Hypoglycemia and fear of hypoglycemia have been identified as barriers to effective insulin therapy that may prevent PWD from achieving their personal glycemic targets.6
Achieving targeted glycemic goals for people with type 1 diabetes continues to be a challenge. Several studies have shown that on average, people with type 1 diabetes (PwT1D) in the United States do not meet the current American Diabetes Association A1C goal of <7%.1
Afrezza (insulin human) inhalation powder was approved by the Food and Drug Administration in 2014 as a mealtime insulin to improve glycemic control in adult persons with diabetes (PWD). Inhaled human insulin, also referred to as inhaled Technosphere insulin, is a powder that is administered through inhalation. It is a fast-acting insulin available to adults with diabetes.2 It is composed of human insulin, water, polysorbate 80, and fumaryl diketopiperazine (FDKP), a biologically inert carrier that is excreted unchanged in the urine.3
Afrezza is commercially available in the United States as 4-, 8-, and 12-unit color-coded cartridges and is contraindicated in individuals with chronic lung diseases, such as asthma and chronic obstructive pulmonary disease.2 Copay costs for Afrezza are consistent with other insulins on the market.4 In a randomized 24-week trial by Bode et al5 in 2011-2013, noninferiority of Afrezza for A1C reduction in PwT1D was demonstrated with less hypoglycemia compared to insulin aspart.
Hypoglycemia and fear of hypoglycemia have been identified as barriers to effective insulin therapy that may prevent PWD from achieving their personal glycemic targets.6 The ultra-rapid time-action profile of inhaled Technosphere insulin is associated with a lower risk of hypoglycemia compared to subcutaneous rapid-acting insulin that enables greater flexibility in dosing.6 This ultra-rapid time frame allows for dosing at the beginning of or 20 minutes after the start of a meal and again between meals without insulin stacking, a feature that is beneficial to people in reaching their glycemic goals.6
Although A1C provides an assessment of glucose management, it is unable to provide insight into the incidents of acute glycemic excursions. A1C does not reflect the magnitude and frequency of glucose variation and can be confounded by anemia, hemoglobinopathies, iron deficiency, and pregnancy among other conditions.7 The need for metrics beyond A1C is met using continuous glucose monitoring (CGM) data. Time in range (TIR), Time above range (TAR), and time below range (TBR) are metrics that allow one to assess the quality of glucose management.
The International Consensus on Time in Range identified core CGM metrics that can be used in clinical practice to assess glycemic management.7 These established target percentages of time in the various glycemic ranges facilitate safe and effective therapeutic decision-making, enables people with diabetes to reach their glycemic goals, and improves outcomes. The actual time in these various ranges (TIR, TAR, and TBR) is expressed as a percentage of CGM readings, average hours and minutes spent in each range per day, or both, depending on the circumstances and established targets by risk group. Goals for adults with diabetes are listed in Table 1.
Although A1C provides an assessment of glucose management, it is unable to provide insight into the incidents of acute glycemic excursions.
An investigator-led, collaborative, open-label, multicenter, clinical research trial by Akturk, et al8 studied both TIR and postprandial glucose excursions (PPGE) at 1 h to 4 h using a realtime CGM with inhaled Technosphere insulin versus insulin aspart in PwT1D on multiple daily injections (MDI). When doses of insulin were delivered as instructed, inhaled Technosphere insulin significantly improved postprandial glucose without increasing hypoglycemia. In addition, the TIR also increased along with a decrease in daytime glucose variability (6 am to midnight) and reduced time spent in hypoglycemia.8 PPGE levels have been determined to be an important factor in overall metabolic parameters in diabetes. Various studies have illustrated a closer association between PPGE levels and A1C than between fasting plasma glucose levels and A1C.9 Reducing postprandial excursions is a valuable strategy for improving glucose values in diabetes, and inhaled Technosphere insulin has been shown to be effective in facilitating these improvements without increasing the risk of hypoglycemia.
The concept of individualized care is useful in diabetes management because diabetes is not a singular disease state. Health care providers understand how to use available options to guide people in shared decision-making to identify what works best for them throughout the course of their lifetime.
The case study format was chosen for this article on the use of inhaled Technosphere insulin to provide detailed descriptions of actual situations that illustrate individualized diabetes management. As a case study presentation with examples that exist in real life, the strict conditions of a clinical study with a control group do not exist. However, these findings are still relevant despite the limitations, especially when added to the body of clinical studies that currently exist.
We present 3 case studies in which people with diabetes were switched from an intensive diabetes regimen using MDI or insulin pump therapy in open loop, to a regimen that included inhaled Technosphere insulin as the prandial insulin. The case studies were provided by 3 diabetes health care providers to illustrate the value of inhaled Technosphere insulin as a mealtime bolus insulin to enable people with diabetes to meet their glycemic goals. In each case, the health care provider decided to change their patient’s mealtime insulin to inhaled Technosphere insulin to address issues the patient was experiencing with their current insulin regimen and to improve glucose management and quality of life.
We present 3 case studies in which people with diabetes were switched from an intensive diabetes regimen using MDI or insulin pump therapy in open loop, to a regimen that included inhaled Technosphere insulin as the prandial insulin.
