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Post by caesar on Aug 18, 2018 13:36:30 GMT -5
www.diabetesselfmanagement.com/blog/the-accord-trial-findings-what-you-should-know/In light of the ACCORD trial’s findings, the American Diabetes Association (ADA) has released a statement advising people with diabetes who have cardiovascular disease or multiple risk factors for it to consult with their diabetes care team about their treatment goals and to make sure that their blood pressure and cholesterol levels are being properly controlled. However, the ADA also said that it “strongly encourages people with diabetes not to alter their course of treatment without first consulting their health care team” and that it “continues to encourage good control of blood glucose for the management of diabetes and its complications.” The statement went on to say that achieving an HbA1c level of less than 7% has been shown to reduce diabetes complications and “appears to be of great benefit rather than harm.” The ADA currently recommends a general HbA1c goal of less than 7% for people with diabetes, but notes that treatment should be tailored to the individual. For some people it may be best to work toward an HbA1c level as close to normal as possible, while others—such as children, the elderly, and those with other medical conditions—may do best with less stringent goals. Some other groups, such as the American College of Endocrinology and the American Association of Clinical Endocrinologists, recommend an HbA1c target of 6.5% for people with diabetes. Some of the media coverage of the ACCORD trial findings has been alarmist, but it is important to note that the trial is looking at a specific, high-risk group of people and that its findings may not be generalizable to all people with diabetes. In fact, another study published this week in The New England Journal of Medicine showed a reduction in overall death and cardiovascular death associated with intensive blood glucose control in a different high-risk population. The Steno-2 study, which followed 160 middle-aged people with Type 2 diabetes and microalbuminuria (kidney damage) found that people who underwent intensive therapy—with goals of an HbA1c of 6.5% or lower, cholesterol of 175 mg/dl, triglycerides of 150 mg/dl, and blood pressure of less than 130/80 mmHg—had a 20% reduction in risk of death and a 12.5% reduction in risk of cardiovascular death compared to those who received their usual treatment.
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Post by caesar on Aug 18, 2018 13:39:13 GMT -5
Summary
There are several key take-home points from the ACCORD study. I think we should approach setting goals with some caution not only for glucose, but also blood pressure and lipid lowering --particularly in older patients who have established cardiovascular or other disease. Over-aggressive therapy in such people may lead to the development of other problems and may increase mortality without sufficiently reducing their risk. The risk-benefit ratio points toward some increased risk, and in these late-stage patients we need to be more cautious. An alternative possibility is that the very complex regimens used in the ACCORD study to get patients to normal blood pressure and normal glucose may do some harm through mechanisms that we have not yet recognized. Clearly we need to study these in greater detail and develop strategies and new treatments that will not have such effects. And maybe, 1 day, by getting patients to a normal blood glucose, normal blood pressure, and normal lipids, we may eliminate the problem of cardiovascular disease in diabetes.
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Post by nylefty on Aug 18, 2018 15:30:52 GMT -5
The following is an except from an article in the Huffington Post: However elevated sugar is only a symptom, not the cause of the problem. The real problem is elevated insulin unchecked over decades from a highly refined carbohydrate diet, a sedentary lifestyle and environmental toxins. Most medications and insulin therapy are aimed at lowering blood sugar through increasing insulin. In the randomized ACCORD trial of over 10,000 patients, this turns out to be a bad idea. i thought the ACCORD trial had to be suspended due to hypoglycemia being the problem and not the insulin. Notice the dates on that article? THE BLOG 09/20/2009 05:12 am ET Updated Nov 17, 2011 |
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Post by centralcoastinvestor on Aug 18, 2018 16:15:21 GMT -5
The following is an except from an article in the Huffington Post: However elevated sugar is only a symptom, not the cause of the problem. The real problem is elevated insulin unchecked over decades from a highly refined carbohydrate diet, a sedentary lifestyle and environmental toxins. Most medications and insulin therapy are aimed at lowering blood sugar through increasing insulin. In the randomized ACCORD trial of over 10,000 patients, this turns out to be a bad idea. i thought the ACCORD trial had to be suspended due to hypoglycemia being the problem and not the insulin. Notice the dates on that article? THE BLOG 09/20/2009 05:12 am ET Updated Nov 17, 2011Actually I didn’t pay attention to the date. It is interesting how the ACCORD study keeps coming up. It appears that insulin resistance is still a mystery to the medical community. It would be really great if we could do a study that showed what Afrezza could do with intensive treatment using a CGM and how it affected insulin resistance. Or is that the study that mnholdem is referring to when he initiated this thread? It appears that the study mnholdem is referring to is not necessarily an intensive study. However, it should be interesting to see the results as it relates to insulin resistance. |
