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Lipid Club Newsletter

January 2013

 

• HPS-2 THRIVE misses primary end point: No benefit of niacin/laropiprant
• dal-OUTCOMES: why the CETP inhibitor failed to reduce outcomes?
• Lomitapide approved for homozygous familial hypercholesterolemia
• Antisense oligonucleotides (Mipomersen)
• Statins: Diabetes risk outweighed by CV benefit
• Lipid profiles: Fasting not necessary…
• CSL-112( ApoA1 formulation) increases cholesterol efflux in humans
• Two new PCSK9 MAbs for LDL-lowering in phase 2
• Wider fibrate use in mild to moderate CKD?

 

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HPS-2 THRIVE misses primary end point:
No benefit of niacin/laropiprant

Jean Ducobu(UMons) Adapted from the heart.org

- The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS-2 THRIVE) study, a secondary-prevention trial testing the addition of extended-release niacin to statin therapy, has missed its primary end point and shown no clinical benefit for extended-release niacin. The design is illustrated on figure 1.


Figure 1

After nearly four years of follow-up, the combination of niacin with the antiflushing agent laropiprant did not significantly reduce the risk of the combination of coronary deaths, nonfatal MI, strokes, or coronary revascularizations compared with statin therapy. Moreover in a press release announcing the results, the sponsor Merck said the combination significantly increased the risk of nonfatal but serious side effects (but without more precisions).

The combination of extended-release niacin and laropiprant, known as Tredaptive or Cordaptive, was approved by European regulators in 2008, but Merck is advising doctors from starting any new patients on the drug. One day after the Merck announcement, the European Medicines Agency announced that it would be starting a review of the safety and efficacy of Tredaptive, given the results of the HPS-2 THRIVE study.

This is the second major setback for physicians hoping that niacin, a drug that raises HDL-cholesterol levels, might be used clinically to reduce the risk of cardiovascular events. In May 2011, the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study, was halted early after showing no benefit of niacin when given in addition to statin therapy. (Figure 2)


Figure 2

Dr Steve Kopecky (Mayo Clinic, Rochester, MN), the president of the American Society of Preventive Cardiology and one of investigators of the AIM-HIGH study, said he was also disappointed by the results, but these trials show just how difficult it is to provide additional benefit when patients are well-treated with statins. In AIM-HIGH, for example, patients were treated with statin therapy anywhere from one to five years. Kopecky noted that observational studies have shown that raising HDL cholesterol with exercise, eating a lower saturated-fat diet, losing weight, stopping smoking, and drinking small amounts of alcohol raises HDL cholesterol and lowers cardiovascular risk. As a result, it remains unknown if the lack of benefit was the result of ineffectiveness when niacin was added to simvastatin or whether the benefit was canceled out as a result of an off-target effect caused by laropiprant. Dr James Stein (University of Wisconsin Medical School, Madison) noted that laropiprant works by blocking DP1 receptors on vascular cells to prevent flushing, but the DP1 receptors are elsewhere in body, including platelets, neurons, and respiratory tissue.

Coincidentally, a systematic review and meta-analysis by Drs Paul Lavigne and Richard Karas (Tufts Medical Center, Boston, MA) evaluated 11 studies including 9959 subjects, primarily secondary-prevention studies, treated with niacin and was published online December 19, 2012 in the Journal of the American College of Cardiology. The studies included ARBITER-2 and ARBITER-6, as well as the AIM-HIGH study. In this meta-analysis treatment with niacin was associated with a significant 34% reduction in the composite end point of any cardiovascular disease event and a significant 25% reduction in coronary heart disease events.

The landscape of HDL-raising therapies is now littered with failed therapies, including niacin and the negative results with the cholesteryl ester transfer protein (CETP) inhibitors.

 

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dal-OUTCOMES:
why the CETP inhibitor failed to reduce outcomes?

