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Post by agedhippie on Jun 24, 2024 18:17:55 GMT -5
I'm pretty sure you are incorrect about that. Units of insulin represent equivalent monomeric insulin molecules. I have no degree in anything but work. Yet the consistent under dosing suggest to me somethings far less than equal. Personally you put this in my hands given everything I have read to date. I would multiply by six then half it for the sake of quick in and out affect for starters. The reason is that inhaled insulin is not particularly efficient so 1u of Afrezza is actually a lot more raw insulin than 1u of RAA. Turns out MNKD underestimated the amount of insulin needed to reach equivalence hence the need for more apparent units. |
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Post by letitride on Jun 24, 2024 18:40:53 GMT -5
Is the efficiency due to a loss in other than the lungs or in the transfer in the lungs has anyone got a clue? Or is the monomer just unstable in and of itself once exposed to air?
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Post by prcgorman2 on Jun 24, 2024 18:52:31 GMT -5
Is the efficiency due to a loss in other than the lungs or in the transfer in the lungs has anyone got a clue? Or is the monomer just unstable in and of itself once exposed to air? Going from memory its a combination of things like some product remaining in the cartridge, some swallowed (because it didn’t get as far as the lungs) and then differences in the absorption (of the insulin into the bloodstream) in various parts of the lungs. The most efficient is insulin in an IV. That only happens in hospitals. Everything else has an absorption challenge. Afrezza may be inefficient in terms of the amount of raw human monomer insulin that makes it to the bloodstream, but once it’s there, it’s “life changing” because it most closely mimics mealtime insulin response because it is a bolus of human insulin admitted within seconds to the bloodstream. I’m a lay person so there are better explanations, but that’s what I remember reading over the years. |
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Post by peppy on Jun 24, 2024 19:04:32 GMT -5
I have no degree in anything but work. Yet the consistent under dosing suggest to me somethings far less than equal. Personally you put this in my hands given everything I have read to date. I would multiply by six then half it for the sake of quick in and out affect for starters. The reason is that inhaled insulin is not particularly efficient so 1u of Afrezza is actually a lot more raw insulin than 1u of RAA. Turns out MNKD underestimated the amount of insulin needed to reach equivalence hence the need for more apparent units. Afrezza produced by MNKD allows the type 1 diabetic the first phase insulin response. RAA's do not allow for the first phase......insulin response. " Insulin is released from the pancreas in a biphasic manner in response to a square-wave increase in arterial glucose concentration. The first phase consists of a brief spike lasting approximately 10 min followed by the second phase, which reaches a plateau at 2-3 h." pubmed.ncbi.nlm.nih.gov/11815469/#:~:text=Insulin%20is%20released%20from%20the,plateau%20at%202%2D3%20h. "This "first phase" of insulin secretion promotes peripheral utilization of the prandial nutrient load, suppresses hepatic glucose production, and limits postprandial glucose elevation. First-phase insulin secretion begins within 2 minutes of nutrient ingestion and continues for 10 to 15 minutes." . |
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Post by wyattdog on Jun 24, 2024 19:16:49 GMT -5
Dosing: More Afrezza Needed Than Previously Thought
Also discussed at length during the meeting symposium was the discovery, as the study progressed, that higher doses of Afrezza were needed than the label suggests in order to convert from injected short-acting insulin.
Afrezza comes in cartridges of 4, 8, and 12 units. But the units differ from injected insulin, said Hirsch. For example, 8 units of Afrezza equals 5-8 units of injected insulin, and 12 units of Afrezza is the equivalent of 9-12 units of injected insulin. In the trial, patients often needed 2.5 to 3 times higher doses than they had been injecting or infusing.
Giving someone 24 units of insulin "sounds high," but it's not, Hirsch told Medscape Medical News. Patients and clinicians have to keep in mind that a unit of Afrezza is not a unit of injected insulin.
It's a hard concept to grasp, said Shah, who has seen this issue before. "People who are accustomed to taking 2 units are afraid to take the full 4 units."
"To be honest," he added, "I would be biased toward erring on the side of a higher dose in general because I think we're seeing that higher doses are associated with better outcomes without hypoglycemia, because it's cleared so rapidly."
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Post by letitride on Jun 24, 2024 20:13:03 GMT -5
Am I reading this correctly that to achieve 1st phase response requires more insulin and the others fail to provide the same response at the same dose as Afrezza?
