Karen: It looks like the FDA agrees with you. From the FDA's Required Evaluation and Mitigation Strategy sheet aimed at detecting and mitigating the potential lung issues:
http://www.afrezzarems.com/Documents/AFREZZA%20REMS%20Safety%20Info…
As you said, I would think handing out free samples qualifies as "initiating Afrezza" and that "all patients" means all patients.
I'll be sure to tell my doctor that you and Karen disapprove.
Honestly, I could really care less what you tell your doctor. I just know that I'd prefer to find out if I have an undetected lung problem before using an inhaled drug.
Right on, Shadow. My own medical and even my life history prevent any possibility of being prescribed inhaled insulin. Even if doc had samples she would not give them to me. I just wanted folks to be apprised of the need for this spirometry requirement, there is obviously a good reason for it to be done at all.
Hmmm... I haven't run across the potential connection between possible lung cancer and insulin in the type 1 pneumocytes, where it would predominate (see alveolus image above, "squamous alveolar cell"). t1 pneumocytes do pretty much nothing more than provide the thin, permeable barrier between the capillary blood flow and the inhaled air. They have a very flattened, fried-egg-like shape, with a very large surface area of the two flattened, basically touching thin membranes, and the nucleus and all the organelles of the cell bunched up in a compact knot. Molecules diffuse across this double membrane -- abeit much thinner than typical human ce membranes. Pneumocytes are specialized cells, of course :-)
The air-side surface of the t1 pneumocytes it coated with a thin layer of wet mucus that acts like a filter / fly paper to protect the delicate cell membrane underneath. This mucus is secreted by type 2 pneumocytes (Great alveolar cell in illustration).
With Afrezza, the particles are minute compared to the alveolus -- 2 million would fit in the typical alveolus. Keep that proportion in your mind as you imagine a particle contacting the mucus coating, which it must get through to get to the cell membrane of the t1 pneumocyte.
Upon contacting the water in the mucus, it dissolves. The insulin and the FDKP dissociate. I don't yet know what happens to the FDKP.
The insulin, at this point, is still not in contact with any tissue. It can not have any effect -- beneficial or harmful -- until it passes into the blood, or the interior (cytoplasm) of cells in direct contact with the insulin.
So, at this point we need to understand what happens, overall, to all the insulin. Obviously, some large portion diffuses through the t1 pneumocytes encapsulating the alveolus into the bloodstream. Also, though, as you have noted, some significant portion is still present in the mucus many hours after inhalation (30% @ 4rs in your cite).
The question I have is: How physiologically significant is this insulin if it's suspended in the mucus? Mucus is much thicker than blood, so I'm unclear on how insulin would act with IGF-1 receptors (insulin-like growth factor).
All I'm saying here (and it sounds real smart, but really, I'm learning a lot of this as I go), you and your doctor have raised a good point, one I'd like to understand the mitigating arguent to... more research!
In the mean time, I see some big differences in the whole environment in the lungs compared to other tissues vis a vis anything entering from the air side of alveoli, so there may be good reasons the pulmonologists gave the green light.
As always, anything I find I'll share!
Thanks for the science! As a survivor of pulmonary embolism I am (as said before) not a candidate for anything that affects lung function. This is the reason for raising the point at all and if it is a mitigating argument it is from concern and to offer warning regarding walking out of the docs with an inhalent that comes with clear warnings and precautions, and as you said "I'd like to understand the mitigating arguent to... more research!"
Lungs are really hard to replace!!
Yes and yes again!
I am a "slow metabolizer" whcih means I have a fairly rare genetic condition where some of my liver enzymes don't work very well and certain drugs that are eliminated using the specific enzyme build up in my system to toxic levels.
Nevertheless,doctors have several times prescribed drugs for me that bore black box warnings saying the drug could be fatal for slow metabolizers. One did so even after I specifically mentioned the problem to him and asked if it could be a concern. This was a cardiologist who saw no problem in prescribing a beta blocker to someone using insulin. (Beta blockers abolish hypo awareness.)
So you can't trust that doctors to be aware of label warnings, even when they could leave you crippled or dead.
Sam,
Any doctor who prescribes a new drug off-label without following the label requirements is just asking for a very expensive malpractice suit should something go wrong--which they would deserve.
Severe brochospasm can put someone with asthma in the hospital. Worst case if a person had really bad asthma, it could kill them. Since the coughing associated with Afrezza is worst when people first start this drug, I would suggest that doctors who ignore the label have just given you good proof they are not good doctors.
