This is the part 2. Part 1 can be accessed in this link.
This part explores how the future will be like for insulin dependent type 2 if they are exposed to Afrezza. I believe the effect of Afrezza on Type 2 will be more dramatic compared to Type 1. In Type1, the damage is already done to the pancreas as the beta cells secrete little or no insulin. There is no "halt the progression of diabetes effect" for Type1 as compared to Type 2.
In case of Type 2, Afrezza can take the load off the Pancreas during post-meal, reduce postprandial glucose excursion dramatically, reduce gluconeogenesis (shut off the hepatic secretion of glucose), reduce oxidative stress on pancreas, and there by halt the progression of diabetes.
Both Fasting plasma glucose (FPG) and PostPrandial Blood glucose (PPG) influence HbA1C. The contribution of FPG and PPG varies depending on the A1C level. The relationship is given in this diagram.
It is clear from the diagram that at lower A1C's PPG plays a major role. Various studies have suggested that PPG is an independent risk factor for cardiovascular disease. Because impaired glucose tolerance (2-hour values of 140–199 mg/dl) and impaired fasting glucose (FBG of 100–125 mg/dl) are associated with macrovascular disease, whereas micovascular disease appears to be more related to the FPG of > 126 mg/dl,9 it is suggested that a lower glycemic threshold may exist for macrovascular disease.
Indeed, increasing evidence suggests that postprandial glucose excursions, more so than
fasting glycemia, contributes to HbA1c levels in the lower range (Diabetes Care
2003;26:881-5) and to the development of macrovascular complications via endothelial
damage (Arch. Intern. Med. 2004; 164:2090-5).
In the current treatment paradigm for Type 2, insulin comes in the end and it comes in the form of basal insulin. The basal is very poor in targeting PPG. Short acting (rapid acting analogues, NPH etc) is seldom added as this results in too many injections and the risk of Hypos also goes up. Now one can build a strong case of using inhaled insulin to handle PPG and there by better controlling A1C.
There are two studies in the pipeline that you could call "superiority studies" for diabetes treatment – Study 117 and Study 142. Study 117 pits Afrezza and Lantus against Humalog/Lispro and Lantus in 230+ Type 1 diabetics. It started in May 08 and we will see results sometime this year, in time for commercialization. Study 142 will demonstrate that superior control, and even normal A1Cs, can be more readily achieved with Afrezza and a physiologically stable basal insulin.
Here is the exciting part. These tests show how Al is changing the rules of diabetes treatment. The current favored treatment measures the AVERAGE amount of glucose in the blood over time. The glucose swings that cause damage are not factored in aHbA1c reading. A healthy person has a fasting blood glucose level of 70-100 mg/dL. A diabetic may have huge swings because the pancreas does not make enough or any insulin, while they input insulin spikes occasionally to offset food intake. Those swings cause damage to the organs that threaten and shorten health and life. Since low blood glucose (hypoglycemia) is more damaging, doctors manage diabetes to keep a higher base blood glucose level with basal insulin, accepting long term damage to avoid hypos. MNKD is showing the diabetic world that it is possible to manage blood glucose at the same level a normally healthy body does. Huge change.
At the JP Morgan Healthcare Conference, Al Mann said, “You need to be below 140 at peak to avoid long term damage. Problem is, as long as you are operating that high you cannot safely bring fasting blood glucose levels to a normal level under 100. You can only do that with Afresa. Afresa is the only drug that will get you to normal levels. We want to get everyone to a normal A1c, and that will only be possible with a good basal insulin. We are doing two studies. Study 117 is in progress - taking patients on Lantus basal and comparing Afresa versus Humalog while attempting to keep blood glucose under 120. We wanted to keep blood glucose even closer to normal (100) but docs were scared of hypos even though all patients will be on continuous glucose monitors for safety. Study 117 will show superiority of Afresa in A1c or hypos, and probably both. Because we are limited by current basal insulins, we are doing Study 142. We hope to have a better basal in a few years. Until then we want to show what Afresa can do without the basal insulin."
These tests are likely to be very effective in moving the treatment of diabetes and the players in the space.
So it will be a paradigm shift for docs if Afrezza replaces basal or is used in conjunction with Basal for type 2. Mannkind certainly has its task cut out.
I did some research and came across two documents.
One is from Pfizer's Exubera and other is from a UK study. Think of Afrezza as next generation Exubera. Comparing Afrezza to Exubera is like comparing a human to a chimpanzee.
The drawbacks of Exubera (lung issues, poorer PK/PD, increase in anti-bodies, dosage issues, device issues) are completely eliminated in Afrezza. If Exubera looks good, you can bet that Afrezza will be far superior.
Nevertheless, good research has been done by Pfizer to explore this option and I recommend the readers to read this doc that I've uploaded. I'll present a few pages here. BTW, my upload mannkind ppt seems to be quite popular.
Evaluating addition of three different analogue insulin regimens to dual oral antidiabetic therapy
Open-label randomisation to:
1) Twice a day biphasic insulin (NovoMix 30)
2) Three times a day prandial insulin (NovoRapid)
3) Once a day basal insulin (Levemir) before bed, with a morning injection added if necessary
700 patients required to detect a 0.4% difference in achieved HbA1c, allowing for 15% loss to follow up
Outcomes at One Year
To compare HbA1c levels achieved by the three regimens
Secondary outcomes include:
Proportion with HbA1c =6.5%
Proportion with unacceptable hyperglycemia i.e. HbA1c >10% or two successive values >8.5% at or after 24 weeks
Impact on body weight
Quality of Life (EQ-5D)
Eight-point self-measured capillary glucose profiles
Proportion requiring a morning basal insulin injection
Lets see the end-result. This is beautiful. We've to extrapolate this as RAA was novorapid. Afrezza has far better PK/PD compared to RAA. There was one major problem in Prandial case. The prandial cases showed a higher hypo events. Again if Afrezza is used, this issue will be completely eliminated. Who says you can't have your cake and eat it too?
Look at how the glucose levels are lower; again if Afrezza is used, the hypos will be far less or absent.
Now comes the final piece, and this calls for some major extrapolation.
a) The PPG for afrezza will be much better as hepatic glucose is shut off; AUC for Afrezza is the best
b) Afrezza showed drop in weight or is weight neutral compared with RAA
c) Afrezza showed better hypo events (less) compared with RAA
I can't wait to see this used for Type 2's once FDA approves it. It'll be great to come back to this page and see if my understanding was right.