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Post by agedhippie on Jul 7, 2024 9:52:47 GMT -5
In the Juicebox podcast Mike Castagna mentioned that he was frequently asked about a 2U Afrezza cartridge (and remembering that 2U of Afrezza might be equivalent to 1U of insulin) and his first question is why would you want that? And his follow up is, are you (the person asking) using an AID pump? He said the answer was invariably yes to the AID pump. I thought that was interesting because the discussion on the board here had been a smaller than 4U cartridge would most likely benefit young T1s. Listening to the host and Mike describe how hard it is to wrestle with keeping blood glucose in range, it made me wonder if there is a market for an extra small cartridge for AID users and potentially young T1s. AID pumps use small doses because they dose frequently. The Tandem t:slim X2 doses every 5 minutes. By using very small doses (micro-dosing) they can curve fit better. It's the same way that when you drive you continually adjust your steering rather than sudden wrenching the wheel around at the last minute. If someone is asking about 2u cartridges they are probably looking for very tight control and care about the change that 2u will give them - for most of us it's more work than we are willing to do. Young T1s will benefit from small cartridges because they are more insulin sensitive (the start point is usually taken as 1:50 rather than 1:30 for adults) as they have very low bodyweight. Realistically though if the panel was right about Afrezza having a 2.8:1 ratio then a 4u Afrezza cartridge is just under 1.5u of RAA which looks good enough to cover that use case. |
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Post by RainbowUnicorn on Jul 7, 2024 17:35:20 GMT -5
When I listened to the Juicebox podcast what struck me most was the difficulty imposed by the variability of living with diabetes in administration, absorption, and action over time of especially RAA insulin which makes stacking a nightmare. I used to think inhale a cartridge of Afrezza and it will eliminate a stubborn high, and you’re right as rain. But listening to the podcast I realized its not that simple. Afrezza is good about in and out fast, but if used in combination with an RAA and the RAA (or body reaction) kicked in, then a low could be on the way. No free lunch as it were. Are basal insulins as variable as RAA? Or are they better at maintaining a more constant background amount of insulin for a day? If they’re more predictable, it would seem like basal + CGM + Afrezza could make life less complicated. Basal tends to be more stable which is a problem all of it's own. You basal needs fluctuate throughout the day being high in the morning and low around 2am at night. On a pump you usually have profiles that fit that curve. The belief that diabetes is mechanistic is the bane of a Type 1 diabetics life. Your endo will happily accuse you of lying (in a nice way) if they see something that doesn't fit what they expect, but you can literally eat the same meal two days in a row with different results depending on what you ate for the previous meal, or what your level was when you ate, or even the weather. Just something I saw, not sure of the usefulness or importance.
Protein and fat can trigger insulin production even more than carbs
"Some people produce more insulin in response to proteins and fats than carbs, new research has found. Suggesting that insulin production is more individualized than first believed, the findings pave the way for treating conditions through a tailored diet." |
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Post by tomson1355 on Jul 8, 2024 12:08:41 GMT -5
Aged, it's interesting to hear you talk about your experience, and your admission that after a couple of months you would be likely to get a little careless with a regimen of Afrezza. Thanks for your honesty and your contributions.
You often mention follow up doses. I wonder how much follow up dosing the really astute users of Afrezza do. Are they able to adjust the timing of the dose, and the size of the dose so that follow ups are rare? I'd be interested to know.
We had a little excitement here when my recently diagnosed 8 y/o granddaughter jumped in the lake with her pump on and her phone in her pocket. My son watched her do it and didn't stop her. When my DIL figured out what was going on there was a little hell to pay. But all was corrected (by my savvy DIL) and my GD got to spend plenty of time in the lake without her pump.
My wife and I are very careful not to interfere and proselytize about Afrezza, and to let the family and their endo chart my GD's course. She's doing well with the pump, but I will be surprised if in 5 or 10 years she doesn't ditch it for Afrezza, which she wouldn't have to wear 24/7. But who knows? As you say, it's not one size fits all.
