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Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients
The HPS2-THRIVE Collaborative Group
N Engl J Med 2014; 371:203-212
July 17, 2014
BACKGROUND
Patients with evidence of vascular disease are at increased risk for subsequent vascular events despite effective use of statins to lower the low-density lipoprotein (LDL) cholesterol level. Niacin lowers the LDL cholesterol level and raises the high-density lipoprotein (HDL) cholesterol level, but its clinical efficacy and safety are uncertain.
METHODS
After a prerandomization run-in phase to standardize the background statin-based LDL cholesterol–lowering therapy and to establish participants' ability to take extended-release niacin without clinically significant adverse effects, we randomly assigned 25,673 adults with vascular disease to receive 2 g of extended-release niacin and 40 mg of laropiprant or a matching placebo daily. The primary outcome was the first major vascular event (nonfatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization).
RESULTS
During a median follow-up period of 3.9 years, participants who were assigned to extended-release niacin–laropiprant had an LDL cholesterol level that was an average of 10 mg per deciliter (0.25 mmol per liter as measured in the central laboratory) lower and an HDL cholesterol level that was an average of 6 mg per deciliter (0.16 mmol per liter) higher than the levels in those assigned to placebo. Assignment to niacin–laropiprant, as compared with assignment to placebo, had no significant effect on the incidence of major vascular events (13.2% and 13.7% of participants with an event, respectively; rate ratio, 0.96; 95% confidence interval [CI], 0.90 to 1.03; P=0.29). Niacin–laropiprant was associated with an increased incidence of disturbances in diabetes control that were considered to be serious (absolute excess as compared with placebo, 3.7 percentage points; P<0.001) and with an increased incidence of diabetes diagnoses (absolute excess, 1.3 percentage points; P<0.001), as well as increases in serious adverse events associated with the gastrointestinal system (absolute excess, 1.0 percentage point; P<0.001), musculoskeletal system (absolute excess, 0.7 percentage points; P<0.001), skin (absolute excess, 0.3 percentage points; P=0.003), and unexpectedly, infection (absolute excess, 1.4 percentage points; P<0.001) and bleeding (absolute excess, 0.7 percentage points; P<0.001).
CONCLUSIONS
Among participants with atherosclerotic vascular disease, the addition of extended-release niacin–laropiprant to statin-based LDL cholesterol–lowering therapy did not significantly reduce the risk of major vascular events but did increase the risk of serious adverse events. (Funded by Merck and others; HPS2-THRIVE ClinicalTrials.gov number, NCT00461630.)
It probably is a CITI typo. Amarin was one of about 50 bios listed. I copied the $7.50 TP correctly and their "quick thesis". But in another table in the same biotech valuation 9 page article I found a $1.75 TP for AMRN. Quick thesis may have been put together too quickly because yield was spelled incorrectly and the "out" probably was suppose to be our.
CITI on AMRN (6-24-14). We believe the approved MARINE indication for Vascepa could still yeild upside, however are moving to the sidelines untill the commercial execution to capture this potential becomes more clear. Upside from a surprise reversal in the FDA dispute resolution over the ANCHOR SPA, or Irish inversion exist, but both events are a long shot in out view. TP $7.50
After Valeant bought Biovail in 2010 it made a huge blunder. Biovail had previously partnered up an Acadia drug. Valeant decided Pimavanserin didn't fit into its strategic focus so they shot themselves in the foot and gave it back to ACAD. To top it off Valeant actually gave ACAD $8.75 million to end the collaboration!
ICTI is smartly cashing in on mixed trial results. Remember the dose they expected to be their most effective dose flunked. Their excuse was the higher dose must have made their patients too drowsy. But most antipsychotics cause more drowsiness as you rise in dose but still retain their therapeutic effect. 4 week schizo trials with arms under 100 frequently show a placebo effect. Reminds me a little of Lilly's schizo drug LY2140023 which also worked on glutamate receptors. Unfortunately like most of Lilly's recent CNS adventures the larger trial bombed.
"Treatment with LY2140023 or olanzapine resulted in statistically significant improvement in PANSS (Positive and Negative Syndrome Scale) total score (primary outcome) compared to placebo (-20.8, P < 0.001; -26.7, P < 0.001; respectively), After four weeks of treatment, the study showed that both the LY2140023 group (32.0%, P < 0.001) and the olanzapine group (41.2%, P < 0.001) demonstrated significantly greater response rates compared to the placebo group (3.2%). Response was measured primarily by the PANSS, the most common scale used for measuring symptoms of patients with schizophrenia."
