ISSN 0326-646X
 

 
 
 
 
 
 
 
 

 
 

1024x768

 
 
 
 
 
 

Sumario Vol. 42 - Nº 3 Julio - Septiembre 2013

New drugs and lipid lowering mechanisms.
Post statin era

Carlos Alberto Cuneo

Hospital San Bernardo.
José Tobías 69. (4400) Salta, Argentina.
E mail

Recibido 08-JUL-13 – ACEPTADO después de revisión el

The authors declare not having a conflict of interest.

Rev Fed Arg Cardiol. 2013; 42(3): 174-181


Print version Imprimir sólo la columna central

 

 

 

RESUMEN

La dislipidemia, especialmente la hipercolesterolemia de LDL cumple un papel clave en aterogénesis y aterotrombosis. Las estatinas han contribuido como el tratamiento médico más efectivo para la enfermedad coronaria. Sin embargo, algunos pacientes no toleran las estatinas (altas dosis o incluso ninguna dosis) y otros no alcanzan los niveles recomendados para alto riesgo, colesterol LDL <70 mg/dl o colesterol No-HDL <100 mg/dl, a pesar de altas dosis de estatinas.
Recientemente, se han descubierto otros mecanismos para descender el C-LDL, como la inhibición de la producción hepática de apoB (como Mipomersen), la inhibición de la actividad de MTP (proteína microsomal de transferencia de triglicéridos) (como Lomitapide), ambos resultan en menor producción de VLDL, el precursor de LDL; y los inhibidores de PCSK9 (tipo 9 de subtilisina/kexina convertasa de proproteína), promotores de mayor actividad de los receptores de LDL. Adicionalmente, estas nuevas drogas parecen reducir significativamente los niveles de Lipoproteína (a).

Palabras clave: Estatinas. Inhibición de apoB. Inhibición de MTP. Inhibidores PCSK9.
SUMMARY

Dyslipidaemias, specially LDL-hypercholesterolemia, play a key role in atherogenesis and atherothrombosis. Statins have been the most effective medical treatment for coronary artery disease. However, some patients do not tolerate statins (high or even any dose) and others do not achieve the recommended level for high risk, LDL-C less than 70 mg/dl, or non-HDLcholesterol less than 100 mg/dl, despite high statin doses.
Recently other mechanisms for LDL-C lowering were discovered, such as inhibition of hepatic production of apoB (as Mipomersen) and inhibition of MTP (microsomal triglyceride transfer protein) activity (as Lomitapide), both resulting in less production of VLDL (very low density lipoprotein) the precursor of LDL; and inhibitors of PCSK9 (proprotein convertase subtilisin/kexin type 9), promoters of more activity of LDL receptors (LDLr). Additionally, these novel drugs seem to reduce Lipoprotein (a) (Lp(a)) levels significantly.

Keywords: Statins. Inhibition of apoB. Inhibition of MTP. Inhibitor of PCSK9.

 

 

INTRODUCTION
The discovery and subsequent global dissemination of the use of statins (inhibitors of HMG-CoA reductase) was the most significant advancement in the management of dyslipidemias of LDL cholesterol (LDL-C) and cardiovascular risk. The use of strong statins as monotherapy or combined with other lipid loweringdrug revealed to us that atherosclerosis is a reversible disease, one of the most revolutionary concepts in the history of the knowledge of CAD.

However, it is known with a good basis, that in order to stop the advancement of the atherosclerotic vascular disease, especially in the coronary territory, it is necessary to cause a very intense decrease on LDL-C, keeping over time levels below 70 mg/dl.

For the patients reaching and keeping levels of 40 or 50 mg/dl of LDL-C, it is necessary to use strong statins and in high doses, since the studies that attempted using lower doses of statins combining them with other lipid lowering drugs, did not yield satisfactory results.

The use of strong statins as atorvastatin or rosuvastatin, in doses of 40-80 mg/day for the first or 20-40 mg/day for the second, is not free from adverse events, especially muscular or hepatic. And we have also discovered, that quite a significant number of patients tolerate only low doses, and there are patients (luckily not so many) that do not tolerate any dose of any statins.

