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Post by sayhey24 on Oct 5, 2022 7:41:33 GMT -5
Aged - Al Mann use to say the medically correct way to treat the T2s was to address the post prandial glucose excursions. If the RAA does better than the basal thats the way to treat it. The T2 should be making enough insulin for when they are not eating and therefore not need the basal.
The GLP1s are a funny animal. The most benefit they seem to provide is loss of appetite which causes weight loss and reduces need for post prandial insulin.
I am OK with the weight loss. Most people also don't use them that long. If Mike can figure out an angle to combine afrezza use with the GLP1 use, that may be good.
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Post by agedhippie on Oct 7, 2022 17:48:36 GMT -5
Aged - Al Mann use to say the medically correct way to treat the T2s was to address the post prandial glucose excursions. If the RAA does better than the basal thats the way to treat it. The T2 should be making enough insulin for when they are not eating and therefore not need the basal. The GLP1s are a funny animal. The most benefit they seem to provide is loss of appetite which causes weight loss and reduces need for post prandial insulin. I am OK with the weight loss. Most people also don't use them that long. If Mike can figure out an angle to combine afrezza use with the GLP1 use, that may be good. The problem is that he had no evidence to back the claim, it was just his theory. Run a trial to prove that it really does better than basal, and that it retains that lead over four years or so and things will change. Pretty much all treatments result in a rapid drop in the first few months, but then they bottom out and steadily rise over the next few years. If Afrezza can avoid that rise and retain the gain it would change the SoC without question in my mind. The point of basal is to free the body's own insulin from dealing with the basal insulin - dumb insulin can do that just fine. The insulin freed by this can then deal with meal times, and do it far more effectively than any external insulin because it uses all five phases and not just two. It's the advantage of being directly integrated into the body's own system. The benefit of GLP-1 comes from the modification to the secretion cycles which it does without the beta call stress that sulfas cause. The modification is multi-phase touch several metabolism components. The weight loss is a by product of one of those metabolisms, and at normal doses weight loss is not actually that high despite the promotion from the drug companies. When it's used for weight loss the dose is higher than you would use for diabetes hence more side effects. There may be scope to combine GLP-1 or Mounjaro with Afrezza. My old endo prescribed GLP-1 to Type 1s to let them make better use of insulin and so reduce the total insulin dose. He prescribed it for me at one point, but I politely declined - I don't want more drugs! |
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Post by MnkdWASmyRtrmntPlan on Oct 11, 2022 10:29:27 GMT -5
Hey Aged, thanks for continuing to contribute your knowledge to this board. I googled but couldn't find 5 phases of insulin release, although I did see a phase 3 that was discovered in the 80's. Some of the articles I read were really heavy duty medical jargon that was way over my head, but still interesting. Do you have a link to other phases? |
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Post by sayhey24 on Oct 11, 2022 16:00:15 GMT -5
MIMRP - I have not idea what he is talking about. The healthy pancreas releases insulin and a lot until BG is back to baseline and then probably too much and then the liver kicks in. Its not an exact science nor does it have to be as the body will balance things out. The human body is an amazing thing. Afrezza is close enough that the the body thinks the pancreas is releasing it. How much afrezza the PWD is taking is not exact nor does it have to be but a little more is better than too little. Now - to the diabetes community what I just said is way crazy.
With the GLP1 stuff again it gets pretty simple, the users have no appetite. If they kept eating as they were prior the GLP1s would have little effect but they don't. They stop eating for awhile. I can stop a new GLP1 user a mile away. The thing is after about 6 months many GLP1 users start to see little additional results and stop using them. Most within two years stop using. If Mike can figure out how to leverage this he may be able to develop a plan for going after the T2s. Then again, hope springs eternal.
