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Post by stevil on Jun 8, 2022 14:13:33 GMT -5
Great discussion/debate. "If the diagnosis is insulin deficiency, the solution is insulin" One of the main issues seems to be whether insulin deficiency is a symptom or a diagnosis. Insulin deficiency doesn't develop until later in the disease, which is why beta cell exhaustion is the predominant theory. No one really knows the real cause for sure, at least not when I was in medical school and I haven't heard any updates since. During the early stages of type 2, serum insulin levels increase, presumably because muscle/fat/liver become resistant to insulin binding at its receptor. (theoretically) This results in the body telling the pancreas to secrete more insulin since it isn't receiving the normal feedback mechanism that insulin has done what it was supposed to do. Beyond what I have already shared, further evidence exists that would lend support to the insulin resistance theory. There have been insulin receptors identified on muscle, fat, liver, and brain tissue- GLUT receptors- that are believed to either have conformational change (meaning the receptor either changes size/shape so that insulin fits/doesn't fit) or the receptors get up/down regulated depending on the body's needs. The implications of this is that it takes resources to maintain a receptor and if it is no longer needed, it can be recycled for use elsewhere, or it is binding insulin that isn't needed. In layman's terms, GLUT receptors are the insulin binding receptors on muscle/fat/brain/liver etc. In times of high energy need, more insulin receptors are needed because glucose=energy. When energy is not needed, the receptors are no longer needed and the body doesn't want to keep the receptors active when glycogen stores are full, so the receptors either change shape or are eliminated to reduce the uptake of additional energy. It has been proven that exercise will restore this functionality of the receptors since more energy is needed to take up glucose, once again pointing to a metabolic component to the disease. Keep in mind, the GLUT receptors are not the only cells that become resistant to insulin, but they are the predominant ones. You can literally flip them on or off with being sedentary or active. A virus would not behave that way. Having said all that, the question remains, what is the best way to treat a chronic disease? Is insulin the answer? Previous insulins have caused an increase in cardiovascular disease (one of the biggest and worst causes of mortality from the disease) while GLP-1s have shown to decrease cardiovascular disease and many other long-term complications. There has never been an insulin that does its job and then leaves when the job is done, so it's hard to say whether the resulting complications from insulin therapy are the result of long-acting insulin and if this effect would be ameliorated by Afrezza's speed and efficiency. Diabetes is not solely a glucose and insulin problem. There are many other metabolic pathways affected in the disease. Manipulation of which pathway produces the best results? We don't know yet. Insulin has been tried and failed with pretty poor results, but it was different than Afrezza. We don't have too much long term data on GLP-1s yet, but they appear to have fairly promising results with long-term use when judging by the resultant complications of the disease outside of A1c control. We may find that a combination of treatment is ideal with a multi-pronged approach of mixing the two together. Whatever the answer is, it is not a simple one and there is not yet enough information available to definitively answer the question.
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Post by stevil on Jun 8, 2022 12:49:43 GMT -5
Maybe they are playing it safe with a likely bear market on the horizon. I would have rather them taken the loan than ATM, although they may decide to do both.
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Post by stevil on Jun 8, 2022 6:30:33 GMT -5
Insulin is a growth hormone. To answer your question, I don’t know that Afrezza is weight neutral. Not much data has been published. Possible reasons why could be less inflammation, insulin doesn’t hang around as long so less fat production, less metabolic effect. Regardless, more data and study is needed.
mounjaro is hijacking a metabolic mechanism to trick the body into not storing fat and to actually release fat stores in the body. Insulin can actually drive glucose into fat and increase production…
I’ll flip your insulin resistance question back onto you to shed light on why I don’t buy a common etiology between the two diseases. Why is it that you could give a type 2 diabetic 100 units of lantus a day and still not achieve proper basal control, while that same dose would be lethal to probably any single type 1 that exists? The reason is that the issue isn’t solely with insulin production but an actual disruption to the body’s ability to use insulin. The reason an obese person would have hypertrophic beta cells is they likely don’t have the gene that codes for a weaker beta cell and are able to properly compensate. The current prevailing theory is beta cell exhaustion for type 2 and I fins that to be far more plausible than an antibody mediated response to a virus. I do believe type 1s could be viral. But if type 1s modify their lifestyle with diet and exercise, if they have bariatric surgery, if they start early intensive insulin treatment for beta cell rest, there is little to no change to their disease and they still become fully insulin dependent once all beta cells are lost. A viral etiology makes no sense in a reversible disease that does not target antibodies. As I stated before, insulin resistance does not appear to cause diabetes necessarily. There appears to be another component. But it nearly always predates the loss of beta cell function. I would expect the beta cell loss first if viral.