On the other hand, the mechanism of action of statins, inhibiting the production of intrahepatic cholesterol by the inhibition of reductase of hydroxymethylglutaryl coenzyme A reductase (HMG-CoAr) that indirectly leads to a higher uptake of LDL by the activation of more LDL liver receptors, is not an effective mechanism when LDL receptors are defective, scant or absent, as it happens in severe familial, hetero and homozygotic hypercholesterolemia.

For these reasons, the investigation of the post-statins era has achieved the identification of other mechanisms capable of interfering with LDL production or increasing even more the activity of LDL receptors that uptake circulating LDL and degrade it in the liver.

These new mechanisms are:

A- Interference with the production of apolipoprotein B, by messenger RNA block using ASO (antisense oligonucleotides), the interference with apoB synthesis leads to a lower production of VLDL and a lower amount of VLDL released by the liver, and so a lower amount of circulating LDL, since VLDL is the precursor of LDL [1,2]. Figures 1 and 2.

Figure 1. Function of inhibition of apoB synthesis by the action of ASO (antisense oligonucleotides). mRNA is blocked by the antisense oligonucleotide, so translation cannot occur and so, neither the synthesis of proteins, in our case apoB100 [1].

.

Figure 2. Decrease in VLDL and LDL production. The decrease in apoB100 synthesis caused by the antisense oligonucleotide leads to a decrease in apoB100 availability,
so the amount of synthesized VLDL is lower, as is the amount of VLDL released by the liver too, and consequently there is a less amount of VLDL that may be transformed into LDL. As VLDL contains cholesterol esters and triglycerides, both decrease their concentrations in blood [1,2,3,4,5].

 

B- Inhibition of MTP (microsomal triglyceride transfer protein) that is key in the production of VLDL. By MTP being inhibited, the production of VLDL will have its production decreased, which in turn is a precursor of LDL, thus also decreasing the circulating LDL level [3,4]. Figure 3.

Figure 3. Outline of the inhibition of MTP (microsomal triglyceride transfer protein). MTP inhibitors (in this case Lomitapide) decreases the capacity of lipidization of apoB100 with triglycerides, so the production of VLDL decreases, and consequently VLDL release also decreases, and in turn the passage of VLDL into LDL too [12,13].

 

C- Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9). PCSK9 has the function of degrading LDL receptors that are internalized by endocytosis in hepatocytes. When PCSK9 is inhibited or blocked, LDL receptors instead of being degraded are recycled, and may return to the hepatocyte surface and continue uptaking LDL particles, several dozens or hundreds times more [5,6]. Figure 4.

Figure 4. Simplified outline of the effect of the inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) in LDL receptors.Statins reduce the synthesis of intrahepatic cholesterol by inhibiting HMG-CoA reductase. This causes an increase in the synthesis of SREBP (sterol regulatory element-binding protein) that induces an increase in LDL receptors that are heading to the hepatocyte membrane to uptake LDL particles, but at the same time induce the production of PCSK9, which also comes from the hepatocyte, links to the LDL receptor and when this is internalized, it promotes its destruction. The action of PCSK9 is a limitation for the recycling of receptors. The combination of statins with PCSK9 inhibitors may increase LDL receptors recycling that induce statins by the SREBP action. When PCSK9 is inhibited by the action of these specific monoclonal antibodies, LDL receptors are not destroyed after an internalization, they are recycled, often for as long as PCSK9 inhibition lasts. Thus, finally a greater number and greater activity of LDLr is achieved for a longer time [17,18,19].

 

 

Interference in apoB synthesis: MIPOMERSEN

The production of VLDL by hepatocytes mainly depends on two important proteins, apoB and MTP.

