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Post by matt on Oct 29, 2018 15:32:16 GMT -5
All this tells you is that a number of people died while taking Novolog which is inevitable Correct, all it tells you is that a number of diabetics died while on Novolog. If that number is not significantly different from Humalog or some other RAI with a comparable number of patients on therapy, then there really is no information value. I have designed clinical trials for severely ill patients knowing with certainty that some percentage of the enrolled patients would die during the 18 month follow-up period, whether they were in the treatment group or the comparator arm. Deaths are only significant if the number is higher than what is expected given the patient population. 155 deaths over a ten year period for a large insulin-dependent diabetic population is not surprising since these patients almost always have hyperlipidemia, hypertension, chronic kidney disease, an increased risk of major cardiac events, and an increased risk of cerebrovascular stroke. I am sure the real number is much higher than 155.
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Post by mango on Nov 4, 2018 1:37:27 GMT -5
• Nothing new here, these two "additional" cases of have been well known for many years as they were discussed along with the other 2 cases in great detail during FDA review committees, and the commentary is available to read online via FDA website. Here's one of them from CDER: www.accessdata.fda.gov/drugsatfda_docs/nda/2014/022472Orig1s000SumR.pdf• Now what we do know is that Afrezza has been arguably subjected to more safety studies than any other insulin in the world, and Afrezza has the safest profile of any insulin in existence, taboot. We have the demonstrable proof from years of Afrezza use in thousands particpants, with over 600 CT & MRI lung scans, extensive long-term controlled laboratory safety studies in animals, comprehensive safety analysis of the FDA approved inert carrier particle FDKP, long-term comprehensive pulmonary function data in hundreds of Afrezza participants, no new post-approval lung safety concerns since FDA approval, and no cardiovascular safety concerns have been raised period. • It is hypocritical to propose a 5 year lung cancer safety study with thousands of participants based on a spontaneous reporting of two individuls with no supporting pre-trial nor post-trial evidence or information. The two participants that were [former] heavy smokers were not even screened properly by the investigators, and so these two participants caused a ruckus when they should have never been included in the trials in the first place: they met exclusion criteria. • What we do know is FDA review comittee made their decision for a long-term lung safety trial evaluation partially based on data from Exubera FUSE study. FDA used this data in their decision making with Afrezza, especially considering the fact that Pfizer stated that the results were indicative but not conclusive of a potential risk of lung cancer with Exubera. Nevermind you that Exubera and Afrezza are not the same, and are entirely different insulin formulations. • Since FDA is concerned about rDNA insulin human, FDKP and/or polysorbate 80 causing different kinds of lung cancers, one of them of which is heavily linked to being caused by HPV, why don't we just have all insulin manufacturers do a 5 year cancer risk evaluation study? There was a lot of concern years ago about injectable insulins being linked to cancer. Seems like those concerns were never properly addressed in a clinical trial.
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Post by agedhippie on Nov 4, 2018 11:28:41 GMT -5
• Since FDA is concerned about rDNA insulin human, FDKP and/or polysorbate 80 causing different kinds of lung cancers, one of them of which is heavily linked to being caused by HPV, why don't we just have all insulin manufacturers do a 5 year cancer risk evaluation study? There was a lot of concern years ago about injectable insulins being linked to cancer. Seems like those concerns were never properly addressed in a clinical trial. The advantage that the RAAs have is 20 years of use at scale. That means that when there are questions about cancer, as with Lantus a few years ago, there are huge European datasets with cradle to grave coverage that can be evaluated. The researchers can access those datasets and look for trends to confirm or deny a risk. Afrezza suffers from two issues here; it hasn't been on sale for decades, and medical records in the US are extremely fragmented so there is no single database of record. The consequence of this is that Afrezza has to prove that it's safe because it lacks that substantial track record.