Jean Ducobu(UMons) Adapted from the heart.org

Final results of the dal-OUTCOMES study, a phase 3 clinical trial testing the efficacy of the investigational cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib (Hoffman-La Roche, Ltd), were presented at the American Heart Association 2012 Scientific Sessions and published simultaneously in the New England Journal of Medicine, leaving investigators to wrestle with reasons that the drug failed to have an impact on clinical outcomes.(Figure 3) Some experts believe the modest but clinically significant increase in blood pressure might have doomed the drug.

dal-OUTCOMES was stopped after an interim analysis of the study showed the HDL-cholesterol-boosting drug was not significantly reducing cardiovascular adverse events despite increases in HDL cholesterol of approximately 30%. Dalcetrapib is the second CETP inhibitor to fall by the wayside, despite initial excitement that raising HDL-cholesterol levels would translate into a reduction in clinical events. In 2005, Pfizer halted the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) of torcetrapib when it was revealed the drug increased the risk of cardiovascular morbidity and mortality.


Figure 3

Two other CETP inhibitors, evacetrapib (Lilly, Indianapolis, IN) and anacetrapib (Merck, Whitehouse Station, NJ) are currently being tested in large phase 3 morbidity and mortality trials. Dr Alan Tall (Columbia University, New York), who commented on the dal-OUTCOMES trial and CETP inhibition as a whole, said he does not believe the stopping of dal-OUTCOMES is a harbinger of more negative news to come about the drug class.

There is a concern the tiny blood-pressure signal could be a class effect, but in pretty big studies already done with anacetrapib and evacetrapib, there is no trace of that. It's important to note that the two remaining players in the field are really quite different. They lower LDL quite extensively, they lower LDL cholesterol, and they really raise HDL cholesterol a lot more than dalcetrapib.In the DEFINE study, anacetrapib reduced LDL-cholesterol levels 36% and increased HDL-cholesterol levels by 138% in patients with coronary artery disease currently taking a statin. Evacetrapib was shown to have similar potency, reducing LDL cholesterol by as much as 52% when added to statin therapy and increasing HDL cholesterol by 129%.

Dr Gregory Schwartz (University of Colorado School of Medicine, Denver), the lead investigator of dal-OUTCOMES, noted that there was no effect on LDL-cholesterol levels in the 15 871-patient trial. He added that the findings of the dal-OUTCOMES study highlight the importance of conducting large, phase 3 studies in order to detect small but clinically important safety signals. In the phase 2 studies with dalcetrapib, there was no evidence of an increase in blood pressure, but dal-OUTCOMES showed that blood pressure was increased 0.6 mm Hg with the CETP inhibitor.


Figure 4

In addition to the adverse effect on blood pressure, Tall said that the modest 30% increase in HDL cholesterol might have been insufficient in patients optimally treated with statins and other cardioprotective medications. It may be that when other risk factors are controlled as well as we currently can using many, if not all, of our evidence-based treatments, including statins, dual antiplatelet therapies, beta blockers, etc, that the risk that's modifiable by altering HDL-cholesterol levels may not be significant.This hypothesis is supported by the AIM-HIGH study, where a small 15% increase in HDL cholesterol with niacin did not translate into a reduction in the clinical end point.

Equally important, it's possible that CETP inhibition might produce a form of HDL cholesterol that is dysfunctional and incapable of reverse cholesterol transport.(Figure 4)

Full results of the morbidity and mortality trials with anacetrapib and evacetrapib are not expected for a few years.

 

Source

Schwartz GG, Olsson AG, Abt M, et al. effects of dalcetrapib in patients with a recent acute coronary syndrome.
N Engl J Med2012; 10.1056/NEJMoa1206797
Available at: http://www.nejm.org.

 

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Lomitapide approved for homozygous familial hypercholesterolemia
Jean Ducobu(UMons) Adapted from the heart.org

The FDA has approved lomitapide (Aegerion Pharmaceuticals, Cambridge, MA) as an adjunct to a low-fat diet and other lipid-lowering drugs, with or without LDL apheresis, to reduce LDL-C, total cholesterol (TC), apolipoprotein B (apoB), and non-HDL-C in patients with homozygous familial hypercholesterolemia (FH). Lomitapide is a MTP (Microsomial Triglyceride Transfer Protein) Inhibitor;. It inhibits in the liver and in the intestine the transfer of triglycerides to apo B , decreasing by this way the synthesis of VLDL and Chylomicrons ( Figures 5 & 6).