Apoprotein B is a structural component of VLDL. Without apoproteins, lipids that are hydrosoluble, could not be transported outside the liver. In the case of VLDL it is an apoB100. This apoprotein should become “lipidic”; that is to say, be loaded with lipids in a progressive way, until becoming a lipoprotein and being released into blood circulation. If the production of apoB100 is interfered, the production and release of VLDL will also decrease, with a reduction in VLDL levels in blood. VLDL are the substrate of lipases that transform VLDL into IDL and finally into LDL. Since VLDL level is decreased, LDL level will be so too. There is no alternative way of LDL production that is not plasma enzymatic degradation of VLDL.

Mipomersen is the first commercially available drug with this original mechanism of action. The medication (antisense oligonucleotides) is introduced by subcutaneous injection. Antisense oligonucleotides specifically disturb the liver protein synthesis of apoB100. This decrease of production of apoB100 leads to a lower production and release of VLDL, with the subsequent decrease of plasma production of LDL, decreasing the LDL levels and of circulating apoB100, as illustrated in Figures 1 and 2. Moreover, we have to remember that the main lipid component of VLDL are triglycerides, so a decrease in VLDL release rate leads to a significant reduction of triglyceride levels [2,7,8,9].

On the other hand, since the lipoprotein (a)(Lp(a)) indispensably contains apoB100, a decrease in the synthesis of apoB100 is also accompanied by a reduction in Lp(a) levels. Lipoproteins that contain apoB48, such as chylomicrons, are not affected because they do not originate in the liver, but mainly in the intestines.

Mipomersen as monotherapy was investigated in patients intolerant to statins [7], in mild to moderate hyperlipidemia [8], in familial, heterozygous and homozygous hypercholesterolemia [9,10] and in patients with severe LDL hypercholesterolemia, with and without CAD [11,12].

In patients intolerant to statins: Mipomersen was injected in doses of 200 mg/week to 33 patients intolerant to statins, with high LDL-C levels (average 244 mg/dl) for 26 weeks. LDL-C was reduced by 47% in average [7]. Virtually all patients (95%) reported a reaction in the site of injection and this was obviously, the most frequent adverse effect. Another remarkable adverse event was a “flu-like syndrome” in 90% of the patients. There was also a third (33%) that presented increases of ALT>3 times above normal [7]. Below, adverse events are better illustrated.

In mild to moderate hypercholesterolemia: for 13 weeks, 18 patients with LDL-C of 130 mg/dl at least, were treated with several doses of Mipomersen (between 50 and 400 mg/week). LDL-C decreases were from 7 to 71%, with a clear dose-response ratio. Greater doses were more effective to decrease LDL-C, but also added more secondary effects. Once again, reactions in the site of injection were most common, and there was increase of transaminases in approximately half of the patients [8].

In heterozygous familial hypercholesterolemia (HeFH): In a Phase II study, 39 patients were randomized to receive different weekly doses of Mipomersen (50 mg, 100 mg, 200 mg) or placebo during 6 weeks, or Mipomersen 300 mg/week vs. placebo during 13 weeks.

In the study at 6 weeks, the most effective dose was 200 mg/week, which reduced apoB by 23% and LDL-C by 21%; while in the study of 13 weeks, 300 mg/week of Mipomersen reduced apoB 33% and LDL-C 34%. Significant reductions of triglycerides or lipoprotein (a) were not observed.
Once again, almost all patients complained of rash in the site of injection (97%), several accompanied by pain, itching and skin discoloration. There was also liver transaminase elevation, most in the group of 300 mg/week. In this study, liver steatosis was evaluated by computed tomography and it was found in some cases, by effect of the medication being studied [9].

In homozygous familial hypercholesterolemia (HoFH):Undoubtedly, a key study for the current management of this rare and difficult disease. In 51 patients that had documented history of HoFH, treated with the maximal doses tolerated of lipid lowering drugs, 200 mg/week of Mipomersen or placebo were added in a random way, for 26 weeks.

The Mipomersen effect was decreasing LDL-C by 25% in average from a baseline of 440 mg/dl of LDL-C. The levels of apoB were also decreased by 24%, non-HDL by 21% and Lp(a) by 23%.

