Lincy Varughese, Pharm. D.

Candidate
Ambulatory Care 4656

December 4, 2015

Drug Information Question:

The use of injectable insulin is the gold standard when caring for type 1 diabetics and
advanced type 2 diabetics. There is constantly a battle in this market for newer and more
convenient forms of insulin therapy. The product Afrezza [technosphere inhaled insulin],
initially came out in 2007 but, due to poor inhaler design and a different manner of dosing
from standard insulin units, the product did not take flight. Now, however, this novel manner
of insulin dosing is once again, a possibility. Afrezza (insulin human) inhalation powder is a
rapid-acting Technosphere insulin (TI) administered via a breath-powered oral inhaler to
patients with diabetes requiring prandial insulin.1 TI, a dry powdered formulation of
recombinant human insulin adsorbed onto a proprietary carrier, is designed to deliver insulin
to the deep lung, at the level of the alveoli, where it is absorbed into the systemic
circulation.1 Technosphere insulin provides a unique manner of administration by allowing
patients to inhale their insulin dose through a special inhaler. The question at hand is, what
are the benefits, if any, of an inhaled insulin over the standard injectable insulin therapy?
Technosphere insulin [TI] is a rapid-acting insulin that consists of regular human
insulin and an inert excipient [Fumaryl diketopiperazine] which carries the insulin particles. It
is dosed in units [unlike its initial design] and administered through a small, portable
inhalation device. It falls into the category of ultra-fast acting insulin with rapid absorption,
reaching peak values at 10-15 minutes and clears the body after 2-3 hours. This is different
from current prandial insulins that achieve peak at 45-60 minutes and clear the body around
5 hours. Two separate studies have evaluated the use of this drug to test for efficacy in the
type 1 and type 2 diabetic populations. This new research shows promising efficacy of the
drug and avenues for further evaluation.
The study for type 1 diabetics (T1DM) compared TI to prandial insulin in a 24 week
randomized, non-inferiority trial. Study results showed that TI proved to have decreased
hypoglycemic events, increased weight-loss, and improvement in A1c in the study
population.2 It did not have the same level of reduction as insulin aspart in this study but it
did meet the non-inferiority margins that had been set. The mean change in HbA1c at week 24 was
0.21% from a baseline of 7.94% for the TI-Gen2 group and 0.40% from a baseline of 7.92% for the insulin
aspart group based on MMRM analyses.2 The main finding was non-inferiority with the attained A1C

values falling within the agreed-upon study criteria of within 0.4%. Although TI was
associated with less HbA1c lowering, it provided statistically significant lower fasting plasma
glucose levels [P=0.001].2 It also showed a small but statistically significant weight loss (0.4 kg)
compared with a gain (+0.9 kg) for aspart patients (P = 0.0102) and 44% less hypoglycemia, though
this was not statistically significant it may prove to have some clinical significance. 2
A second study evaluated the use of this drug in a randomized, double-blinded,
placebo-controlled, multinational, 24 week, phase III trial (trial 175) in type 2 diabetic
(T2DM) population. This population consisted of individuals who were inadequately
controlled on their oral agents and were insulin nave. Patients were already on a regimen of
either metformin alone or metformin in combination with a sulfonylurea. Results showed that
TI significantly reduced A1c by 0.8% compared to a 0.4% reduction in the placebo group. 4
There was some increase in weight for those with TI 0.5 kg vs. placebo -1.1 kg proving
statistical significance [P<0.0001]. Treatment groups did not experience changes in fasting
blood glucose but post-prandial levels were found to be controlled in the TI group. The main
finding was as expecteda statistically superior lowering of A1C [P<0.0001] with the
inhaled insulin from baseline 8.3% to 7.4% versus 7.8% with the Technosphere placebo. 3
There was also a modest doubling of non-serious hypoglycemia with the inhaled insulin,
mostly in sulfonylurea-treated patients.3
In both of these studies the most common adverse effect was cough, however cough
was generally mild, dry and decreased over time.1 Treatment with TI was associated with
positive patient-reported outcomes.1 The second study did note a small decrease in FEV
[Forced Expiratory Volume] but this resolved upon discontinuation of the drug. 4
Conversion of the injected dose to an inhaled dose is based on the following chart 5:

Lincy Varughese, Pharm. D. Candidate

Ambulatory Care 4656

December 4, 2015

Insulin nave: 4 units

4 units injected dose per meal: 4 units
5 to 8 units injected dose per meal: 8 units
9 to 12 units injected dose per meal: 12 units
13 to 16 units injected dose per meal: 16 units
17 to 20 units injected dose per meal: 20 units
21 to 24 units injected dose per meal: 24 units
Patients should be aware that this drug needs to be administer before the beginning of a
meal, similar to any other prandial insulin. They should also be aware of specific inhalation
cartridge care precautions that need to be followed for the proper life and delivery of this
drug. 5
The use of this drug should be a consideration if patients present with a fear of insulin
related hypoglycemic events, a phobia of injections, or concerns regarding weight gain.
Although the full A1c reduction of injectable insulin may not be experienced in these
patients, there is significant support that Afrezza can help manage post-prandial blood
glucose levels. In a pooled analysis of tolerability data from phase II and III studies, the most
commonly occurring non-hypoglycemia adverse events in T1DM and T2DM patients were
cough and throat pain/irritation.1 Therefore patients with COPD or other lung conditions
should be monitored carefully or avoided when using this drug. In summation, insulin human
inhalation powder is an effective and generally well-tolerated agent for the prandial
treatment of hyperglycemia in T1DM and T2DM patients and may provide a solution to
previously mentioned insulin initiation barriers.1
References
1. Kim ES, Plosker GL. AFREZZA() (insulin human) inhalation powder: A review in
diabetes mellitus. Drugs. 2015;75(14):1679-86. doi: 10.1007/s40265-015-0472-0.
2. Bode BW, McGill JB, Lorber DL, Gross JL, Chang PC, Bregman DB. Inhaled
technosphere insulin compared with injected prandial insulin in type 1 diabetes: A
randomized 24-week trial. Diabetes Care. 2015;38(12):2266-73. doi: 10.2337/dc150075.
3. Leahy JL. Technosphere inhaled insulin: Is faster better? Diabetes Care.
2015;38(12):2282-4. doi: 10.2337/dci15-0002.
4. Rosenstock J, Franco D, Korpachev V, Shumel B, Ma Y, Baughman R, et al. Inhaled
technosphere insulin versus inhaled technosphere placebo in insulin-nave subjects
with type 2 diabetes inadequately controlled on oral antidiabetes agents. Diabetes
Care. 2015;38(12):2274-81. doi: 10.2337/dc15-0629.
5. Product Information: AFREZZA(R) oral inhalation powder, insulin human oral
inhalation powder. MannKind Corporation(TM) (per manufacturer), Danbury, CT,
2014.