterol levels than the current available drugs. Phase II and phase III trials have demonstrated good tolerability and efficacy in lowering LDL choleterol, with exploratory analyses demonstrating a reduction in cardiovascular events^[11]. Although it is biologically plausible that this reduction in LDL would also lead to a reduction in atherothrombotic events, additional clinical trials are ongoing to determine the efficacy of PCSK9 inhibitors in improving CV outcomes.^[12]^[13]^[14]^[15]

PCSK9 Function
Pharmacologic Interventions for PCSK9 inhibition

For more information regarding this approach to lipid management, click here.
For details about specific agents, click on the following links: Alirocumab, Evolocumab, Bococizumab

Microsomal Triglyceride Transfer Protein (MTP) Inhibition

Microsomal triglyceride transfer protein is an endosomal protein found in the hepatocytes and intestinal enterocytes. It catalyses the transfer of cholesterol esters and triglycerides to nascent apo B, leading to the formation of chylomicron and VLDL in the intestine and hepatocyte, respectively.^[16] Chylomicrons and other apo-B48-containing remnant lipoproteins are essential for intestinal fat absorption and its transfer to peripheral tissues. Mutations of the MTTP gene leads to a condition known as abetalipoproteinemia, which causes an absence of apo-B-containing lipoproteins and very low levels of LDL-C and triglycerides.^[17]^[18] Individuals with this recessive condition have severe intestinal malabsorption of fat and fat-soluble vitamins (A, D, E, K) manifesting as fatty liver, night-blindness, rickets or osteomalacia, neuropathy, ataxia, and coagulopathy.

Several MTP inhibitors are being investigated:

Non-intestinal-specific agents
- Lomitapide (AEGR-427, previously known as BMS-201038 - Bristol-Myers-Squibb) by Aegerion Pharmaceuticals
- Implitapide (formerly AEGR-427 or Bayer BAY-13-9952)
- CP-34086 by Pfizer
Intestinal-specific agents
- Dirlotapide by Pfizer
- JTT-130 and SLx-4090 by Surface Logix.

Early clinical trials that enrolled patients with homozygous familial hypercholesterolemia demonstrated up to 50% reductions in total cholesterol, LDL-C and apo B with MTP inhibition.^[19] However, higher doses were associated with transient elevations in liver transaminases and hepatic fat accumulation. Further developments of CP-34086 and implitapide have been placed on hold due to their hepatic adverse effects. Intestinal-specific agents such as dirlotapide, JTT-130, and SLx-4090 were developed to prevent the hepatic effects of the non-specific agents. Thus far, these agents are still early in human clinical trials (except dirlotapide), but several reports have demonstrated significant reductions in postprandial triglyceridemia and total cholesterol in preclinical studies.^[20] Intestinal-specific MTP inhibitors may be effective in treating hyperchylomicronemia but their efficacy as LDL-C lowering agents is uncertain.

Adapted from Nature Reviews Cardiology, 8(5): 253-265 (May 2011).^[21]

Apolipoprotein B Inhibitors

Apolipoprotein B (apo B) is a large protein that is present in all atherogenic lipoproteins i.e., VLDL, LDL, IDL. There is a single copy of apo B-100 in all these lipoproteins, therefore, plasma levels of apo B-100 are proportionate to the concentration of circulating atherogenic lipoproteins and are associated with a higher cardiovascular risk.^[22] Apo B exists in two main isoforms, apo B100 and apo B48. The liver synthesizes apo B-100, whereas the small intestine synthesizes apo B48. Apo B100 serves two main functions - (1) it provides structural stability to the circulating lipoproteins, and (2) it acts as a ligand for LDL receptors (LDLR). On the other hand, apo B48 is a unique structural protein of chylomicrons that originate from the small intestine. The removal of LDL particles from the plasma involves the binding of apo B to LDLR, then, the resulting apo B-100-LDLR complex gets internalized into the hepatocyte for processing.^[23] Mutations that lower the affinity of apo B-100 for LDLR result in decreased clearance of LDLs, a condition known as familial defective apo B, which is associated with an increased risk of atherosclerotic cardiovascular diseases.^[24] In contrast, mutations in apo B that decrease its translation or secretion have been demonstrated to reduce circulating LDL-C and improve cardiovascular risk.^[25] All of these observations have led to the development of therapeutic strategies that target Apo-B for the reduction of LDL cholesterol.

ISIS 301012 or mipomersen

ISIS 301012 or mipomersen, by ISIS Pharmaceuticals, is a second-generation 20 nucleotide antisense oligoneucleotide (ASO) which selectively inhibits apo B gene expression via RNAse H activation.^[26] ASOs are short, deoxyribonucleotide strands which bind to the targeted mRNAs to inhibit their translation leading to their enzymatic degradation by ribonuclease (RNAse H or argonaute 2), thus inhibiting gene expression.^[27] Phases I and II clinical trials of ISIS301012 have demonstrated a dose-dependent reduction in plasma apo B levels by approximately 40% and up to 50% reduction in LDL-C with subcutaneously administered ISIS-301012 or mipomersen, even among patients with defective LDLRs.^[28]^[29]^[30] Furthermore, a randomized phase III trial that enrolled homozygous familial hypercholesterolemia patients demonstrated a 15% elevation in HDL-C.^[31] Despite its efficacy in lowering LDL-C, mipomersen did not receive approval due to a significant increase in adverse effects - injection site reactions (80-100% of patients), flu-like illness, and 3-fold elevation in liver transaminases (15%).

Adapted from Nature Reviews Cardiology, 8(5): 253-265 (May 2011) and Pharmacology & Therapeutics, 135(1): 31-43 (July 2012)^[21]^[32]

Thyromimetics

The association between thyroid hormones and cholesterol metabolism was first discovered in the 1930s, and its use as a cholesterol lowering agent has been investigated in several studies.^[33]^[34]^[35] However, the development of thyromimetic agents was set back by the associated increase in cardiovascular events, thought to be related to contamination of the thyromimetic agent investigated with levothyroxine (LT4), as well as the discovery of statins.^[36]^[37] The discovery of thyroid hormone receptors (TRs) restored some of the investigations into thyromimetics for the reduction of LDL-C. There are two main TRs in humans:

TRα receptors (TRα 1 & 2). TRα 1 is predominantly in the muscles and adipose tissue; also mediates the cardiovascular responses to thyroid hormones such as tachycardia.^[38]
TRβ receptors (TRβ 1 & 2). TRβ 1 is mainly in the liver and it regulates cholesterol homeostasis.^[38] Therefore, the development of TRβ 1-specific thyromimetic would be a promising method of cholesterol management devoid of cardiac effects.^[39]^[40]

Some of the proposed mechanisms of action of these agents include:

Upregualtion of hepatic LDLR expression by TRβ.^[41]^[42]
Stimulation of bile acid synthesis through the upregulation of the rate-limiting enzyme, cholesterol 7-hydroxylase [CYP7A1])
Stimulation of biliary excretion (through increased expression of ATP-binding cassette proteins G5/G8 [ABCG5/G8]
Promotion of reverse cholesterol transport which ultimately increases the formation of HDL, enhances cholesteryl ester transfer protein (CETP) activity, and increases scavenger receptor B-I (SR-BI) activity for the uptake of cholesterol.

Examples of TRβ 1-specific thyromimetics that had been investigated include:

DITPA (3,5-diiodothyropropionic acid) - terminated
Eprotirome (KB2115)^[43] by Karo Bio AB.
Sobetirome (GC-1)
MB07811
KB-141
T-0681

Squalene Synthase Inhibition

Similar to the statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors), inhibitors of squalene synthase prevent the conversion of farnesyl pyrophosphate to squalene at a point on the HMG-CoA-Mevalonate pathway which represents the commitment of cholesterol intermediates to the synthesis of cholesterol. Squalene synthase inhibitors have been shown to inhibit cholesterol production, reduce triglyceride synthesis and apoB secretion, increase LDL receptor expression and LDL uptake in HepG2 cells.^[44] However, they are less likely to be associated with the adverse myopathic effects commonly observed with statins because they do not cause depletion of isoprenoid intermediates within the cholesterol biosynthesis pathway, and as a result, they do not limit the prenylation or lipidation (addition of hydrophobic molecules to a protein) of membrane-directed proteins.^[45]

TAK-475 (lapaquistat acetate) by Takeda Pharmaceuticals was the first squalene synthase inhibitor to reach phase III clinical trials for the treatment of hypercholesterolemia in the United States and Europe. Randomized, double-blinded, placebo and actively controlled, parallel-group studies involving TAK-475 alone and in combination with atovastatin were associated with a dose-dependent reduction of LDL-C up to 27% and 19% when compared with placebo and when combined with atovastatin, respectively in healthy human volunteers. Recent animal studies have demonstrated a protective effect against statin-induced myopathy when isoprenoid intermediates are replenished directly or by the use of TAK-475 given with high-dose statins.^[46] Results from these studies further underscore squalene synthase inhibitors as potential drugs to clinically prevent statin-induced myopathies.

Phase III multi-centered clinical trials are on-going to compare TAK-475 vs simvastatin alone or in combination, vs. ezetimibe, and as add-on in patients already on atorvastatin, rosuvastatin, or a low or high-dose statin. It will also be investigated as add-on treatment in patients with homozygous familial hypercholesterolemia, and in patients with type 2 diabetes.

Inhibition of ACL and Activation of AMPK

ETC-1002 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid), by Esperion Therapeutics, is a small molecule which regulates lipid and carbohydrate metabolism. It modulates the activity of two distinct molecular targets - hepatic adenosine triphosphate-citrate lyase (ACL) and AMP-activated protein kinase (AMPK).^[47] It works by:

Inhibition of ACL - Inhibition of adenosine triphosphate-citrate lyase, an enzyme responsible for the production of ATP citrate, reduces the levels of acetyl co-enzyme A (acetyl-CoA - an important precursor to HMG-CoA which is a vital component in cholesterol and ketone synthesis). It acts on the lipid synthesis pathway upstream of HMG CoA reductase - the molecular targets of statins.^[48]
Activation of adenosine monophosphate activated protein kinase (AMP-activated protein kinase) - AMP-activated protein kinase is a functional enzyme present in the liver, striated muscle, and the brain. It plays a key role in cellular energy homeostasis. It acts as a sensor of the energy-depleted form of ATP (i.e., AMP), and its activation results in stimulation of hepatic fatty acid oxidation and ketogenesis, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, stimulation of skeletal muscle fatty acid oxidation and muscle glucose uptake,^[49] and modulation of insulin secretion by pancreatic beta-cells.^[50]

In a phase II clinical trial involving 177 patients, ETC-1002 was shown to have a dose-dependent reduction of up to 27% in LDL-C (compared with placebo) observed with the maximum dose (120mg), devoid of serious adverse effects.^[48] This approach may represent a new target mechanism to reducing LDL-C, but additional studies are required to determine the safety due to its high possibility of producing similar adverse effects as statins.

Inhibition of SREBP-1

Sterol regulatory element binding proteins (SREBPs) are transcription factors required in the activation of genes involved in cholesterol and fatty acid biosynthesis. Fatostatin, a diarylthiazole derivative, was observed to impair the activation of SREBPs, thereby decreasing the transcription of lipogenic genes in cells.^[51] More studies are required regarding the efficacy of this potential target in reducing circulating LDL-C since it also induces the expression of PCSK9 - a serine protease which promotes degradation of LDLR, thereby preventing the clearing of LDL particles from the plasma.