Figure 5


Figure 6

In a NEJM paper published in 2007, Cuchel et al showed the impressive effects of lomitapide in patients with FH(Figure 7).


Figure 7

But this new drug increased the fat liver content and liver enzymes.(Figure 8)


Figure 8

It will be known by the brand name Juxtapid.

The FDA's Endocrinologic and Metabolic Drugs Advisory Committee approved this drug in October by a vote of 13 to 2,but some panel members were concerned about the potential for liver toxicity with lomitapide, but others felt the risk-to-benefit profile was favorable, given the high risk associated with the extreme LDL-C levels in patients with homozygous FH..Lomitapide will be available only through a restricted program called the Juxtapid Risk Evaluation and Mitigation Strategy (REMS). Aegerion will certify all healthcare providers who prescribe Juxtapid and all pharmacies that dispense the medicine. The goal of the REMS is to educate prescribers about the risk of hepatotoxicity and to ensure that access to therapy is restricted to patients with a clinical or laboratory diagnosis consistent with homozygous FH. The company notes that the safety and effectiveness of lomitapide has not been established in pediatric patients or those with hypercholesterolemia who do not have homozygous FH, nor has its effect on cardiovascular morbidity and mortality been determined.

 

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Antisense oligonucleotides (Mipomersen)
Jean Ducobu(UMons) Adapted from the heart.org

This new kind of drug decreases the synthesis of apo B and all atherogenic lipoproteins, by reducing the translation of the apo B gene.( Figure 9)


Figure 9

The impact on LDL, Apo B and TG is interesting (figure 10)


Figure 10

The European Medicines Agency (EMA) has recommended against approval of mipomersen(Kynamro, Genzyme/Isis Pharmaceuticals) for the treatment of familial hypercholesterolemia (FH) because of safety reasons, including concern about serious cardiovascular events associated with the drug. This decision is in contrast with that taken by a US FDA advisory panel, which recommended approval of the product in October for the same indication.

In addition, the EMA is concerned about flulike symptoms, injection-site reactions, and liver toxicity with the drug ( Figure 11)


Figure 11

Genzyme Europe says it is "disappointed" with the decision and plans to request a reexamination of the CHMP opinion, with the goal of making this important medication available to homozygous FH patients in Europe.Genzyme has informed EMA that patients receiving the medicine in clinical trials will continue to do so as planned. Patients applying for compassionate-use programs will continue to be evaluated and will receive the medicine if eligible.

 

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Statins: Diabetes risk outweighed by CV benefit
Jean Ducobu(UMons) Adapted from the heart.org

“Although it does appear that statins may increase the risk of diabetes in high-risk patients, this should not stop us from using these drugs, as this small risk is outweighed by the substantial reduction in cardiovascular events."
That was the conclusion of Dr Barton Duell (Oregon Health & Science University, Portland), who was the discussant on this issue reported at American Heart Association 2012 Scientific Sessions.
  • A review of 13 trials with a total of 91 140 participants showed a 9% increased risk for incident diabetes with statins vs placebo.This translates into one case of diabetes per 255 subjects over four years (0.4%), so an increased risk of 1% per decade.
  • A meta-analysis of five trials of high-dose vs low-dose statins, with a total of 32 753 participants, which showed a 12% increased risk for incident diabetes over a 2-5 year follow-up. This works out to two cases of diabetes per 1000 patient-years (0.2% per year, 2% over a decade). This is still very low in comparison with cardiovascular benefits.The absolute increase in risk is low and appears to be proportional to the pretreatment risk of diabetes and the statin dose; and diuretics, beta blockers, and antidepressants may synergistically increase the diabetes risk seen with statins.(Figure 12)


Figure 12

The analysis of diabetes risk vs cardiovascular event reduction was analyzed in two large studies of high-dose vs low-/moderate-dose statins: TNT and IDEAL.