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Post by mango on Nov 4, 2018 12:40:35 GMT -5
• Since FDA is concerned about rDNA insulin human, FDKP and/or polysorbate 80 causing different kinds of lung cancers, one of them of which is heavily linked to being caused by HPV, why don't we just have all insulin manufacturers do a 5 year cancer risk evaluation study? There was a lot of concern years ago about injectable insulins being linked to cancer. Seems like those concerns were never properly addressed in a clinical trial. The advantage that the RAAs have is 20 years of use at scale. That means that when there are questions about cancer, as with Lantus a few years ago, there are huge European datasets with cradle to grave coverage that can be evaluated. The researchers can access those datasets and look for trends to confirm or deny a risk. Afrezza suffers from two issues here; it hasn't been on sale for decades, and medical records in the US are extremely fragmented so there is no single database of record. The consequence of this is that Afrezza has to prove that it's safe because it lacks that substantial track record. Problem is, you can't use data from other insulin analogs because they are all different—they have different amino acid sequences, molecular weight, non-active ingredients, PK/PD profiles, molecular interactions, etc...Definitely can't use RAA data to make conclusions about long-acting insulin analogs. Here's a few of those Lantus cancer studies, first one is from 2017. Long-Term Use of Long-Acting Insulin Analogs and Breast Cancer Incidence in Women With Type 2 DiabetesRisk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort studyInsulin glargine use and short-term incidence of malignancies—a population-based follow-up study in Sweden
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Post by agedhippie on Nov 4, 2018 16:18:46 GMT -5
I gave Lantus as an example because I knew there had been a cancer scare with Lantus back around 2009/2010. However the same depth of data exists for each of the other RAAs and the same analysis gets done on them. The key is the existence of large scale data-sets for each RAA. One outcome of the Lantus scare was was that UK researchers could show from the NHS data-sets that there was no cancer link, and as a side line that people who took both Lantus and metformin rather than just Lantus had a lower cancer risk! The advantage of the NHS datasets is that they contain every prescription and diagnosis the person has ever had in their life, as well as outcomes and what people died of. The NHS data-sets are just an example, similar large data-sets exist in other EU countries (the Lantus scare arose from a German data-set). To loop this back to where we started; Afrezza and other new drugs do not have these data-sets because the drugs have not been available for long enough which is why the FDA requires large scale longitudinal studies to get a level of assurance that there is nothing nasty hiding in the woodwork.
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Post by mango on Nov 4, 2018 17:18:16 GMT -5
I gave Lantus as an example because I knew there had been a cancer scare with Lantus back around 2009/2010. However the same depth of data exists for each of the other RAAs and the same analysis gets done on them. The key is the existence of large scale data-sets for each RAA. One outcome of the Lantus scare was was that UK researchers could show from the NHS data-sets that there was no cancer link, and as a side line that people who took both Lantus and metformin rather than just Lantus had a lower cancer risk! The advantage of the NHS datasets is that they contain every prescription and diagnosis the person has ever had in their life, as well as outcomes and what people died of. The NHS data-sets are just an example, similar large data-sets exist in other EU countries (the Lantus scare arose from a German data-set). To loop this back to where we started; Afrezza and other new drugs do not have these data-sets because the drugs have not been available for long enough which is why the FDA requires large scale longitudinal studies to get a level of assurance that there is nothing nasty hiding in the woodwork. FDA did not require any similar long-term longitudinal clinical trials to evaluate Metformin, a fluorescent molecule that crosses the BBB and of which has taken nearly over a half-century to learn of its MOA. • What we know about Metformin is that it's an endocrine disruptor, it down-regulates the transcription activator MafA of the insulin gene and suppresses glucose stimulated insulin secretion, it alters the gut microbiome, it induces beta-amyloid generation in the absence of insulin by inducing and facilitating Alzheimer's biogenesis via several different metabolic pathways, and it chronically dysregulates iron homeostasis. • No clinical trials to-date have been required for Metformin concerning these scientific facts. The recent 2017 study revealed: • In a large cohort of 22,000 women with type 2 diabetes treated with insulin, we found that the use of insulin glargine was associated with an increased risk of breast cancer. • The cohort included 22,395 women who received insulin treatment, with 321 incident breast cancer events occurring during up to 12 years of follow-up (incidence rate 3.3 per 1,000 person-years). • To date, 14 observational studies have been conducted to evaluate the association between insulin glargine and breast cancer incidence. Of these, seven observed an increased risk of breast cancer. • In conclusion, insulin glargine use was associated with an increased risk of breast cancer in a cohort of women with type 2 diabetes, particularly with long-term use. Despite these findings, the benefits and risks of insulin glargine must be considered by drug regulatory agencies before any changes to clinical practice can be made. I'd say that these revelations are far more significant than a couple spontaneously reported cancer cases, especially in those who were heavy cigarette smokers. Also, all scientific data from clinical trials, laboratory studies and and real-life data do not indicate any risk whatsoever of pulmonary malignancies—indicating that those spontaneous incidents were unrelated to Afrezza exposure.
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Post by agedhippie on Nov 4, 2018 18:44:30 GMT -5
FDA did not require any similar long-term longitudinal clinical trials to evaluate Metformin, a fluorescent molecule that crosses the BBB and of which has taken nearly over a half-century to learn of its MOA. ... The recent 2017 study revealed: ... I'd say that these revelations are far more significant than a couple spontaneously reported cancer cases, especially in those who were heavy cigarette smokers. Also, all scientific data from clinical trials, laboratory studies and and real-life data do not indicate any risk whatsoever of pulmonary malignancies—indicating that those spontaneous incidents were unrelated to Afrezza exposure. I think you are missing the point I am trying to make. I am not arguing Lantus or metformin safety, I am arguing about data. That 2017 trial you are talking about is a study run against the NHS data-sets. It took almost zero time to perform because the NHS already had the data so the researchers simply pulled the data for Type 2 female diabetics on Lantus, NPH, or Levemir for a window between 2002, and 2015. That level of data simply does not exist at that sort of scale for Afrezza it has to come from elsewhere - the lung trial.
