|
|
Post by agedhippie on Nov 6, 2022 10:44:23 GMT -5
Aged - yes, what you outlined above is what I have been telling you. The 175 was actually a pretty great study. The ADCOM panel also recommended 14 to 0 for approval. I went back to try and see some reasons it got no traction in addition to conflating it with the Affinity-1. There was article after article about how afrezza was going to cause cancer. Maybe all these fake predictions is where your endo's concerns came from. Your study is to leverage the 175 and replace the placebo with Mounjaro. OK, leverage the 175 is good. Since the 175 we already have some people taking Mounjaro. I would be ok adding another arm and add afrezza to the Mounjaro users. I would also want CGMs as part of the trial along with proper and second dosing of afrezza. It didn't get traction because the message that insulin reduced blood glucose was rather a given. There is still a post-approval five-year, randomized, controlled trial in 8,000-10,000 patients with type 2 diabetes to assess the potential risk of pulmonary malignancy out there, but the FDA have delayed that as I remember. My endo at the time wasn't concerned about cancer (I asked him that), but was concerned that there might be fibrosis which they had thought they were starting to see with Exubera. His view was wait and see. So three arms for the trial? Adding Mounjaro, Mounjaro + Afrezza, and Afrezza to orals. There is no problem with requiring a second dose as far as I can see if it's part of the protocol. Likewise using a CGM. |
|
|
|
Post by stevil on Nov 6, 2022 15:01:21 GMT -5
FWIW, I'm with Aged on this one. I think everyone would have been shocked if Afrezza DIDN'T have a greater A1c reduction compared to orals. At best it just proved that FKDP is an appropriate carrier molecule for insulin. Insulin should always be superior to any other molecule for glucose reduction. That's nearly the entire role of insulin, to reduce serum glucose. It becomes something else entirely if you can show insulin is just as safe or safer than orals and leads to better long term outcomes in a cost/benefit analysis. That work has not yet been completed as far as I have seen.
As far as I personally am concerned, I'll continue to root for Afrezza to become the next standard of care, but I'm still not (yet) convinced it should be. Still far too much to prove. There are numerous disease states with a treat to fail mentality that work just fine. It doesn't make sense to use a bazooka to kill an ant when a shoe will yield the same results. I haven't seen anyone successfully master diabetes in the sense that they can differentiate early in the disease whether you're dealing with an ant or a tank (and thus would need the bazooka sooner). I'm not yet convinced that everyone NEEDS Afrezza. I have seen people do just fine on Metformin for decades, literal decades with an A1c less than 6 the whole time, confirmed by chart review. He even stopped it because he wasn't sure he was even diabetic and his A1c went up to 7 and a half. Then it came right back down again within a few months on metformin.
I will state again that I have immense respect for Bill and VDex but I don't yet agree on Afrezza First, Afrezza Last, Afrezza Always. And I really, really wanted to as a MNKD shareholder. But if I'm being honest with myself, not everyone needs Afrezza and I don't think the data or my own personal experience supports that as a protocol. I don't disagree with Bill or VDex in how they want to go about their business. Someone needs to do that heavy lifting and try it out so the rest of us can see what they are able to do with their results. Their logic makes sense and time will tell what the results are. Hopefully we all get to see the end results.
There is not yet a successful algorithm for diabetes treatment, mostly because nearly ever patient is unique, going back to the ant and the tank analogy. We've identified some markers/genes to go off of, but the great majority of treatment right now is "wait and see". Sure, you could treat them all with insulin and get great A1c results. I would be surprised if Afrezza didn't get better A1c reduction than just about any treatment unless compliance becomes an issue. But it becomes incredibly expensive to kill ants with bazookas when shoes work just as well. Then, during the transformation of the ant to the tank, which medication offers better protection from that little ant turning into the tank and wreaking havoc on the rest of its environment? Theories abound and data is limited.