Combining these two trials gave a total of 15 056 patients (after those with diabetes were excluded), who were divided into two groups: those at low risk of new-onset diabetes (8825 patients with zero to one risk factor), and those at high risk (6231 patients with two to four risk factors).Results showed no difference in the development of new-onset diabetes with high-dose vs low-/moderate-dose statin in the low-risk population, but a 24% increase with the high-dose statin in high-risk patients. However, cardiovascular events were significantly reduced with the high-dose statin in both risk groups.

New-onset diabetes and cardiovascular events: Patients at low risk of diabetes

OutcomeAtorvastatin 80 mg (%)Atorvastatin 10 mg/ simvastatin
20-40 mg (%)
HR (95% CI)p
New-onset diabetes3.23.30.97
(0.77-1.22)
0.773
CV events8.59.80.87
(0.76-0.99)
0.042

New-onset diabetes and cardiovascular events: Patients at high risk of diabetes

OutcomeAtorvastatin 80 mg (%)Atorvastatin 10 mg/ simvastatin
20-40 mg (%)
HR (95% CI)p
New-onset diabetes14.311.91.24
(1.08-1.42)
0.003
CV events10.1120.82
(0.716-0.96)
0.011

The mechanism behind the diabetes risk is unclear.This is likely to be multifactorial and perhaps varies from one population to another.

It is important that people not be discouraged from using statins because of this risk.

 

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Lipid profiles: Fasting not necessary…
Jean Ducobu(UMons) Adapted from the heart.org

Requiring a patient to fast for many hours before a lipid test may soon be a thing of the past.

Although present guidelines encourage doctors to test for total lipids and lipid subclass levels only when a patient has fasted for more than eight hours, a report published online November 12, 2012 in the Archives of Internal Medicine found that there may no longer be a need for a patient to fast [1]. There is very little difference in lipid levels when measured in a fasting or nonfasting state, according to the research.

The incremental gain in information of a fasting profile is exceedingly small for total- and HDL-cholesterol values and likely does not offset the logistic impositions placed on our patients, the laboratories, and our ability to provide timely counseling to our patients.

To investigate the relationship between fasting duration and lipid levels in a large community-based population, the authors designed the study as a cross-sectional analysis of laboratory data.They used secondary data from Calgary Laboratory Services and examined the test results of every individual with lipid-test panels between April 1, 2011 and September 30, 2011.A policy change in 2011 allowed the laboratory to process samples for fasting lipid levels regardless of the duration of fasting time.

Fasting times ranged from one hour to more than 16 hours. Lipid results included the mean levels of HDL cholesterol, LDL cholesterol, total cholesterol, and triglycerides. A total of 209 180 participants were included in the analysis. Authors used linear regression models to project average cholesterol levels at various fasting times.

The study found that variation among mean cholesterol subclass levels was less than 2% for total cholesterol and HDL cholesterol, less than 10% for calculated LDL cholesterol, and less than 20% for triglycerides among individuals with various fasting times. Only a minority of fasting intervals had statistically significant differences among cholesterol subclass levels.

But the study is not without limitations:-The analyses assume that there is no systematic bias introduced by the timing of the blood draw. - No information was available on medications or repeated measures.- More data by age would have been helpful.- Other limitations are that the study did not examine individual meal choices before testing or control for recall errors of self-reported fasting time.

Future research, the authors suggest, should involve examining repeated measurements with differing fasting times in the same individuals.

Nevertheless, this might be presented as a possibility for some patients if further validated

 

Source

1. Sidhu D and Naugler C. Fasting time and lipid levels in a community-based population.
Arch Intern Med 2012; DOI:10.1001/archinternmed.2012.370.
Available at: http://archinte.jamanetwork.com/journal.aspx

 

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CSL-112(ApoA1 formulation) increases cholesterol efflux in humans
Jean Ducobu(UMons) Adapted from the heart.org

Initial clinical trials with the novel apolipoprotein A1 (apoA1) formulation CSL-112 (CSL Laboratories, Victoria, Australia) have shown that it rapidly enhances key biomarkers of the early stages of reverse cholesterol transport. It is thus being positioned as a new therapeutic approach to quickly lower the atherosclerosis burden in an attempt to reduce cardiovascular events in the initial days after an ACS.