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Post by agedhippie on Jul 8, 2024 17:16:35 GMT -5
Aged, it's interesting to hear you talk about your experience, and your admission that after a couple of months you would be likely to get a little careless with a regimen of Afrezza. Thanks for your honesty and your contributions. You often mention follow up doses. I wonder how much follow up dosing the really astute users of Afrezza do. Are they able to adjust the timing of the dose, and the size of the dose so that follow ups are rare? I'd be interested to know. We had a little excitement here when my recently diagnosed 8 y/o granddaughter jumped in the lake with her pump on and her phone in her pocket. My son watched her do it and didn't stop her. When my DIL figured out what was going on there was a little hell to pay. But all was corrected (by my savvy DIL) and my GD got to spend plenty of time in the lake without her pump. My wife and I are very careful not to interfere and proselytize about Afrezza, and to let the family and their endo chart my GD's course. She's doing well with the pump, but I will be surprised if in 5 or 10 years she doesn't ditch it for Afrezza, which she wouldn't have to wear 24/7. But who knows? As you say, it's not one size fits all. I have wondered if you can dose really late with Afrezza, maybe 30 minutes after the meal, and shift the window far enough to cover the tail at the cost of rising further initially. If your GD wants to swim in the lake then she needs an Omnipod as I don't think any other pump is rated for that. Removing the pump (and phone!) is definitely a good idea.  I suspect once she gets to her early teens she will want to get rid of the pump, but then you have the fun of getting her to take her insulin rather than having the pump do it. The key there is getting her to do it without traumatizing her. Pre-pump they used to do it by threatening you with all sorts of nasty complications and an early death. Unsurprisingly that led to mental health issues. |
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Post by sayhey24 on Jul 10, 2024 6:17:08 GMT -5
Aged, it's interesting to hear you talk about your experience, and your admission that after a couple of months you would be likely to get a little careless with a regimen of Afrezza. Thanks for your honesty and your contributions. You often mention follow up doses. I wonder how much follow up dosing the really astute users of Afrezza do. Are they able to adjust the timing of the dose, and the size of the dose so that follow ups are rare? I'd be interested to know. We had a little excitement here when my recently diagnosed 8 y/o granddaughter jumped in the lake with her pump on and her phone in her pocket. My son watched her do it and didn't stop her. When my DIL figured out what was going on there was a little hell to pay. But all was corrected (by my savvy DIL) and my GD got to spend plenty of time in the lake without her pump. My wife and I are very careful not to interfere and proselytize about Afrezza, and to let the family and their endo chart my GD's course. She's doing well with the pump, but I will be surprised if in 5 or 10 years she doesn't ditch it for Afrezza, which she wouldn't have to wear 24/7. But who knows? As you say, it's not one size fits all. I have wondered if you can dose really late with Afrezza, maybe 30 minutes after the meal, and shift the window far enough to cover the tail at the cost of rising further initially. If your GD wants to swim in the lake then she needs an Omnipod as I don't think any other pump is rated for that. Removing the pump (and phone!) is definitely a good idea. I suspect once she gets to her early teens she will want to get rid of the pump, but then you have the fun of getting her to take her insulin rather than having the pump do it. The key there is getting her to do it without traumatizing her. Pre-pump they used to do it by threatening you with all sorts of nasty complications and an early death. Unsurprisingly that led to mental health issues. As Gary Scheiner would say - you have to think like a pancreas. Does a pancreas dose 30 minutes after eating? We are getting into 2nd phase release at that point. |
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Post by prcgorman2 on Jul 10, 2024 6:41:58 GMT -5
I remember Al saying in an interview he would take Afrezza with the meal or a few minutes (5 I think?) into the meal. I never remember the details of what triggers the pancreas to squirt some insulin into the bloodstream at mealtime but I’ve assumed something will trigger a follow-up squirt later as needed. I assume the 2nd pancreas bolus isn’t finely tuned to only the exact right amount of insulin, so it may be something like whatever’s accumulated after the meal gets released and the liver and other stuff takes care of the rest of the work of moderating blood sugar post-meal. The equivalent with Afrezza would be to take a bigger dose with the meal and perhaps a smaller dose afterwards if needed. I get that’s a hassle for folks who would really prefer to not have to keep after their diabetes so compliance may (will?) suffer some, but for patients who can afford it and tolerate Afrezza well, it could beat the living daylights out of roller-coaster RAA. agedhippie - did I correctly understand INHALE-3 trial showed Afrezza is safer for avoiding severe hypoglycemia? |
