Is Afrezza worth the risk?

[RuthW]

Right, obviously it suits you well, then. Though obviously the vast majority of Type 1s don't actually want a completely flat basal dose, either, so again for us, that combination is not ideal.

 

[tim2000s]

I've had a few chats with people about Afrezza combined with pump therapy. If you need the variable basal rate that a pump provides, then I think working with Afrezza is an interesting option. To get it in the UK, it costs something like £220 to import them from the US.

What I'm interested in is the way it gets directly into the blood and seems to act on the Glucagon release that can occur when eating certain food types. I'd like to try it just to see if this effect helps to limit gluconeogenesis on protein rich meals...

 

[RuthW]

Yes, I agree it would be another option. And the short delivery time is appealing. But I am still curious about dosing and whether there has been any independent research into it. I mean, what if 4 units is just too much? Supposedly it is "gone" or "out of the blood stream" after half an hour, more like endogenous insulin. But what if the dose was too high for the meal? Does Afrezza just vanish somehow? Does it send the diabetic hypo? If it doesn't, where DOES it go, and how? Why does Afrezza apparently vanish when unneeded, while injected insulin doesn't? Why is the minimum dose 4 units? Is it ineffective below that? Are there plans to bring out 2 and 6 unit doses?

I imagine many endos will not prescribe it till these questions are answered.

 

[brendan101]

A lot of questions Ruth! I will do my best to answer them. Bear in mind I am not medically qualified and my opinions are from my use of Afrezza. I will address the flat dose query first. I have found Tresiba to flatten my BG levels especially in the morning where I have suffered from Dawn Phenomenon for years so when I refer to flat basal dose, I mean flat BG levels. Apologies for the misunderstanding.
There has been a lot of work done in the States on Afrezza and it has been approved by the FDA. Afrezza users have had amazing results as have I in terms of my overall feeling of health and wellness on Afrezza.
What if the 4 units is too much? I found that I was able to get by BG levels very flat with Afrezza and as the constant highs and lows were obliterated, I got to the point where a high for me was 11mmol. Afrezza works like a first phase insulin and appears to be able to get the liver to function correctly again to control levels. It was not a constant merry go round with BG levels as I get on injectable insulin. The liver normally uses 80% of endogenous insulin in a healthy individual and can store 65% of glucose from a meal. Diabetic livers can do this but are unable to because they do not get the signal from first phase insulin produced by the pancreas and directed to the liver via the hepatic portal vein. This is a real bummer. Afrezza is in fact the only insulin monomer available today. It gets in through the lungs and peaks within 12-15 minutes. I normally take it just before eating or during depending on my BG level. Injectable insulin is a hexamer bound by zinc atoms and breaking this down and getting it to the circulation takes time as we all know and then we go high after a meal and can go low 2 hours later due to the tail effect of injectable insulin. This means we snack and can gain weight etc and tend to feed the insulin. It has now been shown that this glucose variability can cause complications. You definitely will go low on Afrezza if you take too much but I have found that I require far less Lucozade to correct a low (a mouthful compared to 500ml) , your levels stay flat thereafter provided you are on the correct dose of background. My hypo awareness was unaffected. I found that I needed to go from 39 units of Tresiba to 42 units of Tresiba with Afrezza. Because Afrezza is out so quickly you can also know if your background is working well enough and don't need to wonder if the tail effect of your Novorapid is keeping you in range.
I cannot answer your question about where does it go and how but I surmise that the answer will be similar to what happens with endogenous insulin or normal injectable, the limit frame being much shorter and therefore better. This is a huge benefit to Afrezza. Currently Afrezza is available in the States as 4, 8 and 12 unit doses. I call the 4 unit dose a BLUE dose and the 8 unit dose a GREEN dose. I take a green dose at the start of a meal and should I find I start going high after an hour I take a follow up blue dose after an hour. No stacking results as the first dose has had it's affect. There is a little bit of trial and error at the start but there is no complicated carb counting or obvious miscalculation that we have on injectable insulin. The 4 or the 8 works for me. I have not tried a 12 unit dose but I would think that if you ate a larget pizza that you could start eating the pizza and maybe take a 12 unit dose 10 minutes into the meal. Interestingly this dose would be out within the hour too and if a follow-up was needed it could be applied. It's cheaper to buy 12 unit cartridges although I prefer the 4 and the 8 as I don't eat that many massive carb meals as I don't want to gain weight! That said I have found that I trimmed down slightly using Afrezza too.