CSL-112 is a reconstituted formulation of apoA1, the main component of HDL, derived from human plasma and reconstituted to form HDL particles suitable for infusion. As the natural function of HDL is to promote cholesterol efflux (the removal of cholesterol from tissue such as the arterial wall and subsequent transport to the liver for clearance from the body), the hope is that by rapidly raising HDL levels, CSL-112 will quickly reduce cholesterol-loaded plaques that contribute to cardiovascular events.

In one trial presented at the AHA meeting, 57 healthy volunteers were given a single infusion of CSL-112 at dose levels of 5 to 135 mg/kg. Blood samples taken from the volunteers were then tested and showed dose-proportional increases in HDL cholesterol, prebeta1-HDL, and cholesterol-efflux capacity from macrophages. The top dose of CSL-112 increased prebeta1-HDL by 3600% and global cholesterol efflux by 270%. There were no changes in levels of apoB, non-HDL cholesterol, and non-HDL triglycerides.

In a second placebo-controlled study in 36 healthy subjects, three dose regimens were studied: four once-weekly infusions of 3.4 g, four once-weekly infusions of 6.8 g, and eight twice-weekly infusions of 3.4 g. Results showed that infusions of CSL-112 caused immediate large increases in cholesterol-efflux capacity, prebeta1-HDL, and HDL in serum or plasma. Prebeta1-HDL were elevated up to 20-fold. For all three regimens, all biomarker responses were dose dependent and had a similar magnitude and time course after the first and last infusions. Increases in HDL peaked at 24 to 48 hours after infusion, but levels remained elevated after 72 hours. The results suggested that when compared with a single infusion of CSL112, multiple infusions may provide greater efflux of cholesterol.Safety data with CSL-112 will be scrutinized closely, because a previous version of the product, CSL-111, was discontinued due to liver toxicity. The company says it has reformulated the product (to produce CSL-112) to be less likely to cause liver problems.

In the 36-patient study, there where were no treatment-related serious adverse events reported. Overall, a similar proportion of subjects in the placebo group and CSL-112-treatment groups reported at least one adverse event, and none were reported as product-related. The most common adverse event was vessel puncture-site hematoma (seen in 18 of 36 subjects), which was reported by similar proportions of subjects administered CSL-112 or placebo.

In the CSL-112-treatment group, no clinically significant abnormalities were observed in serum biochemistry, hematology, and urine parameters. In addition, there were no remarkable changes seen in platelet function, vital signs, or ECG and no evidence of immunogenicity to CSL-112.

A third study presented at the AHA meeting was reported to show anti-inflammatory properties of CSL-112, which may also be beneficial in reducing cardiovascular events. In the in vitro study using human blood, CSL-112 caused a strong inhibition of the expression of intracellular adhesion molecule-1 (ICAM-1) (CD54) on both monocytes and neutrophils and inhibited the secretion of proinflammatory cytokines (TNFα , IL-1β , and IL-6) and chemokines (IL-8, RANTES, and macrophage inflammatory protein 1β [Mip-1β ]).Phase 2 trials of CSL-112 are currently under way in stable coronary artery disease patients, and a phase 2b study in ACS patients is now planned.

Although there are now doubts surrounding the HDL field following the failure of initial HDL-raising therapies to show any reduction in cardiovascular events, CSL suggests that that not all forms of HDL are equally effective in promoting reverse cholesterol transport and that the HDL formed by the cholesteryl ester transfer protein (CETP) inhibitors so far tested (torcetrapib and dalcetrapib) may not promote cholesterol efflux as effectively as CSL-112.

This is a very different approach from the other HDL-raising drugs we have seen before, in that it is the smaller prebeta-HDL that is being infused. Unlike the alpha HDL, which is raised with niacin and the CETP inhibitors, prebeta-HDL is not already heavily laden with cholesterol, so the theory is that it has more potential to load up with cholesterol from atherosclerotic plaques.