Seventy six percent of the patients receiving Mipomersen presented reactions at the site of injection, but 24% of the placebo group complained of the same. Thirty percent of those receiving Mipomersen also had at the site of injection, bruising, pain or itching. Twelve percent receiving Mipomersen revealed an increase in liver transaminases, and one patient had a significant increase of liver fat, measured by magnetic resonance [10]. A remarkable adverse effect was added with a significant frequency, that of the “flu-like syndrome”, the mechanism of which is not completely clarified, but that in some cases led to dropping the treatment.

This was a very important study, since it reflects the reality of patients with HoFH, who are usually not treated with lipid lowering monotherapy, but with a combination of all the tolerated drugs instead (statins, ezetimibe, intestinal resin and/or niacin), to which Mipomersen was added, since in this polypharmacy setting it is equally effective.

In severe LDL hypercholesterolemia:In 58 patients with LDL-C ≥7.8 mmol/L (301 mg/dl) or LDL-C ≥5.1 mmol/L (197 mg/dl) in the presence of CAD, using the maximal pharmacological treatment tolerated, two arms of treatment were arranged: subcutaneous injections (SC) of Mipomersen 200 mg/week (n=39) or placebo (n=19), without suspending the previous maximal lipid lowering therapy. The study extended for 26 weeks. Mipomersen managed to reduce LDL-C in the treated group by 36% (absolute reduction of 108 mg/dl of LDL-C), while it increased 13% in the group with placebo. Figure 5.

Figure 5. Lipid-lowering effect of Mipomersen on LDL-C [7].

There were also significant reductions of apoB and Lp(a), with no changes in HDL-Cl. Once again, the reactions in the site of injection and the “flu-like” symptoms were the most frequent ones in the treated group. There were also more severe adverse events in the Mipomersen group (15.4%) than in the placebo group (0%). Thirteen percent of the patients treated had liver steatosis and 21% increased ALT in a significant way. There were 5 adverse cardiac events in the treated group (12.8%) and only 1 in the placebo group (5.3%) [11].

Heterozygous familial hypercholesterolemia with CAD: Patients in the maximal tolerated dose of statins and documented CAD, with LDL-C above the goal of 100 mg/dl (n=124) were randomized to weekly injections of Mipomersen 200 mg (n=83) or placebo (n=41), during 26 weeks. Ten patients did not complete the treatment in the Mipomersen group and none from the placebo group. Mipomersen significantly reduced in average 28% the level of LDL-C; while the placebo group increased it 5.2%. The reductions in apoB, total cholesterol and lipoprotein(a) were also significant. There were no changes in HDL-C.

The most frequent adverse events associated to Mipomersen were the reactions in the site of injection and the “flu-like” symptoms. There was also 6% that significantly increased ALT and the liver fat content increased 4.9% in the Mipomersen group vs. 0.4% in the placebo group.

Currently, a study is being developed to compare three-week versus weekly doses by a short period of 6 weeks, in patients HeFH (n=480) (FOCUS-FH Study); the results should be available for the next year. It is possible that a more distant frequency of the injections may make the product be better tolerated [5].

The manufacturing company has not established yet the safety and the efficacy in the pediatric population, which is regrettable, since childhood is the best time to treat HoFH.

It cannot be used in the case of severe renal failure, clinically significant proteinuria or renal dialysis. The safety of the joint use of Mipomersen and LDL apheresis has not been established, so this type of association is not recommended. It is contraindicated in moderate or severe liver involvement (Child-Pugh B or C) or in active liver disease, including transaminase increases in this category [6]. It has been proven that the introduction of Mipomersen to the organism generates antibodies in almost half of the patients of a study; these antibodies do not decrease the lipid lowering effect of the drug, but its effect in the long term is not known yet.

Common adverse effects with Mipomersen: In Figure 6, the most common adverse effects reported by the manufacturer are listed.

Figure 6. Most common adverse events with Mipomersen [10].

In January 2013, the FDA approved the use of Mipomersen in HoFH [13]. The same did not happen with the European agency (EMEA) that rejected the proposal of the producer twice. This negative opinion was based on safety problems (adverse events) and more evaluations are expected in the future.

