High density lipoprotein future or investigational therapies
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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 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 has shifted the scope of HDL therapy towards increasing the qualitative functionality of HDL i.e., cellular cholesterol efflux, HDL-mediated reverse cholesterol transport mechanism, associated enzymatic activities, particle size and electrophoretic mobility, anti-inflammatory, and anti-oxidant properties, rather than the quantitative elevation of serum HDL-C which was the previous target. 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 plasma. 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, now MDCO-216 since 2009) 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 increases 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 - torcetrapib (ILLUMINATE Trial) and dalcetrapib (Dal-OUTCOMES Trial). The ILLUMINATE Trial failed due to the observed off-target 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] Two other new CETP inhibitors (anacetrapib and evacetrapib) are in phase 3 clinical trials with promising results. Both anacetrapib (MK-0859) and evacetrapib (LY248595) raise HDL levels without affecting the blood pressure.[9][10] The effects of evacetrapib on cardiovascular outcomes are being examined in the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High-Risk for Vascular Outcomes (ACCELERATE Trial) by Eli Lilly and Company, currently enrolling 11,000 patients after ACS.[11] The expected date of completion is January, 2016. The REVEAL HPS-3/TIMI-55 trial will assess whether lipid modification with anacetrapib 100mg daily reduces the risk of coronary death, myocardial infarction or coronary revascularization (collectively known as major coronary events) in 30,000 patients with circulatory problems who have their Low-density Lipoprotein (LDL) cholesterol level treated with a statin. The expected date of completion is January, 2017.[11]
CETi-1 Vaccine
The CETi-1 vaccine (developed by AVANT Immunotherapeutics) induces antibodies specific for a portion of the cholesteryl ester transfer protein (CETP). Only one patient out of a total of 36 patients who received a single injection of the vaccine developed anti-CETP antibodies. After the study was extended, out of a total of 23 patients, 53% (8/15) developed anti-CETP antibodies following a second injection of the active vaccine compared with 0% (0/8) in the placebo group. The vaccine was well tolerated and no adverse event was reported. Despite a significant 8.4% increase in HDL among patients not on statins, more human studies are needed to determine whether repeated vaccinations will induce more antibodies which may translate to greater elevations in HDL.[12]
JTT-705
JTT-705, a partial inhibitor of CETP, was first tested in human subjects by Japan Tobacco Inc. in 2002. In a 4-week study to assess the efficacy and safety of ascending doses of JTT-705 in 198 healthy subjects with mild hyperlipidemia, results revealed a 37% decrease in CETP activity (P<0.0001), 34% increase in HDL cholesterol (P<0.0001), 7% decrease in LDL cholesterol (P=0.017), an increase in total HDL, HDL2, HDL3, and apolipoprotein A-I. Although minor gastrointestinal side effects were observed, the long-term effect on coronary artery disease needs to be assessed.[13] Better results were observed when JTT-705 was combined with statins including the preservation of HDL's anti-oxidant properties observed with CETP inhibition.[14]
De-lipidated HDL Infusions
This is a relatively new approach which involves autologous infusion of de-lipidated HDL using the Plasma De-lipidation System-2 (PDS-2) produced by Lipid Sciences.[15] The process involves the selective removal of apoA-I HDL particles, and the delipidation (converting alphaHDL to pre-beta-like HDL) reinfusion of the cholesterol-depleted functional pre-β HDL - the active form of HDL. In the first human trial, 28 patients with ACS undergoing cardiac catheterization received 5 weekly infusions of de-lipidated HDL or placebo. This led to a 73.5% increase in pre-beta-like HDL and 71.9% decrease in the alphaHDL contents of the de-lipidated plasma which was responsible for the 5.2% decreased in the total atheroma volume (measured by IVUS) observed. A third of the patients experienced hypotension due to apheresis.
HDL Mimetics
ApoA-1 Mimetic Peptides
These are short synthetic peptides that mimic the amphipathic α-helix of apoA-I. D-4F, synthesized from D-amino acids, is resistant to degradation by gastric enzymes, thus, it can be administered orally. In animal models, D-4F has been demonstrated to:
- Increase cholesterol efflux from macrophages via ABCA1[16]
- Delivery of cholesterol to hepatocytes via the SCARB1[17]
- Exhibits profound anti-inflammatory properties[18][19]
- Anti-oxidant properties which exceeds native apoA-1 - shows more affinity for oxidized phospholipids and fatty acids[20]
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.