The Figure 13 describes the different HDL-C –raising therapies


Figure 13

 

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Two new PCSK9 MAbs for LDL-lowering in phase 2
Jean Ducobu(UMons) Adapted from the heart.org

PCSK9 binds to the LDL receptor, stopping it from releasing its LDL to be cleared. By binding to the PCSK9, the antibody prevents this from happening, so the LDL receptors can be recycled and more LDL can be cleared. Statins interfere with cholesterol production and stimulate the production of LDL receptors, while this antibody enables more LDL receptors to be available.

Three new phase 2 studies with two anti-PCSK9 monoclonal antibodies, all showing large reductions in LDL cholesterol, were presented at the American Heart Association 2012 Scientific Sessions. These antibodies, although still relatively early in clinical development, are generating much excitement, as their large effects on LDL reduction appear to be additive to that of the statins, and the hope is that they may enable the vast majority of patients to get to LDL goals.(Figure 14)

The antibodies work by inhibiting the PCSK9 protein. This PCSK9 protein binds to LDL receptors, resulting in their degradation, so that fewer are available on liver cells to remove excess LDL-C from the blood. Moreover, traditional LDL-lowering therapies such as statins actually stimulate the production of PCSK9, which limits their own ability to lower LDL-C. By blocking the PCSK9 pathway, these antibodies upregulate the recycling of LDL receptors and therefore represent a potentially novel mechanism for lowering LDL.


Figure 14

There are many of these antibodies in development, with the most data having been presented with the Regeneron/Sanofi product, REGN727/SAR236553. (Figure 15)


Figure 15

Phase 2 data with other antibodies from Amgen and Pfizer were reported, showing broadly similar effects, with LDL lowering of 40% to 60%, as well as moderate reductions in Lp(a): the Gauss Study , the Rutherford study and the Pfizer studies.

GAUSS in statin-intolerant patients

The GAUSS study was presented by Dr Evan Stein (Metabolic and Atherosclerosis Research Center, Cincinnati, OH) and published online simultaneously in the Journal of the American Medical Association [1]. In the study, 160 patients unable to tolerate statins due to muscle-related side effects were randomized to three different doses of AMG-145 (given by subcutaneous injection once every four weeks), a combination of AMG-145 plus ezetimibe 10 mg daily, or ezetimibe alone. Treatment was given for 12 weeks (three injections). Mean LDL at baseline was high at 193 mg/dL. AMG-145 was associated with large reductions in LDL, the greatest effect being seen in the group receiving combination therapy with ezetimibe.

GAUSS: Results at 12 weeks

Outcome AMG-145 280mg AMG-145 350mg AMG-145 420mg AMG-145 420 mg + ezetimibe Ezetimibe alone
Change in LDL from baseline (%) -41 -43 -51 -63 -15
Patients reaching LDL goal of <100 mg/dL (%) 47 53 61 90 7
Patients reaching LDL goal of <70 mg/dL (%) 9 17 29 62 0

Four patients suffered a serious event—acute pancreatitis, coronary artery disease, hip fracture, and syncope, but none of these were considered treatment related.In terms of side effects, muscle issues occurred in roughly 3% of patients on monotherapy, similar to that with ezetimibe, but this was increased to 5% to 6% on combination treatment.Two patients had CK elevations over 10 times the upper limit of normal, one of which was adjudicated as a myopathy event. No liver abnormalities were seen.

RUTHERFORD in FH patients

A second study with AMG-145, RUTHERFORD, in heterozygous familial-hypercholesterolemia patients, was presented by Raal and published simultaneously in Circulation [2].

In the study, 168 patients already on statins but with high LDL levels (average 158 mg/dL) were randomized to one of two doses of AMG-145 (again given once a month for three months) or placebo. Similar results as in the GAUSS study were seen.