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Post by peppy on Jul 10, 2024 7:15:19 GMT -5
I remember Al saying in an interview he would take Afrezza with the meal or a few minutes (5 I think?) into the meal. I never remember the details of what triggers the pancreas to squirt some insulin into the bloodstream at mealtime but I’ve assumed something will trigger a follow-up squirt later as needed. I assume the 2nd pancreas bolus isn’t finely tuned to only the exact right amount of insulin, so it may be something like whatever’s accumulated after the meal gets released and the liver and other stuff takes care of the rest of the work of moderating blood sugar post-meal. The equivalent with Afrezza would be to take a bigger dose with the meal and perhaps a smaller dose afterwards if needed. I get that’s a hassle for folks who would really prefer to not have to keep after their diabetes so compliance may (will?) suffer some, but for patients who can afford it and tolerate Afrezza well, it could beat the living daylights out of roller-coaster RAA. agedhippie - did I correctly understand INHALE-3 trial showed Afrezza is safer for avoiding severe hypoglycemia? Insulin Levels Signal the Liver Whether More Glucose is Needed The steady insulin level as another function, too. A dropping insulin level signals the liver that blood sugar is getting low and that it is time to add more glucose. When this happens, the liver converts the carbohydrate it has stored, (known as glycogen) into glucose, and dumps it into the blood stream. This raises the blood sugar back to its normal level. First Phase Insulin Release When a health person starts to eat a meal, the beta-cells kick into high gear. Their stored insulin is released immediately. Then, if the blood sugar concentration rises over 100 mg/dl, (5.5 mmol/L) the beta-cells start secreting more insulin into the blood stream. This early release of stored insulin after a meal is called "First Phase Insulin Release."Second Phase Insulin ReleaseAfter completing the first phase insulin release, the beta-cells pause. Then, if blood sugar is still not back under 100 mg/dl (5.5 mmol/L) ten to twenty minutes later, they push out another, smaller second phase insulin response which, in a healthy person, brings the blood sugar back down to its starting level, usually within an hour to an hour and a half after the start of a meal. mnkd.proboards.com/post/36728 |
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Post by agedhippie on Jul 10, 2024 9:46:48 GMT -5
I remember Al saying in an interview he would take Afrezza with the meal or a few minutes (5 I think?) into the meal. I never remember the details of what triggers the pancreas to squirt some insulin into the bloodstream at mealtime but I’ve assumed something will trigger a follow-up squirt later as needed. I assume the 2nd pancreas bolus isn’t finely tuned to only the exact right amount of insulin, so it may be something like whatever’s accumulated after the meal gets released and the liver and other stuff takes care of the rest of the work of moderating blood sugar post-meal. The equivalent with Afrezza would be to take a bigger dose with the meal and perhaps a smaller dose afterwards if needed. I get that’s a hassle for folks who would really prefer to not have to keep after their diabetes so compliance may (will?) suffer some, but for patients who can afford it and tolerate Afrezza well, it could beat the living daylights out of roller-coaster RAA. agedhippie - did I correctly understand INHALE-3 trial showed Afrezza is safer for avoiding severe hypoglycemia? Insulin is release in five or so phases with the initial phase being before the meal starts when you are thinking about food (see mouth-watering ) The phase 2 release is actually better tuned to the amount of insulin required because it is a continuous release modulated by the glucose and insulin levels in the blood. What it lacks is the volume that is provided by the first phase. Think of it like a cistern with the initial release and then a steady flow. The whole thing is controlled by the ATP channel and polarization/depolarization of the channel membranes. I confess that the detailed mechanism is far to complicated for me to understand and I always get lost but I think that is basically right. The only reference I could find on severe hypoglycemia was that there was one in the Afrezza group and none in the usual care group. There was one DKA case in the usual care group (I suspect a pump). Hypoglycemia in general was the same across all groups. " As for safety, 77% of those in the technosphere insulin group experienced adverse events (AEs), with only 1 severe hypoglycemia even, and 64% in the usual care group experienced AEs with 1 experiencing hospitalization for hyperglycemia/ketosis and 1 for appendectomy." I would expect the primary AE for Afrezza to be cough so nothing I really care about. |
