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Post by wgreystone on Jul 4, 2018 18:43:53 GMT -5
No manufacturer can compel the ADA to do anything. STAT, while helpful, did not exactly provide earth shattering results as the conclusion was pretty much predetermined. Physicians look to "levels of evidence" when making treatment recommendations and if you are not familiar with the levels, in the United States these are: Level I: Evidence obtained from at least one properly designed randomized controlled trial. Level II-1: Evidence obtained from well-designed controlled trials without randomization. Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group. Level II-3: Evidence obtained from multiple time series designs with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence. Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees Some countries have additional levels of evidence but the framework is similar. STAT was not a controlled trial since only the patients on the Afrezza arm were allowed to adjust their insulin dose following the meal in response to the CGM. That makes it a Level III study at best, and that is the least persuasive form of evidence. If MNKD wants to move the needle they need to sponsor a large randomized mullti-center controlled trial where all patients are given the opportunity to adjust their insulin dose after seeing the results from a glucose meter. If the results from that study demonstrate that time in range is statistically better with Afrezza than other RAI products, or if Afrezza has similar time in range but with fewer hypoglycemic events that require a visit to the ER, then they will have a compelling argument. The two big problems with STAT are these: 1. The cohort sizes were too small. In order to get the necessary statistical power, a proper study would require 300-500 patients over a longer period such as 90-180 days. 2. Allowing the Afrezza patients to adjust their dosing in response to the CGM results, not once but twice, stacked the deck against the comparator. Both arms must be allowed to adjust the dose after seeing the initial results for the trial to be credible. Some will say that patients on injectable insulin will avoid multiple needle sticks or that they will have too many severe hypo events, but that is precisely what the trial needs to show. If so many needle sticks is a major issue then patients on RAI will not be in range as long, and if the second bolus causes hypo events that should show up in the data as well. Opinions are not Level I evidence; data from a well-designed trial is evidence. Level I evidence, preferably with some parallel economic evidence showing that Afrezza is cost effective, is what it will take. Bummer!š Is this recommended to stack multiple analog injections to bring down high BG? If not, then the trial design makes sense. |
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Post by wgreystone on Jul 4, 2018 18:49:42 GMT -5
Again, common sense, I will take my lead from the qualified chief medical officer who was a former head of the ADA and chief global scientist for one of the leading BP's in the space rather than someone that trolls the boards with ulterior motives and recommends via direct messaging to people to sell their shares  thank you. So which bit of Matt's assessment do you disagree with? - The evidence requirement is smack on the money. - The observation that STAT was too small to influence the standard of care was also correct (even Mannkind described it as a pilot). STAT was useful in that it showed that a second bigger trial (STAT-2?) was worth funding, but as a tool to change the Standard of Care it is never going to do it. And Chief Global Scientist is a nice title, if fictitious, and not one that Dr Kendall ever claimed or could have claimed given how Eli Lilly is structured and his role there. STAT trial was not designed for FDA approval. Even though size is small, it still provides informative data for physicians to provide proper dosing guidance to the patients and the expected results they could observe from the patients. |
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Post by agedhippie on Jul 4, 2018 18:51:01 GMT -5
Semantics. The odds of an overdose increase with IOB since it is another variable in the equation. The sooner IOB is no longer a variable, the less chance of miscalculating proper dosing. The longer insulin takes to clear your system, the more time is spent calculating dose adjustments. Just applying simple logic. Iām sure thereās some philosopher that has articulated a statement about complex equations that would put my attempt to shame. That is sort of true, but insulin stacking is a fact of life. For example it was used in STAT to improve the Afrezza results so it's not something that is unique RAA. It doesn't take any longer to calculate IOB if the insulin takes more or less time to clear your system, it's just a number. Personally my CGM tells me what to take - currently it says 3.05u onboard and that takes me to 98. If it had landed me higher it would have told me what to take to hit 100 which is my target. Most modern meters will do this if you are outside the US (the FDA seems to have a real dislike for this function so it's disabled in the US). |