Personally, I like GLP-1s/Mounjaro for my obese patients who likely would be nondiabetic if they lost their excess weight. I also like it for the cardiac risk patients. Also like SGLT-2s for renal and CHF patients. Early in the disease? I'd try to go Afrezza to avoid complications. Until Afrezza shows superiority in the comorbidities, it's going to be a hard sell, even for this shareholder. There's just too much evidence to support the use of the other medications while there is an abyss of data for Afrezza's use. I can't give patients Afrezza when I'm not sure if it's the superior medication for their ailments when I have an avalanche of data to show that GLP-1s and SGLT-2s are so effective, beyond even diabetes. They're using SGLT-2s in renal/CHF patients without diabetes, which suggests their benefits extend beyond glucose control. There's a separate mechanism at play that Afrezza cannot even account for.
|
|
|
|
Post by sayhey24 on Nov 6, 2022 19:33:42 GMT -5
Stevil - for you to say "not everyone needs Afrezza" you are basically saying not everyone needs insulin. Come on man!
The problem the "T2s" have is they have lost beta cell mass and their bodies are not properly using the remaining insulin they are making. However, if dosing is properly timed with afrezza their insulin resistance nearly goes "POOF". Then over time they need less and less afrezza.
To quote Ralph Defronzo on your wait and see approach “The most waste in type 2 diabetes is to continuously put people on metformin and sulfonylureas (glyburide, glimepiride, etc.). These drugs have no protective effect on the beta cell, and by the time you figure out what you’re doing, there are no beta cells left to save".
Now why do we have all these comorbidities? If you ask Rich Bernstein he swears its because of not properly controlling BG, especially the post meal spikes. What I do know is Dr. Bernstein is now 88 and has been able to avoid the typical diabetes comorbidities. My dad was not as lucky but he followed his doctors advice and had is first heart attack at 62. While Bernstein did it the hard way with his diet, afrezza now makes it so easy. Is he right IDK but it sure seems he may be. BTW - not that long ago Bernstein's glucose meters were also not the standard of care and the community did all they could to stop him. They use to throw him out of meetings because he was not a doctor.
Do me a favor and give us some of the AGPs of the people on the SGLT2 and GLP1s. If Bernstein is correct that controlling the post meal spike is crucial lets see how they stack up with the spike. Also, we clearly know they fail otherwise the ADA would not need the step program. Also, how long are your patients staying on the GLP1s? The insurance data says most stop using GLP1s within a year. Is that what you are seeing?
Just to be clear - its not about A1c results. You said "Sure, you could treat them all with insulin and get great A1c results" Its about controlling the post meal spike and getting the pwd back under 140 within 2 hours. Thats what Bernstein does with his diet by avoiding the spike. With afrezza you can just knock it down before you hit the resistance. Thats what makes afrezza special.
Now - you can argue with the results Bill is seeing at VDex and say you don't agree. OK, but I bet you are not getting similar results and as Al Mann said there is a really good chance afrezza will stop progression. Is your SGLT2 going to do that? As a doctor you need to follow the standard of care. No one here wants you to not follow the standard of care. As they say the standard of care is evolving. What I am telling you is afrezza kills your standard of care. I always liked what Kevin Sayer said about afrezza when asked and I quote "I have never seen anything like it".
Also - no one here wants to kill ants with bazookas when shoes work just as well. Genetech came up with a way to make human insulin for next to nothing and Lilly then brought it to market in 1982. The freeze drying process with FDKP is not that expensive but what is the cost of a human life? I was in a local hospital not long ago and saw a guy getting his foot cut off because of his diabetes. How about the family of the Ozempic user who now has thyroid cancer? Really, is cost now the issue?