ACAD at Roth replay
http://www.wsw.com/webcast/roth28/#table2
I was lucky to start buying shortly after you put ACAD on your watch list. Pimavanserin is unique in that it selectively blocks just the 5ht2a receptor. That allows for fewer side effects in a world that has been turning against the current antipsychotics which hit 5HT2A but also a bunch of other targets that increase weight, diabetes, cognitive impairment and mortality. I expect ACAD's price to reach $40 later this year after Pima's NDA has been submitted to the FDA. ACAD owns 100% of Pima, has no debt and will have >$300 million in the bank after this stock offering.
A FDA decision delay is a positive sign imo. A FDA reversal won't come easy. Remember that classic movie 12 angry men. The longer the discussion takes the more likely the FDA is starting to listen to different voices.
Thero presents for AMRN on 1-15-14 at JP Morgan. Should be an interesting talk with all the changes and the 15th is also the last day for a FDA response.
http://jpmorgan.metameetings.com/confbook/healthcare14/agenda.php
Positive EPA/AA paper in Jan 2014 Diabetic Care
http://care.diabetesjournals.org/content/37/1/e7.full.pdf+html
Two AMRN supported CE presentations
http://www.powerpak.com/course/content/109621
Vascepa Coverage Update
http://whatcounts.jobson.com/dm?id=3FCAD4F2EE70DCC7F389141CBD7E4C48
Lipidworld Paper shows higher trigs = higher CVD
We quantitatively assessed the association between blood triglyceride levels at baseline and CVDs mortality in 33 studies with 17,018 cases among 726,030 participants, as well as all-cause mortality in 38 studies with 58,419 cases among 360,566 participants. Compared to the referent, the risks of CVDs and all-cause mortality were increased by 15.0% and 9.0% in the borderline hypertriglyceridemia group, and 25% and 20% in the hypertriglyceridemia group, respectively. Overall, the risks of CVDs and all-cause death were increased by 13% and 12% per 1-mmol/L increase in TG level.
These findings were robust. We incorporated a large number of participants and deaths (a total of 17,018 CVDs deaths in 726,030 participants and 58,419 all-cause deaths in 330,566 participants), which improved the statistical power for detecting potential associations. Additionally, the studies included in our sample were carried out worldwide, with participants from the America, Europe, Asia, and Australia, thus enhancing generalizability. Furthermore, only prospective cohort studies were considered. The participants in 33 of the studies had no history of CVDs at baseline and the follow-up duration in 44 was more than 10 years, largely eliminating the possibility of reverse causation relationship. Participants were also selected from the general population, thus reducing potential selection bias. In addition, we used the Newcastle-Ottawa Scale to evaluate the quality of studies and most of the studies (50 studies) included in this meta-analysis were high-quality (score >6, full score?=?9). Finally, there was a large degree of consistency between the continuous and categorical analyses.
We observed that elevated TG levels were associated with an increased risk of CVDs mortality echoing the findings of several other meta-analyses of prospective studies demonstrating a relationship between higher TG levels and an increased risk of cardiovascular events [4,5,23]. In 1996, Hokanson et al. [4] performed a meta-analysis comprising 46,413 men and 10,864 women from the USA and Europe. Their summary crude RRs for fatal CVDs from seven prospective studies were 1.24 in men and 1.84 in women per a 1-mmol/L increase. In the present meta-analysis, the RRs of CVDs mortality was lower. However, the discrepancy was unlikely to be caused by geographic variations as we observed similar results in the European and American and Asia-Pacific samples in the present study. Hypertriglyceridemia is commonly associated with diabetes, obesity, hypertension, and smoking, which are independent risk factors for CHD [24,25]. The pooled crude RR in the study by Hokanson et al. might be confounded by these factors as the adjusted overall RR of fatal and non-fatal CVDs for women declined from the crude value of 1.76 to 1.37 [4]. The subgroup analysis of the seven studies that reported both maximally and minimally adjusted data demonstrated that the overall RRs were significantly lower for the maximally adjusted original data, than that for the minimally adjusted. In the present meta-analysis, the data in the majority of the studies were adjusted for common potential confounders, such as age, gender, blood pressure, BMI, diabetes, smoking and TC, and would thus have better validity than unadjusted data.