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Post by agedhippie on Jul 4, 2018 18:54:04 GMT -5
Is this recommended to stack multiple analog injections to bring down high BG? If not, then the trial design makes sense. Yes it is recommended to stack RAA. The general guidance you are given is test after two hours and correct if you are over 180. It's widely ignored though and I suspect you are seeing the same pattern develop with the non-compliant users in STAT. |
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Post by wgreystone on Jul 4, 2018 18:54:25 GMT -5
The label for insulin Aspart: ā¢ Subcutaneous injection Novolog: ā5-10 minutes before a meal ... ā¢ The investigator that initiated the trial had the participants in the insulin Aspart arm to continue their usual diabetes care, which is seen above, per the label. It was not the investigator's job to do what you think should have been done, causing a butt load of severe hypos just to prove a point. The point has been proven without needless sufferingāAfrezza is superior to insulin Aspart. ā¢ STAT was an investigator-initiated, prospective, randomized, multicenter, parallel, open-label, pilot clinical trial. ā¢ The participant size was sufficient and adequate. I am waiting for you to provide the appropriate literature which states otherwise. You have the label for Novolog wrong, it says is " NovoLog should generally be given immediately (within 5-10 minutes) prior to the start of a meal." In other words dose at the start of the meal, and if you pre-bolus do not do so by more than 10 minutes. The Afrezza arm is flawed because the investigator intensified the Afrezza arm (the Afrezza label says, " Administer at the beginning of a meal.") by changing the dosing from the label, but did not do the same for the Novolog arm. Arguing that you left people to their own devices is fine, but you are then comparing an intensified regime with a regular regime so of course the intensified regime performed better. Actually STAT was not multi-centered, it was carried out at Barbara Davis Center, Aurora, Colorado. That's a single location. There were enough participants for a pilot study, there were not enough participants for a pivotal study. Changing the Standard of Care will take a pivotal study. No physicians would dare to ask patients to stack multiple injections to bring down high BG as it will likely cause severe hypo. The trial proved that with Afrezza, patients can administrate multiple doses without increasing the probability of severe hypo. Isn't that the main beauty of Afrezza? |
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Post by agedhippie on Jul 4, 2018 18:56:01 GMT -5
So which bit of Matt's assessment do you disagree with? - The evidence requirement is smack on the money. - The observation that STAT was too small to influence the standard of care was also correct (even Mannkind described it as a pilot). STAT was useful in that it showed that a second bigger trial (STAT-2?) was worth funding, but as a tool to change the Standard of Care it is never going to do it. And Chief Global Scientist is a nice title, if fictitious, and not one that Dr Kendall ever claimed or could have claimed given how Eli Lilly is structured and his role there. STAT trial was not designed for FDA approval. Even though size is small, it still provides informative data for physicians to provide proper dosing guidance to the patients and the expected results they could observe from the patients. Why did the trial have a Novolog arm then? If STAT was for dosing and guidance all they needed to show was that the STAT protocol outperformed the 171 protocol. |
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Post by agedhippie on Jul 4, 2018 19:12:30 GMT -5
No physicians would dare to ask patients to stack multiple injections to bring down high BG as it will likely cause severe hypo. The trial proved that with Afrezza, patients can administrate multiple doses without increasing the probability of severe hypo. Isn't that the main beauty of Afrezza? I have that feeling I am being trolled, but for the benefit of those who might otherwise that that statement seriously... It is standard procedure to stack RAA insulin. There is nothing magical, just make sure you account for IOB and you are taught to do that before they turn you loose with MDI. As for "no physicians would dare to ask patients to stack multiple injections to bring down high BG" - that is flatly wrong. Part of the MDI protocol is a correction (when you take a dose because you are higher than you expected to be) and is stacking insulin. It seems to be an article of faith that you cannot stack insulin without getting a hypo and I have no idea where the idea comes from, but it is just wrong. You can get a severe hypo off Afrezza just as you can off RAA. In fact if you look at the Affinity-1 paper that Mannkind based their hypo poster on you see that Afrezza users in the HbA1c 7.5 - 8.0 group had more severe hypos than the Novolog users in that group did (that was the only group where that happened, but the 6.5-7.0 group was very close as well). |