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Post by sayhey24 on Jul 11, 2024 6:10:32 GMT -5
I remember Al saying in an interview he would take Afrezza with the meal or a few minutes (5 I think?) into the meal. I never remember the details of what triggers the pancreas to squirt some insulin into the bloodstream at mealtime but I’ve assumed something will trigger a follow-up squirt later as needed. I assume the 2nd pancreas bolus isn’t finely tuned to only the exact right amount of insulin, so it may be something like whatever’s accumulated after the meal gets released and the liver and other stuff takes care of the rest of the work of moderating blood sugar post-meal. The equivalent with Afrezza would be to take a bigger dose with the meal and perhaps a smaller dose afterwards if needed. I get that’s a hassle for folks who would really prefer to not have to keep after their diabetes so compliance may (will?) suffer some, but for patients who can afford it and tolerate Afrezza well, it could beat the living daylights out of roller-coaster RAA. agedhippie - did I correctly understand INHALE-3 trial showed Afrezza is safer for avoiding severe hypoglycemia? When you start to eat you are suppose to get 1st phase release which should shut off sugar release from the liver and then 2nd phase release until the BG is brought back to baseline. Afrezza replaces that 1st phase and 2nd phase release and mushes them together. The short coming is you may still be digesting food and still need an active 2nd phase as afrezza fades and thats when a follow-up hit of afrezza is needed. For purposes of afrezza we don't care about the cephalic release phase or 3rd phase and we only care about basal secretion with the T1s as it relates to the basal insulin they are taking which when combined with afrezza will cause hypos. Al's theory was to properly time afrezza hitting the blood with the digestion of food and sugar rising in the blood. You want to stop the spike. You don't want to take afrezza too soon as it will fade or too late after your blood has already spiked. This is especially true with T2s as it will take significantly more afrezza to bring down the high BG after their pancreas has been releasing its insulin. When Al talked about afrezza he was usually talking in relation to T2 use. |
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Post by dh4mizzou on Jul 11, 2024 10:34:57 GMT -5
The whole Non-Inferior versus Superiority discussion out of the Inhale 3 interim results publication had me struggling to understand how that whole process worked. I finally found a link that may help those wondering whether MNKD can claim Superiority based on the interim Inhale-3 results. www.ncbi.nlm.nih.gov/pmc/articles/PMC5472861/Pulled from the article...... "...Background
Current regulatory guidance and practice of non-inferiority trials are asymmetric in favor of the test treatment (Test) over the reference treatment (Control). These trials are designed to compare the relative efficacy of Test to Control by reference to a clinically important margin, M.
Main text
Non-inferiority trials allow for the conclusion of: (a) non-inferiority of Test to Control if Test is slightly worse than Control but by no more than M; and (b) superiority if Test is slightly better than Control even if it is by less than M. From Control’s perspective, (b) should lead to a conclusion of non-inferiority of Control to Test. The logical interpretation ought to be that, while Test is statistically better, it is not clinically superior to Control (since Control should be able to claim non-inferiority to Test). This article makes a distinction between statistical and clinical significance, providing for symmetry in the interpretation of results. Statistical superiority and clinical superiority are achieved, respectively, when the null and the non-inferiority margins are exceeded. We discuss a similar modification to placebo-controlled trials....."Of course, we'll all have to wait for the final reports but, in my humble opinion, it looks like MNKD WILL be able to claim Superiority. What do you all say? |
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Post by agedhippie on Jul 11, 2024 11:36:04 GMT -5
The whole Non-Inferior versus Superiority discussion out of the Inhale 3 interim results publication had me struggling to understand how that whole process worked. I finally found a link that may help those wondering whether MNKD can claim Superiority based on the interim Inhale-3 results. www.ncbi.nlm.nih.gov/pmc/articles/PMC5472861/Pulled from the article...... "...Background
Current regulatory guidance and practice of non-inferiority trials are asymmetric in favor of the test treatment (Test) over the reference treatment (Control). These trials are designed to compare the relative efficacy of Test to Control by reference to a clinically important margin, M.
