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Inhaled insulin therapy in diabetes mellitus

Inhaled insulin therapy in diabetes mellitus
Author:
Anastassios G Pittas, MD, MS
Section Editor:
David M Nathan, MD
Deputy Editor:
Katya Rubinow, MD
Literature review current through: Dec 2022. | This topic last updated: Aug 24, 2021.

INTRODUCTION — Therapy with insulin is effective at lowering blood glucose in patients with diabetes, but there is resistance to its use by patients and health care providers because of its need to be injected subcutaneously and because of concern regarding interference with patients' lifestyle, risk of hypoglycemia and weight gain, and perception that people treated with insulin are "sicker" [1-3]. Consequently, patients with type 1 diabetes may hesitate to embrace multiple-dose injection regimens or use of insulin pumps, while patients with type 2 diabetes may defer initiating insulin therapy, resulting in inadequate glycemic management. Therefore, less invasive options for insulin therapy are desirable.

Inhaled insulin represents a paradigm shift for insulin delivery as it differs not only in route of administration but also patient eligibility (due to exclusions related to lung disease and smoking) and need for periodic testing for safety. This topic reviews the efficacy, safety, and patient acceptability of inhaled insulin therapy. An overview of pharmacologic therapy for type 1 and type 2 diabetes, including insulin therapy, is presented separately.

(See "Management of blood glucose in adults with type 1 diabetes mellitus".)

(See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus".)

(See "Management of persistent hyperglycemia in type 2 diabetes mellitus".)

(See "Insulin therapy in type 2 diabetes mellitus".)

(See "General principles of insulin therapy in diabetes mellitus".)

GENERAL INFORMATION — Polypeptides used for therapy, such as insulin, require parenteral delivery as oral administration results in loss of biopotency owing to breakdown in the stomach. Several non-oral routes of insulin administration other than subcutaneous and intravenous routes have been studied, including transdermal, buccal, nasal, and pulmonary delivery. Among these, the lung provides an attractive option for insulin therapy, given its accessibility and large alveolar-capillary network for drug absorption [4]. (See "Delivery of inhaled medication in adults".)

Preparations — An inhaled form of insulin (Exubera) was available for a short time (August 2006 to October 2007) before it was discontinued by the manufacturer as the new technology failed to gain broad acceptance by patients and clinicians [5]. The experience with Exubera represented a major setback for the field, with most pharmaceutical companies reevaluating and canceling their inhaled insulin research and development programs.

In June 2014, the US Food and Drug Administration (FDA) approved a new formulation of inhaled insulin (Afrezza [human insulin] inhalation powder) to cover prandial insulin requirements in nonsmoking adults with diabetes who are free of pulmonary disease [6]. The new drug-device combination product, which became available for clinical use in the United States in February 2015, consists of a dry powder formulation of recombinant regular human insulin (Technosphere insulin [TI]), packaged in prefilled cartridges and delivered through a hand-held, pocket-sized, breath-powered inhalation device [7].

Delivery system — For insulin to be delivered through the lungs, inhalation devices that provide dose accuracy and consistency are critical. The first inhaled insulin delivery system (Exubera) involved use of a bulky device to dispense insulin with a complicated dosing scheme. TI is a different formulation delivered through a much smaller and more convenient delivery device [7-11]. This new inhaled insulin platform is based on Technosphere particles, which are formed by the self-assembly of crystals of a metabolically inert excipient (fumaryl diketopiperazine) [12]. After inhalation and upon contact with the lung surface, Technosphere particles carrying regular insulin molecules dissolve rapidly at physiologic pH, and both excipient and insulin are rapidly absorbed in the circulation [13-15]. TI is nearly completely cleared from the lungs compared with the Exubera formulation (0.3 versus 9 percent remaining in the lungs 12 hours after TI versus Exubera administration) [16,17]. Due to decreased bioavailability (approximately 25 percent that of subcutaneous insulin), more insulin must be administered through inhalation than by subcutaneous injection to achieve an equivalent therapeutic response [9,18].

