By Gary Scheiner MS, CDCES, FADCES; Gary Scheiner MS, CDCES, FADCES; Jennifer Smith, RD, LD, CDCES; Alicia Downs, RN, MSN, CDCES, BC-ADM; Tavia Vital, BSN, RN, CDCES; Kathryn Gentile-Alvarez, MS, ACSM-CEP, CSNC, CDCES; Dana Roseman, MPH, CDCES, RDN, LDN; Anna Sabino, LMSW, CDCES
Most diabetes care & education specialists are familiar with Afrezza – Mannkind Corp’s inhaled insulin product approved for use in adults with diabetes. For those who are not, Afrezza is a form of human insulin that comes in dry power form and is contained in cartridges labeled as 4, 8 and 12 “Afrezza” units. The cartridges are loaded into a whistle-like device and inhaled through the mouth and into the lungs, where it absorbs rapidly into the bloodstream.
With an onset, peak and duration that is approximately half that of traditional “rapid acting” insulin taken subcutaneously, Afrezza is touted for its ability to minimize post-meal glucose spikes without the need to pre-bolus. Its rapid clearance minimizes the risk of hypoglycemia several hours after meals. Elevated glucose levels can be brought down quickly, and there is no need for multiple daily needlesticks.
On the down side, Afrezza candidates must first be screened for pulmonary issues. It is not indicated for smokers and people with chronic lung disease, and there may be a very slight decline in lung function over time. The conversion from traditional insulin units to/from “Afrezza” units can be confusing. A common approach is to multiply the injected/infused insulin dose by two and then round down to the nearest increment of four to determine the Afrezza dose – see table below.
| SC Units | Afrezza Units |
| 1-3 | 4 |
| 4-5 | 8 |
| 6-7 | 12 |
| 8-9 | 16 |
| 10-11 | 20 |
| 12-13 | 24 |
| 14-15 | 28 |
The limited dosing increments can be an issue for those who are very sensitive or resistant to insulin. Basal insulin (via pump or injection) is still required when using Afrezza. The rapid peak and clearance can produce post-meal hypoglycemia and delayed hyperglycemia with slower-digesting foods, requiring a “split-dose” approach. Coughing is a common side-effect, and access to Afrezza may be limited within certain health insurance plans. Spirometry (FEV1) testing is required before starting Afrezza to rule out chronic lung disease which may produce acute bronchospasm.
Since its approval in 2014, Afrezza has not been commonly prescribed or used. Fewer than 5% of people on intensive insulin therapy utilize Afrezza as their bolus insulin. However, we have discovered through treatment of a diverse patient base at our practice that a significant proportion of insulin-users can benefit from Afrezza: specific populations that can use Afrezza as their primary bolus insulin, as well as those on pump or MDI programs who can use Afrezza as their bolus insulin in special situations.
SUB-POPULATIONS WELL-SUITED FOR AFREZZA
1. Pregnancy
The use of Afrezza in pregnancy is considered off-label, so the benefit/risk ratio must be taken into account. Published studies have not shown an association between inhaled insulin and adverse fetal outcomes. Many forward-thinking maternal fetal medicine experts (as well as endocrinologists) are using Afrezza in gestational diabetes as well as pregnancy with type 1 or type 2 diabetes, with excellent results.
Afrezza’s rapid onset and peak make it a very effective option for achieving postprandial glucose targets of <140 mg/dl at 1 hour and <120 mg/dl at 2 hours during pregnancy. Those who experience nausea in the first trimester have the luxury of taking Afrezza shortly after eating – once the quantity of carbohydrate is better known and with confidence that the food will stay down. For those with gestational or type-2 diabetes who are insulin-naive (and may be averse to the idea of taking shots), Afrezza provides a more acceptable option than multiple daily injections.
Progression through the second and third trimesters often comes with doubling or tripling of insulin requirements. For women with type-1 diabetes who use insulin pumps, this may result in infusion site irritation as well as premature pump reservoir depletion. Occasional or regular use of Afrezza at mealtimes can keep infusion sites healthier and lessen the burden of frequent reservoir and infusion set changes.
2. Overweight/Obese
Managing blood sugar while trying to lose weight can be particularly difficult. Hypoglycemia adds to the challenge by forcing individuals to consume calories they would not have otherwise had. In many cases, hypoglycemia contributes to binge eating high-calorie foods. For those trying to lose weight, frequent bouts of hypoglycemia can also be emotionally deflating. Afrezza can lend itself to weight loss due to the reduced incidence of hypoglycmia between and before meals.
Since Afrezza can be given with meals (rather than in advance), users can dose for what was eaten rather than eating to “cover” the insulin that was already taken. This allows freedom of choice with regard to portion sizes. In addition, unless basal insulin doses are set too high, snacking between meals becomes optional when Afrezza is used to cover meals.
