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HD: Just for fun, how about setting up a contest for “Guess the PPS” for an arbitrary time in 2019. Interesting what #s board members would come up and how close these may be to the actual PPS at that time !
AVII : Despite having an MD, PhD, I have always looked upon the assistance of more Stat savvy individuals in both my prior basic and clinical research. I find the knowledge in statistics shared by you, TTE, VBru and other more seasoned members on the Board of great value. If one looks at the HR and p values of some of the more recent CV trials and earlier trials, it does make one appreciate the magnitude of the Topline results from Reduce-It;
1) Fourier : PE HR; 0.85, P < 0.001
2) Leader; PE HR 0.87, P = 0.01 (superiority) ; Received FDA indication for CV reduction based on PE.
3) Empareg : PE HR 0.86, p=0.04;
SE: CV Death HR 0.62, p <0.001.
Did not get the nod from the FDA for PE but received the indication for reducing CV Death.
4) Ascend : PE HR 0.97; p=0.55.
With this landscape, the amazing result from R-It in comparison is still digested, and the subgroups, particularly Diabetics, may be of particular interest.
Thank you for your very academic and insightful input and thanks as well to TTE, V Bru, JL, HD, North, BB, Sam, and many others who similarly bring their own expertise to the board. Exciting times lay ahead on finally having an answer to the perplexing question of significantly reducing the residual CV burden beyond Statins not only in the US but on a global level! There was clearly a paradigm shift with the introduction of Statins years ago. We are now entering a new paradigm shift with V so effectively targeting inflammation and beautifully translating its pleiotropic in vitro to diverse clinical benefits with this perhaps being only the first chapter in the unfolding of this exciting and dynamic story !
Thanks TTF ! RRR of close to 25% with that magnitude of p value is going to simply blow the minds of Cardiologists at the AHA with SE and TE providing further shock value !!!! Can’t wait for AHA !
TTF: Question: why do you state a p value of <0.00000001 when the PR mentions <0.001 ?
Thanks FFS!
FFS: any thoughts on the effects of raising some cash ( dilution ) and effect on stock price ?
Agree AV! Reduce-It is so close to Prove-It Timi 22, which showed a HR of 0.60 when LDL-C was maintained with high dose Statins below 70 in the TG >200 group. Better compliance in R-It may have probably brought the RRR closer to 40%, in line with Chas’s careful analysis ! Taking 2 capsules bid for 5 years is bound to be associated with compliance challenges ! In this context 25% is amazing to say the least !!
FFS: Anything new on the Options front ?
In context: R-It is adding a TG lowering drug to Statins. To date no trial ( except for Jelis with it’s caveat) Statin plus TG lowering agent has been successful to date. Niacin and Fibrates failed in numerous trials. In the LDL lowering space, addition of Exetimibe to Statin was effective to the order of 6% and the addition of expensive PCSK9 to Statins in the order of 15%. That is the sketch of the playing field at the present time and R-It data will be looked upon by both the Clinical world and Big Pharma with this landscape in mind, have no doubt about it. Yes, Statins impact LDL-C as well as inflammation, Ezetimibe and PCSK9 do not appear to have meaningful anti-inflammatory effects and we know the story about V on CRP, LPA2, oxidized LDL-C etc etc
FFS; any signal from options activity today?
This is the short article ref;
JAMA 2017, Nov 21; (19) 1925-1926,
Mendelian Randomization.
I believe you may find this interesting.
JL, there is a very illuminating article from a preventative Cardiologist at Harvard ( engaged in Genetic Research) who published a paper on Mendelian Dominance in 2017. He compared Mendelian Dominance with Observational Studies in reference to 3 Lipid components: LDL-C, HDL-C and TG. While Observational studies supported the relationship of LDL and HDL ( inverse) to CVD, Mendelian Dominance only supported this CVD Association with LDL-C and TG and NOT HDL-C. He makes the point that low HDL-C is invariably associated with elevated TG and thus these confounding variables are difficult to separate in Observational Studies whereas Mendelian Dominance can examine a single factor more clearly. I have listened to his presentations and spoken to him personally - he is a rising star in this area and makes the point how such Genetic Studies explain why HDL-C raising Studies have been universally such a failure. A really refreshing and brilliant presentation. When I have more time I will locate the article!