The situation with pumps, CGMS, and the rest is very different. These are not counterindicated because of a danger they pose, they are just not part of the practice recommendations for people with Type 2 or well controlled Type 1, mostly because the practice guidelines are written taking expense into consideration. And they also require intelligence on the part of the user, which, sadly, many people with diabetes don't have. So the people demanding these devices by the fact they are even aware of them are already demonstrating the intelligence that suggests they can use them properly.
But this is why I was made really uncomfortable by the investors crowing about how wonderful it is that Afrezza is already being prescribed off label to teens. It is only a matter of time until some teen with an exquisitely high insulin sensitivity does hypo on this stuff or some kid with poorly controlled asthma ends up in the ER.
And the fallout from that kind of disaster could keep the people who could have benefited from the drug from every getting a prescription for it. (And it won't do good things for the stock price, either.)
Jenny, You make some valid points. However, handing out a free sample is not the same as prescribing. Also, a good doctor evaluates a patient as a whole. They take many things into consideration including things as diverse as a patients history, their intelligence level (since you brought it up) etc when determining to what extent to follow established guidelines. Certainly a doctor would probably insist on rigidly following the PFT guidelines for a 50 year old substantially overweight lifelong smoker who just quit smoking to try to get the afrezza rx. They might quite reasonably decide to skip it for a 21 year old vegan cross country runner. Good doctors make fun of doctors they believe are less skilled in the practice of medicine by only rigidly following guidelines instead of thinking and making judgments for themselves. They mockingly refer to this as "practicing cookbook medicine"
Either way I'm perfectly content with mine's recommendation to try it and if I want a long term rx to go do the PFT. That's quality evidence based medicine as far as I'm concerned. Doctors are allowed to think for themselves and make decisions as they see fit. That's why they have to go to tremendous lengths to become doctors, and they don't just allow anyone who knows how to read labels and promises to follow guidelines to practice medicine.
Wow-Dave, amazing! These health hurdles are the only things I want to get over before trying it for myself. Thanks for taking so much to give thorough explanations.
Though I suspect you are right that until the drug has been around longer most doctors will opt to have a baseline PFT done around the time of first prescribing, and periodic follow-ups as per the recommendations. I'll be the first to wager that within a few years those won't even be recommended anymore. I could be wrong, time will tell.
I see Sam's, Karen's, and Shadow's points on the issue and there are bits of all of your viewpoints that I agree with, but it was my understanding that the initial lung testing wasn't in any way, shape, or form to be diagnostic. Instead, the initial lung testing was to establish a "baseline" so they'd know how your lung function was performing over time as one continues on the Afrezza therapy.
The stated purpose in the REMS is "to identify potential lung disease in all patients," but as you say, for myself the establishment of a baseline would also be why I'd want it.
This is really interesting stuff. But, in my own patients, I have yet to see a single patient on Afrezza yet. Not even endocrinologists are prescribing it yet. You guys might be ahead of the curve. The only problem is I'm not really quite sure if there are any long-term side effects. It seems like side effects of these medications always seem to come out after the drug has been on the market for awhile, like pancreatic cancer for Januvia and Bladder Cancer for Actos. I would probably air on the side of caution, but I'm hoping this stuff works. It would be pretty amazing for patients (and me).
How are people taking it? Using a long-acting basal subcutaneous injection, then using the Afrezza for meals to cover for post-prandials?
That could really work for me, since I only have high post-prandials.
Quick followup on the fate of FDKP... it is simply absorbed and excreted in the urine, like metformin.
Apparently metabolically inert. I'll post some references later, I'm going through them.
Hi Sey,
Keep in mind that, unlike Januvia and Actos, or even insulin analogs, this is simple normal monomer human insulin -- indistinguishable by the body from the stuff coming out of beta cells.
The same can not be said for any other diabetes pharmaceutical. Not even humulin-R.
If there was going to be a problem in the class you're referring to, it seems it would have to be some adverse reaction to the technosphere molecule, FDKP. Mitigating that concern is a decade or so of trial study data that, so far, shows the stuff to be safe.
One of the reasons I went on this research journey was remembering the issues with the failure of Exubera. Exubera used active absorbtion enhacers than alter the joints between phneumocytes, loosening them, and other changes to the permeability of the cell membranes.
This, unsurprisingly, caused some longer term problems, and is scary stuff to be doing to the lungs.
Afrezza is different in that it gets its fast action through mechanical distribution in the lungs, maximizing surface-area coverage, dissolving, and basically delivering a coating of monomer insulin all over the alveolar inner surface. This easily and rapidly diffuses into the blood, at which point it's indistinguishable from endogenous monomer insulin, acts, and is cleared quickly like the "real" stuff.