Summary Table

Class	Drug Company	Agent Name	Mechanism of Action	Efficacy on Lowering LDL-C	Route of Administration	Adverse Effects	Published Clinical Trials
Inhibition of Apo B/Antisense oligonucleotides	ISIS Pharmaceuticals	ISIS-301012 or Mipomersen	Inhibits apo B mRNA gene expression	Up to 50% reduction	Subcutaneous injection (SC)	Injection site reactions, flu-like illness, 3-fold asymptomatic elevation of liver transaminases	Phase I, II, III
PCSK9 Inhibition	Merck, Sanofi-Aventis–Regeneron, Pfizer–Rinat, Amgen, Santaris, Alnylam, Medicines company, ISIS, Adnexus, Roche/Genentech, Novartis	AMG 145, SAR236553/REGN727, RN316, 1D05-IgG2, RG7652, LGT-209, 1B20, J10, J16, J17	Inhibition of PCSK9 which promotes degradation of LDLR	38% reduction in LDL-C in animal studies	ASO (SC), monoclonal antibody (SC), SiRNA (IV)		Phase I, II, III
MTP Inhibition	Aegerion Pharmaceuticals, Pfizer, Surface Logix	Intestinal non-specific (lometapide, implitapide, CP-34086); Intestinal-specific (SLx-4090, dirlotapide, JTT-130)	Inhibits Microsomal triglyceride transfer protein	Lometapide (up to 50%), CP-34086 (up to 70%)	PO	Intestinal non-specific agents causes GI adverse effects, increases in hepatic fat	Lometapide (Phase I, II, III), JTT-130 (Phase I, II)
Thyromimetics	Karo Bio AB	DITPA, eprotirome, sobetirome (GC-1), MB07811, KB-141, T-0681	TRβ1-selective	Up to 32% reduction of LDL-C	PO	Adverse cardiac effects	Phase II
Squalene Synthase Inhibitors	Takeda	TAK-475	Inhibits squalene synthase in the HMG CoA-Mevalonate pathway	Up to 27% reduction in LDL-C			Phase II
Inhibition of ACL and Activation of AMPK	Esperion	ETC-1002	Regulation of lipid and carbohydrate metabolic subtrates	Up to 27% reduction in LDL-C		No serious adverse effects	Phase II
Inhibition of SREBP-1		Inhibition of SREBP-1	Impair the activation of SREBPs, thereby decreasing the transcription of lipogenic genes in cells

References

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↑ Young, WF.; Gorman, CA.; Jiang, NS.; Machacek, D.; Hay, ID. (1984). "L-thyroxine contamination of pharmaceutical D-thyroxine: probable cause of therapeutic effect". Clin Pharmacol Ther. 36 (6): 781–7. PMID 6499357. Unknown parameter |month= ignored (help)
↑ ^38.0 ^38.1 Angelin, B.; Rudling, M. (2010). "Lipid lowering with thyroid hormone and thyromimetics". Curr Opin Lipidol. 21 (6): 499–506. doi:10.1097/MOL.0b013e3283402e9c. PMID 20935564. Unknown parameter |month= ignored (help)
↑ Gullberg, H.; Rudling, M.; Saltó, C.; Forrest, D.; Angelin, B.; Vennström, B. (2002). "Requirement for thyroid hormone receptor beta in T3 regulation of cholesterol metabolism in mice". Mol Endocrinol. 16 (8): 1767–77. PMID 12145333. Unknown parameter |month= ignored (help)
↑ Johansson, C.; Vennström, B.; Thorén, P. (1998). "Evidence that decreased heart rate in thyroid hormone receptor-alpha1-deficient mice is an intrinsic defect". Am J Physiol. 275 (2 Pt 2): R640–6. PMID 9688704. Unknown parameter |month= ignored (help)
↑ Erion, MD.; Cable, EE.; Ito, BR.; Jiang, H.; Fujitaki, JM.; Finn, PD.; Zhang, BH.; Hou, J.; Boyer, SH. (2007). "Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index". Proc Natl Acad Sci U S A. 104 (39): 15490–5. doi:10.1073/pnas.0702759104. PMID 17878314. Unknown parameter |month= ignored (help)
↑ Tancevski, I.; Demetz, E.; Eller, P.; Duwensee, K.; Hoefer, J.; Heim, C.; Stanzl, U.; Wehinger, A.; Auer, K. (2010). "The liver-selective thyromimetic T-0681 influences reverse cholesterol transport and atherosclerosis development in mice". PLoS One. 5 (1): e8722. doi:10.1371/journal.pone.0008722. PMID 20090943.
↑ Ladenson, PW.; Kristensen, JD.; Ridgway, EC.; Olsson, AG.; Carlsson, B.; Klein, I.; Baxter, JD.; Angelin, B. (2010). "Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia". N Engl J Med. 362 (10): 906–16. doi:10.1056/NEJMoa0905633. PMID 20220185. Unknown parameter |month= ignored (help)
↑ Tavridou, A.; Kaklamanis, L.; Megaritis, G.; Kourounakis, AP.; Papalois, A.; Roukounas, D.; Rekka, EA.; Kourounakis, PN.; Charalambous, A. (2006). "Pharmacological characterization in vitro of EP2306 and EP2302, potent inhibitors of squalene synthase and lipid biosynthesis". Eur J Pharmacol. 535 (1–3): 34–42. doi:10.1016/j.ejphar.2006.02.006. PMID 16545796. Unknown parameter |month= ignored (help)
↑ Mühlhäuser, U.; Zolk, O.; Rau, T.; Münzel, F.; Wieland, T.; Eschenhagen, T. (2006). "Atorvastatin desensitizes beta-adrenergic signaling in cardiac myocytes via reduced isoprenylation of G-protein gamma-subunits". FASEB J. 20 (6): 785–7. doi:10.1096/fj.05-5067fje. PMID 16467371. Unknown parameter |month= ignored (help)
↑ Nishimoto, T.; Ishikawa, E.; Anayama, H.; Hamajyo, H.; Nagai, H.; Hirakata, M.; Tozawa, R. (2007). "Protective effects of a squalene synthase inhibitor, lapaquistat acetate (TAK-475), on statin-induced myotoxicity in guinea pigs". Toxicol Appl Pharmacol. 223 (1): 39–45. doi:10.1016/j.taap.2007.05.005. PMID 17599378. Unknown parameter |month= ignored (help)
↑ Pinkosky, SL.; Filippov, S.; Srivastava, RA.; Hanselman, JC.; Bradshaw, CD.; Hurley, TR.; Cramer, CT.; Spahr, MA.; Brant, AF. (2013). "AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism". J Lipid Res. 54 (1): 134–51. doi:10.1194/jlr.M030528. PMID 23118444. Unknown parameter |month= ignored (help)
↑ ^48.0 ^48.1 Ballantyne, CM.; Davidson, MH.; Macdougall, DE.; Bays, HE.; Dicarlo, LA.; Rosenberg, NL.; Margulies, J.; Newton, RS. (2013). "Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial". J Am Coll Cardiol. 62 (13): 1154–62. doi:10.1016/j.jacc.2013.05.050. PMID 23770179. Unknown parameter |month= ignored (help)
↑ Holmes, BF.; Kurth-Kraczek, EJ.; Winder, WW. (1999). "Chronic activation of 5'-AMP-activated protein kinase increases GLUT-4, hexokinase, and glycogen in muscle". J Appl Physiol (1985). 87 (5): 1990–5. PMID 10562646. Unknown parameter |month= ignored (help)
↑ Winder, WW.; Hardie, DG. (1999). "AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes". Am J Physiol. 277 (1 Pt 1): E1–10. PMID 10409121. Unknown parameter |month= ignored (help)
↑ Kamisuki, S.; Mao, Q.; Abu-Elheiga, L.; Gu, Z.; Kugimiya, A.; Kwon, Y.; Shinohara, T.; Kawazoe, Y.; Sato, S. (2009). "A small molecule that blocks fat synthesis by inhibiting the activation of SREBP". Chem Biol. 16 (8): 882–92. doi:10.1016/j.chembiol.2009.07.007. PMID 19716478. Unknown parameter |month= ignored (help)

Template:WikiDoc Sources

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[Rader-1993-18] Rader, DJ.; Brewer, HB. (1993). "Abetalipoproteinemia. New insights into lipoprotein assembly and vitamin E metabolism from a rare genetic disease". JAMA. 270 (7): 865–9. PMID 8340987. Unknown parameter |month= ignored (help)

[Cuchel-2007-19] Cuchel, M.; Bloedon, LT.; Szapary, PO.; Kolansky, DM.; Wolfe, ML.; Sarkis, A.; Millar, JS.; Ikewaki, K.; Siegelman, ES. (2007). "Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia". N Engl J Med. 356 (2): 148–56. doi:10.1056/NEJMoa061189. PMID 17215532. Unknown parameter |month= ignored (help)

[Li-2007-20] Li, J.; Bronk, BS.; Dirlam, JP.; Blize, AE.; Bertinato, P.; Jaynes, BH.; Hickman, A.; Miskell, C.; Pillai, UA. (2007). "In vitro and in vivo profile of 5-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid benzylmethyl carbamoylamide (dirlotapide), a novel potent MTP inhibitor for obesity". Bioorg Med Chem Lett. 17 (7): 1996–9. doi:10.1016/j.bmcl.2007.01.018. PMID 17276061. Unknown parameter |month= ignored (help)

[Brautbar-2011-21] 21.0 ^21.1 Brautbar, A.; Ballantyne, CM. (2011). "Pharmacological strategies for lowering LDL cholesterol: statins and beyond". Nat Rev Cardiol. 8 (5): 253–65. doi:10.1038/nrcardio.2011.2. PMID 21321561. Unknown parameter |month= ignored (help)

[22] van der Steeg, WA.; Boekholdt, SM.; Stein, EA.; El-Harchaoui, K.; Stroes, ES.; Sandhu, MS.; Wareham, NJ.; Jukema, JW.; Luben, R. (2007). "Role of the apolipoprotein B-apolipoprotein A-I ratio in cardiovascular risk assessment: a case-control analysis in EPIC-Norfolk". Ann Intern Med. 146 (9): 640–8. PMID 17470832. Unknown parameter |month= ignored (help)

[Hussain-1999-23] Hussain, MM.; Strickland, DK.; Bakillah, A. (1999). "The mammalian low-density lipoprotein receptor family". Annu Rev Nutr. 19: 141–72. doi:10.1146/annurev.nutr.19.1.141. PMID 10448520.

[pmid2280177-24] Innerarity TL, Mahley RW, Weisgraber KH, Bersot TP, Krauss RM, Vega GL; et al. (1990). "Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia". J Lipid Res. 31 (8): 1337–49. PMID 2280177.

[Schonfeld-2005-25] Schonfeld, G.; Lin, X.; Yue, P. (2005). "Familial hypobetalipoproteinemia: genetics and metabolism". Cell Mol Life Sci. 62 (12): 1372–8. doi:10.1007/s00018-005-4473-0. PMID 15818469. Unknown parameter |month= ignored (help)

[Ito-2007-26] Ito, MK. (2007). "ISIS 301012 gene therapy for hypercholesterolemia: sense, antisense, or nonsense?". Ann Pharmacother. 41 (10): 1669–78. doi:10.1345/aph.1K065. PMID 17848425. Unknown parameter |month= ignored (help)

[Bennett-2010-27] Bennett, CF.; Swayze, EE. (2010). "RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform". Annu Rev Pharmacol Toxicol. 50: 259–93. doi:10.1146/annurev.pharmtox.010909.105654. PMID 20055705.