In terms of Adverse Events, Vascepa is clearly one of the safest if not the safest in the Lipid Space. The traditional FDA threshold for AE is 3%, however with V when this was used in the P3 trials Zero AE were observed. The FDA thus lowered this to 2% and then Arthralgia at 2.3% surfaced.
Correct. A slight increase in Bleeding Time but within the normal range.
Agree North. Have heard Matt present many times before with his very measured and very balanced responses. In my mind his knowledge in this space supersedes that of Christie Balantyne, Harold Bayes and others. Glad that he concluded with comments about Residual CV Risk as published in Prove-It Timi 22 where high dose Lipitor achieving LDL<70 in ACS patients still had Residual CV risk when separating Triglycerides above vs below 200 in this population resulting in 40% difference in CV events.
JLs prediction of a positive interview was spot on !
He is interviewing one of the most knowledgeable Cardiologists in the Omega 3 space and Vascepa in particular. Should be interesting.
Kiwi,
Due to time constraints a very brief reply.
Your statement regarding p value is inaccurate and non-scientific!!
In Table 3 with regard to TG levels >=200 vs TG <200, the first two lines are pertinent:
As you can see each set are paired with the upper line indicating a 1.00 HR vs its lower pair.
Therefore, as is clearly evident, when one compares TG = or > 200 vs TG <200 in the setting of LDL-C <70, the HR is 0.60 with a SIGNIFICANT p value of 0.001 !!
A 40% significant RRR ( p=0.001) when LDL-C is <70 is the interest and crux of this scientific finding when examined using a graded TG threshold and in this context a threshold of 200 mg/dL ( a threshold which may be of relevance to R-It ).
I have no more time to engage in further dialogue with you Kiwi and usurping my time in correcting scientific misrepresentations !
This is not the first of such an exchange.
All the best and farewell!
I trust that RAF, to whom this message was originally sent, found this scientific study of interest.
RAF,
An interesting study that addresses the important question in the CV space pertaining to Residual CV risk in high CV Risk patients is the Prove-it TIMI-22 Study published in the J of Am College of Cardiology by Miller et al. This study looked at aggressive vs less aggressive LDL-C lowering in high CV risk patients. In those patients who received aggressive Statin therapy to reach LDL-C goal of <70 mg/dL, when remaining CV risk was measured in those patients with TG >200 vs TG <200, the latter had a HR of 0.60 vs the higher TG subgroup. A 40% RRR when TG were below rather than above 200 in patients achieving LDL-C <70. If one pauses to consider that the addition of expensive PCSK9 inhibitors on top of Statins achieves only a further 15% CV reduction in Fourier. This certainly prompts some food for thought on the potential impact of Residual CV risk in the R-It population using 4G daily of EPA which not only effectively reduces TG but more so has Pleiotropic effects that Statins have been demonstrated to somewhat emulate while sadly the expensive PCSK9s tend to fall short on their impact on markers of inflammation.
“Is the key to this Inflammation after all ???” Makes one wonder??? Interesting times ahead in the CV space!
He is the PI of the Strength Trial with AZN’s Epanova scheduled to be completed at the end of November, 2019 - more than a year after R-It is projected to be wrapped up. Interesting times ahead??
Hi North, thank you for sharing.
1) As you know not only do O3s have the potential to modulate beta cells but there is a growing evidence that Vitamin D may also promote beta cell function. It is rather intriguing that the clinical case report you provided of the Type 1 Diabetic being administered both EPA/DHA Omega 3 but also Vitamin D. Such a single case does warrant a larger clinical study as some critics may just attribute the improvement in beta cell function to Honeymoon Period which is typical in onset soon after the diagnosis of Type 1 DM.
2) The commonest reason for a decrease in Insulin requirements for both Type1 and Type 2 DM is declining GFR. I am confident that with your meticulous care you have been monitoring your eGFR over time. If this is stable, that’s good. If there is a progressive decline, share this fact and the decrease in Insulin requirements with your Endocrinologist.