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Post by agedhippie on Oct 14, 2022 15:00:08 GMT -5
Hey Aged, thanks for continuing to contribute your knowledge to this board. I googled but couldn't find 5 phases of insulin release, although I did see a phase 3 that was discovered in the 80's. Some of the articles I read were really heavy duty medical jargon that was way over my head, but still interesting. Do you have a link to other phases? I need to go and dig it out again. From memory the cephalic phase insulin release is the initial phase and is triggered by sensory input and starts the insulin release - this is the effect where you are looking at or smelling food and your mouth is watering. What is traditionally seen as the first and second phase follow in response to the arrival of glucose. On the back of those responses you have the incretin hormones release which happens in the gut and is the mechanism that GLP-1 enhances. I think there is a process that front runs the cephalic phase which is neurological (thinking about eating) as well. All of these phases involve insulin release to a greater or lesser extent. To be clear here; the direct effect of glucose acting on the beta cells are the most prominent stimulus of insulin secretion. If you look at the total insulin secretion though there is an argument that 70 to 80% of the insulin released does not come from that stimulus. Fun facts like bypassing the mouth and smell means the cephalic phase is not triggered and produces glucose intolerance. Most of this work that I read was done back in the 1980s so it's well understood. Unfortunately I don't have the links as those are on a now long dead browser, but searching for "cephalic phase" and insulin will probably turn stuff up. |
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Post by agedhippie on Oct 14, 2022 15:23:01 GMT -5
... With the GLP1 stuff again it gets pretty simple, the users have no appetite. If they kept eating as they were prior the GLP1s would have little effect but they don't. They stop eating for awhile. I can stop a new GLP1 user a mile away. The thing is after about 6 months many GLP1 users start to see little additional results and stop using them. Most within two years stop using. If Mike can figure out how to leverage this he may be able to develop a plan for going after the T2s. Then again, hope springs eternal. The idea that GLP-1 owes it's effectiveness purely to appetite suppression is a misconception. The appetite suppressant effect is directly proportional to the dose size which is why the anti-obesity version of the GLP-1 drugs are simply larger doses of the anti-diabetics drugs. The weight lost aspect gets heavily promoted because at a population level obesity is a major problem, and at a personal level a magic shot that makes you thin is very marketable! For diabetes GLP-1 works by enhancing the activity of the incretin hormones in the gut which increases the insulin secretion amongst other things. You absolutely can carry on eating as before and it will lower your glucose levels. This diagram shows the effect of GIP and GLP-1 on the metabolism and lets you see why it's so popular - it doesn't just deal with insulin deficiency by just adding more insulin (although is does that via increased secretion), but also makes the insulin more effective.  This was the paper I took the image from - cardiab.biomedcentral.com/articles/10.1186/s12933-021-01412-5 |
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Post by MnkdWASmyRtrmntPlan on Oct 15, 2022 12:49:18 GMT -5
Hey Aged, thanks for continuing to contribute your knowledge to this board. I googled but couldn't find 5 phases of insulin release, although I did see a phase 3 that was discovered in the 80's. Some of the articles I read were really heavy duty medical jargon that was way over my head, but still interesting. Do you have a link to other phases? I need to go and dig it out again. From memory the cephalic phase insulin release is the initial phase and is triggered by sensory input and starts the insulin release - this is the effect where you are looking at or smelling food and your mouth is watering. What is traditionally seen as the first and second phase follow in response to the arrival of glucose. On the back of those responses you have the incretin hormones release which happens in the gut and is the mechanism that GLP-1 enhances. I think there is a process that front runs the cephalic phase which is neurological (thinking about eating) as well. All of these phases involve insulin release to a greater or lesser extent. To be clear here; the direct effect of glucose acting on the beta cells are the most prominent stimulus of insulin secretion. If you look at the total insulin secretion though there is an argument that 70 to 80% of the insulin released does not come from that stimulus. Fun