Learning how it works has given me much more comfort and confidence in the potential risks of long-term side-effects appearing.
However, Denise raises some good questions about the IGF issues with insulin, and of course having concentrations of insulin like this around pneumocytes is a new, unnatural condition.
I'm researching that one to find out what the experts say. Obviously this is something that wasn't ignored by Mannkind of the FDA, so there's an answer. Just haven't had the hour or two so far this weekend to look in to it.
I am "wary" and also amazed at the number of users I see reporting via the DOC that have received samples and even RX's without the required (it is in fact required not recommended) testing. As Jenny said earlier and to which I totally agree - "I would suggest that doctors who ignore the label have just given you good proof they are not good doctors."
The malpractice is just waiting to happen! The bit about teens made me even more "wary", and when I think about little kids who are certainly needle phobic getting samples because unaware parents don't know about the requirements well it is NOT OKAY. Afrezza has not been studied in patients younger than 18 - so strange in my opinion when kids are likely very needle phobic.
This insulin was given over to JDRF and Sansum for research and it's near impossible to get information much less results other than the most current headline: "INHALED INSULIN SHOWS VALUE IN ARTIFICIAL PANCREAS STUDY".
Now, all that wariness is not a dis on the product, it is to remind folks that there are some indications to be considered. My interest is not in the market, how much a person can eat now that he can sniff his insulin, or suing doctors for not doing the right thing for her patient.
In fact I would probably inhale my bolus insulin if I could.
I think that inhaling Afrezza multiple times a day long term is going to affect the lungs in some way. Whether it will be copd / cancer or something else I don't know, it may not happen for everyone and there will probably be multiple factors involved and different time factors also. These diseases often take years to develop.
I read elsewhere that a portion stays in the lungs for 1-4 hours I think. Even if tests show that everything, the insulin and the carrier particle, is cleared from the lungs at some shorter time frame, whatever that may be, it is still there for whatever portion of time and imo on a much smaller level there will be interactions and effects with habitual use. Over time there could be mucosal damage etc. if irritation develops which seems to be the cause of the initial cough symptoms and things other people have reported.
The spirometry should be done for everyone= in some, often asthmatics, it's normal unless they are having an attack or a flair up. The spirometry test and evaluation is also given to have a baseline so they can see if changes happen while using Afrezza, it's supposed to be done every 6 months.
I hope I'm wrong about this and that Afrezza won't have these longterm effects but so far this is still something I'm worried about to the point that I don't know yet if I will go ahead and try it even if I'm approved to. Obviously the wonderful results some people are having so far are not worth any of this. I think we should all be cautious about weighing benefits vs potential longterm results of using Afrezza on a daily basis.
There's always a possibility of the unknown not being a good thing, I for one am willing to trust that the experts who evaluated it and determined it was safe (unanimously) should know far, far, more about these subjects than the laymen (which includes all of us, even Dave). I think the best information available, and supported by science, is that it is perfectly safe. Hopefully the best information and science as experts understand it today doesn't end up changing, but its the understanding I'm willing to move forward with at this point.
The same experts evaluated and determined that Avandia was safe, and kept on saying it was safe long after there was solid evidence it was causing permanent osteoporosis in an unusual configuration in people who took it. Now those long-term older female users are suffering breaking bones. They also ignored the evidence that it was causing edema and heart failure in people who had no signs of heart failure before starting the drug.
Experts are telling people it is safe to take SSRIs during pregnancy though there is some fairly strong data suggesting that they are a major reason for the huge increase in autism diagnoses in offspring--and that this happens because SSRIs remodel brain wiring. Not a good thing to do to a fetus.
So because I do keep up with drug news and have done so for almost 20 years I don't have all that much confidence in these experts. They are too deeply entwined with the system and too dependent on the huge payments they get from Big Pharma to be able to be truly objective in assessing drugs. The attitude they take is that if we did what it would take to be sure drugs were safe it would cost so much no drugs could be developed, so the compromise is that they approve drugs that don't look too dangerous and then hope for the best.
The FDA mandates safety studies after drugs are released, but many of them aren't done when they are supposed to be done and there are no penalties for this. The system that tracks side effects is pretty much broken. Doctors don't report and often don't connect side effects with the drugs they prescribe--even for drugs where the side effects are very well known.
So one doesn't have to be paranoid to be worried that companies that have billions of dollars riding on the success of a drug that has made it to Phase III might analyze their data in ways that make it very hard to tease out what the drug's serious side effects really are. And the data that the Experts reviewed did not include raw data, just summaries.
It's the raw data that usually has all the interesting stuff, and that is what the drug companies never let you see.