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Post by tarheelblue004 on Jun 24, 2024 20:15:51 GMT -5
Dosing: More Afrezza Needed Than Previously Thought "To be honest," he added, "I would be biased toward erring on the side of a higher dose in general because I think we're seeing that higher doses are associated with better outcomes without hypoglycemia, because it's cleared so rapidly." Complete. Paradigm. Shift. |
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Post by uvula on Jun 24, 2024 20:52:55 GMT -5
It sounds like important people are now saying what some of us have been saying for 10 years.
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Post by prcgorman2 on Jun 24, 2024 21:00:33 GMT -5
Am I reading this correctly that to achieve 1st phase response requires more insulin and the others fail to provide the same response at the same dose as Afrezza? I’ve seen the acronym YMMV (Your Mileage May Vary) used often to express the concept that what works well for one person with diabetes may not work as well for another. I think that is reflected in Irl Hirsch’s comments regarding a range of units versus a fixed ratio of units of Afrezza to so many units of RAA insulin. From what I can tell, the pancreas does not have some very finely granular measurement of blood glucose saturation and some special ability to predict BG over time after a measurement in order to know precisely how much insulin to spill into the bloodstream. Instead, it’s more like some threshold in BG or increase of BG over time triggers the pancreas to administer a bolus of human insulin and the body’s ability to use and or sequester BG takes it from there. Perhaps the most important point about Afrezza is it’s like the not-very-precise mechansim operating within the pancreas which works well because the human insulin is in-and-out so quickly that severe hypoglycemia is avoided. That’s the “safety” aspect that I’ve yammered on about for years here. SAFETY SAFETY SAFETY! And, “It’s the safety, stupid” in homage to “It’s the economy, stupid” mantra of the Clinton campaign. A momentary hypoglycemic dip in BG is one thing. A persistent hypoglycemic event is “severe” (and potentially very dangerous). Again, I’m a lay person explaining it as I understand it so take my comments with a grain of salt.  |
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Post by anderson on Jun 24, 2024 23:59:04 GMT -5
With all this asking about unit equivalence do we have any chemist that can figure out how many moles of insulin are in 1u of injectable and 1u of inhaled insulin? This would give a more fair comparisons of how much is lost in inhaling vs injecting.
Normal insulin==The correct conversion factor between conventional and SI units for human insulin is 1 μIU/mL = 6.00 pmol/L
Afrezza===The sponsor’s designation of U refers to Units of Afrezza not International Units of insulin. For example 300 U Afrezza=99 mg TI= mg insulin + mg Technosphere (FDKP).
So what is the real concentration of Afrezza?
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Post by agedhippie on Jun 25, 2024 7:15:14 GMT -5
I tried to find the exact ratio but failed miserably. The best I could do was an earlier reference is a paper trying to establish that equivalence. They dosed 25, 50, and 100 units to try and establish which had the equivalent effect of 10u of RAA. That feels like the pre-conversion units since I would expect to see 4, 8, and12 units. In theory 10u of RAA would be bracketed by 8u and 12u of Afrezza. The reason why Afrezza takes more insulin than RAA is because more of it gets lost enroute to the bloodstream (prcgorman2 outlined several of the issues). Lungs are an effective, but not terribly efficient delivery mechanism. The trial estimated the efficiency at 23% of RAA. Getting the ratio of the conversion is important assuming it was 4x should it really be 10x? At this point someone usually asks about all that extra insulin API, and the answer is that it is utterly irrelevant - what matters is the insulin that hits the bloodstream and not what goes astray enroute. Insulin API is free to a first approximation. Reference for the paper: www.ncbi.nlm.nih.gov/pmc/articles/PMC4634344/ |
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Post by peppy on Jun 25, 2024 7:27:14 GMT -5
