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Thanks HR for being so frank in expressing your opinion. As you well know things can become very fluid in a hurry and rather than being caught up in the flow of emotions, it is perhaps prudent to plan ahead for different permutations and to act accordingly when one of such possible scenarios manifest.
Thanks for your swift response.
For the sake of discussion, if R-It is successful, based on your experience, does smart money invariably take profits after results are announced, or do other factors prompt them to sell in the run up prior to announcement.
Very interesting analysis.
Question:
If there is a run up in price before R-It results are out (in anticipation) would you sell perhaps half your position then and leave the rest until results are out or would you do something else. Are their any signals that you study in this context which provide you a framework to plan accordingly such as smart money investing more etc etc ...
No worries!! I was rather hoping for the benefit of the patients that your initial conclusion was so !!
I did not specifically address the question of automatic switching to Generic L during the conversation. However, I have never experienced such an automatic switch over for my patients prescribed V. Typically I would receive a call back from some Pharmacists for Generic L as a preferred alternative. After explaining to the Pharmacist the stark difference in LDL-C between L and V, the up to the remarkably 65% reduction in TG when V is combined with a Statin ( which has not been demonstrated by L ) and the fact that L carries an additional safety burden of Atrial Fibrillation under Warnings, it is a universally expedient process of obtaining a quick approval for V. It is not uncommon for some Pharmacists to acknowledge appreciation for the summary of the clear benefits of V when compared to L. I typically avoid PA paperwork and get a very swift and unchallenged response of approval over the telephone!
Good question!
I called SouthernScripts ( as specifically listed on BB's link ) and spoke to a Pharmacist who first confirmed that I was a Healthcare provider and then proceeded to check the current formulary status of L and V for my patients on SouthernScripts network. She then searched the list on her end and responded.
I personally have stopped prescribing L ( including Generic L ) for several years now, since the science of V was clearly unique not only in terms of the in vivo data when it comes to humans but more so many other sources ( some of which you have frequently quoted over the years ) and in my opinion the research of Preston Mason ( from Harvard ) not only in terms of the blatant limitations of DS but more so the in vitro data of effect of EPA on oxidized LDL, Cholesterol crystal formation, and numerous athero-inflammatory markers has the made the singular choice of V as an Omega 3 quite an effortless one.
I just spoke with a Pharmacist to verify;
Brand Lovaza is Tier 3.
Generic Lovaza is Tier 1.
Vascepa is Tier 2.
Correction:
All Generics are considered first line - which of course includes Generic Lovaza.
If one looks at the Omega 3 Class on the list: you will notice a double or superimposed 'S' symbol next to this class category. On the last page of this list is a Key table explaining these symbols! This 'S' symbol indicates that are Generics in the class and generics are preferred first line; i.e. Generic Lovaza is therefore preferred. Interestingly there is no prior authorization required for Vascepa. It therefore appears that Brand Lovaza is no longer covered.
Interesting question!
The Triglyceride threshold for clinically triggering Pancreatitis had previously been 1000 mg/dl.
In more recent years this threshold was lowered to 500 mg/dl.
Thus the NCEP guidelines have called for primarily addressing TG when 500 or > and thereafter targeting LDC-C and Non HDL-C in order to initially offset the risk for Pancreatitis.
Hence due to this association, drugs such as Omega3s ( L and V ) and Fibrates have the indication in place to decrease TG when 500 or > to prevent Pancreatitis although none of these agents have been studied to address the prevent Pancreatitis per se - this has been inferred.
This study does raise the question whether Omega 3 agents such as V may potentially lower the incidence of Pancreatitis in the Anchor Population!!