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Post by wgreystone on Jul 4, 2018 19:28:43 GMT -5
No physicians would dare to ask patients to stack multiple injections to bring down high BG as it will likely cause severe hypo. The trial proved that with Afrezza, patients can administrate multiple doses without increasing the probability of severe hypo. Isn't that the main beauty of Afrezza? I have that feeling I am being trolled, but for the benefit of those who might otherwise that that statement seriously... It is standard procedure to stack RAA insulin. There is nothing magical, just make sure you account for IOB and you are taught to do that before they turn you loose with MDI. As for "no physicians would dare to ask patients to stack multiple injections to bring down high BG" - that is flatly wrong. Part of the MDI protocol is a correction (when you take a dose because you are higher than you expected to be) and is stacking insulin. It seems to be an article of faith that you cannot stack insulin without getting a hypo and I have no idea where the idea comes from, but it is just wrong. You can get a severe hypo off Afrezza just as you can off RAA. In fact if you look at the Affinity-1 paper that Mannkind based their hypo poster on you see that Afrezza users in the HbA1c 7.5 - 8.0 group had more severe hypos than the Novolog users in that group did (that was the only group where that happened, but the 6.5-7.0 group was very close as well). Maybe you are really good at stacking RAA, but from many forum posts, suger surfing with stacking RAA is a difficult task to master. The reason is fairly easy to understand: when you BG is high 2 hrs later after meal, the dosing of the followup injection is tricky. If the dosing is too small, it may not be effective. If the dosing is too high, the long tail will likely cause hypo as the digestion of food is almost done at the time point. It also makes sense to require the control arm to follow their typical routine of applying RAA. Otherwise, the hypo data comparison becomes less convincing. |
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Post by agedhippie on Jul 4, 2018 20:05:54 GMT -5
I have that feeling I am being trolled, but for the benefit of those who might otherwise that that statement seriously... It is standard procedure to stack RAA insulin. There is nothing magical, just make sure you account for IOB and you are taught to do that before they turn you loose with MDI. As for "no physicians would dare to ask patients to stack multiple injections to bring down high BG" - that is flatly wrong. Part of the MDI protocol is a correction (when you take a dose because you are higher than you expected to be) and is stacking insulin. It seems to be an article of faith that you cannot stack insulin without getting a hypo and I have no idea where the idea comes from, but it is just wrong. You can get a severe hypo off Afrezza just as you can off RAA. In fact if you look at the Affinity-1 paper that Mannkind based their hypo poster on you see that Afrezza users in the HbA1c 7.5 - 8.0 group had more severe hypos than the Novolog users in that group did (that was the only group where that happened, but the 6.5-7.0 group was very close as well). Maybe you are really good at stacking RAA, but from many forum posts, suger surfing with stacking RAA is a difficult task to master. The reason is fairly easy to understand: when you BG is high 2 hrs later after meal, the dosing of the followup injection is tricky. If the dosing is too small, it may not be effective. If the dosing is too high, the long tail will likely cause hypo as the digestion of food is almost done at the time point. It also makes sense to require the control arm to follow their typical routine of applying RAA. Otherwise, the hypo data comparison becomes less convincing. I am average at stacking RAA. There are a lot of things said in this forum about stacking by people who are repeating what they have heard, but that doesn't make them correct. Corrections are routine and everyone has to do them occasionally if they take insulin. Dealing with post-prandial highs at the two hour mark is easy; subtract half your bolus insulin (after two hours about half your insulin is gone) and see if the remainder is enough to bring you to baseline. If the answer is no then take enough insulin to close the gap - do that and you are golden. The point about digestion is interesting because it is a common misunderstanding. Digestion places glucose into the blood stream, but it does that typically faster than the insulin takes it out. The long tail in an RAA is useful because it is clearing up the remaining glucose, in a non-diabetic this is done by the second phase insulin release, in Afrezza it is done by the second dose.You can get into carb absorption rates but that is pretty exotic and only the loop system pumps do that because it is a lot of work. The hybrid closed loop pumps like the 670G or T:Slim do all this for you without even telling you. You just tell it how many carbs you ate. Medtronics have just done a deal with Aetna where they supply Aetna with 670G pumps and Aetna pay by results based on the amount the pump lowers a user's A1c. |