Inhibition of the microsomal triglyceride transfer protein (MTP): LOMITAPIDE: MTP is found in the endoplasmic reticulum of hepatocytes and enterocytes, and acts mediating the formation of the lipoproteins that contain apoB in the liver and the intestine [3]. The mutations in the MTP gene may cause abetalipopoteinemia, a rare genetic disease characterized by the absence of lipoproteins that contain apoB, that evolves clinically with severe malabsorption of fat and liposoluble vitamins, in the first months of life there is diarrhea, acanthosis, steatorrhea and steatohepatitis. This evidence suggests that inhibiting MTP would lead to a reduction in the synthesis of lipoproteins that contain apoB, as VLDL and consequently LDL.

Lomitapide is an MTP-inhibiting drug, which is administered orally, in monotherapy or combined with other lipid lowering drugs. This medication has completed satisfactorily the tests of phase III in patients with HoFH [3,4] and in hypercholesterolemic patients [14].

In homozygous familial hypercholesterolemia: In one of the first studies, 6 patients were treated with hypofatty diet (<10% of fat calories) to prevent steatorrhea and received 0.03, 0.1, 0.3 and 1 mg/kg/day of Lomitapide for 4 weeks, orally. Basal LDL-C was 614 mg% and decreased by 51% with 1 mg/kg/day. ApoB also decreased by 56% and triglycerides by 65% with this dose. In 4 of 6 patients, transaminases increased, and in all patients liver fat increased from 10 to 30%. Other adverse events, mainly intestinal, were increased in the frequency of defecation, frequently attributed to the ingestion of fatty food [3].

In another study, Lomitapide was added to conventional lipid lowering therapy in 29 patients with HoFH and doses of 5 to 60 mg/day were used. An average dose of 40 mg/day. Basal LDL-C was 336 mg/dl and decreased 50% at 26 weeks at 166 mg/dl. Figure 7. They remained in 44% less at 56 weeks in the group of 40 mg/day [4]. After 78 weeks, LDL-C was 38% less than the basal one.

Figure 7. Lipid-lowering effect of Lomitapide in HoFH.

The adverse effects were mostly gastrointestinal. From 29 patients, 4 had transaminases increase, which was solved by reducing the dose or suspending the administration of Lomitapide temporarily. No patient interrupted the treatment because of these adverse liver events. No bilirubin or alkaline phosphatase increases were observed.

The fatty content of the liver was evaluated by magnetic resonance and it was observed that it increased from 0.9% in the baseline to 9% at 26 weeks and 7.3% at 56 weeks [4]. It was also shown that the liver changes were solved by suspending the medication.

Currently, a long-term follow-up is being carried out on the patients with HoFH that completed this study, and results are expected in 2014 [15].

In hypercholesterolemic patients, therapy combined with ezetimibe: In a 12-week study, 84 patients with LDL hypercholesterolemia (130 to 250 mg/dl) were treated withlow-fat diet (<20% of fat calories) and were randomized into 3 groups: Group 1: Ezetimibe 10 mg/day for 12 weeks; Group 2: Lomitapide in increasing doses of 5, 7.5 and 10 mg/day for 4 weeks at each level of doses, and Group 3: the combination of ezetimibe 10 mg/day for the 12 weeks along with the increasing doses of Lomitapide as in Group 2.

LDL-C was reduced 20% with ezetimibe, 30% with Lomitapide and 46% with the combination at the end of 12 weeks. Moreover, reductions were observed in Group 3 of total cholesterol 34%, non-HDL 41%, apoB 37% and Lp(a) 17% [14].

The adverse events were predominantly gastrointestinal. In 9 of 56 patients that received Lomitapide in groups 2 and 3 this treatment had to be suspended by increase of transaminases, which did not occur in group 1 with ezetimibe.

Just as with Mipomersen, the safety and efficacy in the pediatric population has not been investigated yet, when childhood is the best time to treat HoFH. The manufacturer contraindicates using Lomitapide during pregnancy, concomitant administration of CYP3A4 inhibitors, and in moderate to severe liver involvement or liver disease including increase of transaminases.