Whilst the RI Trial is addressing the question of CVE and if positive will open the window for the Anchor population in benefiting from decrease in CVE which all of us know will be huge as an add on to Statins, this study raises the interesting question whether the Anchor population may potentially benefit right at this moment in a decrease in the risk of developing Pancreatitis - an interesting independent indication to be considered??? Food for thought?? Will the FDA require another similar study to confirm these findings before giving the nod for Anchor in preventing Pancreatitis! While the percentage increase in Pancreatitis does increase with higher TG levels, the absolute numbers may be small in this modestly elevated TG window of the Anchor population - this may prompt a cost benefit analysis and the benefit may lag when measured against the cost.
Very accurate JL.
In fact Eliot Brinton has often expressed at the Lipid Meetings that for his more challenging patients he has used doses up to 8G daily ...based on the dose response effect ....this is of course using it off label ....
For what is worth - taking into account the limitations in the study the Omega 3 used in the study was Omacor subsequently marketed as Lovaza in the USA.....
I agree ; the drugs were not withdrawn but the indication as coadministration with statins was WITHDRAWN ...and not "limited or changed"...due to the benefits no longer outweighing risks .. from the clinical perspective this is very important in treatment decisions moving forward ...the fact that there are still prescriptions in this combination category may be a combination of factors including automatic prior refills and some prescribers not aware of the new evidence ...
HD : Sorry I left out two words after "coadministration" ... "With statins"...in my prior post ...
HD - the wording from the FDA is clearly stronger than you imply : ..." The benefits of the co-administration of Niacin or Fibrates no longer outweigh the risks., and the approval for this indication withdrawn.."
Nevertheless, I always enjoy your very insightful and deeply analytical posts which reflect in depth research and very evidence based comments .... Thank you!
Benny, I believe that you do raise some interesting points.
Although this is a single case report the difference in lipid parameters from switching L to V is very striking.
In the Type 2 Diabetes literature it is well established that if A1C is not at goal, there is no further A1C efficacy when switching one oral diabetes agent to another - hence adding another oral agent or injectable is more efficacious than switching and this has been incorporated in numerous diabetes treatment algorithms over the years. Those switch over trials are typically done without a washout period as the prior existing treatment is used the baseline.
If this effect of changing L to V is confirmed with larger patient numbers over this length of time of two years, this will certainly provide a strong argument for never using L in this patient population .... and such difference in LDL may open the door for potential medical liability with future use of L ...... I have certainly switched all my patients from L to V for a good while now .......it really is a no brainer .....this is not even including the other effects of EPA such decrease in oxidized LDL, LPA2, CRP, ApoC III, cholesterol crystal domains etc..a great deal of these studies have been published by Preston Mason from Harvard where he has elegantly demonstrated how EPA is clearly differentiated in these interesting effects from Niacin and Fibrates .....
Kiwi, why don't you spend your time doing some elementary Math. Examine the global diabetes market share of GLP-1 since about 2010. Then look at the percentage market share of Victoza for the GLP-1 family, as you would expect it is the leading GLP-1 used currently. You will easily be able to calculate what percentage market share Victoza occupies today of the entire Diabetes therapeutic options . I certainly do know the answer to this but I believe that you would benefit from the exercise. Please do not omit in your calculations to note that the Diabetes market share for Victoza was considerably less going back to 2010. I look forward to your chronological calculations. I can state much more on the subject but I believe I have stated enough for now.
It is not LDL per se that is so atherogenic but modified LDL - in particular oxidized LDL which enters the sub-endothelial space and is taken up by scavenger receptors on macrophages to form foam cells.
What is intriguing in this context is that EPA has been demonstrated to significantly inhibit oxidation of small dense LDL under hyperglycemic conditions by as much as 94% ( research by Preston Mason from Harvard ).
Oxidation of LDL occurs in those with high CV risk such as Diabetes, Metabolic Syndrome etc.
The RI population may be well suited to capture patients where such a high prevalence of oxidized LDL exists. The potential benefits of V are really well beyond TG reduction as many on this board have allured to.
BB, JL and others
Is this news known to the board ?
http://ahrp.org/former-fda-commissioner-charged-in-federal-racketeering-lawsuit/
JL,
The statement that L is more effective in reducing TG is not accurate and in fact can only be made if a head to head study is undertaken which has been done to date.