[Kastelein-2006-28] Kastelein, JJ.; Wedel, MK.; Baker, BF.; Su, J.; Bradley, JD.; Yu, RZ.; Chuang, E.; Graham, MJ.; Crooke, RM. (2006). "Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B.". Circulation. 114 (16): 1729–35. doi:10.1161/CIRCULATIONAHA.105.606442. PMID 17030687. Unknown parameter |month= ignored (help)

[Akdim-2010-29] Akdim, F.; Visser, ME.; Tribble, DL.; Baker, BF.; Stroes, ES.; Yu, R.; Flaim, JD.; Su, J.; Stein, EA. (2010). "Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia". Am J Cardiol. 105 (10): 1413–9. doi:10.1016/j.amjcard.2010.01.003. PMID 20451687. Unknown parameter |month= ignored (help)

[Akdim-2011-30] Akdim, F.; Tribble, DL.; Flaim, JD.; Yu, R.; Su, J.; Geary, RS.; Baker, BF.; Fuhr, R.; Wedel, MK. (2011). "Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia". Eur Heart J. 32 (21): 2650–9. doi:10.1093/eurheartj/ehr148. PMID 21593041. Unknown parameter |month= ignored (help)

[Raal-2010-31] Raal, FJ.; Santos, RD.; Blom, DJ.; Marais, AD.; Charng, MJ.; Cromwell, WC.; Lachmann, RH.; Gaudet, D.; Tan, JL. (2010). "Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial". Lancet. 375 (9719): 998–1006. doi:10.1016/S0140-6736(10)60284-X. PMID 20227758. Unknown parameter |month= ignored (help)

[Joy-2012-32] Joy, TR. (2012). "Novel therapeutic agents for lowering low density lipoprotein cholesterol". Pharmacol Ther. 135 (1): 31–43. doi:10.1016/j.pharmthera.2012.03.005. PMID 22465160. Unknown parameter |month= ignored (help)

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[STRISOWER-1959-34] STRISOWER, B.; ELMLINGER, P.; GOFMAN, JW.; DELALLA, O. (1959). "The effect of 1-thyroxine on serum lipoprotein and cholesterol concentrations". J Clin Endocrinol Metab. 19 (1): 117–26. PMID 13620737. Unknown parameter |month= ignored (help)

[HOLLISTER-1962-35] HOLLISTER, LE.; ARONS, WL. (1962). "Effect of dextro-isomers of thyroid hormones on serum cholesterol levels in euthyroid hypercholesterolemic patients". Ann Intern Med. 56: 570–6. PMID 13908447. Unknown parameter |month= ignored (help)

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[Young-1984-37] Young, WF.; Gorman, CA.; Jiang, NS.; Machacek, D.; Hay, ID. (1984). "L-thyroxine contamination of pharmaceutical D-thyroxine: probable cause of therapeutic effect". Clin Pharmacol Ther. 36 (6): 781–7. PMID 6499357. Unknown parameter |month= ignored (help)

[Angelin-2010-38] 38.0 ^38.1 Angelin, B.; Rudling, M. (2010). "Lipid lowering with thyroid hormone and thyromimetics". Curr Opin Lipidol. 21 (6): 499–506. doi:10.1097/MOL.0b013e3283402e9c. PMID 20935564. Unknown parameter |month= ignored (help)

[Gullberg-2002-39] Gullberg, H.; Rudling, M.; Saltó, C.; Forrest, D.; Angelin, B.; Vennström, B. (2002). "Requirement for thyroid hormone receptor beta in T3 regulation of cholesterol metabolism in mice". Mol Endocrinol. 16 (8): 1767–77. PMID 12145333. Unknown parameter |month= ignored (help)

[Johansson-1998-40] Johansson, C.; Vennström, B.; Thorén, P. (1998). "Evidence that decreased heart rate in thyroid hormone receptor-alpha1-deficient mice is an intrinsic defect". Am J Physiol. 275 (2 Pt 2): R640–6. PMID 9688704. Unknown parameter |month= ignored (help)

[Erion-2007-41] Erion, MD.; Cable, EE.; Ito, BR.; Jiang, H.; Fujitaki, JM.; Finn, PD.; Zhang, BH.; Hou, J.; Boyer, SH. (2007). "Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index". Proc Natl Acad Sci U S A. 104 (39): 15490–5. doi:10.1073/pnas.0702759104. PMID 17878314. Unknown parameter |month= ignored (help)

[Tancevski-2010-42] Tancevski, I.; Demetz, E.; Eller, P.; Duwensee, K.; Hoefer, J.; Heim, C.; Stanzl, U.; Wehinger, A.; Auer, K. (2010). "The liver-selective thyromimetic T-0681 influences reverse cholesterol transport and atherosclerosis development in mice". PLoS One. 5 (1): e8722. doi:10.1371/journal.pone.0008722. PMID 20090943.

[Ladenson-2010-43] Ladenson, PW.; Kristensen, JD.; Ridgway, EC.; Olsson, AG.; Carlsson, B.; Klein, I.; Baxter, JD.; Angelin, B. (2010). "Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia". N Engl J Med. 362 (10): 906–16. doi:10.1056/NEJMoa0905633. PMID 20220185. Unknown parameter |month= ignored (help)

[Tavridou-2006-44] Tavridou, A.; Kaklamanis, L.; Megaritis, G.; Kourounakis, AP.; Papalois, A.; Roukounas, D.; Rekka, EA.; Kourounakis, PN.; Charalambous, A. (2006). "Pharmacological characterization in vitro of EP2306 and EP2302, potent inhibitors of squalene synthase and lipid biosynthesis". Eur J Pharmacol. 535 (1–3): 34–42. doi:10.1016/j.ejphar.2006.02.006. PMID 16545796. Unknown parameter |month= ignored (help)

[Mühlhäuser-2006-45] Mühlhäuser, U.; Zolk, O.; Rau, T.; Münzel, F.; Wieland, T.; Eschenhagen, T. (2006). "Atorvastatin desensitizes beta-adrenergic signaling in cardiac myocytes via reduced isoprenylation of G-protein gamma-subunits". FASEB J. 20 (6): 785–7. doi:10.1096/fj.05-5067fje. PMID 16467371. Unknown parameter |month= ignored (help)

[Nishimoto-2007-46] Nishimoto, T.; Ishikawa, E.; Anayama, H.; Hamajyo, H.; Nagai, H.; Hirakata, M.; Tozawa, R. (2007). "Protective effects of a squalene synthase inhibitor, lapaquistat acetate (TAK-475), on statin-induced myotoxicity in guinea pigs". Toxicol Appl Pharmacol. 223 (1): 39–45. doi:10.1016/j.taap.2007.05.005. PMID 17599378. Unknown parameter |month= ignored (help)

[Pinkosky-2013-47] Pinkosky, SL.; Filippov, S.; Srivastava, RA.; Hanselman, JC.; Bradshaw, CD.; Hurley, TR.; Cramer, CT.; Spahr, MA.; Brant, AF. (2013). "AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism". J Lipid Res. 54 (1): 134–51. doi:10.1194/jlr.M030528. PMID 23118444. Unknown parameter |month= ignored (help)

[Ballantyne-2013-48] 48.0 ^48.1 Ballantyne, CM.; Davidson, MH.; Macdougall, DE.; Bays, HE.; Dicarlo, LA.; Rosenberg, NL.; Margulies, J.; Newton, RS. (2013). "Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial". J Am Coll Cardiol. 62 (13): 1154–62. doi:10.1016/j.jacc.2013.05.050. PMID 23770179. Unknown parameter |month= ignored (help)

[Holmes-1999-49] Holmes, BF.; Kurth-Kraczek, EJ.; Winder, WW. (1999). "Chronic activation of 5'-AMP-activated protein kinase increases GLUT-4, hexokinase, and glycogen in muscle". J Appl Physiol (1985). 87 (5): 1990–5. PMID 10562646. Unknown parameter |month= ignored (help)

[Winder-1999-50] Winder, WW.; Hardie, DG. (1999). "AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes". Am J Physiol. 277 (1 Pt 1): E1–10. PMID 10409121. Unknown parameter |month= ignored (help)

[Kamisuki-2009-51] Kamisuki, S.; Mao, Q.; Abu-Elheiga, L.; Gu, Z.; Kugimiya, A.; Kwon, Y.; Shinohara, T.; Kawazoe, Y.; Sato, S. (2009). "A small molecule that blocks fat synthesis by inhibiting the activation of SREBP". Chem Biol. 16 (8): 882–92. doi:10.1016/j.chembiol.2009.07.007. PMID 19716478. Unknown parameter |month= ignored (help)