facts like bypassing the mouth and smell means the cephalic phase is not triggered and produces glucose intolerance. Most of this work that I read was done back in the 1980s so it's well understood. Unfortunately I don't have the links as those are on a now long dead browser, but searching for "cephalic phase" and insulin will probably turn stuff up. Thanks Aged. Google shows: cephalic phase of insulin secretion lasts for around 10 min and is initiated by the anticipatory sight, smell and taste of food and further enhanced by chewing and swallowing the food. The incretin effect—the amplification of insulin secretion after oral vs intravenous administration of glucose as a mean to improve glucose tolerance—was suspected even before insulin was discovered, and today we know that the effect is due to the secretion of 2 insulinotropic peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The Phase 3 stuff that I saw is all about in vitro, so I'm not sure if that's even a real-life thing or not. Eh, it doesn't matter. I was expecting that they would be understandable to laymen (or, less)  , but it doesn't seem to be. |
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Post by agedhippie on Oct 15, 2022 18:31:10 GMT -5
... The incretin effect—the amplification of insulin secretion after oral vs intravenous administration of glucose as a mean to improve glucose tolerance—was suspected even before insulin was discovered, and today we know that the effect is due to the secretion of 2 insulinotropic peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The Phase 3 stuff that I saw is all about in vitro, so I'm not sure if that's even a real-life thing or not. ... The incretin effect is a big deal because it joins several of the body's systems together. For blood sugar it increases the insulin output in proportion to the glucose level in the gut (this is why GLP-1 rarely causes hypos - no glucose, no insulin secretion). It also links to the muscles which is an insulin independent way glucose gets removed from the blood as muscle contractions pull in glucose for energy. The muscle mechanism is interesting and why you see people talk about walking to reduce levels. There is the hepatic mechanism as well which regulates the level by removing insulin, or causing glucagon release to put glucose into the blood. In Type 2 the later, glucagon mechanism is overactive and pushes up resting levels. This is why simply looking at glucose levels is only part of the story. You can always reduce glucose with insulin, but in doing so regularly you can down-regulate the receptors which worsens insulin resistance and raises the other risks (down-regulation can be handled by more insulin). This is why you have long term trials looking at outcomes in the SoC, and not simply asking if it reduces glucose levels. It's also why the medical world likes GLP-1 - it addresses more than one problem and there is trial data to support that. The old saying that if you have a hammer everything looks like a nail applies to insulin. However, that's not to say that sometimes there aren't nails (to twist at a metaphor) and TIR could prove to be a nail. Right now though there is no long term trial data on TIR, but those trials are being prepared. In my view the likely outcome for Type 2 will be incretin drugs AND insulin. Sayhey's idea of joint Mounjaro and Afrezza trials is a good one for this reason. |
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Post by sayhey24 on Oct 16, 2022 7:54:31 GMT -5
MIMRP - in the bigger picture the body's goal is to get insulin into the blood to stop the post meal spike. Afrezza solves this problem. The healthy body has no idea when you are going to eat until after the fact and then its running a sprint to get the insulin into the blood. The incretin effect helps in the sprint by providing a head start.
The entire GLP1 thing is kind of a hoax with T2s. The big effect they have on T2s is they lose their appetite and stop eating. When they stop eating they lose weight and they need a lot less insulin. Ralph DeFronzo has been presenting the above picture for years on the GLP1 benefits. The problem is within 2 years most GLP1 users start eating more again and their body's pancreas is still damaged and they still can't produce the insulin they need. For nearly half its within about 6 months.
At one point MNKD was developing a GLP1. I would like to know what happened. I think it would be interesting for Mike to share the internal MNKD records. For some reason MNKD stopped development and then Al Mann told DeFronzo GLP1s as a T2 solution where kind of a hoax.
The thing is GLP1 sales are around $14B. Thats an amazing number for a hoax but the users do initially lose a lot of weight. Thats what Mike needs to leverage so he can partner afrezza into the GLP1 market. Step one is the Mounjaro and Afrezza trial.