RUTHERFORD: Results at 12 weeks

Outcome AMG-145 350 mg (n=55) AMG-145 420 mg(n=56) Placebo(n=56)
Change in LDL from baseline (%) -43 -55 +1
Patients reaching LDL goal of <100 mg/dL (%) 70 89 2
Patients reaching LDL goal of <70 mg/dL (%) 44 65 0

Two patients had a serious event (atrial fibrillation and acute appendicitis), neither of which were considered treatment-related.Three patients given AMG-145 had CK elevations, all related to strenuous exercise, which resolved spontaneously. Other side effects were nasopharyngitis (12%), injection-site pain (3% to 9%), and headache (5%).

The latest phase 2 study with the product, published online October 31, 2012 in the New England Journal of Medicine, was conducted by a team led by Dr Eli Roth (Sterling Research Group, Cincinnati, OH)(3).

The study involved 92 patients with LDL levels of 100 mg/dL or higher after receiving atorvastatin 10 mg for at least seven weeks. They were randomized to eight weeks of treatment with atorvastatin 80 mg daily plus REGN727/SAR236553; atorvastatin 10 mg daily plus REGN727/SAR236553; or atorvastatin 80 mg daily plus placebo. REGN727/SAR236553 was given once every two weeks by subcutaneous injection.

Results showed a much greater reduction in LDL in the two groups receiving the anti-PCSK9 antibody than in those receiving atorvastatin 80 mg alone.(Figure 16)

LDL lowering with atorvastatin alone or plus REGN727/SAR236553

Group Lowering of LDL from baseline (%) p (vs atorvastatin 80 mg plus placebo)
Atorvastatin 80 mg plus antibody 73.2 <0.001
Atorvastatin 10 mg plus antibody 66.2 <0.001
Atorvastatin 80 mg plus placebo 17.3 -


Figure 16

All patients who received the antibody achieved an LDL below 100 mg/dL, compared with 52% of those who received atorvastatin 80 mg alone. And 90% of those who received the antibody achieved an LDL below 70 mg/dL, compared with 17% of those who received atorvastatin 80 mg alone.As in previous studies with REGN727/SAR236553, there was a reduction of nearly one-third in levels of Lp(a) in patients given the antibody.

The observation that there was not a great difference between the LDL lowering in patients taking atorvastatin 10 mg plus REGN727/SAR236553 and those taking atorvastatin 80 mg plus REGN727/SAR236553 may suggest that there is a maximal effect when the antibody is on board and additional amounts of statin then won't make much difference.

But despite this observation, high-dose statins will remain the mainstay of treatment.

Statins have been proven to reduce events and so must be the basis of lipid-lowering therapy. While we do believe that further lowering of LDL should translate into clinical benefit, we don't know this for sure with these antibodies yet, and so until outcome data are available, they can be viewed only as add-ons to statin therapy. However, many patients can't take high-dose statins, and even if they can, there appear to be more benefits from adding in this antibody.

In terms of side effects, the antibody seems to have a good profile, with only a few minor injection-site reactions and some minor elevations in liver enzymes. The next step will be now focused on safety and long-term outcomes..

Much more information on all these issues will become available from large-scale phase 3 trials that are now starting with both the Regeneron/Sanofi and Amgen products in post-ACS patients. Also today, Sanofi and Regeneron announced the start of a phase 3 outcomes trial with SAR236553/REGN727. The ODYSSEY Outcomes trial will enroll approximately 18 000 patients who recently suffered an ACS and are not at their LDL goal, testing the efficacy and safety of SAR236553/REGN727 (a 75-mg subcutaneous injection once every two weeks) added to maximal doses of statins in reducing cardiovascular events.

LDL levels under 30 mg/dL will be seen

The issue of very low LDL levels (<30 mg/dL) induced by PCSK9 inhibitors will probably not be problematic. Noting that Brown and Goldstein have stated that physiological LDL should be around 25 mg/dL, Kastelein presented his own meta-analysis (as yet unpublished) of seven large statin trials suggesting that events continue to be reduced with LDL lowering right down to 30 mg/dL.Lower levels of LDL seem to confer cardiovascular protection right down to physiological levels of under 30 mg/dL.