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@@ Line 4: / Line 4: @@
 ==Overview==
-There is a direct relationship between levels of circulating LDL cholesterol and the risk of cardiovascular disease.  There is an unmet need for more effective and tolerable therapies for reducing LDL-C, which is a direct consequence of failures observed with the available therapies at achieving target LDL-C levels.  This section describes novel therapeutic targets currently under development, including anti-sense oligonucleotides (ASOs) to apolipoprotein B (apo B), proprotein convertase subtilisin/kexin type 9 ([[PCSK9]]), [[microsomal triglyceride transfer protein]] (MTP), thyromimetics, [[squalene synthase]], adenosine triphosphate-citrate lyase, [[AMP-activated protein kinase]], and [[sterol regulatory element binding protein]]s.
+There is an association between the concentration of circulating LDL cholesterol (LDL-c) and the risk of cardiovascular disease.  There is an unmet need for more effective and tolerable therapies for the reduction of LDL-c.  Ongoing studies are evaluating novel lipid-lowering therapeutic strategies, including anti-sense oligonucleotides (ASOs) to apolipoprotein B (apo B), proprotein convertase subtilisin/kexin type 9 ([[PCSK9]]), [[microsomal triglyceride transfer protein]] (MTP), thyromimetics, [[squalene synthase]], adenosine triphosphate-citrate lyase, [[AMP-activated protein kinase]], and [[sterol regulatory element binding protein]]s.
-==The Unmet Need Driving Research into Lowering LDL==
+==The Unmet Need Driving Research Towards a Lower LDL Cholesterol Goal==
-Although the relative rate of death attributable to cardiovascular disease declined by 32.7% in the past decade, the burden of disease remains very high at 1 out of every 3 deaths in the United States,<ref name="Go-2013">{{Cite journal  | last1 = Go | first1 = AS. | last2 = Mozaffarian| first2 = D. | last3 = Roger | first3 = VL. | last4 = Benjamin | first4 = EJ. | last5 = Berry | first5 = JD. | last6 = Borden | first6 = WB. |last7 = Bravata | first7 = DM. | last8 = Dai | first8 = S. | last9 = Ford | first9 = ES. | title = Executive summary: heart disease and stroke statistics--2013 update: a report from the American Heart Association. | journal = Circulation | volume = 127 | issue = 1 | pages = 143-52 |month = Jan | year = 2013 | doi = 10.1161/CIR.0b013e318282ab8f | PMID = 23283859 }}</ref> and the direct medical cost is expected to triple by 2030.<ref name="Heidenreich-2011">{{Cite journal  | last1 = Heidenreich | first1 = PA. | last2 = Trogdon | first2 = JG. | last3 = Khavjou |first3 = OA. | last4 = Butler | first4 = J. | last5 = Dracup | first5 = K. | last6 = Ezekowitz | first6 = MD. | last7 = Finkelstein | first7 = EA. | last8 = Hong | first8 = Y. | last9 = Johnston | first9 = SC. | title = Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. | journal = Circulation | volume = 123 | issue = 8 | pages = 933-44 | month = Mar | year = 2011 | doi = 10.1161/CIR.0b013e31820a55f5 | PMID = 21262990 }}</ref>  LDL cholesterol remains the dominant determinant of cardiovascular heart diseases,<ref name="Cohen-2006">{{Cite journal  | last1 = Cohen | first1 = JC. | last2 = Boerwinkle | first2 = E. | last3 = Mosley | first3 = TH. | last4 = Hobbs | first4 = HH. | title = Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. | journal = N Engl J Med | volume = 354 | issue = 12 | pages = 1264-72 | month = Mar | year = 2006 | doi = 10.1056/NEJMoa054013 | PMID = 16554528 }}</ref> thus making [[statins]] (HMG CoA reductase inhibitors) central in the fight against [[atherosclerosis]].  However, 40% and 80% of individuals with high- and very-high cardiovascular risk, respectively, still do not achieve their LDL-C goals with optimal doses of statins.<ref name="Yan-2006">{{Cite journal  | last1 = Yan | first1 = AT. | last2 = Yan | first2 = RT. | last3 = Tan | first3 = M. | last4 = Hackam | first4 = DG. | last5 = Leblanc | first5 = KL. | last6 = Kertland | first6 = H. | last7 = Tsang | first7 = JL. | last8 = Jaffer | first8 = S. | last9 = Kates | first9 = ML. | title = Contemporary management of dyslipidemia in high-risk patients: targets still not met. | journal = Am J Med | volume = 119 | issue = 8 | pages = 676-83 | month = Aug | year = 2006 | doi = 10.1016/j.amjmed.2005.11.015 | PMID = 16887414 }}</ref>  Therefore, alternative therapeutic targets to effectively and safely reduce LDL cholesterol are actively being investigated.
+Although the relative rate of death attributable to cardiovascular disease has declined by 32.7% in the past decade, the disease burden remains high. Cardiovascular disease (CVD) accounts for 1 out of every 3 deaths in the United States,<ref name="Go-2013">{{Cite journal  | last1 = Go | first1 = AS. | last2 = Mozaffarian| first2 = D. | last3 = Roger | first3 = VL. | last4 = Benjamin | first4 = EJ. | last5 = Berry | first5 = JD. | last6 = Borden | first6 = WB. |last7 = Bravata | first7 = DM. | last8 = Dai | first8 = S. | last9 = Ford | first9 = ES. | title = Executive summary: heart disease and stroke statistics--2013 update: a report from the American Heart Association. | journal = Circulation | volume = 127 | issue = 1 | pages = 143-52 |month = Jan | year = 2013 | doi = 10.1161/CIR.0b013e318282ab8f | PMID = 23283859 }}</ref> with direct medical costs due to CVD estimated to triple by 2030.<ref name="Heidenreich-2011">{{Cite journal  | last1 = Heidenreich | first1 = PA. | last2 = Trogdon | first2 = JG. | last3 = Khavjou |first3 = OA. | last4 = Butler | first4 = J. | last5 = Dracup | first5 = K. | last6 = Ezekowitz | first6 = MD. | last7 = Finkelstein | first7 = EA. | last8 = Hong | first8 = Y. | last9 = Johnston | first9 = SC. | title = Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. | journal = Circulation | volume = 123 | issue = 8 | pages = 933-44 | month = Mar | year = 2011 | doi = 10.1161/CIR.0b013e31820a55f5 | PMID = 21262990 }}</ref>  LDL cholesterol is a major determinant of atherosclerotic CVD and has been an important target for improving cardiovascular outcomes.<ref name="Cohen-2006">{{Cite journal  | last1 = Cohen | first1 = JC. | last2 = Boerwinkle | first2 = E. | last3 = Mosley | first3 = TH. | last4 = Hobbs | first4 = HH. | title = Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. | journal = N Engl J Med | volume = 354 | issue = 12 | pages = 1264-72 | month = Mar | year = 2006 | doi = 10.1056/NEJMoa054013 | PMID = 16554528 }}</ref> The abundance of data on [[statins]] (HMG CoA reductase inhibitors) for the primary and secondary prevention of CVD has contributed to their universal adoption as first-line therapies for LDL-C reduction.  However, approximately 40% and 80% of individuals with high- and very-high cardiovascular risk, respectively, do not achieve their LDL-C goals with optimal doses of statins. <ref name="Yan-2006">{{Cite journal  | last1 = Yan | first1 = AT. | last2 = Yan | first2 = RT. | last3 = Tan | first3 = M. | last4 = Hackam | first4 = DG. | last5 = Leblanc | first5 = KL. | last6 = Kertland | first6 = H. | last7 = Tsang | first7 = JL. | last8 = Jaffer | first8 = S. | last9 = Kates | first9 = ML. | title = Contemporary management of dyslipidemia in high-risk patients: targets still not met. | journal = Am J Med | volume = 119 | issue = 8 | pages = 676-83 | month = Aug | year = 2006 | doi = 10.1016/j.amjmed.2005.11.015 | PMID = 16887414 }}</ref>  With data demonstrating that a lower limit for LDL-C reduction may not be applicable (particularly that values lower than those achieved with statins alone are associated with a further reduction in cardiovascular events<ref name=ewr>http://www.acc.org/latest-in-cardiology/clinical-trials/2014/11/18/16/25/improve-it</ref>), and given the 5-10% rate of statin-associated myalgia that has been linked to higher doses, as well as more potent statins, there seems to be a growing need for new therapeutics that effectively and safely reduce LDL cholesterol, and are associated with a reduction in cardiovascular events. <ref name="pmid19528564">{{cite journal| author=Joy TR, Hegele RA| title=Narrative review: statin-related myopathy. | journal=Ann Intern Med | year= 2009 | volume= 150 | issue= 12 | pages= 858-68 | pmid=19528564 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19528564  }} </ref>
 ==Investigational Therapies==
-===Inhibition of Apolipoprotein B Production===
+===PCSK9 Inhibitiors===
-Apolipoprotein B (apo B) is a large protein that is present in all atherogenic lipoproteins i.e., [[VLDL]], [[LDL]], [[IDL]].  There is a single copy of apo B-100 in all these lipoproteins, therefore plasma levels of apo B-100 is proportionate to the concentration of circulating atherogenic lipoproteins and a predictor of cardiovascular risk.<ref>{{Cite journal  | last1 = van der Steeg | first1 = WA. | last2 = Boekholdt | first2 = SM. | last3 = Stein | first3 = EA. | last4 = El-Harchaoui | first4 = K. | last5 = Stroes | first5 = ES. | last6 = Sandhu | first6 = MS. | last7 = Wareham | first7 = NJ. | last8 = Jukema | first8 = JW. | last9 = Luben | first9 = R. | title = Role of the apolipoprotein B-apolipoprotein A-I ratio in cardiovascular risk assessment: a case-control analysis in EPIC-Norfolk. | journal = Ann Intern Med | volume = 146 | issue = 9 | pages = 640-8 | month = May | year = 2007 | doi =  | PMID = 17470832 }}</ref>  From the apoB gene, the liver synthesizes apo B-100; and the intestine synthesizes apo B-48 which is required for chylomicron assemly and fat absorption.  The apo B-100 serves two functions - provides structural stability to the circulating lipoproteins as well as acts as a ligand for LDL receptors (LDLR).  The removal of LDL from the plasma involves the binding of apo B to LDLR, then, the resulting apo B-100-LDLR complex gets internalized into the [[liver]] for processing.<ref name="Hussain-1999">{{Cite journal  | last1 = Hussain | first1 = MM. | last2 = Strickland | first2 = DK. | last3 = Bakillah | first3 = A. | title = The mammalian low-density lipoprotein receptor family. | journal = Annu Rev Nutr | volume = 19 | issue =  | pages = 141-72 | month =  | year = 1999 | doi = 10.1146/annurev.nutr.19.1.141 | PMID = 10448520 }}</ref>  Mutations that lower the affinity of apo B-100 for LDLR result in decreased clearance of LDLs, a condition known as familial defective apo B with an increased risk of atherosclerotic cardiovascular diseases.<ref name="Humphries-2006">{{Cite journal  | last1 = Humphries | first1 = SE. | last2 = Whittall | first2 = RA. | last3 = Hubbart | first3 = CS. | last4 = Maplebeck | first4 = S. | last5 = Cooper | first5 = JA. | last6 = Soutar | first6 = AK. | last7 = Naoumova | first7 = R. | last8 = Thompson | first8 = GR. | last9 = Seed | first9 = M. | title = Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. | journal = J Med Genet | volume = 43 | issue = 12 | pages = 943-9 | month = Dec | year = 2006 | doi = 10.1136/jmg.2006.038356 | PMID = 17142622 }}</ref><ref name="Marsh-2002">{{Cite journal  | last1 = Marsh | first1 = JB. | last2 = Welty | first2 = FK. | last3 = Lichtenstein | first3 = AH. | last4 = Lamon-Fava | first4 = S. | last5 = Schaefer | first5 = EJ. | title = Apolipoprotein B metabolism in humans: studies with stable isotope-labeled amino acid precursors. | journal = Atherosclerosis | volume = 162 | issue = 2 | pages = 227-44 | month = Jun | year = 2002 | doi =  | PMID = 11996942 }}</ref>  In contrast, mutations in apo B that decrease its translation or secretion, or increase its breakdown have been demonstrated to reduce the circulating LDL-C and improve cardiovascular risk.<ref name="Schonfeld-2005">{{Cite journal  | last1 = Schonfeld | first1 = G. | last2 = Lin | first2 = X. | last3 = Yue | first3 = P. | title = Familial hypobetalipoproteinemia: genetics and metabolism. | journal = Cell Mol Life Sci | volume = 62 | issue = 12 | pages = 1372-8 | month = Jun | year = 2005 | doi = 10.1007/s00018-005-4473-0 | PMID = 15818469 }}</ref>