|
|
|
|
Post by agedhippie on Nov 7, 2022 8:52:46 GMT -5
Stevil - for you to say "not everyone needs Afrezza" you are basically saying not everyone needs insulin. Come on man! The problem the "T2s" have is they have lost beta cell mass and their bodies are not properly using the remaining insulin they are making. However, if dosing is properly timed with afrezza their insulin resistance nearly goes "POOF". Then over time they need less and less afrezza. ... Stevil gives you an example of a patient on metformin with Type 2 that is perfectly controlled so everyone doesn't need extra insulin even if others do. That is the point of treat to fail - don't overtreat conditions. That said the follow on is that you should escalate promptly or treat to fail doesn't work. That is a particular problem with chronic diseases in general when there is no visible penalty until there is damage. There is a percentage of patient who will be just fine on oral meds because that works for their Type 2 variants and Stevil's point is that the only way to find those is to monitor. Al Mann may well have said Afrezza will stop progression, or the idea that Afrezza somehow eliminates insulin resistance, but to Stevil's point until that's proven in a decent trial it's just talk as far as the medical world is concerned - they want data and not theories. They cannot say to a patient that we feel this should work, but we have no hard evidence. This puts the focus is on quantifiable outcomes from the treatment and not what does it do on the way to that outcome. Think of it as selling benefits not features. As to why there are comorbidities I suggest reading up on Syndrome X. That's just one Type 2 variant, and as Stevil says there are many. |
|
|
|
Post by sayhey24 on Nov 7, 2022 9:53:47 GMT -5
Aged - lets see the AGP of that patient on metformin. What does the post meal spike look like today and what will it look like in a year or 2? The problem all diabetics have is they lose post prandial control. As Ralph DeFronzo now says metformin is a waste of time. Thats not me saying it, its DeFronzo.
What Sevil is seeing is metformin masking the problem. If diabetes is truly viral based its very well possible the immune system will fight the infection but the best way to do that is by getting the load off the pancreas and have the pancreas produce as little insulin as possible until the body naturally gets things under control. There is no reason to mess with what the liver is doing with metformin.
If we are to believe the Wensveen's and their figure 2 the less the pancreas releases the better until things get under control. Now you say "we can not say to a patient that we feel this should work", are you kidding me??? That is what doctors say ALL the time. The difference with diabetes is they should be saying with metformin/SGLT2 and GLP1s - "we know this is NOT going to work long term and when it fails we will give you something else which will fail and when all this junk fails BP will have gotten a good payday and we will give you insulin."
Provide the link for Syndrome X which you want me to read. I am believing Bernstein that we need to control BG and the fact is we DON'T do it today with T2s. We mask the issue and the body incurs micro/macro vascular degeneration and then they say we have a collection of issues so lets call them Syndrome X. Treat it early with afrezza and as Al Mann said we may be able to stop the progression. What have we got to lose??? We know the current ADA step program fails. Who knows maybe Al Mann's approach will work. Worst case is it fails too but I doubt it.
|
|
|
|
Post by agedhippie on Nov 7, 2022 10:28:34 GMT -5
Aged - lets see the AGP of that patient on metformin. What does the post meal spike look like today and what will it look like in a year or 2? The problem all diabetics have is they lose post prandial control. As Ralph DeFronzo now says metformin is a waste of time. Thats not me saying it, its DeFronzo. What Sevil is seeing is metformin masking the problem. If diabetes is truly viral based its very well possible the immune system will fight the infection but the best way to do that is by getting the load off the pancreas and have the pancreas produce as little insulin as possible until the body naturally gets things under control. There is no reason to mess with what the liver is doing with metformin. If we are to believe the Wensveen's and their figure 2 the less the pancreas releases the better until things get under control. Now you say "we can not say to a patient that we feel this should work", are you kidding me??? That is what doctors say ALL the time. The difference with diabetes is they should be saying with metformin/SGLT2 and GLP1s - "we know this is NOT going to work long term and when it fails we will give you something else which will fail and when all this junk fails BP will have gotten a good payday and we will give you insulin." Provide the link for Syndrome X which you want me to read. Once you get below 6.5 your probability of complications is virtually back to baseline. At that point who cares if you have spikes or what their AGP looks like because it is having zero impact on the outcome. Stevil's patient has been stable on metformin for years so he shouldn't be moved as it works for him. There is no one size fits all in diabetes. Ok - I will rephrase, "we can not say to a patient that based on anecdotes we feel this should work" The Wensveen theory is interesting but it focuses on obesity and ignores thin T2 diabetics. In other words they are likely looking at just one of the variants. That's useful, but only for those people. This link looks reasonable. There is a large body of literature on this topic - www.mayoclinicproceedings.org/article/S0025-6196(11)60770-2/fulltext |