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Post by MnkdWASmyRtrmntPlan on Aug 18, 2018 16:44:10 GMT -5
The question of how insulin resistance works is still confusing to me. I had a surgeon explain to me that diet was the principal cause of insulin resistance. That there was too much sugar on board in a persons body and that the pancreas was overloaded and could not deal with more sugars and more insulin would do no good. So how would Afrezza overcome that? Here is my understanding. Afrezza is recognized completely by the body as insulin. That's because it IS HUMAN insulin. It is an exact, identical molecular structure. Put them under two microscopes and you cannot tell the difference - identical. Although the body recognizes all the other synthetic aspart RAA insulins as insulin in some regards, it is not recognized entirely. Most importantly, it is not recognized by the pancreas for First Phase Insulin Response. The pancreas recognizes Afrezza as insulin, but it does not recognize synthetic insulins because it knows they are not human insulin. (you can't fool mother nature?) Because Afrezza is recognized by the pancreas as insulin, it creates homeostasis by restoring communication between the pancreas and the liver. The pancreas monitors the blood for the amount of insulin. If it sees too much insulin, it tells the liver to stop gluconeogenesis (putting even more glucose into the blood), and it consequently stops the cascade of glucose. The blood is already full of glucose from the meal that was just consumed, and since there is no homeostasis with synthetic insulin, the liver continues to pump even more glucose and stoke the cascade of glucose even more. Afrezza does not have that problem. Afrezza arrests that cascade by stopping the liver from putting out more glucose. This is (arguably) the best advantage Afrezza has over all other meal-time insulins - it keeps BG in check much better than synthetic insulins. Also, being HUMAN insulin, Afrezza is fast in and fast out, whereas all the other RAA synthetic insulins are not. It is fast in due to the fact that it is delivered through the lungs ... the best, and safest way to be delivered. The Technosphere capsule that transports it opens up immediately in the warm and moist alveoli and releases the insulin particles directly into the blood. The fast out is, again, because it is HUMAN insulin and it has the same PD profile as human insulin ... fast. Again, synthetic RAA Analog insulins are not human insulin. They are synthetic. I am not sure of the exact mechanism that delays synthetic insulin's PD, but I suspect it is again some body part (kidneys?) that does not recognize it and efficiently rid it from the blood. In any case, this is how Afrezza reduces hypos. That one-two punch is how Afrezza both lowers A1c (and more importantly, increases time-in-range), AND reduces hypos. I know, that doesn't really address the concept of insulin resistance, but it answers the question of one way that Afrezza Human insulin overcomes the cascade of glucose and manages BG highs and lows much better than synthetic insulins. |
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Post by sayhey24 on Aug 18, 2018 17:01:43 GMT -5
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If you take 2x the amount of afrezza than you should have how low will you go and how fast will you recover? Dr. Kendall is doing a dosing study now to try and answer that question. We should have some answers the medical community will accept soon.
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You already have those results from the Safety and Efficacy of Technosphere® Insulin Inhalation Powder (TI Inhalation Powder)When an Optimal Dose is Taken With Varied Carbohydrate Intake trial. The outcome at 50% for Type 1 was that everybody crashed ( Original Protocol Type 1 Diabetes Mellitus Technosphere Insulin Treated; 50% carbohydrate load was administered but not completed due to all subjects having hypoglycemia, 0% carbohydrate load was deemed unsafe by PI). It was a small trial though. Aged - you are usually telling me we don't have enough study results. Its good to see you are going through the old studies.
This study is different than my understanding of what Dr. Kendall is doing. This study was based on a average diabetic meal and could the patient's favorable dose be used safely, regardless of change in meal carbohydrate content. My understanding of what Dr. Kendall is doing is changing the dose to see how far he can push it incurring hypos.
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Post by babaoriley on Aug 18, 2018 17:06:05 GMT -5
My understanding is that the more insulin that is released into your system over time, the more you're likely to gain weight, as the body tends to store fat when insulin is coursing through the veins (or wherever it is that it courses).