+The function of PCSK9 was first described in 2003 when a gain-of-function mutation of PCSK9 gene (leading to increased activity) was associated with [[familial hypercholesterolemia]] in 4 french families.<ref name=abifadel>{{cite journal | author = Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C | title = Mutations in PCSK9 cause autosomal dominant hypercholesterolemia | journal = Nat. Genet. | volume = 34 | issue = 2 | pages = 154–6 | year = 2003 | month = June|pmid = 12730697 | doi = 10.1038/ng1161 }}</ref>  The association was further clarified in 2005 after the discovery of loss-of-function mutations of PCSK9 in patients with low [[LDL-C]]. This loss-of-function was linked to a 40% reduction in plasma levels of [[LDL-C]] in the studied population.<ref name="Cohen-2005">{{Cite journal  | last1 = Cohen | first1 = J. | last2 = Pertsemlidis | first2 = A. | last3 = Kotowski | first3 = IK. | last4 = Graham | first4 = R. | last5 = Garcia | first5 = CK. | last6 = Hobbs | first6 = HH. | title = Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. | journal = Nat Genet | volume = 37 | issue = 2 | pages = 161-5 | month = Feb | year = 2005 | doi = 10.1038/ng1509 | PMID = 15654334 }}</ref> PCSK9 has a major role in the metabolism of hepatic cholesterol.  It is a serine protease that binds to the epidermal growth factor-like repeat A (EGF-A) domain of the [[low-density lipoprotein]] receptor (LDLR), inducing LDLR degradation in the lysosomes.  Reduced LDL receptor levels result in decreased metabolism of [[low density lipoprotein]] (LDL), which could lead to hypercholesterolemia.<ref name=uendo>*{{cite web | url =http://www.uendocrine.com/presentations/hyperlipidemia/the-evolving-role-of-pcsk9-modulation-in-the-regulation-of-ldl-cholesterol| title = The Evolving Role of PCSK9 Modulation in the Regulation of LDL-Cholesterol |author = | authorlink = | coauthors = | date = 2012-11-11 }}</ref>  The [[Sterol regulatory element binding protein|sterol regulatory element-binding protein-2 (SREBP-2)]], which is activated in the presence of low intracellular levels of cholesterol, also induces the expression of PCSK9, thereby increasing the amount of circulating LDL-cholesterol.<ref name="Maxwell-2003">{{Cite journal  | last1 = Maxwell | first1 = KN. | last2 = Soccio | first2 = RE. | last3 = Duncan |first3 = EM. | last4 = Sehayek | first4 = E. | last5 = Breslow | first5 = JL. | title = Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. | journal = J Lipid Res | volume = 44 | issue = 11 | pages = 2109-19 | month = Nov | year = 2003 | doi = 10.1194/jlr.M300203-JLR200 | PMID = 12897189 }}</ref>  Several drugs have been investigated for the inhibition of PCSK9, and have demonstrated a more potent lowering of LDL cholesterol levels than the current available drugs. Phase II and phase III trials have demonstrated good tolerability and efficacy in lowering LDL choleterol, with exploratory analyses demonstrating a reduction in cardiovascular events<ref name="pmid25773607">{{cite journal| author=Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J et al.| title=Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events. | journal=N Engl J Med | year= 2015 | volume=  | issue=  | pages=  | pmid=25773607 | doi=10.1056/NEJMoa1500858 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25773607  }} </ref>. Although it is biologically plausible that this reduction in LDL would also lead to a reduction in atherothrombotic events, additional clinical trials are ongoing to determine the efficacy of PCSK9 inhibitors in improving CV outcomes.<ref name=lopez>{{cite journal | author = Lopez D|title = Inhibition of PCSK9 as a novel strategy for the treatment of hypercholesterolemia | journal = Drug News Perspect. | volume = 21|issue = 6 | pages = 323–30 | year = 2008 | pmid = 18836590 |doi = 10.1358/dnp.2008.21.6.1246795 }}</ref><ref name=steinberg>{{cite journal|author = Steinberg D, Witztum JL | title = Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 106 | issue = 24 | pages = 9546–7 | year = 2009 | month = June | pmid = 19506257 | pmc = 2701045|doi = 10.1073/pnas.0904560106 }}</ref><ref name=mayer>{{cite journal | author = Mayer G, Poirier S, Seidah NG | title = Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels | journal = J. Biol. Chem. | volume = 283|issue = 46 | pages = 31791–801 | year = 2008 | month = November | pmid = 18799458 | doi = 10.1074/jbc.M805971200 }}</ref><ref name=bms>{{cite web | url =http://www.fiercebiotech.com/press-releases/bristol-myers-squibb-selects-isis-drug-targeting-pcsk9-development-candidate-preventi| title = Bristol-Myers Squibb selects Isis drug targeting PCSK9 as development candidate for prevention and treatment of cardiovascular disease | author = | authorlink = | coauthors = |date = 2008-04-08  | format = | work = Press Release | publisher = FierceBiotech | pages =| language = | archiveurl = | archivedate = | quote = | accessdate = 2010-09-18 }}</ref>
-The DNA contains two strands - 'sense' and 'antisense' which run complementary to each other.  The antisense strand encodes a sequence of events that initiates protein synthesis and production of messenger RNA (mRNA) which later serves as a template for protein synthesis through a process called translation.  Antisense oligoneucleotides (ASOs) are short, deoxyribonucleotide strands which bind to the targeted mRNAs to inhibit gene expression.  They can inhibit mRNA translation and mRNA splicing leading to its enzymatic degradation by [[ribonuclease]] (RNAse H or argonaute 2); inhibit translation or prevent the maturation of mRNA.<ref name="Bennett-2010">{{Cite journal  | last1 = Bennett | first1 = CF. | last2 = Swayze | first2 = EE. | title = RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. | journal = Annu Rev Pharmacol Toxicol | volume = 50 | issue =  | pages = 259-93 | month =  | year = 2010 | doi = 10.1146/annurev.pharmtox.010909.105654 | PMID = 20055705 }}</ref>
+{{Gallery
+|width=550
+|height=550
+|align=center
+|File:PCSK9 function 01.jpg|PCSK9 Function
+|File:Pharmacologic-interventions-for-PCSK9.jpg|Pharmacologic Interventions for PCSK9 inhibition
+}}
-ISIS 301012 or mipomersen, by ISIS Pharmaceuticals, is a second-generation 20 nucleotide ASO which selectively inhibits apo B gene expression via RNAse H activation.<ref name="Ito-2007">{{Cite journal  | last1 = Ito | first1 = MK. | title = ISIS 301012 gene therapy for hypercholesterolemia: sense, antisense, or nonsense? | journal = Ann Pharmacother | volume = 41 | issue = 10 | pages = 1669-78 | month = Oct | year = 2007 | doi = 10.1345/aph.1K065 | PMID = 17848425 }}</ref>  Phases I and II clinical trials have demonstrated a dose-dependent reduction of plasma apo B levels by 40% and up to 50% reduction in LDL-C of a subcutaneously administered ISIS-301012 or mipomersen, even with a defective LDLR.<ref name="Kastelein-2006">{{Cite journal  | last1 = Kastelein | first1 = JJ. | last2 = Wedel | first2 = MK. | last3 = Baker | first3 = BF. | last4 = Su | first4 = J. | last5 = Bradley | first5 = JD. | last6 = Yu | first6 = RZ. | last7 = Chuang | first7 = E. | last8 = Graham | first8 = MJ. | last9 = Crooke | first9 = RM. | title = Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B. | journal = Circulation | volume = 114 | issue = 16 | pages = 1729-35 | month = Oct | year = 2006 | doi = 10.1161/CIRCULATIONAHA.105.606442 | PMID = 17030687 }}</ref><ref name="Akdim-2010">{{Cite journal  | last1 = Akdim | first1 = F. | last2 = Visser | first2 = ME. | last3 = Tribble | first3 = DL. | last4 = Baker | first4 = BF. | last5 = Stroes | first5 = ES. | last6 = Yu | first6 = R. | last7 = Flaim | first7 = JD. | last8 = Su | first8 = J. | last9 = Stein | first9 = EA. | title = Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. | journal = Am J Cardiol | volume = 105 | issue = 10 | pages = 1413-9 | month = May | year = 2010 | doi = 10.1016/j.amjcard.2010.01.003 | PMID = 20451687 }}</ref><ref name="Akdim-2011">{{Cite journal  | last1 = Akdim | first1 = F. | last2 = Tribble | first2 = DL. | last3 = Flaim | first3 = JD. | last4 = Yu | first4 = R. | last5 = Su | first5 = J. | last6 = Geary | first6 = RS. | last7 = Baker | first7 = BF. | last8 = Fuhr | first8 = R. | last9 = Wedel | first9 = MK. | title = Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia. | journal = Eur Heart J | volume = 32 | issue = 21 | pages = 2650-9 | month = Nov | year = 2011 | doi = 10.1093/eurheartj/ehr148 | PMID = 21593041 }}</ref> Furthermore, a phase III randomized clinical trial involving homozygous FH revealed a 15% elevation in HDL-C.<ref name="Raal-2010">{{Cite journal  | last1 = Raal | first1 = FJ. | last2 = Santos | first2 = RD. | last3 = Blom | first3 = DJ. | last4 = Marais | first4 = AD. | last5 = Charng | first5 = MJ. | last6 = Cromwell | first6 = WC. | last7 = Lachmann | first7 = RH. | last8 = Gaudet | first8 = D. | last9 = Tan | first9 = JL. | title = Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. | journal = Lancet | volume = 375 | issue = 9719 | pages = 998-1006 | month = Mar | year = 2010 | doi = 10.1016/S0140-6736(10)60284-X | PMID = 20227758 }}</ref>  Despite its efficacy in lowering LDL-C, its approval have been hampered with the development of adverse effects - injection site reactions (80-100% of patients), flu-like illness, and 3-fold elevation in liver transaminases (15%).
-===PCSK9 Inhibition===
+''For more information regarding this approach to lipid management, '''click [[PCSK9|here]].'''''<br>
-PCSK9 has a major role in the metabolism of hepatic cholesterol.  It is a serine protease which binds to the epidermal growth factor-like repeat A (EGF-A) domain of the [[low-density lipoprotein]] receptor (LDLR), inducing LDLR degradation in the lysosomes.  Reduced LDL receptor levels result in decreased metabolism of [[low density lipoprotein]] (LDL), which could lead to hypercholesterolemia.<ref name=uendo>*{{cite web | url =http://www.uendocrine.com/presentations/hyperlipidemia/the-evolving-role-of-pcsk9-modulation-in-the-regulation-of-ldl-cholesterol| title = The Evolving Role of PCSK9 Modulation in the Regulation of LDL-Cholesterol |author = | authorlink = | coauthors = | date = 2012-11-11 }}</ref>  The [[Sterol regulatory element binding protein|sterol regulatory element-binding protein-2 (SREBP-2)]], which is activated in the presence of low intracellular levels of cholesterol, also induces the expression of PCSK9, thereby increasing the amount of circulating LDL-cholesterol.<ref name="Maxwell-2003">{{Cite journal  | last1 = Maxwell | first1 = KN. | last2 = Soccio | first2 = RE. | last3 = Duncan |first3 = EM. | last4 = Sehayek | first4 = E. | last5 = Breslow | first5 = JL. | title = Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. | journal = J Lipid Res | volume = 44 | issue = 11 | pages = 2109-19 | month = Nov | year = 2003 | doi = 10.1194/jlr.M300203-JLR200 | PMID = 12897189 }}</ref>