Pharmacokinetics and pharmacodynamics — Following inhalation of TI in healthy, nonsmoking adults, blood insulin concentration peaks faster than with subcutaneous regular insulin, at approximately 15 minutes, and declines to baseline in a linear fashion based on dosing (60 minutes for 4 units of TI; 240 minutes for 48 units of TI) [9,19,20]. Postprandial blood glucose excursion with TI is lower when compared with subcutaneous regular insulin and approximately the same when compared with rapid-acting insulin in the first two to four hours after administration. The duration of glucose-lowering activity (maximum metabolic response) of TI is comparable with that of subcutaneous regular insulin and increases linearly with higher doses (120 minutes for 4 units of TI; 360 minutes for 48 units of TI) [7,9,19-21]. Systemic insulin uptake observed with TI in healthy volunteers is linear [20,22]. In a dose-response study, increasing doses of TI resulted in marginally better glucose-lowering effect, suggesting a potential plateau of its glycemic effect [23].

CANDIDATES FOR INHALED INSULIN

Type 1 diabetes — We recommend subcutaneous, rapid-acting insulin rather than inhaled insulin for first-line prandial insulin replacement therapy for type 1 diabetes, based on the lack of data demonstrating superior glycemic benefit of inhaled insulin and perhaps worse long-term glycemic management compared with subcutaneous delivery. (See 'Glycemic efficacy' below.)

Importantly, in "noninferiority" studies of inhaled insulin, neither the inhaled insulin nor the comparator arms achieved optimal glycemic management that has been achieved with subcutaneous insulin regimens in previous trials (see 'Glycemic efficacy' below). In addition, dose adjustments with inhaled insulin cannot accommodate finer, small-increment dosing that may be needed to avoid hypoglycemia, especially in insulin-sensitive patients, or hyperglycemia in patients requiring large insulin doses (see 'Dosing' below). Moreover, the added expense (three to six times that of subcutaneous rapid-acting insulin [24]) and requirements for pulmonary monitoring detract from the clinical role of inhaled insulin. (See 'Monitoring for safety' below.)

Afrezza TI can serve as an alternative prandial insulin option in patients with type 1 diabetes who prefer not to use an insulin pump, are unwilling to use injectable prandial insulin, but are willing to use an injectable, long-acting (basal) insulin formulation.

Type 2 diabetes — For the majority of patients with type 2 diabetes, we suggest intermediate- or long-acting ("basal") insulin administration as the first step in insulin therapy when it becomes necessary. For patients who require prandial insulin, we suggest subcutaneous, rapid-acting insulin rather than inhaled insulin based upon glycemic efficacy data, the added expense of inhaled insulin (compared with rapid-acting subcutaneous insulin), and requirements for pulmonary monitoring. (See 'Glycemic efficacy' below and 'Monitoring for safety' below.)

Afrezza TI can serve as an alternative, noninvasive and simpler prandial-insulin option in patients with type 2 diabetes who would otherwise delay initiating or intensifying insulin therapy because they are unwilling or unable to use injectable insulin.

Other — In one case report, inhaled insulin (Exubera) was used successfully to manage subcutaneous insulin resistance syndrome, an exceedingly rare condition thought to be due to rapid degradation of insulin in the subcutaneous tissue [25].

OUTCOMES

Glycemic efficacy — In patients with type 1 diabetes or insulin-requiring type 2 diabetes, reduction in glycated hemoglobin (A1C) with inhaled insulin (Technosphere insulin [TI] or Exubera) was generally less than that of subcutaneous insulin, and a lower proportion of patients achieved the A1C general target of less than 7 percent. In addition, the degree of glycemic improvement with TI (absolute mean A1C decrease of approximately 0.55 percent from baseline) and proportion achieving desired goals (approximately 19 percent) were much lower compared with historical trials with subcutaneous insulin [26,27].

The modest absolute glycemic efficacy of TI may be due to suboptimal treatment employed in the pre-marketing clinical trials and raises the question of whether therapy with subcutaneous insulin was applied appropriately in the comparator arm and truly represented "standard of therapy," or whether the comparison was between inhaled insulin and substandard subcutaneous insulin therapy. Indeed, with a few exceptions [28-30], structured insulin titration regimens to reach prespecified glycemic goals were either lacking or were not enforced in the trials with TI, which may have resulted in inadequate optimization of both TI and reference treatment, including background therapy (eg, basal insulin). Had the reference insulin regimens been adequately titrated, it is possible that there may have been larger differences favoring subcutaneous insulin.