Another rare but very important etiology for decrease in Insulin requirements in Type 1DM is declining adrenal function and the development of Addison’s Disease which may Co-exist with Type 1 DM as part of an Auto-Immune Polyglandular Syndrome. This is also something that your Endocrinologist can easily check for.
Other more obvious causes of decrease in Insulin requirements include stricter adherence to a healthier diet and increase in exercise regimen.
If the above are all excluded, than your suggestion of potential benefit of V is more valid. Although I have no supportive data to quote by recall, I do believe that benefit of immuno-modulation may be greater the closer the intervention is to the onset of Type 1 DM. I believe that Jay Skyler out of Miami has studied twins with Type 1 DM where the unaffected twin with positive Islet Cell Antibodies became a subject for early drug intervention and study.
3) Finally, while ethically ( and rightly so ) I am unable to advise you of your treatment regimen, you did list two shots of N Insulin as your basal Insulin in addition to a newer analog for mealtimes. I am sure that you are aware that there are newer basal Insulin with less variability, with more stable PK and PD characteristics than N Insulin and with lower risks for hypoglycemia. In my opinion, it may be worth chatting to your Endocrinologist about this as well.
4) Finally, I enjoyed the rodent paper on O3 and the beta cell.
I do think that JT may find your background of great interest and may well reach out to you ! Your attention to detail and care is exemplary.
All the best.??
Hi Iwfal, Thank you sharing the healthy and important pro vs con perspective.
1) with regard to hemorrhage in Jelis, this has certainly been mentioned at Clinical meetings over the years when Jelis data are reviewed and presented. The mentioned areas of hemorrhage in the Jelis paper include: cerebral, fundal, epistaxis and subcutaneous. It was the first mentioned which caused me reason to pause as it sounded somewhat similar to Statins which we know do decrease ischemic stroke on the one hand and yet have been associated with increasing intra- cerebral hemorrhage on the other.
The paper by Tanaka et al ( Stroke, 2008, 39, 2052-2058) in a Jelis Sub-analysis, observed a significant reduction of recurrent stroke in the the Secondary Population.
Stroke in the Primary Arm 1.3% (-EPA) and 1.5% (+EPA) HR 1.08; CI 0.95-1.22.
Stroke in the Secondary Arm 10.5 % (-EPA) and 6.8% (+EPA) HR 0.80 CI 0.64-0.997. No significant intergroup differences in Cerebral hemorrhage was observed. As R-It resembles more the Secondary population of Jelis, I believe that this is an important paper and point to include in your comments to make it more comprehensive.
It does not diminish your comment about significant observation of hemorrhage with V - I believe that the relevance of this may correspond to what many of us observe in clinical practice, namely subcutaneous manifestations such as bruising - as this is the most common in this category expressed by patients. I am of the opinion that increase in hemorrhage in the V Arm will in all likelihood be reported when R-It is finally published but I think of the more superficial variety while CVE may well show reduction not only in MI but also in Stroke.
2) with regard to mortality decrease, I do agree with you this is a greater hurdle to overcome. However, this is not new in the Lipid space. Statins have been notoriously inconsistent in Mortality benefit. Even the newest PCSK9 inhibitor add on to Statins in Fourier showed only a modest reduction in MACE with mortality leaning on the other side with a HR of 1.05.
You correctly quoted All cause death in Jelis 2.8 vs 3.1% HR 1.09 CI 0.92-1.28.
If one looks at Secondary Prevention in Jelis ( in my opinion somewhat closer to the R-It population) the HR of Coronary Death was 0.87 with a wide CI of 0.46-1.64. At least Coronary Death in Jelis Sec prevention Arm was on the favorable side. I do think that Mortality benefit may be a huge hurdle for V to overcome in R-It. If MACE and several SEs are significant I think that will be of huge clinical benefit without Mortality benefit, as most of us know how challenging such a hurdle is when adding an agent on top of Statins. This may well be more robust than adding Zetia (RRR 8%) or a PCSK9 (RRR 15%) on top of a Statin - and if the RRR exceeds 15%, V certainly will be occupying the value of an add on to Statins never seen before. If the Diabetes subgroup exceeds this, that will capture yet another clinical important clinical indication. Now if Mortality benefit is also observed, well then we all surely will be waking up to Breaking News not only locally but globally.