+''For details about specific agents, click on the following links:'' '''''[[Alirocumab]], [[Evolocumab]], [[Bococizumab]]'''''
-In addition to the effect on LDL-C, PCSK9 deficiency has also been shown to lower cardiovascular risk factors by reducing postprandial triglyceridemia.<ref name="Le May-2009">{{Cite journal  | last1 = Le May | first1 = C. | last2 = Kourimate | first2 = S. | last3 = Langhi | first3 = C. | last4 = Chétiveaux |first4 = M. | last5 = Jarry | first5 = A. | last6 = Comera | first6 = C. | last7 = Collet | first7 = X. | last8 = Kuipers | first8 = F. | last9 = Krempf |first9 = M. | title = Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia. | journal = Arterioscler Thromb Vasc Biol | volume = 29 | issue = 5 | pages = 684-90 | month = May | year = 2009 | doi = 10.1161/ATVBAHA.108.181586 | PMID = 19265033 }}</ref>  In another study, PCSK9-deficient mice were also demonstrated to have a reduced lymphatic apoB secretion,<ref name="Sun-2012">{{Cite journal  | last1 = Sun | first1 = H.| last2 = Samarghandi | first2 = A. | last3 = Zhang | first3 = N. | last4 = Yao | first4 = Z. | last5 = Xiong | first5 = M. | last6 = Teng | first6 = BB. |title = Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor. | journal = Arterioscler Thromb Vasc Biol|volume = 32 | issue = 7 | pages = 1585-95 | month = Jul | year = 2012 | doi = 10.1161/ATVBAHA.112.250043 | PMID = 22580899 }}</ref> as well as an increased ability to clear [[chylomicrons]].
-For more information regarding this novel approach to lipid management, Click [[PCSK9|here]].
+===Microsomal Triglyceride Transfer Protein (MTP) Inhibition===
+[[Microsomal triglyceride transfer protein]] is an endosomal protein found in the [[hepatocytes]] and intestinal enterocytes. It catalyses the transfer of cholesterol esters and [[triglycerides]] to nascent apo B, leading to the formation of [[chylomicron]] and [[VLDL]] in the intestine and hepatocyte, respectively.<ref name="Wetterau-1997">{{Cite journal | last1 = Wetterau | first1 = JR. | last2 = Lin | first2 = MC. | last3 = Jamil | first3 = H. | title = Microsomal triglyceride transfer protein. | journal = Biochim Biophys Acta | volume = 1345 | issue = 2 | pages = 136-50 | month = Apr | year = 1997 | doi = |PMID = 9106493 }}</ref> Chylomicrons and other apo-B48-containing remnant lipoproteins are essential for intestinal fat absorption and its transfer to peripheral tissues. Mutations of the MTTP gene leads to a condition known as [[abetalipoproteinemia]], which causes an absence of apo-B-containing lipoproteins and very low levels of [[LDL-C]] and [[triglycerides]].<ref name="Sharp-1993">{{Cite journal | last1 = Sharp | first1 = D. | last2 = Blinderman |first2 = L. | last3 = Combs | first3 = KA. | last4 = Kienzle | first4 = B. | last5 = Ricci | first5 = B. | last6 = Wager-Smith | first6 = K. | last7 = Gil |first7 = CM. | last8 = Turck | first8 = CW. | last9 = Bouma | first9 = ME. | title = Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia. | journal = Nature | volume = 365 | issue = 6441 | pages = 65-9 | month = Sep | year = 1993 | doi = 10.1038/365065a0 |PMID = 8361539 }}</ref><ref name="Rader-1993">{{Cite journal | last1 = Rader | first1 = DJ. | last2 = Brewer | first2 = HB. | title = Abetalipoproteinemia. New insights into lipoprotein assembly and vitamin E metabolism from a rare genetic disease. | journal = JAMA | volume = 270 | issue = 7 | pages = 865-9 |month = Aug | year = 1993 | doi = | PMID = 8340987 }}</ref> Individuals with this recessive condition have severe intestinal malabsorption of fat and fat-soluble vitamins (A, D, E, K) manifesting as [[fatty liver]], [[Nyctalopia|night-blindness]], [[rickets]] or [[osteomalacia]], [[neuropathy]], [[ataxia]], and [[coagulopathy]].
-===Microsomal Triglyceride Transfer Protein (MTP) Inhibition===
+Several MTP inhibitors are being investigated:
-[[Microsomal triglyceride transfer protein]] is an endosomal protein found in the [[hepatocytes]] and intestinal enterocytes. It catalyses the transfer of cholesterol esters and [[triglycerides]] to nascent apo B, leading to the formation of [[chylomicron]] and [[VLDL]] in the intestine and hepatocyte respectively.<ref name="Wetterau-1997">{{Cite journal | last1 = Wetterau | first1 = JR. | last2 = Lin | first2 = MC. | last3 = Jamil | first3 = H. | title = Microsomal triglyceride transfer protein. | journal = Biochim Biophys Acta | volume = 1345 | issue = 2 | pages = 136-50 | month = Apr | year = 1997 | doi = |PMID = 9106493 }}</ref> Chylomicrons and other apo-B48-containing remnant lipoproteins are essential for intestinal fat absorption and its transfer to peripheral tissues. Mutations of the MTTP gene leads to a condition known as [[abetalipoproteinemia]], which causes an absence of apo-B-containing lipoproteins and very low levels of [[LDL-C]] and [[triglycerides]].<ref name="Sharp-1993">{{Cite journal | last1 = Sharp | first1 = D. | last2 = Blinderman |first2 = L. | last3 = Combs | first3 = KA. | last4 = Kienzle | first4 = B. | last5 = Ricci | first5 = B. | last6 = Wager-Smith | first6 = K. | last7 = Gil |first7 = CM. | last8 = Turck | first8 = CW. | last9 = Bouma | first9 = ME. | title = Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia. | journal = Nature | volume = 365 | issue = 6441 | pages = 65-9 | month = Sep | year = 1993 | doi = 10.1038/365065a0 |PMID = 8361539 }}</ref><ref name="Rader-1993">{{Cite journal | last1 = Rader | first1 = DJ. | last2 = Brewer | first2 = HB. | title = Abetalipoproteinemia. New insights into lipoprotein assembly and vitamin E metabolism from a rare genetic disease. | journal = JAMA | volume = 270 | issue = 7 | pages = 865-9 |month = Aug | year = 1993 | doi = | PMID = 8340987 }}</ref> Individuals with this recessive condition have severe intestinal malabsorption of fat and fat-soluble vitamins (A, D, E, K) manifesting as [[fatty liver]], [[Nyctalopia|night-blindness]], [[rickets]] or [[osteomalacia]], [[neuropathy]], [[ataxia]], and [[coagulopathy]].
+* Non-intestinal-specific agents
+**'''Lomitapide''' (AEGR-427, previously known as BMS-201038 - Bristol-Myers-Squibb) by Aegerion Pharmaceuticals
+**'''Implitapide''' (formerly AEGR-427 or Bayer BAY-13-9952)
+**'''CP-34086''' by Pfizer
+* Intestinal-specific agents
+**'''Dirlotapide''' by Pfizer
+**'''JTT-130''' and '''SLx-4090''' by Surface Logix.
+Early clinical trials that enrolled patients with homozygous [[familial hypercholesterolemia]] demonstrated up to 50% reductions in total cholesterol, LDL-C and apo B with MTP inhibition.<ref name="Cuchel-2007">{{Cite journal | last1 = Cuchel | first1 = M. | last2 = Bloedon | first2 = LT. | last3 = Szapary | first3 = PO. | last4 = Kolansky | first4 = DM. | last5 = Wolfe |first5 = ML. | last6 = Sarkis | first6 = A. | last7 = Millar | first7 = JS. | last8 = Ikewaki | first8 = K. | last9 = Siegelman | first9 = ES. | title = Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. | journal = N Engl J Med | volume = 356 | issue = 2 | pages = 148-56 |month = Jan | year = 2007 | doi = 10.1056/NEJMoa061189 | PMID = 17215532 }}</ref> However, higher doses were associated with transient elevations in liver transaminases and hepatic fat accumulation. Further developments of CP-34086 and implitapide have been placed on hold due to their hepatic adverse effects. Intestinal-specific agents such as dirlotapide, JTT-130, and SLx-4090 were developed to prevent the hepatic effects of the non-specific agents. Thus far, these agents are still early in human clinical trials (except dirlotapide), but several reports have demonstrated significant reductions in postprandial triglyceridemia and total cholesterol in preclinical studies.<ref name="Li-2007">{{Cite journal | last1 = Li | first1 = J. | last2 = Bronk | first2 = BS. | last3 = Dirlam | first3 = JP. | last4 = Blize | first4 = AE. | last5 = Bertinato | first5 = P. | last6 = Jaynes | first6 = BH. | last7 = Hickman | first7 = A. |last8 = Miskell | first8 = C. | last9 = Pillai | first9 = UA. | title = In vitro and in vivo profile of 5-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid benzylmethyl carbamoylamide (dirlotapide), a novel potent MTP inhibitor for obesity. | journal = Bioorg Med Chem Lett | volume = 17 |issue = 7 | pages = 1996-9 | month = Apr | year = 2007 | doi = 10.1016/j.bmcl.2007.01.018 | PMID = 17276061 }}</ref> Intestinal-specific MTP inhibitors may be effective in treating [[hyperchylomicronemia]] but their efficacy as [[LDL-C]] lowering agents is uncertain.
+[[File:MTP Inhibitors.jpg|500px|center|MTP Inhibitors]]
+<font size="1"><center>''Adapted from Nature Reviews Cardiology, 8(5): 253-265 (May 2011).<ref name="Brautbar-2011">{{Cite journal  | last1 = Brautbar | first1 = A. | last2 = Ballantyne | first2 = CM. | title = Pharmacological strategies for lowering LDL cholesterol: statins and beyond. | journal = Nat Rev Cardiol | volume = 8 | issue = 5 | pages = 253-65 | month = May | year = 2011 | doi = 10.1038/nrcardio.2011.2 | PMID = 21321561 }}</ref>''</center></font>
+===Apolipoprotein B Inhibitors===
+Apolipoprotein B (apo B) is a large protein that is present in all atherogenic lipoproteins i.e., [[VLDL]], [[LDL]], [[IDL]].  There is a single copy of apo B-100 in all these lipoproteins, therefore, plasma levels of apo B-100 are proportionate to the concentration of circulating atherogenic lipoproteins and are associated with a higher cardiovascular risk.<ref>{{Cite journal  | last1 = van der Steeg | first1 = WA. | last2 = Boekholdt | first2 = SM. | last3 = Stein | first3 = EA. | last4 = El-Harchaoui | first4 = K. | last5 = Stroes | first5 = ES. | last6 = Sandhu | first6 = MS. | last7 = Wareham | first7 = NJ. | last8 = Jukema | first8 = JW. | last9 = Luben | first9 = R. | title = Role of the apolipoprotein B-apolipoprotein A-I ratio in cardiovascular risk assessment: a case-control analysis in EPIC-Norfolk. | journal = Ann Intern Med | volume = 146 | issue = 9 | pages = 640-8 | month = May | year = 2007 | doi =  | PMID = 17470832 }}</ref>  Apo B exists in two main isoforms, apo B100 and apo B48. The liver synthesizes apo B-100, whereas the small intestine synthesizes apo B48. Apo B100 serves two main functions - (1) it provides structural stability to the circulating lipoproteins, and (2) it acts as a ligand for LDL receptors (LDLR). On the other hand, apo B48 is a unique structural protein of chylomicrons that originate from the small intestine. The removal of LDL particles from the plasma involves the binding of apo B to LDLR, then, the resulting apo B-100-LDLR complex gets internalized into the hepatocyte for processing.<ref name="Hussain-1999">{{Cite journal  | last1 = Hussain | first1 = MM. | last2 = Strickland | first2 = DK. | last3 = Bakillah | first3 = A. | title = The mammalian low-density lipoprotein receptor family. | journal = Annu Rev Nutr | volume = 19 | issue =  | pages = 141-72 | month =  | year = 1999 | doi = 10.1146/annurev.nutr.19.1.141 | PMID = 10448520 }}</ref>  Mutations that lower the affinity of apo B-100 for LDLR result in decreased clearance of LDLs, a condition known as familial defective apo B, which is associated with an increased risk of atherosclerotic cardiovascular diseases.<ref name="pmid2280177">{{cite journal| author=Innerarity TL, Mahley RW, Weisgraber KH, Bersot TP, Krauss RM, Vega GL et al.| title=Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia. | journal=J Lipid Res | year= 1990 | volume= 31 | issue= 8 | pages= 1337-49 | pmid=2280177 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2280177  }} </ref>  In contrast, mutations in apo B that decrease its translation or secretion have been demonstrated to reduce circulating LDL-C and improve cardiovascular risk.<ref name="Schonfeld-2005">{{Cite journal  | last1 = Schonfeld | first1 = G. | last2 = Lin | first2 = X. | last3 = Yue | first3 = P. | title = Familial hypobetalipoproteinemia: genetics and metabolism. | journal = Cell Mol Life Sci | volume = 62 | issue = 12 | pages = 1372-8 | month = Jun | year = 2005 | doi = 10.1007/s00018-005-4473-0 | PMID = 15818469 }}</ref> All of these observations have led to the development of therapeutic strategies that target Apo-B for the reduction of LDL cholesterol.