 

[brendan101]

Afrezza is the new inhaled insulin by MannKind (Sanofi). It looks like one of those asthma inhalers and you puff it, like an asthma inhaler. But, they say it's risky, especially if you've ever had lung problems or have ever smoked. Take a look at their website: https://www.afrezza.com/ It's a lot more discreet than having to give yourself insulin injections, especially if you're always out and about, which I am.

It's a really great insulin in my opinion. I love using it. I feel like a new person. I surmise that diabetics don't realise how sick they are until they suddenly feel better. This was my experience. I feel so healthy using Afrezza. It carries warnings that you should not use it if you yourself are a smoker or less than 6 months has passed since you quit, if you have Chronic Pulmonary Disorder or asthma. I surmise that the absorption may be affected if your lungs are covered in mucus and tar. Another warning is that it can cause hypos. I found out to my delight that I don't get as many lows with Afrezza despite having my glucose levels within range. Try that on injectable insulin! I hope this info helps Sweeeeeeeeeet.

 

[tim2000s]

In answer to the commentary about Hypos, in the FDAs analysis of the Hypo data during the (3rd) NDA process, there were a number of observations. The first interesting one from a T1 perspective is:

In active comparator studies where Afrezza TI was compared with another insulin, the incidence of hypoglycemia was generally lower for Afrezza TI than comparator, but in these studies the comparator groups had better glycemic efficacy than the Afrezza TI groups, confounding the hypoglycemia analyses.

The second looks at incident rate analysis and states that there wasn't a statistically significant difference between Insulin Aspart and Afrezza, although incidence rates were lower.

The incidence of any hypoglycemia during the randomized treatment period of the study was comparable in the Afrezza TI Gen2 (167 subjects, 96.0%) and the Afrezza TI MedTone (166 subjects, 96.0%) groups and in the insulin aspart group (170 subjects, 99.4%) (Table 33).

The exposure-adjusted incidence per subject-month was similar across groups for any hypoglycemia and mild/moderate hypoglycemia.

The incidence of severe hypoglycemia during the randomized treatment period of the study was slightly lower in the Afrezza TI Gen2 (32 subjects, 18.4%) and the Afrezza TI MedTone (37 subjects, 21.4%) groups than in the insulin aspart group (50 subjects, 29.2%).

The exposure adjusted incidence per subject-month for severe hypoglycemia was also lower among Afrezza TI-treated patients vs. aspart-treated patients (exposure-adjusted incidence per subject-month was 0.48, 0.52, and 0.67, for Gen2, MedTone and insulin aspart, respectively).

The FDA Reviewer noted:

For the T1DM trial, conclusions regarding hypoglycemia are confounded by the difference in efficacy observed between the two study arms and are entirely consistent with the fact that Afrezza was demonstrated to be less effective than comparator. For the T2DM trial, the result of greater hypoglycemia risk vs. placebo is expected.

It's worth noting that there's a huge amount of data relating to the mechanism by which titration of Afrezza dosage was undertaken in the trials and how, if hypo- or hyper-glycaemia was observed post meals, doses were then adjusted.

The full set of documents is available here.