We also found that an association between elevated TG levels and an increased risk of all-cause mortality. In fact, TG levels were found to have a similar predictive power for CVDs and all-cause mortality. It was thus reasonable to hypothesize that there was a positive relationship between TG and non-CVDs death. Prospective studies have found that elevated TG levels increases the risk of non-CVDs mortality [26]. A collaborative study of metabolic syndrome and cancer (Me-Can) involving 514,097 participants with a 13.4-year follow-up, demonstrated a positive association between serum TG and risk of cancer overall and at several sites. The RR (95% CI) for the top quintile versus the bottom quintile of triglycerides for overall cancer was 1.16 (1.06 to 1.26) in men and 1.15 (1.05 to 1.27) in women [3]. Previous studies have also reported that elevated TG levels increased the risks of other deaths, such as from kidney disease [27,28] or suicide [29]. Hence, non-CVDs mortality may contribute to the relative risk of all-cause mortality.
There are several possible explanations for these findings. Firstly, TG is associated with atherogenic remnant particles, which have a high uptake into macrophages leading to foam cell formation. Furthermore, triglyceride-rich lipoproteins and their remnants promote inflammation and increase the expression of coagulation factors or leukocyte adhesion molecules [2]. An increased number of atherogenic particles may thus adversely influence CVDs risk. Secondly, hypertriglyceridemia is associated with the development of oxidative stress and reactive oxygen species (ROS) [30]. ROS directly influences cell proliferation and apoptosis and modulates DNA methylation patterns; and thus may contribute to the multistage carcinogenesis process [31]. Additionally, increased oxidative stress in fat has been shown to be an important pathogenic pathway in metabolic syndrome. In addition, elevated triglyceride-rich lipoproteins may adversely influence the risk of chronic kidney diseases, as triglyceride-rich apolipoprotein B-containing lipoproteins promote the progression of renal insufficiency [32]. Moreover, oxidative stress and endothelial dysfunction may cause atherosclerosis-related kidney damage in older people [33]. Finally, hypertriglyceridemia has been associated with increased cortisol levels in response to stress and symptoms of depression, which may lead to an increased risk of suicide [29].
In the present study, we found that elevated blood TG was associated with greater total death and CVDs death risk in women than in men, which was consistent with prior studies [4,5]. A collaborative study and a large prospective study also showed that TC and HDL-c were more predictive of CVDs mortality in women than in men [34,35]. However, the mechanism remains unclear and further studies are needed to clarify this issue. The subgroup analysis in the present study showed that studies with longer follow-up periods had significantly higher risk estimates for mortality, possibly due to the greater cumulative risks associated with longer TG exposure.
This meta-analysis has several limitations. First, there was considerable heterogeneity among the studies included with analysis showing that the major sources of heterogeneity to be gender, adjustment for TC, and follow-up duration. Second, 28 studies that included participants with a prior history of CVDs at baseline were not excluded. Previous studies have reported that excluding participants with a history of CVDs at baseline did not substantially change the risks of CVDs mortality [36]. In addition, subgroup analysis suggested that the overall RRs for all-cause and CVDs mortality in relation to TG were not markedly influenced by prior CVDs history. Third, elevated TG levels were accompanied by low HDL-c and high TC, both of which have been associated with a higher CVDs risk [1,2]. In the present meta-analysis, subgroup analysis observed that the effect sizes were significantly decreased after adjustment for TC although the positive relationship remains significant. The overall effect estimates were unlikely to be biased by TC since most of original studies (45/61) reported TC-adjusted RRs, but it tended to be overestimated because few (10/61) studies reported HDL-adjusted RRs. Fourth, the studies included in the present meta-analysis were mainly based on a one-time measurement of baseline blood TG (five studies adjusted for regression dilution bias), which may underestimate the associations due to regression dilution effects. Finally, the relatively small number of studies that included categorical analysis limited the ability to detect heterogeneity in the subgroup analysis.
In conclusion, elevated blood TG levels were dose-dependently associated with a greater risk of both CVDs and all-cause mortality. The findings of this meta-analysis suggest that controlling TG can help to prevent CVDs and other causes of death.