Another explanation for the modest efficacy of TI might be a "ceiling" effect. In contrast with subcutaneous insulin, TI exhibits a dose-response relationship where increasing doses do not result in proportional glucose-lowering effect [23,31], suggesting a plateau effect for TI. Finally, because of dosing inflexibility relative to subcutaneous insulin, it may be difficult to achieve narrow glucose goals with TI (see 'Dosing' below). Therefore, having patients replace their current, effective subcutaneous therapy with inhaled insulin may not result in the same degree of glycemic management. Importantly, in trials with TI, perceived lack of efficacy by patients or clinicians was the most common reasons for patient withdrawal.

Type 1 — There are five open-label, noninferiority trials (n = 1364, 4 to 52 weeks follow-up) in patients with type 1 diabetes on basal insulin (glargine, detemir, or NPH) with a baseline A1C range of 7.7 to 8.9 percent, comparing TI with subcutaneous, rapid-acting insulin (aspart or lispro) [18,21,30,32,33]. One open-label trial, which was designed for long-term (two years) pulmonary safety, included patients with type 1 diabetes and compared TI with usual care (subcutaneous insulin) [11]. In all studies, TI and subcutaneous, rapid-acting insulin (active comparator) were administered with meals, and doses were adjusted according to general guidelines for glucose management; however, with the exception of two studies [21,30], titration was not enforced during the treatment period.

In patients with type 1 diabetes, change in A1C nonsignificantly favored subcutaneous insulin (net difference 0.13 percent for TI versus subcutaneous insulin, 95% CI -0.02 to 0.27) [11,18,30,32-34]. The a priori noninferiority margin of 0.4 percent was met in two of five studies [18,32]. In two studies, doses of basal insulin were higher in patients treated with TI versus aspart [30,32]. In two trials that reported such data, only 13 and 18 percent of patients treated with TI met the A1C goal of less than 7 percent, compared with 14 and 31 percent, respectively, of patients treated with subcutaneous insulin [30,32]. However, in another trial, more patients treated with TI met the A1C goal of less than 6.5 percent compared with those treated with subcutaneous insulin (10 versus 3 percent, respectively) [18]. In a pilot, short-term (four weeks) trial, patients treated with TI were equally likely to have glucose values "in range" (70 to 180 mg/dL) assessed by a continuous glucose monitor compared with those treated with aspart insulin, although aspart insulin was not titrated as aggressively as TI [21].

A higher incidence of diabetic ketoacidosis (DKA) was observed among TI-treated patients (4.8 times more frequent than with subcutaneous insulin) [35]. Therefore, inhaled insulin is not recommended for treating DKA and should be avoided in patients at high risk for DKA.

Type 2 — There are four trials (n = 1093) in patients with insulin-requiring type 2 diabetes comparing TI with placebo [23], TI with subcutaneous aspart insulin [28,36], or TI with NovoLog split mix [10]. There are additional trials in patients with type 2 diabetes on oral antidiabetic drugs comparing TI with placebo [8,37] or with existing oral pharmacotherapy [38]. One trial, which was designed for long-term (two years) pulmonary safety, included patients with type 2 diabetes and compared TI with usual care (subcutaneous insulin or oral antidiabetic drugs) [11]. All trials comparing TI with an active comparator (subcutaneous insulin or oral antidiabetic drug) were open label. Trials comparing TI with subcutaneous insulin were designed as noninferiority.

TI consistently reduced A1C when compared with placebo (Technosphere powder without insulin; net difference -0.43 percent, 95% CI -0.65 to -0.29) [8,23,29,37].

Change in A1C nonsignificantly favored subcutaneous insulin (net difference 0.19 percent, 95% CI -0.09 to 0.44) [10,28,36].

In one dose-response study, increasing doses of TI resulted in only marginally better glucose-lowering effect, suggesting a plateau effect for TI [23].

A trial compared TI alone or TI with metformin versus combination oral agents (metformin and insulin secretagogue) [38]. TI alone was less effective in lowering A1C than the combination of oral agents (net difference 0.91 percent for TI versus metformin-insulin secretagogue, 95% CI 0.69-1.14), while TI plus metformin was not different from the combination of oral agents (net difference 0.08 percent for TI-metformin versus metformin-insulin secretagogue, 95% CI -0.11 to 0.27). The finding that TI did not improve glycemia more than oral agents contrasts with evidence [26] and experience from clinical practice that support a higher glycemic efficacy of subcutaneous insulin versus oral therapy.