Hi North,
I do apologize bringing this up.
As you know the 2 FDA approved O3s L and V are indicated for TG =500/>. However, both products have published data in the 200-499 TG space. Hence many MDs use O3s in the Marine and Anchor population - although the latter is off label it has supporting science, V is very safe and with the 1st Amendment Ruling of truthful and non-misleading many of us are comfortable using V in the Anchor population. Although we may anecdotally observe patients commenting on decrease DES symptoms or other improvements, such observations have up to this time not been studied in a dedicated clinical trial. Therefore, using V solely for patients with DES will not be supported by current science. Should such a patient develop any untoward complications ( realizing that V has thus far a very safe profile) the prescribing health provider will be held liable as no supporting science for such indication exists.
If R-It is successful, I believe that the Type 2 Diabetic population may be the group garnering the greatest benefit. In such a situation I wouldn't be surprised to see both the ADA and AACE guidelines be revised to include such application to both Type1 and Type2 DM as over time Insulin Resistance has gradually been creeping up in the Type 1 population as well . That may then be wonderful for you as well North ! This is a very important ethical and medico-legal issue. Perhaps others like JL may want to provide their input as well which I highly respect. The above is just my opinion of course. North please accept my apology if I do not reply to your response to this message as I am immersing myself in work for the next several days. All the best to you !
Kiwi, please look at this very carefully.
Let us call this 90% containing EPA product from the U.K. Product X.
X is being studied to address potential benefit in certain GI diseases. Let us fast forward and hypothesize that X in the future receives FDA for the GI population studied and V receives FDA approval for CVE reduction in the R-It population. Can V be used in GI population benefited by X and X be used in the R-It population. In that scenario the answer to both is negative. Evidence based science would call for V being used in the R-It population and X in the GI population and that's it. If a physician were to prescribe X for the R-It population and that patient were to develop a CV event- the physician could be rightly sued and the patient rightly awarded damages. Human Physiology is a very delicate dynamic living system- it needs to be treated with the utmost respect and the scientific evidence has to be sound and significant.
If product X is "close" to V in EPA make up - such closeness is meaningless without the supporting science. A minor minor difference in chemical structure can translate to dramatic differences in vivo. There is a very serious and sound reason why the practice of Medicine is an Evidence Based structure. We are not dealing with trying to find the closest matching paint color or tile product in a building project- this is far far more subtle than that - human physiology is far more intricate than what our brains can fathom - Mother Nature has repeatedly demonstrated this to us who work in the field of Medicine how intricate the various cellular and sub cellular processes really are. I prefer to close this topic on my side Kiwi. All the best !
Thanks BB !
I do read many others including those you mentioned - I just could not recall all in my quick short list. My lack of mention does not imply exclusion of others in any way whatsoever!
Kiwi, I apologize for not including cost in my prior post. As the practice of Medicine is based on scientific evidence based data, my approach in evaluating any therapeutic option for a patient is to analyze the efficacy and risks independent of cost. Once the best scientific fit with the greatest benefit and lowest risk is identified then and only then does the important practical reality of cost come into the equation. If V is covered by the Insurance there is no issue. For those that require prior authorization, the elevation of LDL-C by up to 45% with L and the atrial fibrillation warning for L makes the PA of V a smooth and easy process. L is the only competing omega 3 product out there and the benefits of V over L make the PA process swift and immediate. The sad reason why many people look to DS is because of cost. I have had health care providers show me a bottle of DS they would like to take in place of V. When I discuss the lack of clinical scientific data on DS and the disgusting findings on contamination, oxidation and impurities of DS, most drop their bottles in horror. There is no scientific data on the clinical efficacy and safety of DS. The only data on DS is the varying degree of contamination, oxidation and impurities. The authors you mention are in engaged in chemical analysis not in clinical studies of the safety or efficacy of DS. As there have been no clinical trials to study the clinical efficacy or safety of DS, I find it an exercise in futility to try to tirelessly identity the one DS with the least contamination and impurities when at the end of the day after such an exhausting search one is left with the question: "Is there scientific evidence of clinical efficacy and safety of any DS ?" The answer is clearly no. In my mind this should be the first question- and as the answer is in the negative to then try to identify a "better DS" is really a meaningless activity. For my patients who have cost constraints, I ensure that their Statins, ACE-I, ARBs, DM meds are generics and help them with V samples to supplement their V prescriptions when I can. DS is never a consideration due to absence of scientific data on clinical efficacy and safety. DS are classified by the FDA as a food although it now appears that some DS are actually "drugs" disguised as DS trying to "avoid" the required FDA approval and Clinical Studies - until someone catches on to them. I do enjoy reading JL, HD, VBru, AV, BB, Sam, Tasty, Kiwi and others. As I have no background in economics I find HD very informative. Furthermore, I think that the recent ITC development is a stroke of genius by Amarin ( using HDs description ) and I find the Board very informative in this area as it is not a topic I come across in the literature I read - thank you all.