Main text
Non-inferiority trials allow for the conclusion of: (a) non-inferiority of Test to Control if Test is slightly worse than Control but by no more than M; and (b) superiority if Test is slightly better than Control even if it is by less than M. From Control’s perspective, (b) should lead to a conclusion of non-inferiority of Control to Test. The logical interpretation ought to be that, while Test is statistically better, it is not clinically superior to Control (since Control should be able to claim non-inferiority to Test). This article makes a distinction between statistical and clinical significance, providing for symmetry in the interpretation of results. Statistical superiority and clinical superiority are achieved, respectively, when the null and the non-inferiority margins are exceeded. We discuss a similar modification to placebo-controlled trials....."Of course, we'll all have to wait for the final reports but, in my humble opinion, it looks like MNKD WILL be able to claim Superiority. What do you all say? I don't think that means what you are concluding. The problem they are raising is that you can get divergent results depending if you are measuring statistical superiority or clinical superiority. Where margins are set in both dimensions it is possible for a result to be superior in one and non-inferior in the other which raises an ambiguity. What the paper says is that a drug should be superior by both statistical and clinical margins (" Statistical superiority and clinical superiority are achieved, respectively, when the null and the non-inferiority margins are exceeded".) Currently Afrezza fails to exceed the clinical margin and so could not be judged superior. |
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Post by sayhey24 on Jul 11, 2024 14:28:16 GMT -5
The whole Non-Inferior versus Superiority discussion out of the Inhale 3 interim results publication had me struggling to understand how that whole process worked. I finally found a link that may help those wondering whether MNKD can claim Superiority based on the interim Inhale-3 results. www.ncbi.nlm.nih.gov/pmc/articles/PMC5472861/Pulled from the article...... "...Background
Current regulatory guidance and practice of non-inferiority trials are asymmetric in favor of the test treatment (Test) over the reference treatment (Control). These trials are designed to compare the relative efficacy of Test to Control by reference to a clinically important margin, M.
Main text
Non-inferiority trials allow for the conclusion of: (a) non-inferiority of Test to Control if Test is slightly worse than Control but by no more than M; and (b) superiority if Test is slightly better than Control even if it is by less than M. From Control’s perspective, (b) should lead to a conclusion of non-inferiority of Control to Test. The logical interpretation ought to be that, while Test is statistically better, it is not clinically superior to Control (since Control should be able to claim non-inferiority to Test). This article makes a distinction between statistical and clinical significance, providing for symmetry in the interpretation of results. Statistical superiority and clinical superiority are achieved, respectively, when the null and the non-inferiority margins are exceeded. We discuss a similar modification to placebo-controlled trials....."Of course, we'll all have to wait for the final reports but, in my humble opinion, it looks like MNKD WILL be able to claim Superiority. What do you all say? I am going to put my tin foil hat on and say BP will do what they can so some participants don't properly dose so they can pull down the overall A1c of afrezza so afrezza A1c is about the same as RAA. MNKD needs to figure out what they are going to do with those in the study who are not properly dosing. Why are they not properly dosing? Can they be put in a separate category so we only count those that properly dosed? With the CGMs they could not hide the fact they were not following dosing protocol. We heard it from some of the presenters. If their numbers can be removed from the overall A1c average - afrezza wins and will be superior. I say we will have to wait until after October to see how Mike and team addresses this. |
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Post by ktim on Jul 11, 2024 14:45:14 GMT -5
I am going to put my tin foil hat on and say BP will do what they can so some participants don't properly dose so they can pull down the overall A1c of afrezza so afrezza A1c is about the same as RAA. MNKD needs to figure out what they are going to do with those in the study who are not properly dosing. Why are they not properly dosing? Can they be put in a separate category so we only count those that properly dosed? With the CGMs they could not hide the fact they were not following dosing instructions. We heard it from some of the presenters. If their numbers can be removed from the overall A1c average - afrezza wins and will be superior. I say we will have to wait until after October to see how Mike and team addresses this. Like breaking into trial participants homes and hiding their inhalers?? That's heavy duty aluminum foil hat time, not the light weight stuff.  |
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Post by uvula on Jul 11, 2024 14:53:38 GMT -5
"Like breaking into trial participants homes and hiding their inhalers??"
There are more creative ways to accomplish this. "Guess what? I won free milkshakes for life and I don't even remember entering the contest."
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Post by sayhey24 on Jul 11, 2024 14:57:59 GMT -5
I am going to put my tin foil hat on and say BP will do what they can so some participants don't properly dose so they can pull down the overall A1c of afrezza so afrezza A1c is about the same as RAA. MNKD needs to figure out what they are going to do with those in the study who are not properly dosing. Why are they not properly dosing? Can they be put in a separate category so we only count those that properly dosed? With the CGMs they could not hide the fact they were not following dosing instructions. We heard it from some of the presenters. If their numbers can be removed from the overall A1c average - afrezza wins and will be superior. I say we will have to wait until after October to see how Mike and team addresses this. Like breaking into trial participants homes and hiding their inhalers?? That's heavy duty aluminum foil hat time, not the light weight stuff. A little suggestion by the doctor at a testing center who BP has visited can go a long way. For example, that doctor telling some of their participants that dosing before bed is a really bad idea is one way to put BP's finger on the scale. |
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