In patients with type 2 diabetes, Exubera was found to have similar glycemic efficacy as subcutaneous insulin, but only a minority of participants reached the A1C goal of 7 percent. In short-term (12 weeks) studies, Exubera titrated to a glucose target was superior to fixed doses of oral antidiabetic drugs [39], which is consistent with previous observations that have reported a higher efficacy of subcutaneous insulin versus oral therapy in achieving glycemic targets [26]. In two studies lasting 24 weeks where the dose of the oral agents was titrated to glucose goals, there was little difference between Exubera and oral agents in glycemic efficacy, even though the studies were designed to show superiority of inhaled insulin [40,41].

Hypoglycemia — Hypoglycemia is a common adverse reaction of insulin therapy, including inhaled insulin. In patients with type 2 diabetes, severe hypoglycemia occurred in 5.1 percent of patients treated with TI versus 1.7 percent treated with placebo (Technosphere powder without insulin), and nonsevere hypoglycemia occurred in 67 versus 30 percent, respectively [42]. In clinical trials with type 1 or type 2 diabetes, severe hypoglycemia was reported less frequently with TI versus subcutaneous insulin (11.7 percent of patients treated with TI versus 17.8 percent with subcutaneous insulin; odds ratio [OR] 0.61, 95% CI 0.35-0.92) [10,18,21,30,32,34,36]. In studies with Exubera, there was no difference between inhaled versus subcutaneous insulin in reporting of severe hypoglycemia [39].

In a single study that compared TI alone or TI with metformin versus the combination of metformin and oral insulin secretagogue, there were very few cases of severe hypoglycemia (n = 2 with TI and n = 0 with the oral therapy) [38]. The rate of hypoglycemia in clinical practice is difficult to predict due to the novelty of using a new delivery device and because dose adjustments with TI have yet to be optimized for finer, small-increment dosing needed to minimize hypoglycemia, especially in insulin-sensitive patients.

Weight gain — In patients with type 1 or type 2 diabetes, TI was associated with less weight gain compared with subcutaneous insulin (net difference -1.6 kg, 95% CI -2.1 to -1.6) [10,18,21,30,32,34,36]. In a two-year trial in patients with type 1 or type 2 diabetes, weight gain was not different between TI and usual care consisting of subcutaneous insulin and/or oral pharmacotherapy (1 versus 1.64 kg, respectively) [11].

Less weight gain was also reported with Exubera versus subcutaneous insulin in a pooled analysis of six-month data from five phase III Exubera studies [43]. Exubera resulted in more weight gain compared with metformin or sulfonylureas (net difference 1.85 kg, 95% CI 0.98-2.73) [40,44,45], but there was no difference when compared with rosiglitazone (net difference 0.95 kg, 95% CI 0.18-2.09) [46].

Cardiovascular effects — Treatment with TI appears not to be associated with excess cardiovascular risk or clinically significant effects on heart rate, electrocardiogram (ECG) findings (PR and QRS interval duration), or cardiac morphology, although these findings have only been reported in abstracts and were likely underpowered [47-49]. A large trial to evaluate the cardiovascular safety of TI has been requested by the US Food and Drug Administration (FDA) [50,51].

Patient satisfaction — In one study where patients received educational information, the availability of inhaled insulin as a treatment option increased approximately threefold the proportion of patients who would theoretically choose insulin overall [52]. In three studies with TI that lasted over 45 weeks in patients with type 1 or type 2 diabetes, there was no difference in quality of life, overall patient satisfaction, or treatment preference between TI and subcutaneous insulin [10,53,54].

In pre-marketing trials, patients treated with TI were more likely to discontinue participation compared with those treated with an active comparator (29.5 percent for TI versus 15.3 percent for subcutaneous insulin or oral antidiabetic drugs [OR 2.30, 95% CI 1.71-3.40]), without any differences between type 1 and type 2 diabetes [8,10,11,23,34,36]. In a two-year trial, almost 50 percent of patients assigned to TI withdrew, compared with 30 percent receiving usual care [11]. The most common reasons for withdrawal were patient or clinician decision, inadequate glycemic efficacy, and treatment-emergent, intolerable adverse events (see 'Cough' below). A high withdrawal rate limits conclusions that can be drawn about the long-term efficacy and safety of TI from the available evidence.

In trials with Exubera (all less than 24 weeks' duration), there was a statistically significant increase in overall patient satisfaction and quality of life with inhaled compared with subcutaneous insulin [55-59]. Areas of improvement included:

Ease of administration, including taking insulin many times a day

Social comfort

Convenience

Mealtime flexibility

It is important to note that in older Exubera studies, inhaled insulin was compared with subcutaneous insulin delivered with syringes. The widespread use of pen devices for subcutaneous insulin administration has significantly improved ease of administration and compliance with subcutaneous insulin [60].