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Post by babaoriley on Aug 18, 2018 17:08:41 GMT -5
Notice the dates on that article? THE BLOG 09/20/2009 05:12 am ET Updated Nov 17, 2011Actually I didn’t pay attention to the date. It is interesting how the ACCORD study keeps coming up. It appears that insulin resistance is still a mystery to the medical community. It would be really great if we could do a study that showed what Afrezza could do with intensive treatment using a CGM and how it affected insulin resistance. Or is that the study that mnholdem is referring to when he initiated this thread? It appears that the study mnholdem is referring to is not necessarily an intensive study. However, it should be interesting to see the results as it relates to insulin resistance. Holdem will have to answer that, CCI, but I don't think the small trial he referenced will be studying that. Check it out on his initial link. |
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Post by peppy on Aug 18, 2018 17:47:59 GMT -5
The question of how insulin resistance works is still confusing to me. I had a surgeon explain to me that diet was the principal cause of insulin resistance. That there was too much sugar on board in a persons body and that the pancreas was overloaded and could not deal with more sugars and more insulin would do no good. So how would Afrezza overcome that? Here is my understanding. Afrezza is recognized completely by the body as insulin. That's because it IS HUMAN insulin. It is an exact, identical molecular structure. Put them under two microscopes and you cannot tell the difference - identical. Although the body recognizes all the other synthetic aspart RAA insulins as insulin in some regards, it is not recognized entirely. Most importantly, it is not recognized by the pancreas for First Phase Insulin Response. The pancreas recognizes Afrezza as insulin, but it does not recognize synthetic insulins because it knows they are not human insulin. (you can't fool mother nature?) Because Afrezza is recognized by the pancreas as insulin, it creates homeostasis by restoring communication between the pancreas and the liver. The pancreas monitors the blood for the amount of insulin. If it sees too much insulin, it tells the liver to stop gluconeogenesis (putting even more glucose into the blood), and it consequently stops the cascade of glucose. The blood is already full of glucose from the meal that was just consumed, and since there is no homeostasis with synthetic insulin, the liver continues to pump even more glucose and stoke the cascade of glucose even more. Afrezza does not have that problem. Afrezza arrests that cascade by stopping the liver from putting out more glucose. This is (arguably) the best advantage Afrezza has over all other meal-time insulins - it keeps BG in check much better than synthetic insulins. Also, being HUMAN insulin, Afrezza is fast in and fast out, whereas all the other RAA synthetic insulins are not. It is fast in due to the fact that it is delivered through the lungs ... the best, and safest way to be delivered. The Technosphere capsule that transports it opens up immediately in the warm and moist alveoli and releases the insulin particles directly into the blood. The fast out is, again, because it is HUMAN insulin and it has the same PD profile as human insulin ... fast. Again, synthetic RAA Analog insulins are not human insulin. They are synthetic. I am not sure of the exact mechanism that delays synthetic insulin's PD, but I suspect it is again some body part (kidneys?) that does not recognize it and efficiently rid it from the blood. In any case, this is how Afrezza reduces hypos. That one-two punch is how Afrezza both lowers A1c (and more importantly, increases time-in-range), AND reduces hypos. I know, that doesn't really address the concept of insulin resistance, but it answers the question of one way that Afrezza Human insulin overcomes the cascade of glucose and manages BG highs and lows much better than synthetic insulins. The importance of first-phase insulin secretion: implications for the therapy of type 2 diabetes mellitus. Abstract Type 2 diabetes is a heterogeneous disorder characterized by defects in insulin secretion and action. Insulin resistance is a key feature of type 2 diabetes. However, insulin resistance alone does not appear to be sufficient to cause diabetes. Longitudinal studies have shown that the development of overt hyperglycemia is associated with a decline in beta-cell secretion. In patients with impaired glucose tolerance or in the early stages of type 2 diabetes, first-phase insulin release is almost invariably lost despite the enhancement of second-phase secretion. Both animal and human studies support the critical physiologic role of the first-phase of insulin secretion in the maintenance of postmeal glucose homeostasis. This effect is primarily mediated at the level of the liver, allowing prompt inhibition of endogenous glucose production (EGP) and thereby restraining the mealtime rise in plasma glucose. In type 2 diabetes, the loss of the early surge of insulin release is a precocious and quite common defect that plays a pathogenic role in postmeal hyperglycemia and one that may require specific therapeutic intervention. This becomes even more