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Post by agedhippie on Oct 16, 2022 9:35:08 GMT -5
MIMRP - in the bigger picture the body's goal is to get insulin into the blood to stop the post meal spike. Afrezza solves this problem. The healthy body has no idea when you are going to eat until after the fact and then its running a sprint to get the insulin into the blood. The incretin effect helps in the sprint by providing a head start. The entire GLP1 thing is kind of a hoax with T2s. The big effect they have on T2s is they lose their appetite and stop eating. When they stop eating they lose weight and they need a lot less insulin. Ralph DeFronzo has been presenting the above picture for years on the GLP1 benefits. The problem is within 2 years most GLP1 users start eating more again and their body's pancreas is still damaged and they still can't produce the insulin they need. For nearly half its within about 6 months. At one point MNKD was developing a GLP1. I would like to know what happened. I think it would be interesting for Mike to share the internal MNKD records. For some reason MNKD stopped development and then Al Mann told DeFronzo GLP1s as a T2 solution where kind of a hoax. The thing is GLP1 sales are around $14B. Thats an amazing number for a hoax but the users do initially lose a lot of weight. Thats what Mike needs to leverage so he can partner afrezza into the GLP1 market. Step one is the Mounjaro and Afrezza trial. The body does know you are going to eat before the fact, that's the cephalic phase of insulin release where the body is responding to thinking about food (neurological input) as well as sight and smell. I linked to a paper describing this earlier in this thread. The incretim effect doesn't give a head start, it gives a follow on action since it is triggered by the L-cells that exist between the duodenum and colon which causes insulin secretion. Hypos with GLP-1 are rare because the body's own regulatory mechanisms prevent this as the insulin is released from the pancreas via the hepatic portal vein (something that external insulin cannot do for obvious reasons). The idea that GLP-1 is a hoax and this is all due to weight loss is flatly wrong. GLP-1 and GIP are hormones just like insulin, and just as you can supplement insulin you can supplement these hormones as well. There are literally thousands of published research papers on the topic of GLP-1 and diabetes explaining the role of GLP-1 and GIP in relation to glucose levels. This diagram if from a paper by DeFronzo on why GLP-1 should replace metformin and shows the sources of hypoglycemia that GLP-1 addresses (insulin addresses Decreased Insulin Secretion)  The paper is here ( Is It Time to Change the Type 2 Diabetes Treatment Paradigm? Yes! GLP-1 RAs Should Replace Metformin in the Type 2 Diabetes Algorithm) for those that want to read it and see why GLP-1 works. Medically this is not new or controversial - the research is well established, the trial data exists, and the problem was packaging GLP-1 for delivery. I think Afrezza as an add-on for Mounjaro is workable and they should trial that ASAP. |
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Post by sayhey24 on Oct 16, 2022 17:52:36 GMT -5
Aged - afrezza is not a replacement for GLP1s when it comes to addressing BG control. It eliminates the GLP1 hoax. If the PWD continued to eat like they did before taking the GLP1 its effect on A1c reduction would not be much better than metformin. You can "increase" all that stuff in your picture but if the T2 was eating what they ate prior you would not seem much benefit. You have a damaged pancreas. The body needs insulin. The last thing you want to do is make the damaged pancreas work harder. The good news is because they are eating less they need less insulin. Its about that simple. The argument you are making reminds me of when "they" tell you that you will get better gas mileage if you properly inflated your tires. Its true but not dramatic and the GLP1 without food reduction is also true but not dramatic.
The GLP1 as a weight loss agent is fine as long as the patient understands the risks on the label. How many do? As an agent to reduce BG its a bust. The body needs insulin and that research is well established. If DeFronzo's GLP1 was so good why are they always talking about combination therapy? Does adding an SGLT2 to a GLP1 really make any sense when you have afrezza? Neither can do what afrezza can and clearly when you are using afrezza its best not to use this other junk. If Mike can leverage the GLP1 hoax to jump start afrezza sales, I am all for it.