Kiwi, please take my comments above as my personal view on DS and V and in no way written as an affront to you or anyone else. If I did state anything to upset anyone, I do apologize.
Fully Agree with your comments!
Preston Mason from Harvard has published numerous articles on the concerns about the safety of DS - he has measured and published widely on oxidation products and contaminants of numerous DS. I have been to several of Preston Mason's presentations in the past few years - his research on DS has been a real eye opener to us in the audience who comprise predominantly of Lipidologists and specialists. As the practice of Medicine is one of evidence based science, it is glaring that there is none for DS - the contamination and oxidation products and the presence of other fats in DS may not only negate the benefits of the EPA content in the DS but may even potentially increase the CV risk. If my patients are unable to afford V, I advise them to pursue healthy lifestyle measures and certainly do not advocate DS as an alternative as not only is there is ZERO science to support their use but more so if one examines the research on oxidation and contamination of DS it makes one shudder why any person with a very basic level on intelligence would ever contemplate placing such sealed capsules of decay and contamination into one's system!
There is no OTC omega 3 !
Tasty, thank you for taking the time to respond. My thoughts were similar to yours with regard to the contrasting p values for the Primary endpoint decrease of 14 % (p value = 0.04) vs the CV mortality SE decrease of 38 % (p value <0.001) in the Jardiance trial.
With the Liraglutide trial, the Primary endpoint was decreased 13% (p value = 0.01) whereas CV mortality decreased 22% (p=0.007).
Based on this, my initial reaction was that the FDA was also likely to grant Liraglutide a decrease CV mortality indication rather than an indication in decreasing the Primary endpoint - whereas in actuality, the FDA granted Liraglutide a new CV indication in decreasing the composite Primary endpoint of 13%.
It did raise the question in my mind how the FDA looks at the % magnitude decrease in the endpoint on the one hand and the strength of the p value on the other hand in determining a new indication. Would similar FDA thresholds be applied to Primary endpoints and SE in R-It ?
In addition to the Primary endpoint of R-It there are numerous SE. I believe it is in the SE category where a meaningful RRR may allow this off label promotion to be sought. In terms of cancer specifically, I do not know the answer to that. However, CV and total mortality may certainly be clinically meaningful.
"Amarin will have the right to submit to the FDA up to two new off label indications per calendar year through December 31, 2020".This is what the Amarin legal team got the FDA to agree upon during the 1st Amendment win. Maybe Amarin foresees needing to fill this new position in order to address the above moving forward?
Tasty, JL and others:
Of interest:
1) Jardiance recently received FDA Indication for decreasing CV mortality in Type 2 DM with CV disease. This is based on the Empareg trial which showed a 14% significant decrease in the Primary MACE endpoints and a 38 % significant decrease in CV mortality. The FDA gave the nod for the latter indication (SE ) but not the Primary Endpoint of the trial.
2) liraglutide is the second diabetes medication to recently receive a CV indication in Diabetics after the Leader Trial demonstrated a 13% significant decrease in the composite Primary endpoint and a 22% decrease in the SE of CV death. Interestingly, although the Primary endpoint was mainly driven by a decrease in CV death, compared with Jardiance, the FDA elected to grant Novo Nordisk a CV indication for reducing the Primary endpoint by 13% rather than giving the nod to the SE driver of this decrease, namely CV death as the FDA had done with Jardiance.