there are also a myriad of other metabolic issues that are linked to diabetes. Obesity, hypertension, hyperlipidemia, fatty liver. Why would other metabolic conditions increase diabetes I viral? I suppose you could take the immunocompromised angle, but a metabolic cause seems to be far more consistent.
i keep forgetting to add one of the most compelling pieces to the argument against a viral etiology- gestational diabetes. How can a woman go in and out of diabetes (sometimes multiple times) and not later go on to develop the disease after child birth if a virus causes the disease? Why would gestational diabetes increase the risk of later developing the disease if purely viral? Again, I feel a metabolic cause is the far more likely answer.
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Post by stevil on Jun 7, 2022 20:08:09 GMT -5
Stevil - I bet I will win. I also realize diabetes is a metabolic disease which in most PWDs the issues start because of their high BG. Not all but most. Their high BG starts because of a loss of beta cell function and if Joslin is correct it is a viral attack on the beta cells. With covid and the increase we are seeing there is now addition support for the claims Josil made years ago. Why would we now do a trial against other GLP1s when the new kid on the block is a GIP and claiming its the new Champ? How long would you like the trial, 24 weeks? Mounjaro vs afrezza - I say afrezza kicks butt on A1C but we play by my rules in the trial. If you want to do a weight loss study I honestly do not understand what Lilly is claiming. We know Mounjaro made people vomit and up to 8% dropped out. We also know they reduced caloric intake and had health coaches monitoring their diet and their increase in exercise. Thats why I am saying if we knew what they did I really don't think it would make much difference if we subbed the afrezza for the GLP1. If Mounjaro is going to make them not want to eat because they have a bellyache if we sub the afrezza they will still have the bellyache. Give us a level field and afrezza/Mounjaro should do as well as Mounjaro/GLP1 for weight loss. Also adding the GIP or GLP1 to afrezza is also OK if we are trying to reduce weight but afrezza is about reducing BG. They use to give out amphetamines like candy to reduce weight and they worked for the weight but yes they caused other issues. If properly dosed and the T2 still has fasting insulin we should not need the GIP/GLP1. Worst case is an evening puff of afrezza should hold them over night or if they really need the basal that too is an option. But early T2s should still be producing and if we can get them early in most cases afrezza will stop the progression. I would argue we can most definitely use other insulin trials as they apply. For example trials which demonstrated early insulin intervention. Insulin is insulin once its in the blood stream although the jury is still out on the analogs and long term safety. BTW- I gave my first insulin shot to my dad 51 years ago today as he could not give himself shots. My aunt was the head nurse at a major NYC hospital and knew more about treating diabetics than any doctor at the time because she had to do it. When she heard my Dad was put on orinase when first diagnosed she called up his doctor, gave him hell and predicted what would happen. Then he was put on diabinese like that was going to make a difference. He should have been put on insulin day 1 and back then we did not have todays insulins nor did we have the thin needles. We used to boil them before use and we would sharpen them ourselves when they got dull. With now having afrezza I can think of few good reasons not to start the new T2 on afrezza day 1. I have not seen an oral which does not end up causing other issues or bigger issues. Read what Philip Home wrote a few months back diatribe.org/type-2-diabetes-start-earlyYou can't make this stuff up. Give the PWD all this crap and in 5-15 years they will probably need insulin anyway. So why don't we just give them the afrezza day 1 aside from cutting into the $25B GLP1s and SGLT2 are generating yearly? From Philip Home- "Newer tools of glucose monitoring are a great help in managing insulin doses, which vary a lot from person to person. If you aren’t able to achieve the results you and your healthcare team want after trying to manage your glucose levels with other medications, you will most likely be offered insulin (you can also ask your HCP about it at any time). Indeed, after 5-15 years, it is very common to need insulin anyway to manage your glucose levels and to stay healthy for another 20-plus years." Unless you have intimate knowledge about Afrezza that no one else has, there is no basis for your hypothesis from history or current understanding of insulin therapy. Weight gain is nearly ubiquitous amongst insulin users. In all data published by MNKD, at best Afrezza was weight neutral, a far cry from the claims Mounjaro is proposing. Are you sure you're not confusing type 2 with type 1? In type 2, I don't buy that hypothesis at all