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Post by agedhippie on Oct 17, 2022 9:00:09 GMT -5
Aged - afrezza is not a replacement for GLP1s when it comes to addressing BG control. It eliminates the GLP1 hoax. If the PWD continued to eat like they did before taking the GLP1 its effect on A1c reduction would not be much better than metformin. You can "increase" all that stuff in your picture but if the T2 was eating what they ate prior you would not seem much benefit. You have a damaged pancreas. The body needs insulin. The last thing you want to do is make the damaged pancreas work harder. The good news is because they are eating less they need less insulin. Its about that simple. The argument you are making reminds me of when "they" tell you that you will get better gas mileage if you properly inflated your tires. Its true but not dramatic and the GLP1 without food reduction is also true but not dramatic. The GLP1 as a weight loss agent is fine as long as the patient understands the risks on the label. How many do? As an agent to reduce BG its a bust. The body needs insulin and that research is well established. If DeFronzo's GLP1 was so good why are they always talking about combination therapy? Does adding an SGLT2 to a GLP1 really make any sense when you have afrezza? Neither can do what afrezza can and clearly when you are using afrezza its best not to use this other junk. If Mike can leverage the GLP1 hoax to jump start afrezza sales, I am all for it. In summary; the NHS data on GLP-1 in the real world says that on average GLP-1 patients lose less that 5% of their weight so their eating habits haven't changed. This is why the weight lose dose is so much higher. Beyond that I don't really know what to say about GLP-1; the data is clear, the mechanisms for insulin control are well established, and medically this is taken as settled. There seems to be some confusion about the pancreas and Type 2. Type 2 is not the result of a damaged pancreas (taking that to mean dead beta calls) in the early days in the case of Type 1. Type 2 is the result of the body not being able to use the insulin it produces effectively. This causes the pancreas to produce more insulin and over time (years) the pancreas can no longer keep up and beta cells become over-stressed. Even then though new beta cells are still produced as normal. What happens in Type 2 is that insulin is used to supplement the bodies own insulin and fill that gap. You can also fill that gap by addressing the causes of hyperglycemia (see my earlier diagram) and so allowing the body to meet it's own needs. This is what metformin does, but as Type 2 is progressive it can only help for so long. The same would apply to GLP-1 which is why the SoC is a step therapy. GLP-1 is emphatically not a cure for Type 2, nor is Afrezza, they are both treatments. TBH I am not sure why you would add an SGLT2 to GLP-1 and not use insulin instead unless you were trying to fix one of the other symptoms of Type 2 like high blood pressure, or kidney disease (GLP-1 will handle CVD just fine as will SGLT2 so it's redundant there) Mike will never stand up in a medical meeting and attack GLP-1 as a hoax, he would be laughed out of the room and not invited back - GLP-1s are well understood and arguing counter to the evidence is seldom a winning strategy in the world of science. |
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Post by sayhey24 on Oct 17, 2022 11:55:40 GMT -5
Aged - just take an autopsied pancreas from a T2. You will see the beta cell mass is significantly less. The problem the T2 has is 2 fold; first is they lose post prandial control; second is the insulin which they are releasing is not being use properly by the body. Now these two things are related. The PWD with the damaged beta cells is not releasing enough insulin and then what they do is not being properly used.
Here is the interesting thing. If we give the PWD afrezza before the PWD's BG spikes post meal their body uses that insulin nearly like a non-diabetic and the insulin "resistance" is significantly less than if their body first releases its insulin and the BG is high and then we give the afrezza. Why is that? If the PWD was truly "insulin resistant" then it should not matter if it was afrezza or their body's insulin - they should be insulin resistant but they are not. For whatever reason their body's are rejecting the insulin made by there body but blocking the insulin receptors.
The interesting thing is we also see this rejection with a few afrezza users. For some reason a few afrezza users report that afrezza nolonger works for them as their body's have built up an immune response.
I agree, Mike will never stand up in a medical meeting and attack GLP-1 as a hoax but Al did and he was not laughed out of the room. At the time Al was developing a GLP1 med and something happened. I don't know what. What we do know is the lasting effect of GLP1s is short lived. If it wasn't we would not need the ADA's step program. The good news is Mike does not need to fight the battle, he just needs to figure out how to leverage the fact that within a year most stop using and within 2 years nearly all stop prescribing.
To answer your question - TBH I am not sure why you would add an SGLT2 to GLP-1 and not use insulin instead - the answer is very simple, its about the money. BP is in the business of making money not solving issues. The ADA is BP's marketing arm to provide credibility. If the ADA said use afrezza first, they may be significantly helping the T2 but they would be putting themselves out of business.