FULL PAPER AT THIS LINK
http://www.lipidworld.com/content/12/1/159
AHA November Conference Abstracts
19343/2016 - Pharmacokinetic and Triglyceride-Lowering Pharmacodynamic Effects of Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) Across Clinical Studies
Rene Braeckman, Amarin Pharma Inc., Bedminster, NJ; Harold E. Harold, Louisville Metabolic and Athersclerosis Res Ctr, Louisville, KY; Christie M. Ballantyne, Baylor Coll of Med and the Methodist DeBakey Heart and Vascular Ctr, Houston, TX; William G. Stirtan, Paresh N. Soni, Amarin Pharma Inc., Groton, CT
------------------------------
19342/2069 - High-Sensitivity C-Reactive Protein Effects of Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) With and Without Stable Statin Therapy in Hypertriglyceridemic Patients With Metabolic Syndrome Harold Bays, L-MARC Res Ctr, Louisville, KY; Christie M. Ballantyne, 2Baylor Coll of Med and the Methodist DeBakey Heart and Vascular Ctr, Houston, TX; Rene A. Braeckman, Amarin Pharma, Inc., Bedminster, NJ; William G. Stirtan, Paresh N. Soni, Amarin Pharma, Inc., Groton, CT
------------------------------
17413/2054 - The Ratio of EPA/AA Associates With Age of Patient Undergoing Coronary Intervention and Frequency of ST-segmental Elevation Myocardial Infarction
------------------------------
14551/2189 - Lower Omega-3 Fatty Acid Levels Could Predict Coronary Plaque Vulnerability in Patients With Coronary Artery Disease
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15319/4019 - Low Serum Eicosapentaenoic Acid Level is a Risk for Ventricular Arrhythmia in Patients With Acute Myocardial Infarction: A Possible Link to J-Waves
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15404/7113 - Eicosapentaenoic Acid Ameliorates Pulmonary Hypertension via G Protein-Coupled Receptor 120 Pathway in Rats
------------------------------
14678/2186 - Lower Serum Eicosapentaenoic Acid Predicts the Incidence of Paroxysmal Atrial Fibrillation During Hospital Stay in Patients With Acute Coronary Syndrome
-----------------------------
Debate: Treat HDL-C and Triglycerides Alberico Catapano, Milan, Italy Sunday Morning Program
SMP.205. Clinical Lipidology: Controversies in Cardiovascular Risk Reduction
Sun, Nov 17, 8:00 - 11:00 AM
-----------------------------
Debate: Do Not Treat HDL-C and Triglycerides Neil J Stone, Chicago, IL Sunday Morning Program
SMP.205. Clinical Lipidology: Controversies in Cardiovascular Risk Reduction
Sun, Nov 17, 8:00 - 11:00 AM
----------------------------
http://www.abstractsonline.com/Plan/SSResults.aspx
Pima approval for PDP ensures usage for LBD. Like parkinson's these patients frequently get dopamine supplementation but have a much higher rate of psychosis. Same docs treat both diseases so imo this is an automatic add on that investors are missing.
JL I think the AMD indication would be the easier trial to run. Dry eye is the larger indication but its endpoint is not as easy to define as AMD 's lines for visual acuity. A small cheap P2 might be worth the cost if it could be done quickly.
All patients improved in this AMD study. Note that Dr Sears is a co-author.
Pilot Study for Treating Dry Age-related Macular Degeneration (AMD) with High-Dose Omega-3 Fatty Acids
Tassos Georgioua, , , Anastasia Neokleousa, Despina Nikolaoua, Barry Searsb
a Ophthalmos Research and Educational Institute. Morfou 48, EngomiNicosia, 2417 Cyprus
b Inflammation Research Foundation, Marblehead, MA 01945 USA
Abstract
Age-related macular degeneration (AMD) is the primary cause of blindness in individuals older than 50 years of age. Studies were carried in patients with dry AMD using high-dose omega-3 fatty acids providing 3.4 grams of eicosapentaenoic acid (EPA) and 1.6 g of docosahexaenoic acid (DHA) on a daily basis for 6 months. In patients with dry AMD, significant improvement in vision acuity occurred in 100% of patients was observed within four and half months after omega-3 supplementation.
http://www.sciencedirect.com/science/article/pii/S221343441300042X
Imo a Big Pharma would be very interested in AMRN with a NCE. BP probably has little interest in waiting for Vascepa's late 2017 results without the NCE. The NCE provides the generic protection that a outcome trial needs.