3. Impaired renal function
People with impaired renal function who require insulin face several challenges, including:
- Increased risk of hypoglycemia due to prolonged insulin clearance times
- Decreased, altered and unpredictable appetite
- Potential for dehydration
Dosing with Afrezza after meals can lower the risk of hypoglycemia caused by pre-meal dosing for food that was not consumed due to nausea, food aversion, or early satiety. Afrezza’s direct absorption into the bloodstream via the lungs mitigates impaired subcutaneous absorption due to dehydration. Although the pharmacokinetics of Afrezza have not been studied formally in patients with renal impairment, some reports indicate that Afrezza’s rapid-on, rapid-off properties can partially offset issues created by prolonged insulin clearance times.
4. Widespread lipodystrophy
A key to safe and effective insulin therapy is consistent, predictable insulin absorption and action. Injecting/infusing insulin into the subcutaneous adipose tissue can create a number of issues. Insulin pharmacodynamics can be affected by the state of hydration, injection technique, depth of the injection, and even skin temperature. More significantly, we see the impact of changes to the adipose layer itself. Lipohypertrophy, a thickening or “scarring” of the adipose layer, can be caused by overuse of an area of skin for injection or infusion of insulin. As the density of adipose and connective tissue cells in the area increases, the space for fluid circulation decreases. Insulin infused into this space will not absorb consistently or predictably into the capillaries below he skin. Lipoatrophy, characterized by loss of fat tissue in areas that receive repeated insulin injections/infusions, is more rare than lipohypertrophy. However, it can also result in significant changes to insulin absorption.
Inconsistent insulin absorption can result in stubborn and frustrating periods of hyperglycemia followed by bouts of unexpected hypoglycemia. Teaching patients to “rotate” injection sites and avoid areas affected by lipodystrophy may help temporarily, but for many patients – especially those with long-term diabetes – injection site options become severely limited. We can overcome this issue by using an alternate route of insulin administration. Inhaled insulin acts with predictable speed and efficacy over the long-term. This produces desired postprandial glucose and reduces the risk of “stacking” that often leads to hypoglycemia.
5. Hyperglycemia anxiety
It is well understood that people with diabetes are twice as likely to experience anxiety and depression related to both acute and long term complications. One of the acute concerns facing insulin users is the fear of high blood sugar. This fear may originate from past trauma such as a hospitalization at diagnosis, DKA, or experiences with people who have suffered the ravages of long-term diabetes complications.
Fear often overwhelms individuals, leading to impulsivity and stacking of insulin due to impatience whenever glucose levels are elevated. The terms “angry bolus” and “rage bolus” are often used to describe this behavior. Afrezza, because of its fast action and consistent/predictable delivery, can reduce the user’s perceived need to over-correct hyperglycemia. This applies to those who take injections as well as those who use insulin pumps, as lack of confidence in subcutaneously-delivered insulin can be a source of potentially-dangerous behavior.
6. Needle-Aversion
Approximately 10% of the general population reports a significant fear of needles. Needle phobia may delay necessary treatment with insulin due to patient resistance, or it could result in frequently-missed doses. Each injection may produce a stress response that raises blood glucose levels. Any degree of needle phobia is associated with worse glucose management and greater risk of long-term complications.
Once-daily injection regimens (for basal insulin) can often be accepted and followed by those with needle phobia, whereas multiple daily injections cannot. The use of inhaled insulin alleviates the need for frequent daily injections, and allows for progression to intensive insulin therapy for patients with all forms of diabetes.
SITUATIONAL USE OF AFREZZA
Many people are content and achieve reasonable results with their current intensive insulin program, whether it utilizes injections or pump therapy. However, there are a number of temporary situations in which users can benefit from using Afrezza as a supplement to their traditional insulin delivery method.
a) Acute hyperglycemia
Due to its rapid onset, early peak and short duration, inhaled insulin corrects acute hyperglycemic up to 70% faster than injected rapid-acting insulin (see Figure 1 below)
(insert Figure 1)
In most cases, Afrezza brings elevated glucose levels down towards normal within 90 minutes, whereas rapid-acting insulin delivered subcutaneously takes three to five hours.
For pump or injection users who prefer traditional rapid-acting insulin for covering their meals, Afrezza may be added to cover only the correction portion of their bolus. This will allow the glucose level to begin falling before the effects of the meal kick in. Use of Afrezza purely for correction dosing can significantly reduce time spent above one’s target range. However, care must be given when using Afrezza to correct hyperglycemia accompanied by Hyperosmolar Hyperglycemic Syndrome (HHS) or DKA due to the risk of other health decompensations.
