High density lipoprotein future or investigational therapies: Difference between revisions
| Line 21: | Line 21: | ||
==Cholesterol Ester Transfer Protein (CETP) Inhibition== | ==Cholesterol Ester Transfer Protein (CETP) Inhibition== | ||
The goal of this therapy is to prevent the transfer of esterified cholesterol from HDL to triglyceride-rich lipoproteins in exchange for triglycerides. This method not only increased the cholesterol content per HDL particle, but also affects the compositions and serum levels of VLDL, VLDL remnants, and LDLs. The cardiovascular benefits of this therapy is unclear due to the failures observed with earlier trials - [[torcetrapid]] ([[ILLUMINATE Trial]]) and [[dalcetrapid]] ([[Dal-OUTCOMES Trial]]). [[ILLUMINATE Trial]] failed due to the observed off-targets effects on blood pressure which led to increased mortality in subjects.<ref name="pmid17984165">{{cite journal| author=Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M et al.| title=Effects of torcetrapib in patients at high risk for coronary events. | journal=N Engl J Med | year= 2007 | volume= 357 | issue= 21 | pages= 2109-22 | pmid=17984165 | doi=10.1056/NEJMoa0706628 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17984165 }} </ref> Despite a 31–40% elevation in HDL-C observed with [[dalcetrapib]], it failed to show a positive cardiovascular outcome in patients with ACS.<ref name="pmid23126252">{{cite journal| author=Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J et al.| title=Effects of dalcetrapib in patients with a recent acute coronary syndrome. | journal=N Engl J Med | year= 2012 | volume= 367 | issue= 22 | pages= 2089-99 | pmid=23126252 |doi=10.1056/NEJMoa1206797 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23126252 }} </ref> | |||
===CETi-1 Vaccine=== | ===CETi-1 Vaccine=== | ||
===JTT-705=== | ===JTT-705=== | ||
==De-lipidated HDL Infusions== | ==De-lipidated HDL Infusions== | ||
==HDL Mimetics== | ==HDL Mimetics== | ||
Revision as of 23:47, 19 September 2013
|
High Density Lipoprotein Microchapters |
|
Diagnosis |
|---|
|
Treatment |
|
Clinical Trials |
|
Case Studies |
|
High density lipoprotein future or investigational therapies On the Web |
|
American Roentgen Ray Society Images of High density lipoprotein future or investigational therapies |
|
FDA on High density lipoprotein future or investigational therapies |
|
CDC on High density lipoprotein future or investigational therapies |
|
High density lipoprotein future or investigational therapies in the news |
|
Blogs on High density lipoprotein future or investigational therapies |
|
Risk calculators and risk factors for High density lipoprotein future or investigational therapies |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
The association between HDL level and cardiovascular disease has been widely reported in the literature. In fact, 1 out of every 7 statin treated patients has residual cardiovascular disease,[1] which sheds light to the importance of developing new therapies targeting HDL quantity and quality in high risk patients.[2]
The Need
The importance of increasing serum levels and functionality of HDL-C in lowering residual cardiovascular risks in patients with acute coronary syndromes cannot be over-emphasized. First of all, some recent studies reported failures of orally active medications that increase serum levels of HDL-C to potentially improve cardiovascular outcomes, such as niacin in the AIM-HIGH Trial. This have shifted the focus of researchers to other targets of HDL therapy aimed at increasing the serum levels of HDL as well as its functionality i.e., cellular cholesterol efflux and HDL-mediated reverse cholesterol transport mechanisms. Secondly, since the available oral medications elevate HDL over weeks to months, there is the need for medications which rapidly improve outcomes during acute vascular events.
Direct Infusion of Apo A-1
This methods aim at directly increasing the serum levels of HDL through the infusion of reconstituted and recombinant preparations of HDLs (rHDLs). Recombinant HDLs are made from apo A-1 derived from cellular expression systems while recombinant HDLs are apo A-1 derived from human. Both preparations have been complexed with phospholipids. The reconstituted forms are relatively cheaper and easier to produce.
ApoA-1 Milano
Some individuals in rural Italy were identified with a genetic variant of apo A-1 which conferred some protection against atherosclerosis despite the presence of very low HDL levels (10-30 mg/dl), elevated plasma LDL, and moderate hypertriglyceridemia.[3] Studies indicated that intravenous infusion of recombinant apoA-I Milano (ETC-216) promoted regression of atherosclerotic lesions to a greater extent than wild type apo A-I as measured by intravascular ultrasound within 5 weeks of treatment.[4] However, further studies regarding these agents have been halted by procedural and manufactural difficulties.