Common adverse events with Lomitapide: In a large majority they are gastrointestinal (Figure 8). In the study of patients with HoFH, 17% had to interrupt the treatment by adverse events related to the medication of the study. Lomitapide has been authorized by the FDA to be commercialized in December 2012 and by the EMEA in June 2013 [16].

Figure 8. Most common adverse events with Lomitapide [15,16]

 

PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition
There are several drugs, all monoclonal antibodies, that inhibit this convertase and allow LDL receptors that have been internalized along with the LDL particle, to return to the liver surface and uptake a new particle loaded with apoB. This recycling process stops when PCSK9 is linked to the receptor and promotes its degradation; inhibiting PCSK9 allows the receptor to recycle many times, which increases its half life and efficiency.

Some people have PCSK9 mutations that decrease their function, evolve with low LDL-C levels and with a low rate of cardiovascular events. While the increase in the activity of PCSK9 is associated to hypercholesterolemia.

The mechanism of action of PCSK9 inhibitors increase the activity of LDL receptors, makes it very attractive to be combined with statins, since both mechanisms of action could enhance each other. To this date, there is half a dozen drugs, PCSK9 inhibitor monoclonal antibodies that are being studied in phases II and III of clinical investigation [17,18,19]. They are injected subcutaneously twice per month.

The two most investigated ones are SAR236553/REGN727 and AMG145. Studies have been published, using PCSK9 inhibitors in monotherapy [19,25] and associated to statins, without [20] or with ezetimibe [21,22,23] or in patients with primary hypercholesterolemia [20,21,22,24,25], HeFH [20,26] and in patients intolerant to statins [27].

In all these studies, PCSK9 inhibitors (PCSK9i) proved to be strong LDL-C reducers, even in patients with HeFH. LDL-C levels decreased around 50-60%. In Figure 9, effect curves of PCSK9 are seen with two different doses of atorvastatin. The enhancement of the effect with low doses of atorvastatin (10 mg) combined with PCSK9i (group A10 + PCSK9i) compared to the group of 80 mg of atorvastatin (A 80) and the group of 80 mg of atorvastatin plus PCSK9i (A 80 + PCSK9i) stands out [22].

Figure 9. Effect of a PCSK9 (SAR236553) on different lipid parameters combining it with 10 or 80 mg of atorvastatin vs. atorvastatin alone.

PCSK9 inhibitors tested until now have an acceptable profile of safety, antiPCSK9 antibodies are well tolerated, no severe adverse events have been observed in liver function parameters or in other lab tests. It is still too early to make a statement on the long-term adverse events, since the studies have only started recently or are about to being this year 2013 or next one. Due to their injectable administration they produce reactions at the site of injection, including rash, itching, bruising and edema.

PCKS9 seems to modulate the protection against hepatitis, so it would not be convenient to inhibit it in patients with this condition [28]. Studies in phase III are ongoing, which will assess events, which will provide results probably by the end of this decade.

 

CONCLUSIONS
Although statins are the foundations of the optimal treatment of CAD, especially in the presence of hypercholesterolemia, there are still some problems when target levels of treatment suggested by guidelines from scientific societies are attempted. Some patients do not reach the target levels even with high doses of statins, others do not tolerate high doses and in some cases no dose at all. Other classical lipid lowering drugs have not shown the clear effectiveness of statins, so the advancements that the investigation proposes, with lipid lowering drugs with novel mechanisms of action, provide a real hope of reaching more easily the targets proposed and thus preventing coronary ischemic events more efficiently.