The PWD refused insulin pump therapy, feeling it would affect her body image and be difficult with her busy schedule. It was decided to try inhaled human insulin to determine if better glycemia could be achieved, particularly with regard to mitigating hypoglycemia and, more importantly, her fear of hypoglycemia. The PWD also wanted to achieve A1C values less than 7%.
This PWD was evaluated at age 23 years, after being diagnosed with type 1 diabetes at age 16 years. She was on MDI with Lantus (insulin glargine) and Humalog (insulin lispro) and using CGM. She was highly motivated but had a fear of hypoglycemia due to the fact she had a demanding job with sporadic intense physical activity, lived alone, and traveled often. As a result, her mother utilized the share capability, which allowed them both a measure of comfort.
The person’s usual Lantus dose was 17 units per day, split 10 units every night at bedtime and 7 units in the morning. She had an insulin-to-carbohydrate ratio of 1:12 for breakfast and 1:15 for the remainder of the day and a correction factor of 60. She followed this insulin regimen for 3 years with minor adjustments and had A1C values obtained quarterly between 7.1% and 7.6%. She experienced episodes of nocturnal hypoglycemia and hyperglycemia and prandial hyperglycemia and intermittent daytime high and low glucose values as demonstrated in Figures 1 and 2.
After initiating inhaled Technosphere insulin, the PWD’s diabetes management plan consisted of the following:
Basal insulin was switched to Tresiba (insulin degludec) at 13 units taken at bedtime.
Inhaled human insulin 4 units was used for small meals, 8 units for medium meals, and (rarely) 12 units for large meals.
Additional dosing of inhaled Technosphere insulin 4 units was given 60 to 90 minutes post initial dose if glucose values were greater than 160 mg/dL in the post-meal time period.
The PWD achieved her glycemic goals with the switch to inhaled Technosphere insulin. Her A1C levels have been 6.1% to 6.8%. Her level 2 hypoglycemia percentage is less than 1%, and she has effectively eliminated most postprandial hyperglycemia, as observed in Figure 3.
Most importantly, she has been able to exercise and live her busy lifestyle with less glycemic variability as assessed by both the reduction in her glucose standard deviation (SD) and coefficient of variation (CV). Her ambulatory glucose profile reports suggest a flat and narrow glucose overlay report. She has achieved the kind of glycemic outcomes remaining on MDI desired for her with perceived reduction in diabetes burden and less fear of hypoglycemia.
This PWD was 67 years of age when she was evaluated with the major concern of hypoglycemia unawareness. She was diagnosed with type 1 diabetes at 35 years and had been using an insulin pump (Medtronic) in open loop with insulin aspart. The PWD was experiencing more post-meal hypoglycemia than she desired despite achieving a high percentage of glucose values between 70 and 180 mg/dL with a TIR of 87% (Figure 4).
The PWD desired better postprandial glycemic management and was concerned about the prolonged effect of her injected prandial insulin. Her current rapid-acting insulin was not sufficient for managing the postprandial rise, and the only way that it was successful was at the cost of inducing hypoglycemia. This hypoglycemia was due to the prolonged “tail” of the rapid-acting insulin action profile. The provider chose to use inhaled Technosphere insulin for its rapid onset and short duration of action along with minimal occasional bolus insulin through the pump.
The PWD started with meal dosing between 4 and 12 units as directed by her physician using a dosing conversion based on a small pilot study10 looking at comparing dose conversion from the United States Prescribing Information versus a 2-times round-down conversion (Tables 2 and 3).
The use of inhaled human insulin in this situation was undertaken with the goal to improve postprandial glucose without resulting in postmeal hypoglycemia. As can be seen from the CGM reports (Figures 4-7) and data comparison (Table 4), this regimen met these goals.
This PWD was evaluated at 19 years for type 1 diabetes. Upon diagnosis at 2 years of age, the PWD was started on MDI, and she transitioned to a pump within the first few years of diagnosis. She had been on insulin pump therapy for over 12 years, the most recent being the Medtronic 770G with Guardian sensor CGM.
Over the course of 9 years, her A1C was historically less than 8%, ranging from 6.9% to 8%. It was not until the last 2 years of care that it surpassed 8% and reached 8.7%. At this visit, she expressed significant diabetes burnout and was especially concerned with her upcoming transition to college. She wanted to discontinue insulin pump therapy and felt less motivated with bolus insulin dosing with her pump.
The PWD was tearful during the visit, tired of using her insulin pump, and experiencing frequent sensor issues that caused her to not use her CGM on a regular basis. She also expressed her fear of hypoglycemia that prevented her from adequately using correction dosing that led to an increase in hyperglycemia. She was dosing with less bolus than recommended or skipping boluses completely. Her data showed that she spent 35% of her time in auto mode and 65% in manual mode and had a 33% sensor wear time.
The change to inhaled Technosphere insulin resulted in a positive impact on her glycemic values: TIR increased, TAR decreased, and TBR stayed the same.