The patient satisfaction reported in pre-marketing trials of Exubera did not translate into clinical practice, as patients or clinicians did not embrace the first inhaled insulin formulation. Similarly, patients and health care providers have not broadly embraced the newly available inhaled insulin formulation (TI), which is delivered through a thumb-size, easy-to-use device.

SAFETY AND PRECAUTIONS

Pulmonary safety — A concern with inhaled insulin, especially in the long term, is the potential for pulmonary toxicity, partly because of the immunogenic and growth-promoting properties of insulin and partly due to the potential effects of the carrier used to deliver the insulin molecules [61]. All trials of inhaled insulin included patients who had normal chest radiograph and pulmonary function tests (forced expiratory volume at one second [FEV1] and other measures were at least 70 percent of predicted levels for healthy individuals), no significant pulmonary disease (eg, asthma, chronic obstructive pulmonary disease [COPD], or interstitial lung disease), and no recent history of smoking (at least six months) [62].

The magnitude and pattern of pulmonary safety with Technosphere insulin (TI) in pre-marketing trials is comparable with other inhaled insulin formulations [39,62-66]. Because of the apparent reversibility of changes in pulmonary function tests upon discontinuation following short-term therapy [67], the use of a metabolically inert excipient (fumaryl diketopiperazine) that is excreted unchanged in the urine [68], and rapid clearance from the lungs (0.3 versus 9 percent remaining in the lungs 12 hours after TI versus Exubera administration) [16,17,22], which suggests that the potential for accumulation on chronic administration is small [13], TI may theoretically be less likely than prior formulations of inhaled insulin to cause structural and irreversible alterations in the lungs, leading to clinically significant pulmonary toxicity.

However, despite the small, relatively nonprogressive nature of pulmonary function decline over two years [11,62], it has not been established that longer-term exposure to inhaled insulin would not have a clinically significant impact on pulmonary function and risk of lung cancer, especially in patients with diabetes who have reduced baseline pulmonary function and accelerated rate of declines in function compared with healthy controls [69-73] and who are also at high risk for both chronic lung disease and acute respiratory infections. Therefore, a better characterization of the long-term (>2 years) pulmonary safety of TI is warranted, and such studies are in progress [74].

Cough — The most common pulmonary symptom associated with inhaled insulin, reported by as many as 44 percent of patients treated with TI, is dry cough. In clinical trials, cough was reported approximately six times more frequently with TI than the active comparator group, with no difference between type 1 and type 2 diabetes [34,62]. Cough is predominantly mild, mostly limited to a single defined event that occurs within 10 minutes of inhalation, and is not associated with changes in pulmonary function tests [10,11,36,62]. Cough is noted early in the treatment course (within the first month) and declines in frequency and severity over time [10,11], but it was still reported by 17 percent of patients in a long-term (up to four years) safety follow-up study [74]. Cough was also the most common pulmonary symptom associated with Exubera [39]. Given its timing immediately following the inhalation, and the reporting of no difference in cough in studies that compared TI with placebo powder (odds ratio [OR] 1.07, 95% CI 0.65-1.59) [8,23,29,34], the cough is likely explained by transient airway irritation or mild bronchospasm due to the delivery method or the excipient. Cough is the most common adverse event leading to early discontinuation of inhaled insulin (approximately 3 percent of patients) [10,11,36]. Other respiratory treatment-related adverse events (such as wheezing, bronchospasm) were uncommon with TI [62].

Pulmonary function decline — FEV1 is the primary measure to assess pulmonary function while on inhaled insulin. Prior to starting inhaled insulin, patients should have spirometry to assess FEV1 to identify potential lung disease. There is no specific cutoff below which TI is contraindicated; however, because trials of TI excluded patients with baseline FEV1 <70 percent predicted, TI should not be initiated in this population. (See 'Contraindications' below.)