The L label indicates that for very high TG, L decreased TG by 45% with an increase in LDL-C of 49%. ( Baseline TG were >800 ).
With V, in the Marine trial, TG were decreased by 33% with a neutral (-2% decrease) effect on LDL-C. When the data were analyzed for TG >750, then V decreased TG by also 45%. Interestingly when V effect analyzed in Marine in a sub-group with Statins, TG were reduced 65%.
That is the data.
JL, Continued response from prior message.
With regard to your comments related to the medical scientific community being unwilling to be receptive to the important role of inflammation. This does not reflect "laziness", "arrogance", or the like. The answer is very, very simple. Over the years, medical scientists have discovered over and over again, the frequent lack of correlation between biochemical subcellular observations and in-vivo research. I had similar experience when I did my Ph.D. and then subsequent clinical research. I will just mention a few of these examples which have been well imprinted in the minds of physicians over the years. HRT was considered for years to be cardio-protective as menstruating women had a lower incidence of CVD than their postmenopausal counterparts. This protective effect was hypothesized to be due to the HDL raising property of Estrogen. Well, as you know after many years the HERS CV outcome trial dispelled that hypothesis. In the last decade elevated levels Homocysteine levels was shown to correlate with CV risk. Cardiologists discovered that Vitamin B12, Folic Acid, and Vitamin B6 decreased levels of Homocysteine to "safer" levels. The standard practice of Cardiologists thereafter was to treat their high CV risk patients with this triple Vitamin combination with medications such as Foltx, Metanx, etc. This continued until the Norwegians undertook the NorVit CV outcome trial - to the surprise of the Cardiology community they observed an increase in CV events when this Vitamin combination was used despite a 28% decrease in Homocysteine. The Hope-2 Trial also showed no benefit with this Vitamin supplement. The MOST recent, striking, and highly imprinted research on the limitation of circulating surrogate markers relates to Rosiglitazone(Avandia)-Rz. This insulin sensitizer was considered by most of the leading Endocrinologists to hold the greatest promise in decreasing CV events in the diabetic population. This was based on a great deal of research over a decade studying a number of surrogates - these included improvement in HDL, decrease in CRP, decrease in PAI-1, improvement in markers of endothelial function, improvement in numerous inflammatory cytokines, decrease in ADMA which affects the integrity of Nitric Oxide, decrease in thickness of the intima of the carotid artery, decrease in coronary artery stent re-stenosis rates etc etc. Then came the widely anticipated CV outcome trials - these were disappointing to say the least. This is a VERY SHORT list of how the medical community has built hopes and expectations from favorable trends in surrogates until nature reveals with outcome trials that the hypotheses were just that ..Therefore, today at any conference when a drug shows CV promise, the standard question is .. "What about a CV outcome trial??" This has been the standard question for many years now !!! I therefore believe that any letter that is written about the potential benefit of Vascepa which mentions surrogate markers and inflammation and fails to mention the current limitation of such surrogate markers, the letter may have the opposite effect that the writer intended...
JL, Thanks for your response. The Trilipix (Tx) Adcom in 2011 had a similar preamble as Vascepa(V), after Accord-Lipid results indicated failure in the primary CV endpoint. Tx had been on the market since 2008, and in 2011 the FDA had to decide the fate of Tx based on the failed Fenofibrate data. The lack of CV benefit with Niacin was also available then, but this was another pharmacologic class. The ADCOM voted 13:0 that a further CV outcome trial would be required by Abbott. The resemblance of the Tx ADCOM and that of the recent Oct 16 V ADCOM is amazingly similar. Similar discussions on the importance of primary endpoints and the limitations of subgroup analyses etc etc. The FDA decided in the end not to take Tx off the market, but rather let Tx stay on the market with a label change instead to include the warning of lack of CV outcome benefit. I do understand that with V the FDA has to address the sNDA for V based on the Anchor data and for 50% enrollment for the Reduce-it trial. The question for Tx was whether Tx had to be taken off the market and to wait for completion of the recommended CV outcome trial or to keep it on the market with a label change and await the outcome results in the meantime. The FDA chose the latter in 2011. I believe that with Tx approved with Statin combination with the above conditions( for TG in the 200-499 range), the FDA ought to be able to accommodate V use in the Anchor population with similar label warning regarding lack of conclusive CV benefit while Reduce-It is underway. Continued on next message.....