 

[capsicum]

In answer to the commentary about Hypos, in the FDAs analysis of the Hypo data during the (3rd) NDA process, there were a number of observations. The first interesting one from a T1 perspective is:

In active comparator studies where Afrezza TI was compared with another insulin, the incidence of hypoglycemia was generally lower for Afrezza TI than comparator, but in these studies the comparator groups had better glycemic efficacy than the Afrezza TI groups, confounding the hypoglycemia analyses.

If you read the protocols of these studies, Afrezza is used in an unusual way compared to the comparator, and it would not be used like this in the real world. For good reason too - the studies are designed to prove that Afrezza works as well as injected insulin in an unfavourable, but highly reproducible scenario. It's a shame that so few people have read the studies.

Looking closer at these studies, the results are truly amazing. Let's look at one of the FDA trials you referred to above, which was finally published in December 2015:

The Afrezza group:

• Doses fixed for 7 days at a time
• Only flexibility allowed is a follow up blue (4u) at 90 minutes after eating
• Dose not allowed to be changed until the next week - even if known to be wrong

The Injected group:

• Dose adjustments/modifications were allowed at each meal for:
  • carbohydrate counting
  • meal size
  • self-monitored blood glucose [SMBG] results
  • snacks
  • postprandial glucose [PPG] level

The Afrezza group had to use the same dose for a no-carb meal with a starting glucose of 3.9 mmol/L as for a high-carb meal with a starting glucose of 12.0 mmol/L.

Amazingly, the Afrezza group still had far less hypoglycaemia - with almost the same HbA1c between the groups at the end of the trial (95%CI - 0.02–0.36%).

Even after correcting for the A1c level difference between the groups, Afrezza users had 43% lower rate of severe hypoglycaemic events (p=0.05) and 27% lower rate of total hypoglycaemia (p=0.0001).

These are stellar results, especially considering how users were instructed to use it. For a peek at how the results might look for an Afrezza trial without such unusual constraints, we can look closer at those who did best in both groups:

Comparing those that achieved A1C levels under 6.5% in both treatment groups, the injected insulin users had FIVE TIMES - 400% higher severe hypoglycaemia events per subject-month than the Afrezza users. They also had 20% less non-severe events too!

In patients whose A1c dropped by more than 0.6% by the end of the 6-month trial, the ones using Afrezza had about 40% less hypoglycaemic events per subject-month than the injected insulin users.

It's a shame they didn't use the GlycoMark 1,5AG test as well as HbA1c. The test reflects time spent over 10 mmol/L and doesn't reward hypoglycaemia.

Afrezza is amazing stuff. We have spent a fortune importing it and had great success with it. Unlike trial users, Matt checks his glucose before dosing Afrezza.

 

[tim2000s]

I think the biggest issue with all of the trials demanded by the FDA is that they don't look at the important points in relation to Diabetes Management. While they demonstrate non-inferiority in bringing down Hba1C, is that really the primary purpose of insulin?

I'd far rather see the FDA look at much more useful data such as glycaemic variation for correctly titrated users of injectables and Afrezza. Unfortunately, whilst that is indicated in the data, that's not what it's measured on.

 

[brendan101]

HbA1c is regarded as important as an indicator for risk of diabetic complications. However it is possible to have a HbA1c of 6.2, which for a type 1 diabetic is good and still get complications. A high glycaemic variation over time is now understood to hasten the development of complications. A diabetic can have a good HbA1c such as 6.2 and still have huge glycaemic variability. I found on Afrezza that with little effort, I could keep my BG levels in almost non-diabetic range and was able to live in real time and eat when I wanted. I found this very liberating to say the least. This was after just 4 weeks of using Afrezza.

 

[steve_p6]

The shame is that it seems people already struggle to get a move from Levemir to Tresiba due to cost. A move from novorapid etc no doubt is an even bigger cost increment.

 

[tim2000s]

@brendan101, which Diabetic clinic are you under? I want to attempt to secure a private prescription for Afrezza at my next clinic so that would be helpful...