apparent if the negative impact of prandial glucose spikes is taken into consideration. Epidemiological evidence exists to indicate that 2-h postload plasma glucose levels are strongly associated with all-cause and cardiovascular mortality relative risk. Indeed the acute elevation of plasma glucose concentration triggers an array of tissue responses that may contribute to the development of diabetic complications. Considering that type 2 diabetes begins with meal-related hyperglycemia in many patients, it becomes apparent that normalization of postmeal plasma glucose levels should be the target for rational therapy and the goal in the early stages of the disease. If a primary goal of diabetes therapy is control of postmeal glucose excursion, then the regulation of glucose absorption from the gut and entry into the circulation is an important mechanism to consider. The restoration of the rapid increase in plasma insulin concentration may be quite an efficient therapeutic approach.www.ncbi.nlm.nih.gov/pubmed/11424229 |
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Post by peppy on Aug 18, 2018 18:02:39 GMT -5
The question of how insulin resistance works is still confusing to me. I had a surgeon explain to me that diet was the principal cause of insulin resistance. That there was too much sugar on board in a persons body and that the pancreas was overloaded and could not deal with more sugars and more insulin would do no good. So how would Afrezza overcome that? Here is my understanding. Afrezza is recognized completely by the body as insulin. That's because it IS HUMAN insulin. It is an exact, identical molecular structure. Put them under two microscopes and you cannot tell the difference - identical. Although the body recognizes all the other synthetic aspart RAA insulins as insulin in some regards, it is not recognized entirely. Most importantly, it is not recognized by the pancreas for First Phase Insulin Response. The pancreas recognizes Afrezza as insulin, but it does not recognize synthetic insulins because it knows they are not human insulin. (you can't fool mother nature?) Because Afrezza is recognized by the pancreas as insulin, it creates homeostasis by restoring communication between the pancreas and the liver. The pancreas monitors the blood for the amount of insulin. If it sees too much insulin, it tells the liver to stop gluconeogenesis (putting even more glucose into the blood), and it consequently stops the cascade of glucose. The blood is already full of glucose from the meal that was just consumed, and since there is no homeostasis with synthetic insulin, the liver continues to pump even more glucose and stoke the cascade of glucose even more. Afrezza does not have that problem. Afrezza arrests that cascade by stopping the liver from putting out more glucose. This is (arguably) the best advantage Afrezza has over all other meal-time insulins - it keeps BG in check much better than synthetic insulins. Also, being HUMAN insulin, Afrezza is fast in and fast out, whereas all the other RAA synthetic insulins are not. It is fast in due to the fact that it is delivered through the lungs ... the best, and safest way to be delivered. The Technosphere capsule that transports it opens up immediately in the warm and moist alveoli and releases the insulin particles directly into the blood. The fast out is, again, because it is HUMAN insulin and it has the same PD profile as human insulin ... fast. Again, synthetic RAA Analog insulins are not human insulin. They are synthetic. I am not sure of the exact mechanism that delays synthetic insulin's PD, but I suspect it is again some body part (kidneys?) that does not recognize it and efficiently rid it from the blood. In any case, this is how Afrezza reduces hypos. That one-two punch is how Afrezza both lowers A1c (and more importantly, increases time-in-range), AND reduces hypos. I know, that doesn't really address the concept of insulin resistance, but it answers the question of one way that Afrezza Human insulin overcomes the cascade of glucose and manages BG highs and lows much better than synthetic insulins. Subcutaneous absorption of biotherapeutics is relatively slow and mostly incomplete. Knowledge of the subcutaneous tissue is important to understand the absorption kinetics after subcutaneous administration. T ransport in the subcutis to the absorbing blood or lymph capillaries appears to be a major contributor to the slow subcutaneous absorption. Larger proteins (>20 kDa) are mostly absorbed via the lymphatic system, although potential species differences are not fully understood yet. dmd.aspetjournals.org/content/42/11/1881The Rapid acting analogs work just as fast as afrezza when given IV. |
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Post by agedhippie on Aug 18, 2018 18:08:55 GMT -5
Aged - you are usually telling me we don't have enough study results. Its good to see you are going through the old studies.
This study is different than my understanding of what Dr. Kendall is doing. This study was based on a average diabetic meal and could the patient's favorable dose be used safely, regardless of change in meal carbohydrate content. My understanding of what Dr. Kendall is doing is changing the dose to see how far he can push it incurring hypos.