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Post by mango on Jul 4, 2018 21:03:19 GMT -5
Management of Hyperglycemia in Type 2 Diabetes: ADA-EASD Consensus Report 2018 John B. Buse, MD, PhD ā Chair, Scientific Advisory Board of MannKind is a speaker. Key Knowledge Gaps, Question and Discussion PeriodSpeaker: John B Buse Session: Management of Hyperglycemia in Type 2 DiabetesāDraft ADA/EASD Consensus Report 2018 Congress: 78th Scientific Sessions |
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Post by sayhey24 on Jul 4, 2018 21:05:47 GMT -5
Aged - No one is buying this. PWDs want to stack RAAs? Are you kidding me? You also must like playing Russian Roulette. Here is what they said in the "Clinical Results of an Automated Artificial Pancreas Using Technosphere Inhaled Insulin to Mimic First-Phase Insulin Secretion" "A major rate-limiting factor in the development of an AP is the delay in insulin action associated with currently available rapid acting insulin analogs. Previous investigations have demonstrated that meal control is one of the major challenges of an automated insulin management and even a premeal bolus has its limitation in preventing postprandial hyperglycemia." "The convenience/ease of use(of afrezza) was commented on by all of the study participants. Adding TI to an automated closed-loop AP system results in superior postprandial control as demonstrated by lower postprandial glucose exposure by 81% and 60% for dinner and breakfast, respectively, without additional hypoglycemia. There is less variability in both insulin delivery and glucose concentrations in the TI arm. As seen in most AP studies to date there was no difference in glucose control during the overnight period" www.ncbi.nlm.nih.gov/pmc/articles/PMC4604530/Then you say - "There are a lot of things said in this forum about stacking by people who are repeating what they have heard" Good Grief Man, its not just people on this board it pretty much every RAA user. Not many like playing Russian Roulette. Now here is what Gary Schiener has to say about "angry bolusing" - "Another major limitation to ārapidā insulin is the time it takes to bring above-target blood sugars down to normal. Nobody likes to spend long periods of time with high blood sugar; it turns us into zombies with a major urge to urinate, and drives the A1c up. Many people donāt have the patience to wait 3-5 hours for their high readings to come down, and administer even more insulin before the original correction dose has finished working. āAngry bolusing,ā as this is often called, tends to lead to hypoglycemia."
integrateddiabetes.com/my-review-of-afrezza-fast-acting-inhaled-insulin/ |
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Post by peppy on Jul 4, 2018 21:28:57 GMT -5
Maybe you are really good at stacking RAA, but from many forum posts, suger surfing with stacking RAA is a difficult task to master. The reason is fairly easy to understand: when you BG is high 2 hrs later after meal, the dosing of the followup injection is tricky. If the dosing is too small, it may not be effective. If the dosing is too high, the long tail will likely cause hypo as the digestion of food is almost done at the time point. It also makes sense to require the control arm to follow their typical routine of applying RAA. Otherwise, the hypo data comparison becomes less convincing. I am average at stacking RAA. There are a lot of things said in this forum about stacking by people who are repeating what they have heard, but that doesn't make them correct. Corrections are routine and everyone has to do them occasionally if they take insulin. Dealing with post-prandial highs at the two hour mark is easy; subtract half your bolus insulin (after two hours about half your insulin is gone) and see if the remainder is enough to bring you to baseline. If the answer is no then take enough insulin to close the gap - do that and you are golden. The point about digestion is interesting because it is a common misunderstanding. Digestion places glucose into the blood stream, but it does that typically faster than the insulin takes it out. The long tail in an RAA is useful because it is clearing up the remaining glucose, in a non-diabetic this is done by the second phase insulin release, in Afrezza it is done by the second dose.You can get into carb absorption rates but that is pretty exotic and only the loop system pumps do that because it is a lot of work. The hybrid closed loop pumps like the 670G or T:Slim do all this for you without even telling you. You just tell it how many carbs you ate. Medtronics have just done a deal with Aetna where they supply Aetna with 670G pumps and Aetna pay by results based on the amount the pump lowers a user's A1c. I have read every word of every post. I am not trolling you. help me out here. what is your best guess what happened in each example. What does it feel like to run high aged?      |