 

BIBLIOGRAPHY

  1. Kastelein JJP, Wedel MK, Baker BF, et al. Potent reduction of Apolipoprotein B and Low-Density Lipoprotein Cholesterol by Short-Term Administration of an Antisense Inhibitor of Apolipoprotein B. Circulation 2006; 114: 1729-35.
  2. Visser ME, Witztum JL, Stroes ES, et al. Antisense oligonucleotides for the treatment of dyslipidaemia. Eur Heart J 2012; 33: 1451-8.
  3. Cuchel M, Bloedon LT, Szapary PO, et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med 2007; 356: 148-56.
  4. Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2013; 381: 40-6.
  5. The ongoing Evaluating the saFety and atherOgeniC lipoprotein redUction of mipomerSen in FH (FOCUS FH) study. Disponible en www.clinicaltrials.gov/ct2/show/ NCT01475825
  6. Eventos adversos con Mipomersen. Página web de Mipomersen (Kynamro, Gensyme, A Sanofi company) Disponible en http://www.kynamro.com/healthcare.aspx
  7. Visser ME, Wagener G, Baker BF, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein colesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebocontrolled trial. Eur Heart J 2012; 33: 1142-9.
  8. Akdim F, Tribble DL, Flaim JD, et al. Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia. Eur Heart J 2011; 32: 2650-9.
  9. Akdim F, Visser ME, Tribble DL, et al. Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. Am J Cardiol 2010; 105: 1413-9.
  10. Raal FJ, Santos RD, Blom DJ, et al. 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 2010; 375: 998-1006.
  11. McGowan MP, Tardif J-C, Ceska R, et al. Randomized, Placebo-Controlled Trial of Mipomersen in Patients with Severe Hypercholesterolemia Receiving Maximally Tolerated Lipid-Lowering Therapy. PLoS One 2012; 7 (11): e49006. doi: 10.1371/journal.pone.0049006
  12. Stein EA, Dufour R, Gagne C, et al. Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation 2012; 126 (19): 2283-92.
  13. Información sobre Mipomersen. Disponible en http://ir.isispharm.com/phoenix.zhtml?c=222170&p=irol-news&nyo=0
  14. Samaha FF, McKenney J, Bloedon LT, et al. Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat Clin Pract Cardiovasc Med 2008; 5: 497-505.
  15. Long Term, follow-up study of Lomitapide in patients with homozygous familial hypercholesterolemia. Disponible en http://clinicaltrials.gov/show/NCT00943306
  16. Información sobre Lomitapide Disponible: http://ir.aegerion.com/releasedetail.cfm?ReleaseID=728650
  17. Dubuc G, Chamberland A, Wassef H, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2004; 24: 1454-9.
  18. Cohen JC, Boerwinkle E, Mosley TH Jr, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354: 1264-72.
  19. Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med 2012; 366: 1108-18.
  20. Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 2012; 380: 29-36.
  21. McKenney JM, Koren MJ, Kereiakes DJ, et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012; 59: 2344-53.
  22. Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012; 367: 1891-1900.
  23. Dias CS, Shaywitz AJ, Wasserman SM, et al. Effects of AMG 145 on low-density lipoprotein colesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascendingdose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J Am Coll Cardiol 2012; 60: 1888-98.
  24. Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin / kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebocontrolled, dose-ranging, phase 2 study. Lancet 2012; 380: 2007-17.
  25. Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebocontrolled, phase 2 study. Lancet 2012; 380: 1995-2006.
  26. Raal F, Scott R, Somaratne R, et al. Low density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the reduction of LDL-C with PCSK9 inhibition in heterozygous familial hypercholesterolemia disorder (RUTHERFORD) randomized trial. Circulation 2012; 126: 2408-17.
  27. Sullivan D, Olsson AG, Scott R, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA 2012: 308 (23): 2497-506.
  28. Labonte P, Begley S, Guevin C, et al. PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression. Hepatology 2009; 50: 17-24.
Publication: September 2013

 

 
Editorial Electrónica
de FAC




 
8vo. Congreso Virtual de Cardiología

1º Setiembre al
30 Noviembre, 2013
 

 
XXXI Congreso Nacional de Cardiología

30-31 Mayo,
1º Junio, 2013
Organiza: Región Patagónica
 

 
Búsquedas
Revista de FAC

gogbut

Contenidos Científicos
y Académicos

gogbut

 

 
Accesos rapidos