Moreover,patients with total PCSK9 deficiency have very low LDL, without clinical sequellae( Figure 17)


Figure 17

 

Source

  • 1. Sullivan D, Olsson A G, 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; DOI:10.1001/jama.2012.25790. Available here.
  • 2. 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; DOI:10.1161/CIRCULATIONAHA.112.144055. Available at: http://circ.ahajournals.org.
  • 3. Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N EnglJ Med 2012. DOI:10.1056/NEJMoa1201832. Available at: http://www.nejm.org

 

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Wider fibrate use in mild to moderate CKD?
Jean Ducobu(UMons) Adapted from the heart.org

A new meta-analysis (Jun M et al) shows that fibrate therapy improves lipid profiles and prevents cardiovascular events in people with chronic kidney disease (CKD), cutting CV deaths by 40% [1]. The findings also show that despite increasing serum creatinine—a long-known side effect of fibrates—the drug class caused no harm to the kidneys in the long run and may even provide some renal

Hence, they conducted a search of MEDLINE, EMBASE, and the Cochrane Library from 1950 to January 2012 for prospective randomized controlled trials assessing the effects of fibrate therapy compared with placebo in people with CKD or on kidney-related outcomes. Ten studies including 16 869 participants were identified. Fibrates improved lipid profiles in patients with mild to moderate CKD (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2).

Specifically, fibrates lowered total cholesterol [-0.32 mmol/L, p=0.05] and triglyceride levels [-0.56 mmol/L, p=0.03] but not LDL cholesterol [-0.01 mmol/L, p=0.83]. They increased HDL cholesterol [0.06 mmol/L, p=0.001].Fibrates reduced the risk of major cardiovascular events by 30% (RR 0.70, p=0.004) and cardiovascular death by 40% (RR 0.60, p=0.03) in those with mild to moderate CKD but did not affect all-cause mortality. , This is likely because CKD patients typically have high triglycerides and low levels of HDL, and this is the lipid profile that appears to particularly benefit from fibrates

In people with diabetes, fibrates reduced the risk of albuminuria progression by about 14% (p=0.02). Serum creatinine was elevated in some patients by fibrates, however, by around 25% (p<0.001), and calculated GFR was reduced (-2.67 mL/min/1.73 m2, p=0.01), but there was no detectable effect on the risk of end-stage kidney disease (RR 0.85, p=0.575).

Thus, overall, the results suggest that fibrates could be used more broadly in patients with mild to moderate CKD to prevent cardiovascular disease. Any spike in creatinine seen on starting therapy will reverse, and the meta-analysis shows fibrates reduced proteinuria, so they may even be protective for the kidney. But there was not enough information on people with advanced kidney disease to draw any firm conclusions regarding the use of fibrates in these patients. There is no particular reason to think things are going to be different, but it would be reassuring to have the data before using fibrates widely in that population.

In an accompanying editorial [2], Dr Peter A McCullough (St John Providence Health System, Warren, MI) and Dr Michael J Di Loreto (St John Hospital and Medical Center, Detroit, MI) suggest that the fibrates are some of the best-tolerated drugs to treat dyslipidemia, and the paper by Jun and coworkers supports their use in patients with CKD.Furthermore, there appears to be a cardiorenal benefit of this class of drugs in reducing renal blood flow and, to an extent, attenuating glomerular hyperfiltration and microalbuminuria. Future trials should plan a priori cardiorenal end points for lipid-lowering therapy when off-target pharmacologic effects are possible. Sources

 

Source

  • 1. Jun M, Zhu B, Tonelli M, et al. Effects of fibrates in kidney disease, a review and meta-analysis. J Am Coll Cardiol 2012; DOI:10.1016/j.jacc.2012.07.049. Available at: http://content.onlinejacc.org.
  • 2. McCullough PA and Di Loreto MJ. Fibrates and cardiorenal outcomes. J Am Coll Cardiol 2012; DOI:10.1016/j.jacc.2012.06.058. Available at: http://content.onlinejacc.org.

 

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