The available readings in Figure 8 show a 33% wear time with the Guardian CGM over a 3-day period while using injected rapid-acting insulin. They illustrate significant post-meal glycemic excursions as high as 350 mg/dl, with rebound hypoglycemia as low as 60 mg/dl in auto mode, which as stated previously, was 35% of the time.
Treatment options were discussed with a focus on addressing the PWD’s personal concerns: fear of hypoglycemia and a desire to discontinue using an insulin pump. It was determined to try inhaled Technosphere insulin with a Dexcom CGM.
The PWD started on inhaled Technosphere insulin with bolus instructions of 4 to 12 units with meals, depending on meal size as follows: 4 units for small meals, 8 units for medium meals, and 12 units for large meals. She was also instructed to dose 4 units of inhaled Technosphere insulin 60 to 90 minutes post-initial meal dose if glucose values were >150 mg/dL. Toujeo (insulin glargine) 34 units once daily was used to meet her basal insulin needs.
As standard in many practices to screen for depression, the PWD was administered the WHO-5 Well-Being Index both before (Figure 9) and 3 months after initiation of inhaled Technosphere insulin (Figure 10). This index is a short questionnaire of 5 simple statements and measures the subjective well-being of the respondent.11
At the PWD’s 3-month follow-up post-initiation of inhaled Technosphere insulin, there were findings of a positive experience with her new insulin regimen. She reported that although she was sometimes still skipping mealtime bolus insulin or underdosing and not correcting hyperglycemia after an hour, these behaviors occurred less often, which was supported by her reduction in A1C of 0.5%. In addition, since transitioning to inhaled Technosphere insulin, there was an improvement in her WHO-5 Well- Being Index score. The responses to the surveys showed improvements in well-being at 3 months post-initiation of inhaled Technosphere insulin. Fair glycemic management with less glycemic excursions and a decrease in A1C from 8.7% to 8.2% was observed.
The PWD reported increased confidence in managing her diabetes and feeling better equipped to address hyperglycemia when it does occur. Additional education on how the rapid-acting profile of inhaled Technosphere insulin may help avoid stacking of insulin and better manage post-meal hyperglycemia without increasing the risk of hypoglycemia was provided to support improvements related to her dosing behaviors for meals due to her fear of hypoglycemia.8
These 3 case studies illustrate the use of inhaled Technosphere insulin by 3 different providers. The current insulin dosing was not producing the outcomes that the individuals and their health care teams desired.
Inhaled Technosphere insulin closely mimics the time action profile of endogenous insulin and has the potential to provide a flexible approach for PWD to optimize postprandial glucose management without an increased risk of hypoglycemia.8 The time to peak effect is approximately 2 to 3 times faster than injected rapid-acting insulin, and a 12-unit dose leaves the system within 3 hours.2,12
The profile of inhaled Technosphere insulin with a rapid peak and clearance enables PWD to take subsequent doses after a meal dose with a decreased worry of insulin stacking. Additional insulin can be taken as needed to achieve goals with decreased safety signals (hypoglycemia) over subcutaneous rapid-acting insulin.
Inhaled Technosphere insulin with its unique profile improves TIR, decreases risk for hypoglycemia, improves postprandial glucose and A1C, and decreases risk for insulin stacking.8,10,13 The 3 cases presented demonstrate that inhaled Technosphere insulin is a valuable option for PWD, effectively enabling individualized diabetes management and addressing specific concerns without an elevated incidence of hypoglycemia.
Francine R. Kaufman, MD, is with Senseonics, Incorporated and Children’s Hospital Los Angeles. Carly Haaland, PA-C, is with Center of Excellence in Diabetes and Endocrinology in Sacramento, CA. Gnanagurudasan Prakasam, MD, MRCP, MHA, is with Sutter Medical Center in Sacramento, CA. Kevin Codorniz, MD; Scott Lee, MD; and Christopher (CJ) Jacobson, PharmD, APh, BC-ADM, CDCES, are with Loma Linda University in Loma Linda, CA.
The authors would like to acknowledge the valuable contributions of LaurieAnn Scher, MS, RD, CDCES, FADCES, a paid medical writer, in drafting and editing the article and Joanne Rinker, MS, RDN, BC-ADM, CDCES, FADCES, from MannKind for reviewing the document for accuracy.
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Christopher (CJ) Jacobson is an investigator for clinical trials conducted by MannKind Corporation. Kevin Codorniz has had 2 studies funded by MannKind Corporation. Scott Lee has had 2 studies funded by MannKind Corporation and has done prior consulting/advisory for MannKind Corporation. Gnanagurudasan Prakasam is an investigator and consultant for MannKind Corporation. Francine R. Kaufman is affiliated with Senseonics Incorporated and had a consulting agreement with MannKind in 2023.
The authors declare having received no specific grant from a funding agency in the public, commercial, or not-for-profit sectors related to the content or development of this article.
Christopher (CJ) Jacobson https://orcid.org/0009-0004-6492-6280
Inhaled Technosphere insulin closely mimics the time action profile of endogenous insulin and has the potential to provide a flexible approach for PWD to optimize postprandial glucose management without an increased risk of hypoglycemia.8
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