3) The PCSK9 inhibitor as an add on to Statin reduced LDL-C by 60% and decreased the Primary composite endpoint by only 15% ( significant) with a 5% (insignificant) increase in CV mortality. This was a disappointment for such an expensive add on to Statin.
Many lipidologists argue that the lack luster effect of PCSK9s may lie in the fact that no significant impact on CRP and inflammatory markers have been observed with this new class as a whole while several recent publications have pointed to the fact that the CV benefits of Statins appear to be beyond LDL-C lowering in the pleiotropic effects of Statins.
4) Fibrates as add on to Statins have been disappointing in Primary endpoints in several trials - FDA recently indicating that as add on to Statin the risks of adding Fibrates now outweigh benefits.
5) Niacin as add on to Statin have also suffered a dismal fate similar to Fibrates.
6) Ezetimibe as add on to Statins only resulted in 8% significant decrease in CVE, insufficient in clinical magnitude to allow the FDA to give Merck a CV event reduction indication. This is despite the fact that in subsequent analysis, Ezetemibe as an add on to Statins in Type 2 DM resulted in >20% decrease in CV events.
So it appears that the Cantos trial results do open the door for scientific discussions regarding inflammation and CVD. Although at first glance the results look so so, in the context of the scientific landscape of add on to Statins that many trials have delivered in the past decade or more( negative to weakly positive), it does raise the interest ( as JL has mentioned before ) on the potential CV impact of targeting inflammation. Vascepa has already demonstrated to have a wider impact on underlying inflammatory process ( CRP, Interleukins) and other drivers of atherosclerosis such as oxidized LDL-C and ApoC3 to name just a few. The design of R-It was to identify patients with increased CV risk of which TG may be an indicator, the target therefore being a pleiotropic one and not TG reduction as some such as Ralphey have mistakenly used as a gauge of V efficacy in the CVD prone population.
As a side bar, for Tasty, JL, HD, VBru, AV, and others on the board who have a more detailed analytical approach in reviewing the statistical strength of Primary and SE endpoints, do you believe that the strength of the p value in the Leader trial above may have motivated the FDA to give Liraglutide a composite Primary CVE reduction indication ( 13 %decrease ) while Jardiance with a composite Primary CVE reduction of 14% did not receive the Primary CVE reduction indication but rather the SE indication of reducing CV death ( 38% decrease)? Just a passing thought and question. If there are some defined CV indication thresholds which are used by the FDA, such boundaries may also then apply to the R-It results both Primary and SE.
Thanks.
JL, incorporated in the 1st Amendment win, Amarin will have the right to submit to the FDA up to "two new communications per calendar year for the off label use of Vascepa through December 31st, 2020". This is an interesting addition that the strong legal team representing Amarin was able to get the FDA to agree upon. It does raise the question that the setting of the bar so high for the SE in Reduce It may have been carefully thought out by the Amarin team so that any clinically relevant SE results which have the likelihood of being more robust at the conclusion of Reduce It, may be considered by Amarin to be submitted to the FDA in the previously agreed upon "two new communications per calendar year through the end of 2020". In this context the Type 2 Diabetes subset would be of particular interest! Just a thought?
Correct JL! And when one adds other safety issues with SGLT2 inhibitors such as dehydration, contraindication in advanced renal failure plus risk for DKA, it really makes the clean safety profile of Vascepa a very clinically relevant positive! If Reduce It delivers - the pluses and negatives for Vascepa will be overwhelming to say the least!
Another CV outcome trial with Jardiance in Type 2 Diabetes reported a 14% reduction in Primary MACE endpoints ( p value significant at 0.04) with a 38% decrease in CV Deaths ( p value significant at <0.001) . The FDA awarded an indication for the SE of CV death! This speaks to the importance of SE in Clinical Trials. The presentation of this data at the EASD was so packed that there was standing room only at this European Diabetes meeting!
Of interest in the Fourier Trial with PCSK9 inhibitor add on to Statin the primary endpoint was decreased by also 14% but CV death had a HR of 1.05 ( non significant 5% increase! ). The latter rather hidden in obscurity the publication. Pretty disappointing to say the least for such a costly add on - although Amgen has been trying many ways to conceal this scientific disappointment.