I have always read the old studies. This is why I am not sure where the veins of gold are.  |
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Post by sayhey24 on Aug 18, 2018 18:15:35 GMT -5
Summary There are several key take-home points from the ACCORD study. I think we should approach setting goals with some caution not only for glucose, but also blood pressure and lipid lowering --particularly in older patients who have established cardiovascular or other disease. Over-aggressive therapy in such people may lead to the development of other problems and may increase mortality without sufficiently reducing their risk. The risk-benefit ratio points toward some increased risk, and in these late-stage patients we need to be more cautious. An alternative possibility is that the very complex regimens used in the ACCORD study to get patients to normal blood pressure and normal glucose may do some harm through mechanisms that we have not yet recognized. Clearly we need to study these in greater detail and develop strategies and new treatments that will not have such effects. And maybe, 1 day, by getting patients to a normal blood glucose, normal blood pressure, and normal lipids, we may eliminate the problem of cardiovascular disease in diabetes. My advice on the ACCORD study is to take it and throw it in the trash can. It was one of the most flawed studies of all time and it is still being refereed to as a standard in the community.
The long of short of the study was TZDs were being hailed as the new miracle drug at the time. They used them with insulin to try and get tighter control and the Actos killed the people. No one wanted to kill the new miracle drug so they spun the study to say keeping control under 7 is dangerous. What is dangerous is using TZDs.
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Post by sayhey24 on Aug 18, 2018 18:26:03 GMT -5
Aged - you are usually telling me we don't have enough study results. Its good to see you are going through the old studies.
This study is different than my understanding of what Dr. Kendall is doing. This study was based on a average diabetic meal and could the patient's favorable dose be used safely, regardless of change in meal carbohydrate content. My understanding of what Dr. Kendall is doing is changing the dose to see how far he can push it incurring hypos.
I have always read the old studies. This is why I am not sure where the veins of gold are. Do you have the 118?
Right now Dr. Kendall has a pretty good story with the T1s and reduced hypoglycemia. Whether he has enough study data to change the standard we will have to see. He seems pretty optimistic.
For the T2s its all about how safe is afrezza with regard to hypos. In the 175 the only ones getting hypos were using TZDs. If in fact he can show you can take 2x the dose will only mild hypoglycemia he has enough to start the conversation that afrezza should be step 1. If you have near zero chance of getting a hypo with a 4u, taking it as step 1 would have huge benefits for the early T2s.
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Post by sayhey24 on Aug 18, 2018 18:40:16 GMT -5
The question of how insulin resistance works is still confusing to me. I had a surgeon explain to me that diet was the principal cause of insulin resistance. That there was too much sugar on board in a persons body and that the pancreas was overloaded and could not deal with more sugars and more insulin would do no good. So how would Afrezza overcome that? Its still confusing to everyone because no one is sure what the root cause is. We know TZDs reduce insulin resistance. They basically do this by getting the body to produce new fat cells, and those cells are actually more sensitive to insulin.
Why? It could very well be Joslin is correct and the virus has not yet infected these cells. The same could hold try with exercise and the break down/ build up of new muscle.
What we do know is keep near non-diabetic numbers and insulin resistance decreases. What we also know from the 118 study that afrezza blocks the alpha cells which then shuts off glucose release from the liver thereby reducing glucose in the blood.
In short, afrezza provides a double whammy; reduced resistance; and reduce glucose.
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Post by agedhippie on Aug 19, 2018 9:14:55 GMT -5
Its still confusing to everyone because no one is sure what the root cause is. We know TZDs reduce insulin resistance. They basically do this by getting the body to produce new fat cells, and those cells are actually more sensitive to insulin. It reduces insulin resistance my changing the protein synthesis via gene transcription (it produces a protein that activates a gene). In turn this increases the sensitivity of the glucose transporters and insulin signalling which is what reduces the insulin resistance. As a side line it also reduces free fatty acids. The net effect is improved insulin efficiency (uptake and use) in the organs, and reduced glucose output from the liver. I seem to remember that it also helps with the uptake in muscles but I cannot remember why so that might be wrong. Actos would not be a bad drug is it wasn't for the water retention, and congestive heart failure issues. There was a bladder cancer risk, but a longer term analysis published last year found the rates between Actos and non-Actos users was the same. Separately - I don't believe there is any evidence that Afrezza reduces insulin resistance. If there was long term Type 2 users would be using less Afrezza per meal and I have not seen anyone talking about that. |
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