CSL-112
CSL-112 (CSL Behring), a reformulated version of CSL-111, is a reconstituted HDL complexed with soybean phosphatidylcholine, and has been reported to cause up to 20-fold elevation in serum pre-Beta-1-HDL following a single infusion according to phase 1 trial.[5] Currently, there are pending results regarding phase 2a which was recently completed. ERASE Trial which examined the effect and tolerability of CSL-111, a precursor to CSL-112, showed regression of coronary atherosclerotic lesions in ACS patients but was discontinued due to abnormal liver transaminase elevations observed with the high-dosed group. However, there was no significant change in atheroma volume (measured by IVUS) despite a 64% increase in HDL and a 23% reduction in LDL.[6]
CER-001
Two ongoing trials from Cerenis Therapeutics are assessing the effects of CER-001, an engineered pre-beta-like HDL particle, on total coronary plaque volume (measured by IVUS) in patients with acute coronary syndrome - CHI-SQUARE Study, and on total carotid plaque volume in patients with homozygous familial hypercholesterolemia (measured by MRI) - MODE Study.
Cholesterol Ester Transfer Protein (CETP) Inhibition
The goal of this therapy is to prevent the transfer of esterified cholesterol from HDL to triglyceride-rich lipoproteins in exchange for triglycerides. This method not only increased the cholesterol content per HDL particle, but also affects the compositions and serum levels of VLDL, VLDL remnants, and LDLs. The cardiovascular benefits of this therapy is unclear due to the failures observed with earlier trials - torcetrapid (ILLUMINATE Trial) and dalcetrapid (Dal-OUTCOMES Trial). ILLUMINATE Trial failed due to the observed off-targets effects on blood pressure which led to increased mortality in subjects.[7] Despite a 31–40% elevation in HDL-C observed with dalcetrapib, it failed to show a positive cardiovascular outcome in patients with ACS.[8]
CETi-1 Vaccine
JTT-705
De-lipidated HDL Infusions
HDL Mimetics
ApoA-1 Mimetic Peptides
- D-4F and L-4F
ATI-5261 Synthetic Peptide
Endothelial Lipase Inhibitors
LCAT Modulators
Endocannabinoid Receptor Blockers
ApoA-1 Upregulators
RVX-208
Synthetic Liver X Receptor (LXR) Agonists
Synthetic FXR Agonists
Gene Therapy
References
- ↑ Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C; et al. (2005). "Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins". Lancet. 366 (9493): 1267–78. doi:10.1016/S0140-6736(05)67394-1. PMID 16214597. Review in: ACP J Club. 2006 May-Jun;144(3):62
- ↑ Mora S, Glynn RJ, Ridker PM (2013). "High-density lipoprotein cholesterol, size, particle number, and residual vascular risk after potent statin therapy". Circulation. 128 (11): 1189–97. doi:10.1161/CIRCULATIONAHA.113.002671. PMID 24002795.
- ↑ Sirtori, CR.; Calabresi, L.; Franceschini, G.; Baldassarre, D.; Amato, M.; Johansson, J.; Salvetti, M.; Monteduro, C.; Zulli, R. (2001). "Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study". Circulation. 103 (15): 1949–54. PMID 11306522. Unknown parameter
|month=ignored (help) - ↑ Nissen, SE.; Tsunoda, T.; Tuzcu, EM.; Schoenhagen, P.; Cooper, CJ.; Yasin, M.; Eaton, GM.; Lauer, MA.; Sheldon, WS. (2003). "Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial". JAMA. 290 (17): 2292–300. doi:10.1001/jama.290.17.2292. PMID 14600188. Unknown parameter
|month=ignored (help) - ↑ "http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851". Retrieved 16 September 2013. External link in
|title=(help) - ↑ Tardif JC, Grégoire J, L'Allier PL; et al. (2007). "Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial". JAMA : the Journal of the American Medical Association. 297 (15): 1675–82. doi:10.1001/jama.297.15.jpc70004. PMID 17387133. Unknown parameter
|month=ignored (help) - ↑ Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M; et al. (2007). "Effects of torcetrapib in patients at high risk for coronary events". N Engl J Med. 357 (21): 2109–22. doi:10.1056/NEJMoa0706628. PMID 17984165.
- ↑ Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J; et al. (2012). "Effects of dalcetrapib in patients with a recent acute coronary syndrome". N Engl J Med. 367 (22): 2089–99. doi:10.1056/NEJMoa1206797. PMID 23126252.