I tried to find the exact ratio but failed miserably. The best I could do was an earlier reference is a paper trying to establish that equivalence. They dosed 25, 50, and 100 units to try and establish which had the equivalent effect of 10u of RAA. That feels like the pre-conversion units since I would expect to see 4, 8, and12 units. In theory 10u of RAA would be bracketed by 8u and 12u of Afrezza. The reason why Afrezza takes more insulin than RAA is because more of it gets lost enroute to the bloodstream (prcgorman2 outlined several of the issues). Lungs are an effective, but not terribly efficient delivery mechanism. The trial estimated the efficiency at 23% of RAA. Getting the ratio of the conversion is important assuming it was 4x should it really be 10x? At this point someone usually asks about all that extra insulin API, and the answer is that it is utterly irrelevant - what matters is the insulin that hits the bloodstream and not what goes astray enroute. Insulin API is free to a first approximation. Reference for the paper: www.ncbi.nlm.nih.gov/pmc/articles/PMC4634344/Afrezza www.accessdata.fda.gov/drugsatfda_docs/nda/2014/022472Orig1s000OtherActionLtrs.pdfThe 15 unit cartridge delivers the equivalent of approximately 4 units of subcutaneous insulin The 30 unit cartridge delivers the equivalent of approximately 8 units of subcutaneous insulin Page 3 second letter. |
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Post by sayhey24 on Jun 25, 2024 8:36:31 GMT -5
With all this asking about unit equivalence do we have any chemist that can figure out how many moles of insulin are in 1u of injectable and 1u of inhaled insulin? This would give a more fair comparisons of how much is lost in inhaling vs injecting. Normal insulin==The correct conversion factor between conventional and SI units for human insulin is 1 μIU/mL = 6.00 pmol/L Afrezza===The sponsor’s designation of U refers to Units of Afrezza not International Units of insulin. For example 300 U Afrezza=99 mg TI= mg insulin + mg Technosphere (FDKP). So what is the real concentration of Afrezza? The 4/8/12 units was a terminology by Al Mann to try and help T1s convert from RAA to afrezza to address the Exubera dosing issue. There are actually 10/20/30 "units" of powder in the cartridge and about a 60% loss between tongue, throat, cartridge, etc. but its not exact. 10 - (10 x 0.6) = 4 unit cartridge This "4 unit cartridge" is a marketing term. The entire discussion on trying to compare Afrezza "units" to RAA makes no sense. MNKD should not even be calling afrezza insulin. Human insulin should be in micro print on the box and label. Moreover RAAs are not human insulin. They are analogs so we are talking cats and dogs. |
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Post by prcgorman2 on Jun 25, 2024 9:08:32 GMT -5
The thing I like about this discussion of a conversion ratio between what prescribers and persons with diabetes understand (i.e., units of insulin) and Afrezza is that it is an active area of interest with the endocrinologist KOLs. The fact that they are actively interested in a better understanding of the answer to this question is real progress! It means they want to prescribe more Afrezza but want to be better at how they do that. Excellent. It underscores the importance and value of yet another study (YAS) to better answer this question. Mike shared early this year that the investment in the Insulin Business Unit (IBU) is going to be based on how well received are the current studies. INHALE-3 appears to have hit it out of the park. I expect no less from the pediatric trial. If nothing else it ought to increase the size of the market approved for prescription to a group of persons with diabetes uniquely positioned to most benefit from it. i.e., children (and their parents). Onward and upward.
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Post by sayhey24 on Jun 25, 2024 9:32:41 GMT -5
The thing I like about this discussion of a conversion ratio between what prescribers and persons with diabetes understand (i.e., units of insulin) and Afrezza is that it is an active area of interest with the endocrinologist KOLs. The fact that they are actively interested in a better understanding of the answer to this question is real progress! It means they want to prescribe more Afrezza but want to be better at how they do that. Excellent. It underscores the importance and value of yet another study (YAS) to better answer this question. Mike shared early this year that the investment in the Insulin Business Unit (IBU) is going to be based on how well received are the current studies. INHALE-3 appears to have hit it out of the park. I expect no less from the pediatric trial. If nothing else it ought to increase the size of the market approved for prescription to a group of person with diabetes uniquely position to most benefit from it. Onward and upward. All they have to do is ask Bill from VDex and get his experience in dosing. They could even read some of the VDex whitepapers. Its good they are now curious but its concerning all these experts were MIA for 10 years and some even said afrezza did not work. Now, for scripts to rise we need to fix the cost issue which means getting insurance coverage. Step 1 is SoC updates. As far as the kids, IMO their results will be outstanding but a year away. The great news is the train is now rolling and we need the INHALE-2 results and see that 1.5 - 2.0 A1c reduction Mike mentioned. The big market is the T2s. |
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