Dew I agree the Anchor indication looks dead. But the layoffs could also be a signal that:
1) FDA decided to give AMRN the NCE.
2) Big pharma discussions are getting serious.
3) Lawyers want to show damages the FDA caused with a broken spa.
If AMRN tries to finish the Reduce-it CVD outcomes trial it won't be finished until late 2017. Without a NCE isn't it likely there will already be a generic Vascepa on the market? Just wondering if it makes any economic sense to spend $100 million more on a trial without a NCE in hand. Is the NCE a bone the FDA can give to AMRN as an incentive to finish the CVD trial? Without the NCE or a label expansion I doubt it gets done.
The FDA wants to see the data from Reduce-it, The last thing they want to see is AMRN halting the only trig outcome trial running. AMRN needs to clearly explain to the FDA before PDUFA that a refusal to honor its spa will immediately force it to stop Reduce-it and fire half of its employees. He should explain the Anchor indication was needed to pay for R-I. AMRN should request a conditional FDA approval that can be withdrawn by the FDA if Reduce-it fails. CEO needs to make sure the FDA fully understands the consequences of their action before they break their SPA agreement with AMRN. AMRN fulfilled its part of the SPA with a safe and sig Anchor trial and expect the FDA to honor its SPA.
Thanks. The sticking point I think is the assumption of the CV benefit without an outcomes trial. That is where the spa makes this a special situation and has consequences on future spas and their reliability. I wonder if the FDA could give a conditional approval that is automatically removed if the Reduce-it trial fails.
Dew are you aware of any other lopsided no AdComs that the FDA ignored and gave approval?
Amrn still has a chance in Dec because of the spa. AMRN perhaps should state that they would be willing to ask for removal of the label if the reduce-it fails which might appease the FDA. AMRN should also play hardball and threaten the FDA to stop the outcome trial due to lack of funds to pay for it.
Please cut the dog guy off.
Jefferies predicts 7 to 3 in Favor
Amarin (AMRN) FDA Panel Predicted 7-to-3 in Favor of Approval - Jefferies
October 15, 2013 3:14 PM EDT
After analyzing the last 13 FDA endocrine panel meetings, Jefferies analyst Thomas Wei is confident Amarin Corporation (NASDAQ: AMRN) the panel will support approval.
"We analyzed the last 13 FDA endocrine panel meetings, specifically the votes and relevant commentary from the 10 committee members on AMRN's Wed panel for Vascepa label expansion for the ANCHOR indication," Wei said. "We would predict a 7-3 vote in favor of approval. That said, many of our predicted votes are based on mixed evidence, which could lead to a close outcome on Wed."
Commenting on the seven potential 'Yes' votes, Wei says: "We count four likely Yes votes (Dr. Seely, Dr. Wilson, patient rep, consumer rep). Dr. Seely has the most positive voting record of any panelist in this division,and the reps have shown a natural bias to increased patient access to new drugs. We found comments from Dr. Wilson on the importance of TG as an important CV risk marker and support for surrogate endpoints. We favor a Yes vote for Dr. Hiatt following strong opinions on post-approval CV outcomes testing in other diseases, but we remain concerned about one negative comment on the utility of lipid endpoints for another TG-lowering drug. We are leaning to a Yes vote for Dr. Everett, although he has participated in only one prior panel and his commentary had limited relevance to AMRN's situation. The biostatistician is another tenuous Yes prediction, as he is new to FDA panel meetings, so we base our analysis from past biostatisticians who have generally voted in favor of drug approvals and post-approval CV outcomes testing."
On the three likely 'no' votes, Wei comments: "All three predicted No votes (Dr. Smith, Dr. Cooke, Dr. Gregg) were difficult to call, but we were influenced by commentary in all three cases indicating a bias against surrogate endpoints. That said, the actual votes from these three panelists were generally positive, and for the two panelists on an obesity drug panel, they both voted for approval on the basis of weight loss as a surrogate endpoint."