- ↑ Krishna, R.; Anderson, MS.; Bergman, AJ.; Jin, B.; Fallon, M.; Cote, J.; Rosko, K.; Chavez-Eng, C.; Lutz, R. (2007). "Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies". Lancet. 370 (9603): 1907–14. doi:10.1016/S0140-6736(07)61813-3. PMID 18068514. Unknown parameter
|month=ignored (help) - ↑ Nicholls, SJ.; Brewer, HB.; Kastelein, JJ.; Krueger, KA.; Wang, MD.; Shao, M.; Hu, B.; McErlean, E.; Nissen, SE. (2011). "Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial". JAMA. 306 (19): 2099–109. doi:10.1001/jama.2011.1649. PMID 22089718. Unknown parameter
|month=ignored (help) - ↑ 11.0 11.1 "A Study of Evacetrapib in High-Risk Vascular Disease - Full Text View - ClinicalTrials.gov". Retrieved 20 September 2013.
- ↑ Davidson, MH.; Maki, K.; Umporowicz, D.; Wheeler, A.; Rittershaus, C.; Ryan, U. (2003). "The safety and immunogenicity of a CETP vaccine in healthy adults". Atherosclerosis. 169 (1): 113–20. PMID 12860257. Unknown parameter
|month=ignored (help) - ↑ de Grooth, GJ.; Kuivenhoven, JA.; Stalenhoef, AF.; de Graaf, J.; Zwinderman, AH.; Posma, JL.; van Tol, A.; Kastelein, JJ. (2002). "Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study". Circulation. 105 (18): 2159–65. PMID 11994249. Unknown parameter
|month=ignored (help) - ↑ Bisoendial, RJ.; Hovingh, GK.; El Harchaoui, K.; Levels, JH.; Tsimikas, S.; Pu, K.; Zwinderman, AE.; Kuivenhoven, JA.; Kastelein, JJ. (2005). "Consequences of cholesteryl ester transfer protein inhibition in patients with familial hypoalphalipoproteinemia". Arterioscler Thromb Vasc Biol. 25 (9): e133–4. doi:10.1161/01.ATV.0000179009.60612.28. PMID 16127020. Unknown parameter
|month=ignored (help) - ↑ Waksman, R.; Torguson, R.; Kent, KM.; Pichard, AD.; Suddath, WO.; Satler, LF.; Martin, BD.; Perlman, TJ.; Maltais, JA. (2010). "A first-in-man, randomized, placebo-controlled study to evaluate the safety and feasibility of autologous delipidated high-density lipoprotein plasma infusions in patients with acute coronary syndrome". J Am Coll Cardiol. 55 (24): 2727–35. doi:10.1016/j.jacc.2009.12.067. PMID 20538165. Unknown parameter
|month=ignored (help) - ↑ Song, X.; Fischer, P.; Chen, X.; Burton, C.; Wang, J. (2009). "An apoA-I mimetic peptide facilitates off-loading cholesterol from HDL to liver cells through scavenger receptor BI". Int J Biol Sci. 5 (7): 637–46. PMID 19847320.
- ↑ Smythies, LE.; White, CR.; Maheshwari, A.; Palgunachari, MN.; Anantharamaiah, GM.; Chaddha, M.; Kurundkar, AR.; Datta, G. (2010). "Apolipoprotein A-I mimetic 4F alters the function of human monocyte-derived macrophages". Am J Physiol Cell Physiol. 298 (6): C1538–48. doi:10.1152/ajpcell.00467.2009. PMID 20219948. Unknown parameter
|month=ignored (help) - ↑ Van Lenten, BJ.; Wagner, AC.; Jung, CL.; Ruchala, P.; Waring, AJ.; Lehrer, RI.; Watson, AD.; Hama, S.; Navab, M. (2008). "Anti-inflammatory apoA-I-mimetic peptides bind oxidized lipids with much higher affinity than human apoA-I". J Lipid Res. 49 (11): 2302–11. doi:10.1194/jlr.M800075-JLR200. PMID 18621920. Unknown parameter
|month=ignored (help)