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Post by agedhippie on Oct 17, 2022 16:08:19 GMT -5
Aged - just take an autopsied pancreas from a T2. You will see the beta cell mass is significantly less. The problem the T2 has is 2 fold; first is they lose post prandial control; second is the insulin which they are releasing is not being use properly by the body. Now these two things are related. The PWD with the damaged beta cells is not releasing enough insulin and then what they do is not being properly used. This is covered in the earlier inforgraphic I posted in the thread; GLP-1 and GIP decrease beta cell apoptosis and increase proliferation so you end up with more beta cells. This behavior is particularly interesting because there is a theory that T2 is caused by apoptosis (programmed cell death) outpacing proliferation with the mismatch resulting in a deficit which is compounded by the insulin resistance. At this point we are back to the old problem of Type 2s many variants... The higher the glucose level the greater the insulin resistance so if you correct early, as the body does, you need less insulin. That would mean that by being active earlier Afrezza can deal better with faster carbs. The tricky bit is getting the time right as it will be different for every meal based on carb type, fat, etc. If you get it wrong (pizza) then you may well find that the Afrezza has cleared by the time the glucose arrives. I suspect that's down to their having a particular Type 2 variant. If they had true anti-body response then they would be Type 1 because it wouldn't stop at the Afrezza. I went back and looked at the numbers. The best data I can find was from the BMJ looking at the data in the UK using GLP-1. They found that 64.5% of patients were adherent to GLP-1 RA therapy at 12 months, and that adherence decreased to 59.2% at the cumulative 24-month follow-up. Although it also said, "... Comparatively, this study found that 45.2% and 64.7% of patients discontinued by 12 and 24 months, respectively...". I don't really understand the numbers as I don't see how you can be adherent and discontinue at the same time. The paper is here - drc.bmj.com/content/bmjdrc/10/1/e002517.full.pdf |
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Post by sayhey24 on Oct 17, 2022 17:30:21 GMT -5
So you think GLP-1 and GIP decrease beta cell apoptosis and increase proliferation so you end up with more beta cells. Well that may be true like proper air inflation will result in better gas mileage. The problem we have is a flat tire. Over time the GLP1 fails. If I can get a 300lb PWD a 5% weight reduction in 3 months thats a huge lift off the pancreas but then it stops. If you can get 10% you can spot that person a mile away and a bigger lift off the pancreas. Then it stops and that big decrease in the 6 month A1c stops too. Then the PWD decides the GLP1 is not worth the cost and tummy ache and stops prescribing. There is another theory and a growing one with Covid that T2 is viral based. The thing is its not just one virus but several but Covid has brought new research and people are developing T2 a year later after Covid. My money is its viral based and I suspect the virus is effecting the released insulin which the body resists. You say "The higher the glucose level the greater the insulin resistance so if you correct early, as the body does, you need less insulin." OK - why? Its only after the body has released its own insulin so you should need less unless the insulin the body is releasing is no good and blocking the receptors. At that point you have the body's insulin and then you need 2x or 3x the afrezza to deal with the same carb load. Something is wrong with the insulin or maybe when the insulin is released the pancreas is also releasing an insulin like virus which blocks the receptors. Clearly an area for research but the fix is afrezza early before the pancreas releases a bunch of its insulin and the receptors are blocked. It works every time. We need no research for this, just give them the afrezza. You say you went back and looked at the numbers. The best data you can find was from the BMJ. Here are the prescription numbers which are hard to argue with and I am sticking with them www.ncbi.nlm.nih.gov/pmc/articles/PMC7708309/ More so the proof is in the pudding - the ADA has a step program and says when the GLP1 fails add the SGLT2, then a DDP4 and then basal. Yes when the GLP1 fails. At the end they say give them the basal. Basal really? The first problem T2s have is loss of post prandial control which the GLP1s don't solve, nor the SGLT2 nor the DDP4s nor the basal. Hope springs eternal and I just hope Mike at some point does something to help the T2s. He says he is a T2 and takes afrezza. If the GLP1s were so good why didn't he start with a GLP1? Nope, he started with afrezza. Maybe Mike knows something your studies don't and the ADA doesn't want other T2s to know. |
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, but it doesn't seem to be.