Wei maintained a Buy rating and $20 price target on AMRN.
http://www.streetinsider.com/Analyst+Comments/Amarin+(AMRN)+FDA+Panel+Predicted+7-to-3+in+Favor+of+Approval+-+Jefferies/8778702.html
Zu thanks. This presentation Bays owns the audience.
What tests should we order to define CVD risk in the HTG + DM-2 patient?
http://professional.diabetes.org/Presentations_Details.aspx?session=4121
Adam is backing off his previous tweet about a doc badmouthing pima at Cowen's healthcare conf. But there is a huge vol with this drop so I'm guessing the Baker Boys or RA Capital may be cashing in on some of their huge ACAD gains.
adamfeuerstein11m
$ACAD - None of the docs on Cowen panel taking place right now are slamming pimvanserin, according to a source on the scene.
Dew imo the Accord trial actually supports the Anchor and Jelis studies when you consider the subset pop with trigs >204mg/dl. The Accord trial tested an average trig pop that measured only 162mg/dl.
Meeting Coverage
ACC: ACCORD May Bring Few Changes to Clinic
Published: Mar 17, 2010
By Crystal Phend , Senior Staff Writer, MedPage Today
ATLANTA -- Practice as usual may be the order of the day in the wake of an ACCORD trial finding that there's no cardiovascular risk reduction from intensified lipid and blood pressure management among diabetic patients.
Leading cardiologists here at the American College of Cardiology meeting saw the results as a reaffirmation of current clinical treatment standards and guidelines.
The major fallout from the trial may be yet to come: in an unprecedented action, the FDA announced shortly after the presentation here that it would review the indication for Abbott Laboratories' Trilipix delayed-release formulation of fenofibrate (fenofibric acid). (See ACC: FDA Announces Review of ACCORD Data)
The lipid study within the complex, double two-by-two factorial designed trial showed that adding fenofibrate to statin therapy failed to reduce major adverse cardiovascular events (2.24% versus 2.41% per year, HR 0.92, P=0.32).
The results weren't surprising, given a group of diabetic patients at high risk for coronary events but with varying triglyceride levels that averaged only 162 mg/dL, according to Paul D. Thompson, MD, of the University of Connecticut and Hartford Hospital, who was a discussant at the late-breaking clinical trials session.
Entry criteria included LDL cholesterol between 60 and 180 mg/dL, HDL under 50 mg/dL (55 mg/dL for women and blacks), and triglycerides under 750 mg/dL if not on any therapy or 400 mg/dL otherwise.
This range fits the clinical spectrum most commonly seen in practice, commented Brian O'Murchu, MD, of Temple University in Philadelphia, a co-chair of the ACC's annual scientific sessions planning committee and the late-breaking session.
However, fenofibrates are currently used primarily to bring down high triglycerides, Thompson said.
Notably, one of the few subgroups to show a trend for benefit with fenofibrates consisted of patients with triglycerides over 204 mg/dL and HDL cholesterol of 34 mg/dL or less (12.4% versus 17.3% reporting major adverse cardiovascular events, P=0.057).
These parameters closely match the ATP III guidelines definition of high triglyceride levels (200 mg/dL or more) and low HDL cholesterol level (below 40 mg/dL). For these patients, the guideines recommend adding other agents to a statin regimen.
"I don't think really, quite frankly, [the trial] is going to have a lot of effect on practice," Thompson said. "I don't think the drug at the present time is being used just routinely in diabetes; it's probably being restricted to those with high triglycerides, low HDL."
Henry C. Ginsberg, MD, of Columbia University in New York City, who presented the ACCORD lipid study results, agreed.
If clinicians accept the subgroup findings, fibrate use may actually rise, since even now, few patients who fit into this subgroup currently get it in combination with a statin, Ginsberg said.
"I think that's the role for this drug," he declared.
http://www.medpagetoday.com/MeetingCoverage/ACC/19067
Study points to a key role for triglycerides
posted october 6, 2013
ANN ARBOR, Mich. — A global hunt for genes that influence heart disease risk has uncovered 157 changes in human DNA that alter the levels of cholesterol and other blood fats – a discovery that could lead to new medications.
Each of the changes points to genes that can modify levels of cholesterol and other blood fats and are potential drug targets. Many of the changes point to genes not previously linked to blood fats, also called lipids. A surprising number of the variations were also associated with coronary artery disease, type 2 diabetes, obesity, and high blood pressure.