-Many MTP inhibitors are being investigated, including non-intestinal specific agents such as lomitapide (AEGR-427, previously known as BMS-201038 - Bristol-Myers-Squibb) by Aegerion Pharmaceuticals, implitapide (formerly AEGR-427 or Bayer BAY-13-9952), and CP-34086 by Pfizer; intestinal specific agents such as dirlotapide (by Pfizer), JTT-130, and SLx-4090 by Surface Logix. A clinical trial assessing the efficacy of lometapide in 6 patients with homozygous [[familial hypercholesterolemia]] demonstrated a 58%, 51%, and 55% reductions in total cholesterol, LDL-C and apo B respectively.<ref name="Cuchel-2007">{{Cite journal | last1 = Cuchel | first1 = M. | last2 = Bloedon | first2 = LT. | last3 = Szapary | first3 = PO. | last4 = Kolansky | first4 = DM. | last5 = Wolfe |first5 = ML. | last6 = Sarkis | first6 = A. | last7 = Millar | first7 = JS. | last8 = Ikewaki | first8 = K. | last9 = Siegelman | first9 = ES. | title = Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. | journal = N Engl J Med | volume = 356 | issue = 2 | pages = 148-56 |month = Jan | year = 2007 | doi = 10.1056/NEJMoa061189 | PMID = 17215532 }}</ref> Higher doses were associated with a transient elevation of liver transaminases and hepatic fat. A double-blinded, randomized controlled trial involving 84 subjects further demonstrated a 20%, 30%, and 46% reduction in LDL-C in [[ezetimide]] alone, lometapide alone, and lometapide plus [[ezetimide]] combination study groups respectively, further emphasizing the beneficial effect of lometapide monotherapy or in combination therapy was associated with significantly greater reductions in LDL-C levels compared with ezetimibe monotherapy.<ref name="Samaha-2008">{{Cite journal | last1 = Samaha | first1 = FF. | last2 = McKenney | first2 = J. | last3 = Bloedon | first3 = LT. | last4 = Sasiela | first4 = WJ. | last5 = Rader | first5 = DJ. | title = Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. | journal = Nat Clin Pract Cardiovasc Med | volume = 5 | issue = 8 | pages = 497-505 | month = Aug | year = 2008 | doi = 10.1038/ncpcardio1250 | PMID = 18506154 }}</ref>
+=====ISIS 301012 or mipomersen=====
-Another MTP inhibitor, CP-34086 by Pfizer, showed a 47% and 72% reduction in total cholesterol and LDL-C in healthy human volunteers respectively.<ref name="Chandler-2003">{{Cite journal | last1 = Chandler | first1 = CE. | last2 = Wilder | first2 = DE. | last3 = Pettini | first3 = JL. | last4 = Savoy | first4 = YE. | last5 = Petras | first5 = SF. | last6 = Chang | first6 = G. | last7 = Vincent | first7 = J. | last8 = Harwood | first8 = HJ. | title = CP-346086: an MTP inhibitor that lowers plasma cholesterol and triglycerides in experimental animals and in humans. | journal = J Lipid Res | volume = 44 | issue = 10 |pages = 1887-901 | month = Oct | year = 2003 | doi = 10.1194/jlr.M300094-JLR200 | PMID = 12837854 }}</ref> Currently, further developments of CP-34086 and implitapide have been placed on hold due to their hepatic adverse effects.
-Intestinal-specific agents such as dirlotapide, JTT-130, and SLx-4090 were developed to prevent the hepatic effects of the non-specific agents. Thus far, they are still early in human clinical trials (except dirlotapide) but there were reports of significant reductions in postprandial [[triglyceridemia]] and total cholesterol in preclinical animal studies with dirlotapide.<ref name="Li-2007">{{Cite journal | last1 = Li | first1 = J. | last2 = Bronk | first2 = BS. | last3 = Dirlam | first3 = JP. | last4 = Blize | first4 = AE. | last5 = Bertinato | first5 = P. | last6 = Jaynes | first6 = BH. | last7 = Hickman | first7 = A. |last8 = Miskell | first8 = C. | last9 = Pillai | first9 = UA. | title = In vitro and in vivo profile of 5-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid benzylmethyl carbamoylamide (dirlotapide), a novel potent MTP inhibitor for obesity. | journal = Bioorg Med Chem Lett | volume = 17 |issue = 7 | pages = 1996-9 | month = Apr | year = 2007 | doi = 10.1016/j.bmcl.2007.01.018 | PMID = 17276061 }}</ref> Intestinal-specific MTP inhibitors may be effective in treating [[hyperchylomicronemia]] but their efficacy as [[LDL-C]] lowering agents is uncertain.
+ISIS 301012 or mipomersen, by ISIS Pharmaceuticals, is a second-generation 20 nucleotide antisense oligoneucleotide (ASO) which selectively inhibits apo B gene expression via RNAse H activation.<ref name="Ito-2007">{{Cite journal  | last1 = Ito | first1 = MK. | title = ISIS 301012 gene therapy for hypercholesterolemia: sense, antisense, or nonsense? | journal = Ann Pharmacother | volume = 41 | issue = 10 | pages = 1669-78 | month = Oct | year = 2007 | doi = 10.1345/aph.1K065 | PMID = 17848425 }}</ref>  ASOs are short, deoxyribonucleotide strands which bind to the targeted mRNAs to inhibit their translation leading to their enzymatic degradation by [[ribonuclease]] (RNAse H or argonaute 2), thus inhibiting gene expression.<ref name="Bennett-2010">{{Cite journal  | last1 = Bennett | first1 = CF. | last2 = Swayze | first2 = EE. | title = RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. | journal = Annu Rev Pharmacol Toxicol | volume = 50 | issue =  | pages = 259-93 | month =  | year = 2010 | doi = 10.1146/annurev.pharmtox.010909.105654 | PMID = 20055705 }}</ref> Phases I and II clinical trials of ISIS301012 have demonstrated a dose-dependent reduction in plasma apo B levels by approximately 40% and up to 50% reduction in LDL-C with subcutaneously administered ISIS-301012 or mipomersen, even among patients with defective LDLRs.<ref name="Kastelein-2006">{{Cite journal  | last1 = Kastelein | first1 = JJ. | last2 = Wedel | first2 = MK. | last3 = Baker | first3 = BF. | last4 = Su | first4 = J. | last5 = Bradley | first5 = JD. | last6 = Yu | first6 = RZ. | last7 = Chuang | first7 = E. | last8 = Graham | first8 = MJ. | last9 = Crooke | first9 = RM. | title = Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B. | journal = Circulation | volume = 114 | issue = 16 | pages = 1729-35 | month = Oct | year = 2006 | doi = 10.1161/CIRCULATIONAHA.105.606442 | PMID = 17030687 }}</ref><ref name="Akdim-2010">{{Cite journal  | last1 = Akdim | first1 = F. | last2 = Visser | first2 = ME. | last3 = Tribble | first3 = DL. | last4 = Baker | first4 = BF. | last5 = Stroes | first5 = ES. | last6 = Yu | first6 = R. | last7 = Flaim | first7 = JD. | last8 = Su | first8 = J. | last9 = Stein | first9 = EA. | title = Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. | journal = Am J Cardiol | volume = 105 | issue = 10 | pages = 1413-9 | month = May | year = 2010 | doi = 10.1016/j.amjcard.2010.01.003 | PMID = 20451687 }}</ref><ref name="Akdim-2011">{{Cite journal  | last1 = Akdim | first1 = F. | last2 = Tribble | first2 = DL. | last3 = Flaim | first3 = JD. | last4 = Yu | first4 = R. | last5 = Su | first5 = J. | last6 = Geary | first6 = RS. | last7 = Baker | first7 = BF. | last8 = Fuhr | first8 = R. | last9 = Wedel | first9 = MK. | title = Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia. | journal = Eur Heart J | volume = 32 | issue = 21 | pages = 2650-9 | month = Nov | year = 2011 | doi = 10.1093/eurheartj/ehr148 | PMID = 21593041 }}</ref> Furthermore, a randomized phase III trial that enrolled homozygous familial hypercholesterolemia patients demonstrated a 15% elevation in HDL-C.<ref name="Raal-2010">{{Cite journal  | last1 = Raal | first1 = FJ. | last2 = Santos | first2 = RD. | last3 = Blom | first3 = DJ. | last4 = Marais | first4 = AD. | last5 = Charng | first5 = MJ. | last6 = Cromwell | first6 = WC. | last7 = Lachmann | first7 = RH. | last8 = Gaudet | first8 = D. | last9 = Tan | first9 = JL. | title = Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. | journal = Lancet | volume = 375 | issue = 9719 | pages = 998-1006 | month = Mar | year = 2010 | doi = 10.1016/S0140-6736(10)60284-X | PMID = 20227758 }}</ref>  Despite its efficacy in lowering LDL-C, mipomersen did not receive approval due to a significant increase in adverse effects - injection site reactions (80-100% of patients), flu-like illness, and 3-fold elevation in liver transaminases (15%).
+[[File:Antisense RNA (1).jpg|500px|center|Antisense RNA]]
+<font size="1"><center>''Adapted from Nature Reviews Cardiology, 8(5): 253-265 (May 2011) and Pharmacology & Therapeutics, 135(1): 31-43 (July 2012)''<ref name="Brautbar-2011">{{Cite journal  | last1 = Brautbar | first1 = A. |last2 = Ballantyne | first2 = CM. | title = Pharmacological strategies for lowering LDL cholesterol: statins and beyond. | journal = Nat Rev Cardiol | volume = 8 | issue = 5 | pages = 253-65 | month = May | year = 2011 | doi = 10.1038/nrcardio.2011.2 | PMID = 21321561 }}</ref><ref name="Joy-2012">{{Cite journal  | last1 = Joy | first1 = TR. | title = Novel therapeutic agents for lowering low density lipoprotein cholesterol. | journal = Pharmacol Ther | volume = 135 | issue = 1 | pages = 31-43 | month = Jul | year = 2012 | doi = 10.1016/j.pharmthera.2012.03.005 | PMID = 22465160 }}</ref></center></font>
 ===Thyromimetics===
-The association between [[thyroid hormone]]s and [[cholesterol]] metabolism was first discovered by Mason in the 1930s,  and its use as a cholesterol lowering agent has been investigated in several studies.<ref name="STRISOWER-1954">{{Cite journal  | last1 = STRISOWER | first1 = B. | last2 = GOFMAN | first2 = JW. | last3 = GALIONI | first3 = EF. | last4 = ALMADA | first4 = AA. | last5 = SIMON | first5 = A. | title = Effect of thyroid extract on serum lipoproteins and serum cholesterol. | journal = Metabolism | volume = 3 | issue = 3 | pages = 218-27 | month = May | year = 1954 | doi =  | PMID = 13165045 }}</ref><ref name="STRISOWER-1959">{{Cite journal  | last1 = STRISOWER | first1 = B. | last2 = ELMLINGER | first2 = P. | last3 = GOFMAN | first3 = JW. | last4 = DELALLA | first4 = O. | title = The effect of 1-thyroxine on serum lipoprotein and cholesterol concentrations. | journal = J Clin Endocrinol Metab | volume = 19 | issue = 1 | pages = 117-26 | month = Jan | year = 1959 | doi =  | PMID = 13620737 }}</ref><ref name="HOLLISTER-1962">{{Cite journal  | last1 = HOLLISTER | first1 = LE. | last2 = ARONS | first2 = WL. | title = Effect of dextro-isomers of thyroid hormones on serum cholesterol levels in euthyroid hypercholesterolemic patients. | journal = Ann Intern Med | volume = 56 | issue =  | pages = 570-6 | month = Apr | year = 1962 | doi =  | PMID = 13908447 }}</ref>  However, their development had been hindered by the associated adverse cardiac effects, which was mainly due to the contamination of the investigated thyroid hormone, dextrothyroxine (DT4) with levothyroxine (LT4),<ref name="Brown-1986">{{Cite journal  | last1 = Brown | first1 = MS. | last2 = Goldstein | first2 = JL. | title = A receptor-mediated pathway for cholesterol homeostasis. | journal = Science | volume = 232 | issue = 4746 | pages = 34-47 | month = Apr | year = 1986 | doi =  | PMID = 3513311 }}</ref><ref name="Young-1984">{{Cite journal  | last1 = Young | first1 = WF. | last2 = Gorman | first2 = CA. | last3 = Jiang | first3 = NS. | last4 = Machacek | first4 = D. | last5 = Hay | first5 = ID. | title = L-thyroxine contamination of pharmaceutical D-thyroxine: probable cause of therapeutic effect. | journal = Clin Pharmacol Ther | volume = 36 | issue = 6 | pages = 781-7 | month = Dec | year = 1984 | doi =  | PMID = 6499357 }}</ref> and by the birth of [[statins]].