 

[brendan101]

Hi Guys,

I have needed to secure my Afrezza internationally and the best way of doing this can be found on this link here:
http://afrezzadownunder.com/obtaining-afrezza/

 

[brendan101]

In relation to cost, this appears to be a minor issue according to the doctors I have spoken to. From speaking to endos and GPs they say that safety is most important. They do acknowledge that Afrezza has been approved in the USA and my endo has looked into it and says that the results are amazing but he is based in the UK and it's not approved here yet. We need to approach the local Clinical Commissioning Group, CCG, to put in a funding request. Ensuring a drug is safe is more important and due to the lack of education this side of the pond, it hasn't been fully embraced yet as it's an unknown entity. Try mentioning it to a doctor and a stillness will fill the air. This is somewhat understandable. There is the mention that Exhubera from Pfizer was unsuccessful but the main selling point here was that it was inhalable. The device for inhalation was massive and the absorption rate of the insulin was no better than current injectable insulin. Afrezza is completely different. The device is robust and tiny for inhalation much smaller than a disposable insulin pen. The action is much quicker than injectable and the insulin expires within an hour. It is easy to use. I went high yesterday evening for example, 18mmol so I took extra Humalog to bring myself back into range which took a couple of hours. Unfortunately due to Humalog lasting so long I ended up going low at midnight and then woke up this morning at 16mmol? Sound familiar anyone?! With Afrezza I could bring the 18mmol down fast and the insulin would expire in an hour so no hypo and no feeling **** this morning with another high blood sugar. In my opinion the fact that Afrezza is inhalable is NOT the unique selling point. It's the speed of action and the fact that it can help the liver to balance BG levels that's the real gem for me. If Afrezza was injectable and it could do this, then sign me up for that as well. I think sometimes people think that the inhalable nature is great and yes it's easier to use than dropping your trousers or pulling up your shirt to inject but there is an over emphasis on injections being sore and therefore this new insulin is great. Even some of the media in the USA have jumped on the bandwagon by discussing the end of 'painful' injections. Again from my experience I find injections easy and pain free esp with the Pentapoint needle tech that's around today, I find them virtually painless. There is a mention of needle phobia. I recall as a 10 year old I used to HATE injections but I knew that this was life or death for me. Therefore I took the injection eventually. I don't want to undermine this because there may be some really genuine needle phobes out there and Afrezza would be great but I don't think this represents the majority of users who could do very well on Afrezza for the aforementioned reasons.
In relation to Tresiba I find it works really well for me with very little peak and reduced hypos. It says this in the literature somewhere too. It's about quality of life in my opinion and the doctors I have spoken to tend to agree. My endo reliability informed me that he deals with some patients with other endocrine problems and has to prescribe drugs that are 3 times more expensive that insulin. They work and in the grand scheme of things the patient has a better quality of life and spends more time living and less time sick and at the doctor so the cost is justified.

 

[tim2000s]

@brendan101 The big issue with Exubera was that it caused a statistically significant risk of lung cancer during the clinical trials. As a result, it didn't sell well (would you take it knowing you were six times more likely to get it than a non-user, even if that meant you had a 1 in 790 chance as opposed to a 1 in 4292 chance?) and was eventually pulled by Pfizer at a cost of $2.8bn to the firm.

This informs a lot of the concerns about Afrezza seen in the medical profession, in spite of the trials thus far showing no change in risk of lung cancer.

 

[brendan101]

@brendan101 The big issue with Exubera was that it caused a statistically significant risk of lung cancer during the clinical trials. As a result, it didn't sell well (would you take it knowing you were six times more likely to get it than a non-user, even if that meant you had a 1 in 790 chance as opposed to a 1 in 4292 chance?) and was eventually pulled by Pfizer at a cost of $2.8bn to the firm.

This informs a lot of the concerns about Afrezza seen in the medical profession, in spite of the trials thus far showing no change in risk of lung cancer.

Yes Tim2000 you are right. I am aware of this too. I completely agree with you.