Is there a way to calculate the impact of percentage of dropouts on RRR in Reduce-It. For example how would a 25% dropout rate ( as observed in Jupiter Trial ) impact upon RRR of CV events in Reduce-It ?
The increase in bleeding time with omega 3s is "within the normal range" and this is reflected in the V label.
Correct. Due to this low, albeit significant number p= 0.016, Ezetemibe was denied the CV indication as an add on to Statins.
HD, I am always impressed with your great attention to detail and in depth research with of course data to support your statements.
From the scientific standpoint comparisons between two agents in patient populations are usually considered valid only when head to head studies designed to compare such agents have been conducted.
As there are no head to head studies comparing the efficacy of L vs V in either the Marine or Anchor population, any comparative statements that ensue are mainly inferences that are hypothesis generating. The major sources of such "comparative " inferences stem from meta-analysis on the one hand or analyzing the TG lowering efficacy from the Marine and Anchor type populations for each V and L on the other. I believe your statements stem from the latter approach. In the meta-analysis area I believe that DHA has been suggested to be more efficacious than EPA. Meta analyses as you know are plagued with variations in populations, different baseline TG levels, differences in Omega3 doses, different duration of studies, differences in concomitant lipid lowering agents etc etc. Of interest over the last several years Brinton, Balantyne, Hayes et al at different Lipid Meetings have used the Phase 3 Trials for both V and L where the dose of these agents are similar and the baseline TG levels are known, to draw these inferences - very much as you have done !! HD, I believe that you are in good company, although I can sense JL frowning as I write this.
In fact as you correctly stated that the baseline TG in Marine was in the 600s whereas the baseline TG in the L Phase 3 was slightly above 800. When the Marine TG lowering efficacy of V is analyzed with baseline TG exceeding 750, a 45% lowering in TG is observed and when V is combined with Statins, an intriguing even more robust TG lowering of 65% is observed ( the latter effect has hitherto-fore not been demonstrated with V ). With the inherent limitations in mind, your statements are not only valid but have certainly been articulated by many Lipid experts over the years.
Ins more important note, JL is very accurate in having stated (for a long time ) that athero-inflammation may be the common denominator underlying CVE. There have been some recent analyses of Statin trials where pleotropic effects have been implicated in the genesis of Statin benefits. Patients who manifest TG in the 200 plus range often with underlying Type 2 DM and the Metabolic Syndrome Phenotype - the elevated TG levels and low HDL may be the clinical signal of significant underlying inflammatory processes. The lipids may just be epi-phenomena of a very turbulent underlying process of endothelial dysfunction and inflammation. In fact most Myocardial Infarcts (MI) occur with only about 50% occlusion of Coronary vessels soon prior the MI event. Hence plaque rupture has been incriminated in such Acute MI events resulting in the sudden and dramatic 100% occlusion. Plaque stability has been a prominent subject of both basic science and clinical research in recent years. The publications that have been posted by JL, Zumantu and others ( Authors Preston Mason - Harvard ; and Madoff et al UCLA ) have beautifully demonstrated in vitro and in vivo basic science and Clinical studies of the favorable effect of EPA on cellular processes in the basic science area which has been complemented by clinical studies on the measurement of the Fibrous Cap of Coronary Plaques in the clinical area. It is the sum total of all this data that suggests that the TG lowering effect of EPA may literally be scratching the surface of its potential benefits. The authors of Jelis pointed to the potential Pleotropic effects of EPA when a meager 5% decrease in TG was associated with a significant 19% reduction in CVE.
My apologies if a great deal of this has been rehashed by others on this board. I read comments of posters only intermittently:
The likes of JL, HD, VBru, AV, Whalatane, Zumantu, and others have been real fun to read.
Agree!
Much ado about nothing!
The prior Epanova label was revised 5/14.
The recent label update was 3/17.
I just compared the verbiage of the two labels: the 2014 label included a paragraph on Special Populations ( i.e. Pregnancy ) .
The 3/17 label has the Pregnancy Population excluded.
I have seen nothing else other than this minuscule and Clinically insignificant "label change ".
Insight appreciated.
Would be of great help if you could perhaps share with us what smart money is doing as we get closer to R-It wrapping up.