The research also reveals that triglycerides – another type of blood lipid – play a larger role in heart disease risk than previously thought.
The results, published in two new papers appearing simultaneously in the journal Nature Genetics, come from the Global Lipids Genetics Consortium -- a worldwide team of scientists who pooled genetic and clinical information from more than 188,000 people from many countries and heritages.
The analysis of the combined data was led by a team from the University of Michigan Medical School and School of Public Health. They used sophisticated computing and statistical techniques to search for genetic variations that modify blood lipid levels.
The results increase by more than a third the total number of genetic variants linked to blood lipids. All but one of the variants associated with blood lipids are near stretches of DNA that encode proteins.
"These results give us 62 new clues about lipid biology, and more places to look than we had before," says Cristen Willer, Ph.D., the lead author of one paper and an assistant professor of Internal Medicine, Human Genetics and Computational Medicine & Bioinformatics at the U-M Medical School. "Once we take the time to truly understand these clues, we'll have a better understanding of lipid biology and cardiovascular disease -- and potentially new targets for treatment."
But, cautions senior author and U-M School of Public Health Professor Gonçalo Abecasis, Ph.D., it will take much further work to study the implicated genes and to find and test potential drugs that could target them. The consortium's "open science" approach will include publishing further detail online for other researchers to use freely toward this goal.
A further analysis of the massive dataset, published as a letter with lead authors Sekar Kathiresan and Ron Do from Harvard University and the Broad Institute, suggests that triglyceride levels have more impact on cardiovascular disease risk than previously thought.
This analysis found that genetic variations that increase triglyceride or LDL-cholesterol levels are also associated with higher incidence of heart disease. But the analysis also casts further doubt on the role of high density lipoprotein, known commonly as HDL or "good cholesterol", in heart disease risk. In recent years, many drugs that modify HDL cholesterol have failed to show a benefit in preventing heart disease.
"We couldn't have done this on our own. Great scientists are usually very competitive, but it is great when we come together and accelerate progress." says Abecasis, who is the Felix E. Moore Collegiate Professor of Biostatistics, and director of the U-M Computational and Translational Genomics Initiative.
The right tool for the right SNPs
The GLGC is focused on finding, cataloging and analyzing genetic variations that modify blood lipids and heart disease risk. The researchers had access to a new tool – a custom DNA analysis chip they helped design that allows inexpensive analysis of DNA in studies of cardiovascular and metabolic traits.
Combined with genome-wide association study (GWAS) techniques, and the sheer number and diversity of the participants engaged by the researchers, the chip helped make the research possible on a much larger scale than ever before.
U-M graduate students Ellen M. Schmidt and Sebanti Sengupta – studying Bioinformatics and Biostatistics, respectively – played key roles in analysis of data, blending their skills to handle a massive amount of data and feed it through powerful computers.
Next steps
Willer says the new knowledge published in the papers should fuel drug development and experiments in animal models of cardiovascular risk. But in her specialty, probing huge amounts of genetic data, the next steps include looking for "networks" of genes that interact with one another, to try to glean clues about the function of the lesser-understood genes.
Looking for rare genetic variants that are linked with the most severe forms of lipid disorder and heart disease is another challenge, she says. The overlap between these rare, serious variations, and the more common but less severe variations, could help understanding of basic lipid biology.
http://www.sciencecodex.com/massive_dna_study_points_to_new_heart_drug_targets_and_a_key_role_for_triglycerides-120555
Source: University of Michigan Health System
Thanks for your posts Jim. I own some ZLCS and was encouraged when Corrigan said a few weeks ago the psych side effects seen with Prialt have not been seen in the Z160 trials. Doesn't mean Z160 works on pain relief but is nice to hear that this dose limiting side effect of Prialt is not appearing in the Z160 trials so far. http://www.wsw.com/webcast/rrshq23/zlcs/
JL you'd make a good detective. No to seal trainingI but did up my time on the treadmill from 45 min to 60 min and from 5 days a week to now 6.
Lipitor plus Vascepa vs Lipitor plus Lovaza
Lip10mg +Lovaza.......Lip10mg +Vascepa
.............06-04-13.......09-27-13
Cholesterol--225...........104
Trigs----------268............98
HDL-----------34..............36
LDL/HDL---4.04............1.34
I was on lipitor 10 mg for a year with Lovaza. Switched to lip and Vascepa in June and the numbers are surprisingly good except for the HDL. Maybe its synergy.