|
|
|
Post by sayhey24 on Nov 7, 2022 13:23:04 GMT -5
Aged - OK, I didn't find the Mayo paper interesting. IMO, its outdated using info no later than 2007. Second we know the tech diet companies are seeing the loss of post prandial control before abdominal fat. Of course they would not know that in 2007 since widespread use of CGMs did not become common for diet until 3 or 4 years ago. They say an underrecognized and undertreated condition caused by abdominal obesity and insulin resistance, the metabolic syndrome predisposes people to the development of cardiovascular disease and diabetes. IMO this is not that hard and I am going with Bernstein on this - its not keeping proper BG control. Now an A1c of 6.5 equates to 140mg/dl. Your statement "At that point who cares if you have spikes or what their AGP looks like because it is having zero impact on the outcome". The non-diabetic doesn't typically spike over 140. Its the time over 140 causing the vascular degeneration and leading to the heart disease. If your A1c is 6.5 the broad assumption is you spend 12 hours per day over 140 and thats what is causing the degeneration. God only knows what you are spiking to. Jenny Ruhl use to promote the 5% club and write extensively about it and its importance. I don't know how active she is these days but back in the day she went through a zillion studies and "Zaprudered" each including some in the link you provided. Here is a link to the 5% club. BTW - Rich Bernstein endorsed a lot of her work and she was doing this before CGMs were available. www.bloodsugar101.com/the-5-club BTW - the Wensveen theory is based on viral infection. It doesn't matter whether you are fat or thin to get infected. The virus doesn't care about your weight. However the sterotypical "fat" T2 you know "the guy who wouldn't be diabetic if he wasn't so fat" doesn't typically gain that weight until after they have lost post prandial control. I just saw a commercial for GOLO an they are now promoting the weight gain is after "insulin resistance". Now I would not consider GOLO a tech diet company by any stretch of the imagination but I find it interesting they are now promoting this "insulin resistance" which is what the other companies are seeing. |
|
|
|
Post by agedhippie on Nov 7, 2022 23:57:47 GMT -5
Aged - OK, I didn't find the Mayo paper interesting. IMO, its outdated using info no later than 2007. Second we know the tech diet companies are seeing the loss of post prandial control before abdominal fat. Of course they would not know that in 2007 since widespread use of CGMs did not become common for diet until 3 or 4 years ago. ... That is what I meant by it being regarded as settled science and why there are no newer papers. Subsequent to that you would probably be taught about variants, but at core this is what you would be taught in medical school because nobody has come up with a better version to date although lots of people are trying. There are lots of theories, but this is the consensus. You probably don't like it, but I think on this we are just going to have to agree to differ because you are looking for a one-size fits all answer to diabetes and it doesn't exist. |
|
|
|
Post by sayhey24 on Nov 8, 2022 7:45:10 GMT -5
I love that one - settled science. Aged, I didn't know you were a flat-earther. Yes we will agree to disagree as I sail off over the horizon and maybe fall off the edge.
Now that we have CGMs we can measure and its turned into a fluid dynamics engineering problem. What we need to find out is what is in the feedback loop the Wensveen's have in figure 2. that is causing the resistance. We know we can side-step the resistance by providing afrezza early in the post prandial cycle so at least we have an "engineering fix". We also know that over time "in general" we can reduce the resistance since we need less afrezza and not more.
I had not looked at Jenny's stuff in awhile but I saw the link at the top of her page on the 5% club about covid. I found it interesting the Omaha World Herald article was removed. I wonder why. Maybe others think things are settled science and don't want new info getting circulated. I also did not know Jenny was now following the viral angle. When I was telling her about it years ago and Joslin's work I think she thought I was a bit crazy. Then again maybe she was right.
|
|