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Post by sayhey24 on Nov 4, 2018 18:48:09 GMT -5
• Since FDA is concerned about rDNA insulin human, FDKP and/or polysorbate 80 causing different kinds of lung cancers, one of them of which is heavily linked to being caused by HPV, why don't we just have all insulin manufacturers do a 5 year cancer risk evaluation study? There was a lot of concern years ago about injectable insulins being linked to cancer. Seems like those concerns were never properly addressed in a clinical trial. The advantage that the RAAs have is 20 years of use at scale. That means that when there are questions about cancer, as with Lantus a few years ago, there are huge European datasets with cradle to grave coverage that can be evaluated. The researchers can access those datasets and look for trends to confirm or deny a risk. Afrezza suffers from two issues here; it hasn't been on sale for decades, and medical records in the US are extremely fragmented so there is no single database of record. The consequence of this is that Afrezza has to prove that it's safe because it lacks that substantial track record. Aged - what is it you want to study; human insulin; or FDKP?
Human insulin has been working in the human body for a very long time. Do some non-diabetics who only use human insulin for BG control get cancer, sure. But I would not say human insulin is the cause. More likely a virus.
FDKP has been studied for about 20 years now. Its completely inert. Do inert particle cause cancer? Fat chance.
RAA's on the other hand are not natural to the human body. Do we know of some Frankenstein analogs going bad. Of course we do. The Aspb10 was so bad they started seeing cancer very quickly. Do Lantas users have higher cancer cases, yes. Is lantus the cause, maybe. Then again it could be the elevated BG juicing the viral infection, if the Josalin folks are right. In either case just take the afrezza. If the T2 was taking afrezza they would never need the basal and their BG would be near non-diabetic.
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Post by mnkdfann on Nov 4, 2018 19:37:59 GMT -5
FDKP has been studied for about 20 years now. Its completely inert. Do inert particle cause cancer? Fat chance.
I'm not claiming to be any sort of expert, but a quick search and I found a number of studies linking various inert particles (including certain asbestos fibers, metal particles, gases, etc.) to cancers. So perhaps a blanket declaration that inert particles never cause cancer is not quite accurate.
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Post by mango on Nov 4, 2018 20:58:25 GMT -5
FDA did not require any similar long-term longitudinal clinical trials to evaluate Metformin, a fluorescent molecule that crosses the BBB and of which has taken nearly over a half-century to learn of its MOA. ... The recent 2017 study revealed: ... I'd say that these revelations are far more significant than a couple spontaneously reported cancer cases, especially in those who were heavy cigarette smokers. Also, all scientific data from clinical trials, laboratory studies and and real-life data do not indicate any risk whatsoever of pulmonary malignancies—indicating that those spontaneous incidents were unrelated to Afrezza exposure. I think you are missing the point I am trying to make. I am not arguing Lantus or metformin safety, I am arguing about data. That 2017 trial you are talking about is a study run against the NHS data-sets. It took almost zero time to perform because the NHS already had the data so the researchers simply pulled the data for Type 2 female diabetics on Lantus, NPH, or Levemir for a window between 2002, and 2015. That level of data simply does not exist at that sort of scale for Afrezza it has to come from elsewhere - the lung trial. MannKind laid a solid foundation before they ever pursued FDA approval, and has accumulated a comprehensive safety profile that includes over 600 CT and MRI lung scans, hundreds of pulmonary function studies, years of use in thousands of patients, and so on. We do not need nor require the level of data you describe to establish a conclusion on Afrezza's safety simply because there is no logical reason for it. The basic science is well established, and MannKind has effectively demonstrated that their insulin does not produce any signs of pulmonary malignancy, and their inert carrier particle does not produce any signs of pulmonary malignancy. For these reasons, I do not understand your argument. Not only has Lantus been linked to cancer in 7 observational studies, but even its basic carcinogenicity studies in rodents raises major concerns for it causing cancer. Couple it with the 7 observational studies and you have yourself a legitimate concern for cancer that warrants further and immediate investigation. - Lantus Carcinogenicity: Two year life-time carcinogenicity bioassays with insulin glargine were performed in mice and rats at doses up to 0.455 mg/kg at exposures 10-times in the rat and 5-times in the mouse compared to human exposures at the starting dose of 10 IU (0.008 mg/kg/d) based on body surface area comparisons across species (mg/M2). Female mice had survival issues during the study and the findings were inconclusive as a result of the excessive mortality in all dose groups attributable to hypoglycemia. Malignant histiocytomas were observed at the injection sites in male rats and male mice. The histiocytomas reached statistical significance in the male rats (2-fold human exposure at 10 IU) but was not statistically significant in the male mice. Histiocytomas were not observed in female rats, saline control, or in the insulin comparator group using a different (non-acidic) vehicle. Indices of mitogenicity and relative IGF-1 receptor binding were reported as slightly higher for insulin glargine compared to human insulin.