Yellow GIA is a good strategy if you have a best in class drug. ACAD's ceo has repeatedly stated he doesn't want a US partner. ACAD's stock price has climbed from $2-$28 over the last 12 months. Many wanted ACAD to partner up at 6$ after reporting a successful P3. So far I think the ceo's stubbornness to GIA has paid off well for shareholders. A difference from AMRN is that PDP is a small niche indication and Pima isn't approved yet..
Effects of a fish-based diet and administration of pure eicosapentaenoic acid on brachial-ankle pulse wave velocity in patients with cardiovascular risk factors
Yoshihiro Fukuoka, MD, Norihito Nuruki, MD, Shun Amiya, MD, PhD, Katsunori Tofuku, MD, Shinichiro Aosaki, MD, PhD, Hirohito Tsubouchi, MD, PhD
Received 8 April 2013; received in revised form 4 June 2013; accepted 12 August 2013. published online 30 September 2013.
Abstract
Background and purpose
Brachial-ankle pulse wave velocity (baPWV) and ratio of plasma eicosapentaenoic acid to arachidonic acid (EPA/AA ratio) are surrogate markers for coronary artery disease (CAD). We aimed to evaluate the effects of a fish-based diet and administration of EPA on baPWV and plasma EPA/AA ratio.
Methods and results
The changes in baPWV and plasma EPA/AA ratio were compared before and after a 6-month fish-based diet in 191 patients with cardiovascular risk factors. A fish-based diet resulted in significant increment of plasma EPA/AA ratio (0.40±0.18 vs. 0.49±0.27, p<0.001), with baPWV remaining unchanged. Multivariate analysis revealed that systolic blood pressure (SBP) (6-month SBP-baseline SBP) and CAD were positively associated with increased baPWV (CAD: odds ratio=2.040, p=0.0436, SPB: odds ratio=1.056, p=0.0003). When the patients were divided into three groups: CAD, low-risk, and high-risk with no prior history of CAD according to the number of risk factors at baseline, comparison among the three groups disclosed an inter-group difference in the magnitude of change in baPWV (low-risk: -35±164cm/s, high-risk: -14±190cm/s, CAD: 39±164cm/s, p=0.0071 for trend). In 191 patients who had received a 6-month fish-based diet, 21 patients (primarily CAD patients) sequentially received high purity EPA (1800mg/day) for 6 months. It resulted in marked increment of plasma EPA/AA ratio (0.65±0.57 vs. 1.19±0.46, p<0.001), accompanied by significant reduction in baPWV (1968±344cm/s vs. 1829±344cm/s, p=0.0061). There was a significant negative correlation between changes in baPWV and changes in plasma EPA/AA ratio in patients with a fish-based diet and sequential administration of EPA (r=-0.446, p=0.017).
Conclusion
A fish-based diet was effective against increased baPWV only in low-risk patients, with slight increment of plasma EPA/AA. In high-risk patients and CAD patients, administration of EPA for preventing progression of baPWV endorsed the validity of high purity EPA administration recommended in the current guidelines.
http://www.journal-of-cardiology.com/article/S0914-5087(13)00242-6/abstract
I agree with STS there is a chance that ADCOM may not view the foreign lower dose Jelis data as pertinent. But even if that happens then AMRN can just wait for the opportunity to use Jelis in a rebuttal argument. The negative 2013 Italian NEJM fish oil study is likely to be introduced at ADCOM and that could be the perfect time to respond with the Jelis data.
STS if fish oil is brought up at ADCOM (and I think it will) then it would make sense for AMRN to bring up Jelis. Imo the low dose epa/dha fish oil combo trials are not nearly as relevant to Vascepa as the higher dose epa Jelis trial.
Excellent response to Diabetes Care online letter
http://care.diabetesjournals.org/content/36/7/e110.full.pdf
AMRN at Aegis thurs 1:30 but no webcast apparently. Nothing at the AMRN upcoming presentations website, The Aegis site shows the schedule and AMRN's slot but it doesn't look like we will get a webcast. The Aegis link here: http://www.aegiscapcorp.com/health-care-conference/conference-schedule/