because I don't understand how beta cell destruction adequately explains insulin resistance or the phenomenon of an elevation in serum insulin levels during the early stages of disease to compensate. Insulin resistance alone will NOT lead to type 2 diabetes. Rather, type 2 diabetes develops in insulin-resistant individuals who also show impaired beta cell function. If all type 2 disease had a viral etiology, I don't see how it is reversed by lifestyle modifications or by bariatric surgery. I think it's pretty clear there is some other causative event that is disrupting the system with decreased insulin production being the effect rather than the cause. I'm much more apt to blame fat cells and adipokines or lipotoxicity rather than a virus for type 2s. I have my own theories about the link between covid and diabetes. I think this is a decent place to start. wexnermedical.osu.edu/blog/why-are-people-developing-diabetes-after-having-covid19If A1c is your metric, I would never bet against insulin. Insulin is the most efficient method to decrease serum glucose. I thought we were betting on weight loss? 8% is still a very low number for the potential benefit. It's why having more options for treating disease is great. Those 8% will have another option to choose from. Afrezza also had patients drop out due to cough... It happens... I have had patients that stopped taking GLP-1s due to the GI distress. I think it's likely more tied to gastric emptying as I think this patient already had underlying gastroparesis and the GLP-1 probably made it worse as she already had pretty profound neuropathy elsewhere already. Don't really know since I never saw that patient again. However, I can assure you that the weight loss was not due to vomiting as I have also had many patients with weight loss on GLP-1s that had absolutely no side effects at all, including vomiting up their guts or not wanting to eat because of a belly ache.
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Post by stevil on Jun 7, 2022 19:20:06 GMT -5
To add to my previous post a point I didn't fully communicate. pubmed.ncbi.nlm.nih.gov/28958751/Our bodies are wonderfully made and are complicated beyond belief. It seems that any imbalance causes problems in the system, even providing an excess of what is considered "good". The reason we need new trials with Afrezza is that a lot of damage done by insulin may be mitigated by the rapidity of Afrezza's speed. We know, with certainty, that an excess of insulin causes worsening disease. However, if insulin finishes its job and doesn't hang around afterwards, would that provide better results? We won't know until we do more studies... Are GLP-1s safe by the same logic? We won't know until time tells the tale. As of now, it appears they are profoundly safe. Millions are on the medications and are getting positive results. Time will reveal the negative issues, if any, that come from manipulating glucagon analogues.
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Post by stevil on Jun 7, 2022 17:45:04 GMT -5
I bet if we ran a combo trial with Mounjaro/afrezza this would do as well as the Mounjaro/GLP1 arm for weight loss. I would take that bet. One thing I don't think you realize is that diabetes is a metabolic disease. It's not just a dysfunction of glucose/insulin secretion and absorption, which is all Afrezza addresses. There is a reason GLP-1's use a different mechanism of action and is still relatively successful with glucose control. Insulin is not the only glucose modulating hormone in the body. Multiple systems (in type 2 anyway) are disrupted. You say that no additional tests are needed... Long term data would be needed to prove Afrezza is superior to GLP-1s with improved outcomes. We already see improved cardiovascular outcomes with GLP-1s and have not seen the same with previous insulins. You are quick to point out how different Afrezza is from other insulins, yet you want to pick and choose when to use the former understanding of insulin for your argument. Either Afrezza is similar enough to other insulins that we can use previous understanding and data about insulin treatment, or it's different enough that we need to see- through new data- its differences and nuances. I don't think anyone would argue that anything would be better than insulin at controlling serum glucose levels. That's not really the question anyone is trying to answer. The real question is "which treatment will produce the best outcomes for diabetes as a chronic disease?" We don't have enough information at this point in time to answer that. The benefits of GLP-1s extend beyond glucose control and appear to, at least partially, address the underlying metabolic dysfunction of the disease. For the record, I'm team Afrezza. I've been accumulating shares of MNKD from Sept 2020 until now. I had completely lost faith in the stock and got out, but now am back in for the long haul. I just haven't been convinced that Afrezza is the best or only way to treat the disease. I see how it could be, but I also see how it couldn't.