In clinical trials, TI was associated with a greater decline from baseline in FEV1 than the active comparator group (net difference -38 mL for TI versus subcutaneous insulin or oral antidiabetic drugs, 95% CI -49 to -26) [10,28,30,31,34,62]. Change in FEV1 was not associated with mean daily dose of TI [11]. The decline in FEV1 with TI was noted primarily within three months of initiating therapy, and the rate of decline significantly diminished thereafter in studies lasting at least one year [10,11,32]. In a "follow-on," long-term (up to four years) safety study, the annual rate of FEV1 change from baseline was -48 mL (95% CI -59 to 37) [74]. A similar decline in FEV1 was also seen in studies with Exubera [39,63,64]. Change in FEV1 resolved four weeks after discontinuation of TI [30,37,62,67]. There are no data to assess reversal of the effect on FEV1 following discontinuation of TI after long-term use. In three studies that compared TI with placebo powder, there was no difference in change in FEV1 (net difference -39 mL, 95% CI -117 to 62) [8,23,29,34]. Changes in other pulmonary function tests (eg, forced vital capacity, total lung capacity, diffusing capacity) parallel changes in FEV1.

Lung cancer risk — In postmarketing extension (surveillance) studies, there was an approximately fourfold increase in lung cancer incidence (incidence density ratio 3.75, 95% CI 1.01-20.68) and a threefold increase in lung cancer mortality (incidence density ratio 2.81, 95% CI 0.50-28.46) with Exubera versus the comparator group [75]. All patients diagnosed with lung cancer had a prior history of cigarette smoking. There were too few cases of lung cancer reported in pre-marketing studies (two cases during active participation and two cases two years after study completion, all in patients treated with TI) to assess whether TI increases risk of lung cancer [7,62]. TI should not be used in patients with lung cancer or prior history of lung cancer.

Asthma, chronic obstructive pulmonary disease (COPD) — Acute bronchospasm has been observed with TI in patients with asthma or COPD (29 versus 0 percent in patients with or without asthma/COPD, respectively) [42]. The absorption and pharmacokinetic profile of TI appears to be unaltered in mild to moderate COPD [76]. However, all pre-marketing trials with TI included patients free of chronic lung disease, and there are no published studies in patients with diabetes and asthma or COPD. Therefore, TI is contraindicated in patients with chronic lung disease (such as asthma or COPD) or any other unstable or poorly controlled lung disease. (See 'Contraindications' below.)

Upper respiratory tract infection — Although symptomatic upper respiratory tract infection appears to have no significant impact on inhaled insulin kinetics [77], patients with active upper respiratory tract infection should monitor glucose more closely as some may need to intensify insulin therapy with TI to maintain glycemic management and should administer prandial insulin subcutaneously if unable to conduct proper inhalation.

Smoking — Clinical trials of inhaled insulin excluded patients with recent history of tobacco use because active smoking increases the rate of absorption and bioavailability of inhaled insulin [78] and changes in smoking habits greatly and rapidly alter its pharmacokinetics [79]. The effects of smoking on inhaled insulin are not formulation or device specific; rather, they reflect an increase in the alveolar epithelial permeability associated with smoking [80]. Given the unpredictable absorption with changes in smoking behavior, inhaled insulin is not recommended in patients who smoke or who have stopped smoking less than six months prior [42]. This contraindication excludes one-sixth of the diabetes population in the United States who are smokers [81]. If a patient starts or resumes smoking, inhaled insulin must be discontinued. The use of inhaled insulin may also be problematic in patients who are passive smokers as the absorption may be reduced up to 30 percent [82].

Exercise — There are no studies with that have examined how exercise may influence the pharmacokinetics of TI. In one study of 23 nonsmoking patients with type 1 diabetes treated with a prior formulation of inhaled insulin (AERx, no longer available), 30 minutes of moderate exercise beginning 30, 120, or 240 minutes after dosing changed the shape of the insulin curve compared with no exercise [83]. Starting the exercise 30 minutes after dosing resulted in a shorter time to maximal insulin concentration, but after stopping exercise, the insulin concentration decreased below the level of the no-exercise group. The area under the insulin curve over two hours was either the same (for dosing 30 and 240 min prior to exercise) or decreased (for dosing 120 min prior to exercise) compared with no exercise.

Because of the potential for individual variation in the response to inhaled insulin with exercise, patients should increase frequency of glucose monitoring during exercise (as with the use of subcutaneous insulin).

Insulin antibodies — Higher concentrations of insulin antibodies are seen after inhaled compared with subcutaneous insulin, especially among patients with type 1 diabetes, regardless of the formulation [10,44,55,56,84-87]. The level of insulin antibodies is not associated with glycemic management, including inhaled insulin dosing requirements, or safety (allergic events, pulmonary side effects, or hypoglycemia) [10,84,88]. However, the long-term clinical significance of the increase in antibodies is unknown.