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Post by agedhippie on Jul 4, 2018 21:47:13 GMT -5
Aged - No one is buying this. PWDs want to stack RAAs? Are you kidding me? You also must like playing Russian Roulette. Here is what they said in the "Clinical Results of an Automated Artificial Pancreas Using Technosphere Inhaled Insulin to Mimic First-Phase Insulin Secretion" ... Now here is what Gary Schiener has to say about "angry bolusing" - "Another major limitation to ārapidā insulin is the time it takes to bring above-target blood sugars down to normal. Nobody likes to spend long periods of time with high blood sugar; it turns us into zombies with a major urge to urinate, and drives the A1c up. Many people donāt have the patience to wait 3-5 hours for their high readings to come down, and administer even more insulin before the original correction dose has finished working. āAngry bolusing,ā as this is often called, tends to lead to hypoglycemia." You know, if people don't want to believe that diabetics routinely stack insulin I am fine with that. End of the day people will believe what they want. The truth is that you have to stack, it's not optional. You even have to stack with Afrezza (that pesky second dose). Anger bolusing is irrelevant. It's in the same class as overeating when you are low. You know that you shouldn't do it and that it is a bad idea, but sometimes you still do it anyway (actually I overeat when I am low, but I don't anger bolus). |
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Post by agedhippie on Jul 4, 2018 22:41:39 GMT -5
I have read every word of every post. I am not trolling you. help me out here. what is your best guess what happened in each example. I have never thought you trolled me. Lets have a go at the quiz. First is disclaimer - I have no idea of any context around these images so anything I say is wild conjecture and quite possibly a million miles out. That said let the games begin  I would say they are a lot more insulin sensitive than they think they are. They seem to be over-correcting. Look at that first spike - I would guess they ate at about 10pm, probably about 25g of carbs, and took more insulin than they should. They get mugged by a combination of the natural 3am dip and their basal - a nice example of the benefits of a Dexcom over a Libre btw., the Dexcom would have woken you up when you were crashing and stopped the whole thing. That middle spike is characteristic of eating uncovered carbs while you have insulin running. Basically you take the right insulin to cover your carbs and return you to baseline, but you continue to nibble which produces that table top. Then they over-correct at lunch time, no idea why. Recover and at around 6pm have food before they exercise, but they either take to much insulin, or their basal catches them, hard to say. They went low in the night, took a load of glucose to fix it which sent them flying up and peaking just under 400. When you get that high your insulin resistance goes up so it's hard to manage the return, but they do a pretty good job ending up marginally low at 72. I would give them points for that! The around 6pm something weird happens, did they eat and not bolus? There is a huge spike which they quickly and accurately fix. The story on that one was really the early morning low and sorting out the resulting mess. I would say they have their numbers pretty well dialed in. I wonder if someone gave them a non-diet soda around 5pm. Dawn phenomena or he gets up really early. If I was him I would increase my basal around 3am if I wasn't getting up early. I wonder what sort of oatmeal he is eating. And give up skimmed milk, it's an invention of the devil, regular milk is better for diabetics. I don't think there is anything wrong with his I:C ratio based on the rest of the day. Nice stable graph line There is nothing there to give a clue. Executive summary: 1 really ought to see a decent endo, 2 seems ok and they probably know what they did wrong, 3 should see and endo about adjusting their basal to cope with dawn phenomena, and should probably adjust his morning I:C because he is less insulin sensitive then (I have the same problem), 4 should correct. Thank you for watching me play the ill-informed bystander. Anyone following my suggestions *really* ought to see a doctor. |
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Post by peppy on Jul 4, 2018 22:51:01 GMT -5
ah, the beauty of afrezza.  Bystander with eyeballs. |
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thank you.