- Afrezza Carcinogenicity: The Sponsor performed a 2-year carcinogenicity study in rat and a subcutaneous transgenic mouse study (Tg.rasH2). The results of the carcinogenicity assessment with Technosphere (T) and TI indicate an absence of any drug-induced neoplastic findings with administration either via inhalation (2-year rat) or subcutaneous (Tg.rasH2 mouse) routes at systemic exposures of Technosphere (FDKP) 5X and 1X respectively, compared to the AUC at the MRHD (99 mg). Cell proliferation activity (proliferating cell nuclear antigen; PCNA) was confirmatory of the absence of neoplasias/pre-neoplastic signals as assessed in alveolar and bronchiolar cells across treatment and control groups from the rat carcinogenicity study.
The Sponsor assessed the genotoxicity of Technosphere and insulin in an Ames bacterial mutagenicity assay, chromosome aberration assay in human peripheral blood lymphocytes with and without metabolic activation as well as a mouse micronucleus assay with Technosphere alone. All genotoxicity studies were negative.
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Post by sayhey24 on Nov 5, 2018 6:38:33 GMT -5
FDKP has been studied for about 20 years now. Its completely inert. Do inert particle cause cancer? Fat chance.
I'm not claiming to be any sort of expert, but a quick search and I found a number of studies linking various inert particles (including certain asbestos fibers, metal particles, gases, etc.) to cancers. So perhaps a blanket declaration that inert particles never cause cancer is not quite accurate. Comparing FDKP to asbestos is at best irresponsible. They have ZERO in common. Asbetos accumulates and causes active lung scaring. FDKP is excreted intact from body.
Unlike FDKP asbestos kills cells. It does so by inducing a process called "programmed cell necrosis" that leads to the release of a molecule called high-mobility group box 1 protein (HMGB1). HMGB1 starts a particular type of inflammatory reaction that causes the release of mutagens and factors that promote tumor growth. The patients exposed to asbestos have elevated levels of HMGB1 in their serum.
FDKP has been studied extensive by Al Mann and has none of this.
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Post by lennymnkd on Nov 5, 2018 7:08:34 GMT -5
Technosphere/ “ ORGANIC “ molecules that bind together under acidic conditions and desolve under the proper PH . Take it from there!
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Post by mnkdfann on Nov 5, 2018 8:34:04 GMT -5
I'm not claiming to be any sort of expert, but a quick search and I found a number of studies linking various inert particles (including certain asbestos fibers, metal particles, gases, etc.) to cancers. So perhaps a blanket declaration that inert particles never cause cancer is not quite accurate. Comparing FDKP to asbestos is at best irresponsible. They have ZERO in common. Asbetos accumulates and causes active lung scaring. FDKP is excreted intact from body.
That may be, but I made no such comparison. I never even mentioned FDKP. I simply gave examples of inert particles (several examples, beyond just asbestos) that were linked to cancer in order to address a blanket declaration you put out that did not appear to be FDKP specific ("Do inert particle cause cancer? Fat chance.") The main point remains that saying inert particles never cause cancer is not accurate. It may be true for some, but apparently not for all.
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Post by peppy on Nov 5, 2018 8:41:03 GMT -5
Approved GLP-1 agonists: exenatide (Byetta/Bydureon), approved in 2005/2012. liraglutide (Victoza, Saxenda), approved 2010. lixisenatide (Lyxumia), approved in 2016. albiglutide (Tanzeum), approved in 2014 by GSK. dulaglutide (Trulicity), approved in 2014—manufactured by Eli Lilly. semaglutide (Ozempic), approved in 2017. All GLP-1 have the following warning.
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Post by figglebird on Nov 5, 2018 9:24:00 GMT -5
The reality is fdkp was a Marvel and is a Marvel of science with respect to its non toxicity on cell structure - it leave no Trace on the cell structure unlike enhancers - well established data( some of you I'm sure very familiar with the yellow coloring test and so forth)
after inhalation flushed out in 15 minutes - there may be trace insulin left in lungs - the safety profile is Best in Class based on f d k p - we do not know enough about the revised case but short term still well within norm
Long-term data aside and relevant when collected short term reflects well within normal range in Britain and us....
Predisposition is a risk in general - smokers and former smokers obviously should not be taking this medication or should be advised in general that long-term studies are not done.
At this point information can be skewed particularly due to the lack of it based on time and I would look to someone like David Kendall simply in employment if that changes I would look to Mike C and his discussion regarding flexibility.
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