Hypersensitivity reactions — Although rare, hypersensitivity reactions were reported with TI, and they may be related to nonallergic mechanisms, eg, irritation of oropharynx [42].

CONTRAINDICATIONS — Inhaled insulin is not indicated in patients who smoke, who may represent one-sixth of the diabetes population in the United States [81,89], and in patients with active lung cancer or chronic lung disease, including asthma or chronic obstructive pulmonary disease (COPD) because of increased risk of bronchospasm. Prior to starting inhaled insulin, patients should have spirometry to assess forced expiratory volume at one second (FEV1) to identify potential lung disease. TI has not been studied in patients with FEV1 <70 percent predicted, and therefore, it should not be initiated in this patient population.

It has been estimated that inhaled insulin would be inappropriate in 40 percent of community-based patients with diabetes [90]. Because of the progressive decline in pulmonary function associated with diabetes, the proportion of ineligible patients may further increase over time.

DOSING — Afrezza (insulin human) inhalation powder is a drug-device combination product that consists of a hand-held, pocket-sized, breath-powered inhaler device that accepts single-use cartridges prefilled with a dry powder formulation of recombinant regular human insulin that is optimized for inhalation and rapid absorption through the lung [42]. Similar to other insulin formulations, unopened Afrezza cartridges are stored refrigerated (2 to 8°C). At room temperature, cartridges in sealed foil packages must be used within 10 days, while cartridges in opened foil packages must be used within three days.

Pretreatment evaluation – Before initiating inhaled insulin, all patients should undergo a detailed medical history, physical examination, and spirometry (forced expiratory volume at one second [FEV1]) to identify potential lung disease. TI has not been studied in patients with FEV1 <70 percent predicted. Small respiratory monitors to assess FEV1 can be used at the point-of-care setting.

TimingInhaled insulin is administered at the beginning of a meal. In patients with type 1 diabetes, inhaled insulin should be used together with subcutaneous long-acting insulin. In patients with type 2 diabetes, inhaled insulin can be used as monotherapy or in combination with oral agents or subcutaneous, longer-acting insulin [42].

Dose – TI is available in color-coded cartridges of 4 (blue), 8 (green), and 12 (yellow) units, administered as a single inhalation per cartridge [91]. For patients who are insulin naïve, the starting dose is 4 units with each meal. As with other insulin formulations, the dose is adjusted based upon blood glucose monitoring and A1C assessments. (See "Insulin therapy in type 2 diabetes mellitus", section on 'Titrating dose' and "Management of blood glucose in adults with type 1 diabetes mellitus", section on 'Monitoring blood glucose'.)

If a patient is prescribed a dose exceeding 12 units, inhalations using multiple cartridges are necessary (eg, a patient requiring 16 units with dinner will need two different inhalations of the 8-unit cartridge). In clinical trials, most patients received 12 to 24 Afrezza insulin units per meal.

Afrezza is dispensed in monthly packages, which are available in multiple configurations that include a combination of the three color-coded cartridges, eg, the "Afrezza 4-Unit Cartridges" package contains 90 4-unit cartridges (360 total Afrezza units). Each package of Afrezza includes two inhalers. The patient should use one inhaler at a time and replace it after 15 days.

Converting from subcutaneous, rapid-acting insulin – For patients who switch from subcutaneous mealtime insulin to Afrezza, the official recommendation is approximately 1:1 conversion, as shown in the examples in the table (table 1). However, because the efficacy of Afrezza is overall less than subcutaneous injectable insulin, a more appropriate conversion rate from subcutaneous mealtime insulin to Afrezza may be closer to 1:1.5 to achieve comparable glucose management [92].

Because there are only three types of cartridges, fine adjustments in dosing are difficult, and there is potential risk for hypoglycemia when transitioning patients with high insulin sensitivity to inhaled insulin. For example, a patient requiring 2 units of subcutaneous insulin with meals who is transitioning to a 4-unit cartridge of Afrezza requires close monitoring for development of hypoglycemia.

MONITORING FOR SAFETY — In addition to the typical warnings and precautions that apply to use of any insulin (hypoglycemia, diabetic ketoacidosis [DKA], hypersensitivity reactions, hypokalemia, fluid retention with concomitant use of thiazolidinediones) while on inhaled insulin, patients should be monitored for [42]:

Respiratory symptoms, especially the occurrence of acute bronchospasms.