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Post by stevil on Jun 7, 2022 17:33:09 GMT -5
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Post by stevil on Jun 3, 2022 15:21:00 GMT -5
Stevil…. I agree, but you could say with Afrezza you can eat cake, although I shouldn’t say that, I’m not supposed to say that, but I just said it🤣 My next-door neighbor T1…is getting put on Afrezza very soon because she’s going to Florida for a month on vacation and she does not wanna wear that pump in the ocean! The problem with the way the current management of diabetes is structured, you can eat cake with a GLP-1 and still have a modest A1c. You'll still have the spike, but it won't be as high or last as long as with previous non-insulin treatments. The hard sell for Afrezza is going to come from improved long-term outcomes with better post-prandial control than GLP-1s that comes from improved TIR. Until a compelling case is made to show why treatment should be focused on controlling PPG and better TIR, I fear Afrezza will always be reached for last in the treatment algorithm for most prescribers. Just for the record, I don't always follow guidelines or think they should be used to direct all decisions. If all we were supposed to do was follow algorithms, medical school was an enormous waste of resources and time. I refuse to practice that way. Every patient has their own needs that need to be considered when deciding treatment.
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Post by stevil on Jun 3, 2022 12:52:31 GMT -5
I've been skimming through these longer posts so I'm not sure if all of this has been covered already or not. There were a few points I wanted to make that will hopefully fill in some gaps.
In my opinion, I think the peds trial is the way forward for the company for mass adoption. I don't see it coming first from the type 2 community... or anytime soon for that matter, regardless of how well it goes for peds. The reasons are multifactorial and have been discussed nearly ad nauseum. The biggest reason peds has a higher chance of taking Afrezza to the next step is that it's because parents care more about their child's health than an adult with type 2. The early adopters of Afrezza in the type 1/2 community are unique. Not too many adults care about meticulously managing their disease, have the financial means to do so, or are actively seeking the "latest and greatest" in regard to treatment. For the vast majority of patients, "good enough" is enough.
Unfortunately, people without clinical experience have strong opinions on this matter and it confuses many who understand the benefits of Afrezza on paper and wonder why it hasn't been adopted more quickly and on a wider scale. It really is very simple. Other medications are cheaper, more attainable, better covered by insurance, and require fewer interventions for "good enough". We see this every day. People know going for the salad is the better dietary choice. But they reach for the cake instead. People buy processed foods in the grocery store because they're cheaper than healthier foods. It's not an education problem, it's a convenience problem. Some may say it's easy to inhale a dose with every meal, and it is if no thought goes into a dose. I'm sure for the people who have experience with Afrezza and have it dialed in, it's become second nature. Getting there, though, takes up to months of working to understand the medication and how it affects the body. Diabetes is difficult to manage because there are so many different variables that can affect glucose regulation and doses will change depending on those variables. Some people don't want to be bothered with making daily adjustments to their treatment. Some people would rather inject once a medication week instead of picking up an inhaler 3-6 times a day, regardless of how simple of a task that may be.
So, having said all that, the reason I think peds is the gateway to as much of an adoption of Afrezza as we'll see anytime soon is because parents are willing to spend money on their children. They're willing to work harder to make sure their children are getting "the best" treatments available. They'll not content with "good enough" and will make sure their children are trained well to manage their disease. Also, most children will qualify for CGMs so the benefits of Afrezza will be on display to see. Perhaps the biggest reason is the networking ability of a mother. Moms are all over social media all the time. You can guarantee that if one mother has a good experience that it won't be long for 10 more to hear about it. Word of mouth is the strongest influencer and marketing tool. If I were Mannkind, I'd look for ways to support mothers and make sure they have all they need to equip themselves. I remember reading on here many years ago that there was a website MNKD was working on for people to share their stories and to collaborate with other current users. I think this tool would be invaluable and would help greatly to make peds flourish.
Sure, the type 2 market is way bigger than type 1, and even more so just peds. If I had to put my money on anything, I'm betting on a caring mother and her inability to stop from telling 10 of her friends if she's found something valuable.