If hyperglycemia is accompanied by ketone production, additional caution is required. While Afrezza can assist with glucose lowering, it does not provide basal insulin coverage, which is essential for ketone clearance. In such cases, a subcutaneous injection of rapid-acting and long-acting insulin is typically preferred to ensure both glucose and ketone resolution.
b) Meals prior to exercise
When planning physical activity, managing mealtime insulin becomes especially important to reduce the risk of exercise-induced hypoglycemia. Afrezza offers unique pharmacokinetics that can benefit individuals with diabetes who must take insulin to cover a meal prior to exercise. Afrezza’s short duration of action allows bolus insulin to (mostly) clear in time for physical activity when it is performed one to two hours after a meal.
c) Glucose rises during exercise
Afrezza may also be useful in managing adrenaline-induced hyperglycemia during high-intensity or emotionally charged physical activity. Competitive sports, high-pressure performances, or sudden bursts of anaerobic effort can trigger a surge of counterregulatory hormones, particularly adrenaline, resulting in rapid blood glucose elevations that are not always addressed by existing insulin on board. Afrezza’s rapid onset and short duration make it an excellent option for correcting as well as preventing glucose spikes that may occur immediately prior to, during or immediately after certain forms of exercise. However, due to heightened insulin sensitivity that takes place during and after exercise, conservative dosing and real-time CGM monitoring are recommended to prevent overcorrection.
d) High-GI foods
Afrezza’s quick action pairs well with high-glycemic index (GI) foods. High-GI foods (white rice, potatoes, breads, cereals, jelly and jams, etc) tend to spike glucose levels quickly and dramatically. With traditional rapid-acting insulin, a pre-bolus is necessary to minimize the spike, and even that may not be enough. Afrezza offers a significant advantage over traditional insulin, especially if pre-bolusing is challenging or impractical. Additionally, Afrezza can be used along with subcutaneous insulin when a meal includes both slow- and fast-acting carbs.
e) Dehydration
In a state of dehydration, blood flow to the capillary bed below the skin surface becomes impaired. Insulin injected subcutaneously may not absorb into the bloodstream. If it does, it will likely take much longer than usual to act and may not exhibit full efficacy. If hyperglycemia is the primary cause of dehydration, it may be perpetuated due to inadequate insulin absorption.
Afrezza’s unique method of absorption through the lungs is not directly affected by dehydration. Taking Afrezza during an illness, after heat exposure, after exercising in a hot/humid environment, or during times of insufficient fluid intake can work more effectively than subcutaneous insulin administration.
f) Nausea
Transient nausea can be caused by a number of factors, including:
- gastritis
- influenza
- food poisoning
- radiation/chemotherapy
- pregnancy
- motion sickness
- overeating
- lactose/gluten intolerance
- extreme stress
- incretin mimetics
Nausea is associated with reduced appetite and delayed/incomplete nutrient absorption. Pre-dosing rapid-acting insulin for food when in a state of nausea can produce hypoglycemia soon after eating and up to five hours later. The ability to dose Afrezza after meals affords users the opportunity to more accurately match the insulin dose to the quantity of food actually consumed. When vomiting is likely, as is often the case during the first trimester of pregnancy, the user can allow a reasonable amount of time to pass after eating to make sure food will stay down before administering a dose of Afrezza.
g) Pump Failure
Temporary insulin pump failures due to mechanical issues, infusion set leakage, occlusion or accidental dislodgement, can lead to rapid and extreme hyperglycemia due to the absence of basal insulin delivery. In individuals with type 1 diabetes, even short interruptions in insulin delivery can result in rising glucose levels and, if not addressed promptly, may progress to ketone production or diabetic ketoacidosis (DKA).
Afrezza offers a practical and flexible option for correcting hyperglycemia during insulin delivery disruptions. Because of its quick onset and short duration of action, Afrezza can be used to reduce glucose levels promptly while the user resolves the pump issue or transitions to an alternative insulin delivery method. Providers should consider educating patients on using Afrezza as part of their “pump failure plan,” paying close attention to incorporating Afrezza doses into insulin-on-board estimations.
AN OPPORTUNISTIC INSULIN
For many people, Afrezza may not be ideal for meeting all bolus requirements. Dosing increments are limited. The very rapid on/off properties are not ideal for slowly-digesting foods. And it does not integrate into modern-day automated insulin delivery systems. Multiple members of our clinical team who have T1D have tried Afrezza and struggled to use it exclusively (with basal insulin). However, that does not mean that it can’t play a valuable role in diabetes management for all insulin users.
Certain populations, as outlined above, may benefit from making Afrezza their primary bolus insulin. And for those who use insulin pumps or prefer a traditional MDI approach, there are many situations in which Afrezza offers clear and distinct advantages over rapid-acting insulin.
As Diabetes Care and Education Specialists, it is our job to ensure our patients are equipped with the tools necessary to best manage their diabetes and teach them how to use those tools safely and effectively. We encourage you to consider Afrezza as part of the treatment plan for all insulin users.
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