JL, please look at post #19253 at your convenience - Thanks
JL,
I sent a copy of a letter to your email address 36 hours ago but did not receive acknowledgement of receipt.
I believe that it is important that you review this letter prior to you sending your communication to the FDA. I could re-send it to you, if necessary. My email address starts with the word simonstown . The subject title of the email is : "Of interest" . I am endocrinologist. Thanks. Fred.
drrc1949
Thank you for your comments.
With regard to the NIH article mentioned in post #3700, yes I do agree that the results are interesting. However, as you know, these results are hypothesis generating and not hypothesis testing ( I presume from your title that you have a medical and probably a research backgroud and are familiar with the terminology ).
The Reduce-it outcomes trial with 4g daily of Vascepa, based on a population that closely mimics the segment of patients in the Jelis trial who demonstrated a 53% event reduction with only 1800 mg of EPA, should provide the outcomes that many in the Lipid field are looking forward to, and studies like this NIH article are pointing towards. So drrc, as you can gather, I am not dismissive in my previous post, but cautious in my interpretation of the science, and not to draw conclusions which are not supported by the observations and by the study design... there is much more that one could say, but time does not allow....
RE : Cardiovascular outcomes.
Based on large outcome lipid trials in the last decade or more, the focus among lipidologists has been a movement from LDL to non-HDL, the latter showing a very strong correlation coefficient with Apo-B. The current level of outcomes data with inflammatory markers ( despite the results Jupiter and Jelis )has certainly not reached the level of scientific evidence to expect NCEP to include these as targets for current standards of care. Therefore, prescribing decisions by physicians (and sub-specialists such as myself)have and continue to be driven by the total body of cinical evidence, and when this level of evidence reaches a critical mass then it is adopted by the NCEP, ACC, and NLA etc and becomes part of "Current Guidelines" and "Standards of Care". Despite the growth of basic and clinical research with athero-inflammatory markers, at the present time we do have have any target CRP goals provided in any of the present "Guidelines" to achieve with our patients with increased cardiovascular risk.
Therefore, the clinical message to physicians with regard to Vascepa in my mind is very clear and powerful:
1) 45% reduction of Triglycerides when baseline Triglycerides are are 750 or more.
2) 65% reduction of Triglycerides when Vascepa is combined with Statins in patients with very Triglycerides. This is a unique scientific observation and clinically very relevant.
3)The above achieved without an increase in LDL Cholesterol - another unique finding.
4)Excellent safety profile.
JL et al.... There has been quite a bit of discussion on this board recently on the importance of inflammatory markers. At this stage, that is precisely what these are. There have been several examples in recent years of the promise that therapeutic agents held with favorable inflammatory marker changes, however cardiovascular outcome studies did not bear this out. An example of such an agent was Rosiglitazone(Avandia). The list of favorable changes in various surrogates was very lengthy, CRP; ADMA; Interleukins; PAI-1; reactive oxygen species; IMT of Internal Carotid artery; Coronary stent restenosis etc.. and yet meta-analysis of cardiovascular outcomes were so disappointing that it now is off clinical use with it's REMS designation. The Reduce-It Trial is therefore what clinicians are looking forward to rather than any favorable CRP effect - despite the fact that a favorable CRP change may be in concordance with athero-inlammation - there are too many other in vivo processes at play to equate such changes with cardiovascular event reduction ...
It is vascepasavings.com