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Post by stevil on May 19, 2022 18:48:21 GMT -5
Casper. You know this how? He's our friendly ghost
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Post by stevil on May 19, 2022 13:14:41 GMT -5
Barring new information, I completely agree with Aged. This device doesn't make sense unless you need to bolus small doses with a low basal requirement. The capacity isn't very large so I wouldn't think this would apply to too many people. Generally if a type 2 is on prandial insulin, their basal requirement is already pretty high. So this device really doesn't offer anything new than what a once-daily basal injection already would. They essentially do the same thing. You're just trading a needle stick for a cartridge. This is likely why the company is having trouble finding traction in the industry.
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Post by stevil on May 19, 2022 12:39:28 GMT -5
Can you imagine the packaging for V-GO?? A one month supply must come in a huge box. The device is not small like the G6 transmitter. Hopefully MNKD can reengineer it into a smaller footprint. I'm far from a patent lawyer, but if they were going to redesign the unit, would they still have to buy the technology? Wouldn't that qualify it as a different device entirely. I can't imagine "the process" on such a mechanical and unsophisticated device would be too difficult to work around. This one is really a head-scratcher for me for all of the reasons aged has addressed. I would imagine the value of this system is it's already an approved device and R&D has already been done. I would think if they were planning on modifying it in any way that they wouldn't have purchased the company. I wonder if one of the benefits is to avoid lipohypertrophy? Maybe it offers a more consistent and accurate dosing profile?
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Post by stevil on May 19, 2022 11:00:43 GMT -5
Does anyone really think that millions of people tune in every day to see who is ringing the bell? This is basically an ego booster trip to NY for MC that the shareholders are paying for. I'm pretty ambivalent when it comes to Mike. I typically try to give people the benefit of the doubt until they prove otherwise. There's no doubt he's working hard and trying... I don't agree with a lot of the things he's done but the company continues to operate so... something must be going right... Having said that, this decision ranks very low on the "things that irk me about Mike". He's tried to be creative with a low budget. A lot of the things he's done may or may not have been taking the company car for a joyride. I remember the sports games where he would blast on the jumbotron, the racecar sponsorships, etc. The board should be reigning him in if they disagreed with company money spent. Long, long, long story short, this is a very cheap way to gain a headline. There will likely be a lot of investing websites that pick up on the story... All in all, it's maybe a couple thousand dollar trip, all in... If it brings in just one extra prescription or raises the share price by $0.01, it was money well spent. Low risk investment if you ask me.
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Post by stevil on May 19, 2022 8:59:02 GMT -5
People on insulin progress in their disease as well….
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Post by stevil on May 18, 2022 10:26:18 GMT -5
Sorry to hear you’re struggling with your disease. Hopefully your issue with your neuropathy is just a vitamin B12 deficiency, which can be a common issue with metformin- make sure you had your blood levels checked.
One thing everyone needs to remember who hates the need for more data, until Afrezza, insulin was a last resort because the risks outweigh the benefits until you literally have no other choice than to use it. The current SOC is built on old data. Afrezza hasn’t demonstrated it is different than previous insulins in the data, meaning it improves outcomes without increasing risk. I get that this inherently makes sense when they publish small studies with fewer episodes of hypoglycemia. One hurdle is that basal insulin is currently listed before mealtime insulin in the SOC. Thus, you’re still going to have the fear of hypoglycemia due to a combination of basal+ bolus. MNKD has not proven that earlier use of Afrezza is superior to the GLP-1s and SGLT-2s, especially when they keep coming out with more and more beneficial side effects of weight loss and renal/cardio protection. They’re constantly getting the spotlight as the new and shiny toy because they seem to be giving better benefits beyond A1c control.
MNKD needs head to head studies, or at the very least, needs long term data to show that earlier intervention with Afrezza would produce better outcomes than the current standard of care. It would have to be a retrospective study based on Afrezza users. I really think that is the only path forward in such an established treatment plan. Doctors have not been educated on the advantages of Afrezza. When I spoke to a mannkind rep, it was explained more as a treatment of convenience to avoid needles and not having to worry as much about hypos because it’s in and out so quickly. They can’t speak about better outcomes and metabolic effects because they have nothing to point to.
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