+The association between [[thyroid hormone]]s and [[cholesterol]] metabolism was first discovered in the 1930s,  and its use as a cholesterol lowering agent has been investigated in several studies.<ref name="STRISOWER-1954">{{Cite journal  | last1 = STRISOWER | first1 = B. | last2 = GOFMAN | first2 = JW. | last3 = GALIONI | first3 = EF. | last4 = ALMADA | first4 = AA. | last5 = SIMON | first5 = A. | title = Effect of thyroid extract on serum lipoproteins and serum cholesterol. | journal = Metabolism | volume = 3 | issue = 3 | pages = 218-27 | month = May | year = 1954 | doi =  | PMID = 13165045 }}</ref><ref name="STRISOWER-1959">{{Cite journal  | last1 = STRISOWER | first1 = B. | last2 = ELMLINGER | first2 = P. | last3 = GOFMAN | first3 = JW. | last4 = DELALLA | first4 = O. | title = The effect of 1-thyroxine on serum lipoprotein and cholesterol concentrations. | journal = J Clin Endocrinol Metab | volume = 19 | issue = 1 | pages = 117-26 | month = Jan | year = 1959 | doi =  | PMID = 13620737 }}</ref><ref name="HOLLISTER-1962">{{Cite journal  | last1 = HOLLISTER | first1 = LE. | last2 = ARONS | first2 = WL. | title = Effect of dextro-isomers of thyroid hormones on serum cholesterol levels in euthyroid hypercholesterolemic patients. | journal = Ann Intern Med | volume = 56 | issue =  | pages = 570-6 | month = Apr | year = 1962 | doi =  | PMID = 13908447 }}</ref>  However, the development of thyromimetic agents was set back by the associated increase in cardiovascular events, thought to be related to contamination of the thyromimetic agent investigated with levothyroxine (LT4), as well as the discovery of statins.<ref name="Brown-1986">{{Cite journal  | last1 = Brown | first1 = MS. | last2 = Goldstein | first2 = JL. | title = A receptor-mediated pathway for cholesterol homeostasis. | journal = Science | volume = 232 | issue = 4746 | pages = 34-47 | month = Apr | year = 1986 | doi =  | PMID = 3513311 }}</ref><ref name="Young-1984">{{Cite journal  | last1 = Young | first1 = WF. | last2 = Gorman | first2 = CA. | last3 = Jiang | first3 = NS. | last4 = Machacek | first4 = D. | last5 = Hay | first5 = ID. | title = L-thyroxine contamination of pharmaceutical D-thyroxine: probable cause of therapeutic effect. | journal = Clin Pharmacol Ther | volume = 36 | issue = 6 | pages = 781-7 | month = Dec | year = 1984 | doi =  | PMID = 6499357 }}</ref>
-The recent discovery of thyroid hormone receptors (TRs) have brought this approach back into existence.  There are two main TRs in humans:
+The discovery of thyroid hormone receptors (TRs) restored some of the investigations into thyromimetics for the reduction of LDL-C.  There are two main TRs in humans:
-* TRα receptors (TRα 1 & 2).  TRα 1 is predominantly in the muscles and adipose tissue; also mediates the cardiovascular responses to thyroid hormones such as [[tachycardia]].<ref name="Angelin-2010">{{Cite journal  | last1 = Angelin | first1 = B. | last2 = Rudling | first2 = M. | title = Lipid lowering with thyroid hormone and thyromimetics. | journal = Curr Opin Lipidol | volume = 21 | issue = 6 | pages = 499-506 | month = Dec | year = 2010 | doi = 10.1097/MOL.0b013e3283402e9c | PMID = 20935564 }}</ref>
+* TRα receptors (TRα 1 & 2). TRα 1 is predominantly in the muscles and adipose tissue; also mediates the cardiovascular responses to thyroid hormones such as [[tachycardia]].<ref name="Angelin-2010">{{Cite journal  | last1 = Angelin | first1 = B. | last2 = Rudling | first2 = M. | title = Lipid lowering with thyroid hormone and thyromimetics. | journal = Curr Opin Lipidol | volume = 21 | issue = 6 | pages = 499-506 | month = Dec | year = 2010 | doi = 10.1097/MOL.0b013e3283402e9c | PMID = 20935564 }}</ref>
 * TRβ receptors (TRβ 1 & 2). TRβ 1 is mainly in the liver and it regulates cholesterol homeostasis.<ref name="Angelin-2010">{{Cite journal  | last1 = Angelin | first1 = B. | last2 = Rudling | first2 = M. | title = Lipid lowering with thyroid hormone and thyromimetics. | journal = Curr Opin Lipidol | volume = 21 | issue = 6 | pages = 499-506 | month = Dec | year = 2010 | doi = 10.1097/MOL.0b013e3283402e9c | PMID = 20935564 }}</ref>  Therefore, the development of TRβ 1-specific thyromimetic would be a promising method of cholesterol management devoid of cardiac effects.<ref name="Gullberg-2002">{{Cite journal  | last1 = Gullberg | first1 = H. | last2 = Rudling | first2 = M. | last3 = Saltó | first3 = C. | last4 = Forrest | first4 = D. | last5 = Angelin | first5 = B. | last6 = Vennström | first6 = B. | title = Requirement for thyroid hormone receptor beta in T3 regulation of cholesterol metabolism in mice. | journal = Mol Endocrinol | volume = 16 | issue = 8 | pages = 1767-77 | month = Aug | year = 2002 | doi =  | PMID = 12145333 }}</ref><ref name="Johansson-1998">{{Cite journal  | last1 = Johansson | first1 = C. | last2 = Vennström | first2 = B. | last3 = Thorén | first3 = P. | title = Evidence that decreased heart rate in thyroid hormone receptor-alpha1-deficient mice is an intrinsic defect. | journal = Am J Physiol | volume = 275 | issue = 2 Pt 2 | pages = R640-6 | month = Aug | year = 1998 | doi =  | PMID = 9688704 }}</ref>
 Some of the proposed mechanisms of action of these agents include:
@@ Line 66: / Line 84: @@
 [[Sterol regulatory element binding protein]]s (SREBPs) are transcription factors required in the activation of genes involved in cholesterol and fatty acid biosynthesis.  Fatostatin, a diarylthiazole derivative, was observed to impair the activation of SREBPs, thereby decreasing the transcription of lipogenic genes in cells.<ref name="Kamisuki-2009">{{Cite journal  | last1 = Kamisuki | first1 = S. | last2 = Mao | first2 = Q. | last3 = Abu-Elheiga | first3 = L. | last4 = Gu | first4 = Z. | last5 = Kugimiya | first5 = A. | last6 = Kwon | first6 = Y. | last7 = Shinohara | first7 = T. | last8 = Kawazoe | first8 = Y. | last9 = Sato | first9 = S. | title = A small molecule that blocks fat synthesis by inhibiting the activation of SREBP. | journal = Chem Biol | volume = 16 | issue = 8 | pages = 882-92 | month = Aug | year = 2009 | doi = 10.1016/j.chembiol.2009.07.007 | PMID = 19716478 }}</ref>  More studies are required regarding the efficacy of this potential target in reducing circulating LDL-C since it also induces the expression of PCSK9 - a serine protease which promotes degradation of LDLR, thereby preventing the clearing of LDL particles from the plasma.
-==Table==
+==Summary Table==
 {| class="wikitable sortable" style="font-size:90%"
 ! '''Class'''
@@ Line 77: / Line 95: @@
 ! '''Published Clinical Trials'''
 |-
-|Inhibition of Apo B/Antisense oligonucleotides ||ISIS Pharmaceuticals ||ISIS-301012 or Mipomersen ||Inhibits apo B mRNA gene expression  ||Up to 50% reduction||Subcutaneous injection (SC) ||Injection site reactions, flu-like illness, 3-fold asymptomatic elevation of liver transaminases||I, II, III
+|Inhibition of Apo B/Antisense oligonucleotides ||ISIS Pharmaceuticals ||ISIS-301012 or Mipomersen ||Inhibits apo B mRNA gene expression  ||Up to 50% reduction||Subcutaneous injection (SC) ||Injection site reactions, flu-like illness, 3-fold asymptomatic elevation of liver transaminases||Phase I, II, III
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-|PCSK9 Inhibition|| Merck, Sanofi-Aventis–Regeneron, Pfizer–Rinat, Amgen, Santaris, Alnylam, Medicines company, ISIS, Adnexus, Roche/Genentech, Novartis ||AMG 145, SAR236553/REGN727, RN316, 1D05-IgG2, RG7652, LGT-209, 1B20, J10, J16, J17 ||Inhibition of PCSK9 which promotes degradation of LDLR||38% reduction in LDL-C in animal studies ||ASO (SC), monoclonal antibody (SC), SiRNA (IV)|| ||Phases I, II
+|PCSK9 Inhibition|| Merck, Sanofi-Aventis–Regeneron, Pfizer–Rinat, Amgen, Santaris, Alnylam, Medicines company, ISIS, Adnexus, Roche/Genentech, Novartis ||AMG 145, SAR236553/REGN727, RN316, 1D05-IgG2, RG7652, LGT-209, 1B20, J10, J16, J17 ||Inhibition of PCSK9 which promotes degradation of LDLR||38% reduction in LDL-C in animal studies ||ASO (SC), monoclonal antibody (SC), SiRNA (IV)|| ||Phase I, II, III
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-|MTP Inhibition ||Aegerion Pharmaceuticals, Pfizer, Surface Logix ||Intestinal non-specific (lometapide, implitapide, CP-34086); Intestinal-specific (SLx-4090, dirlotapide, JTT-130)||Inhibits [[Microsomal triglyceride transfer protein]] ||Lometapide (up to 50%), CP-34086 (up to 70%) ||PO ||Intestinal non-specific agents causes GI adverse effects, increases in hepatic fat||Lometapide (I, II, III), JTT-130 (I, II)
+|MTP Inhibition ||Aegerion Pharmaceuticals, Pfizer, Surface Logix ||Intestinal non-specific (lometapide, implitapide, CP-34086); Intestinal-specific (SLx-4090, dirlotapide, JTT-130)||Inhibits [[Microsomal triglyceride transfer protein]] ||Lometapide (up to 50%), CP-34086 (up to 70%) ||PO ||Intestinal non-specific agents causes GI adverse effects, increases in hepatic fat||Lometapide (Phase I, II, III), JTT-130 (Phase I, II)
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 |Thyromimetics ||Karo Bio AB ||DITPA, eprotirome, sobetirome (GC-1), MB07811, KB-141, T-0681 ||TRβ1-selective ||Up to 32% reduction of LDL-C||PO ||Adverse cardiac effects ||Phase II
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-|Squalene Synthase Inhibitors || || || || || || ||
+|Squalene Synthase Inhibitors ||Takeda ||TAK-475 ||Inhibits [[squalene synthase]] in the HMG CoA-Mevalonate pathway ||Up to 27% reduction in LDL-C|| || ||Phase II
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+|Inhibition of ACL and Activation of AMPK ||Esperion ||ETC-1002 ||Regulation of lipid and carbohydrate metabolic subtrates ||Up to 27% reduction in LDL-C|| ||No serious adverse effects ||Phase II
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+|Inhibition of SREBP-1 || ||Inhibition of SREBP-1 || Impair the activation of SREBPs, thereby decreasing the transcription of lipogenic genes in cells || || || ||
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v t e Lipids: lipoprotein metabolism
General	Chylomicron - HDL - LDL - IDL - VLDL - Lp(a)
Apolipoproteins	APOA (1, 2, 5) - APOB - APOC (1, 2, 3, 4) - APOD - APOE - APOH
Other	Lipoprotein lipase - Cholesterylester transfer protein ( Acetyl-CoA C-acyltransferase, LCAT) - LDL receptor - Microsomal triglyceride transfer protein - ABCA1 - Lecithin-cholesterol acyltransferase
see also disorders