Decline in pulmonary function with spirometry (forced expiratory volume at one second [FEV1]) after the first six months of therapy, and annually thereafter, even in the absence of pulmonary symptoms [42]. Small respiratory monitors to assess FEV1 can be used at the point-of-care setting. If there is a decline of ≥20 percent in FEV1 from baseline, inhaled insulin should be discontinued. More frequent monitoring may be needed for persistent symptoms (eg, wheezing, persistent cough).

SUMMARY AND RECOMMENDATIONS

Type 1 diabetes – We recommend subcutaneous insulin rather than inhaled insulin for prandial insulin replacement therapy for type 1 diabetes (Grade 1B). Inhaled insulin is not recommended for treatment of diabetic ketoacidosis (DKA) and should not be used in patients at high risk for DKA. (See 'Candidates for inhaled insulin' above and "Management of blood glucose in adults with type 1 diabetes mellitus".)

Technosphere inhaled insulin (TI) is an alternative, noninvasive prandial insulin administration option for patients who can tolerate potential transient cough with each administration and comply with requirements for monitoring of pulmonary function. Dose adjustments with TI may not accommodate finer, small-increment dosing that may be needed to avoid hypoglycemia, especially in insulin-sensitive patients, or hyperglycemia in patients requiring large insulin doses (see 'Dosing' above). Overall, TI has slightly less glycemic efficacy than subcutaneous insulin; however, because of its rapid action, patients can take supplemental inhalations of TI one to two hours after meals if postprandial glucose values are not within target.

Type 2 diabetes – For the majority of patients who need insulin therapy, we suggest intermediate- or long-acting ("basal") subcutaneous insulin administration as the first step. For patients who require prandial insulin, we suggest subcutaneous insulin rather than inhaled insulin (Grade 2B). (See 'Candidates for inhaled insulin' above and "Management of persistent hyperglycemia in type 2 diabetes mellitus" and "Insulin therapy in type 2 diabetes mellitus", section on 'Insulin initiation'.)

TI is an alternative, noninvasive option in patients with type 2 diabetes who would otherwise delay initiating or intensifying insulin therapy because they are unwilling or unable to use injectable insulin and who can tolerate potential transient cough with each administration and comply with requirements for monitoring of pulmonary function.

In patients with type 1 diabetes or insulin-requiring type 2 diabetes, reduction in glycated hemoglobin (A1C) with inhaled insulin was generally less than that of subcutaneous insulin, and a lower proportion of patients achieved the A1C general target of less than 7 percent. In addition, the degree of glycemic improvement with TI (absolute mean A1C decrease of approximately 0.55 percent from baseline) and proportion achieving desired goals (approximately 19 percent) were lower compared with historical trials with subcutaneous insulin. (See 'Glycemic efficacy' above.)

In patients with type 1 or insulin-requiring type 2 diabetes, severe hypoglycemia was reported less frequently with TI compared with subcutaneous insulin. (See 'Hypoglycemia' above.)

In patients with type 1 or insulin-requiring type 2 diabetes, TI was associated with minimally less weight gain compared with subcutaneous insulin. (See 'Weight gain' above.)

TI is associated with a mild, nonproductive cough that may occur with each inhalation and a small nonprogressive decline in pulmonary function testing (forced expiratory volume at one second [FEV1]). (See 'Pulmonary safety' above.)

Although rare, hypersensitivity reactions can occur with TI. (See 'Hypersensitivity reactions' above.)

TI should not be prescribed for patients who smoke or who have stopped smoking within the past six months. In addition, because of the risk of bronchospasm, TI is contraindicated in patients with active lung cancer or chronic lung disease, such as asthma or chronic obstructive pulmonary disease (COPD). (See 'Contraindications' above and 'Smoking' above and 'Asthma, chronic obstructive pulmonary disease (COPD)' above.)

Before initiating inhaled insulin, all patients should undergo a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease. Because trials of TI excluded patients with baseline FEV1 <70 percent predicted, TI should not be initiated in this population. (See 'Dosing' above and 'Monitoring for safety' above.)

Spirometry (FEV1) should be done at baseline, after the first six months of therapy, and annually thereafter, even in the absence of pulmonary symptoms. More frequent monitoring may be needed for persistent symptoms, eg, wheezing, persistent cough. Small respiratory monitors to assess FEV1 can be used at the point-of-care setting. In patients with a decline of ≥20 percent in FEV1 from baseline, Afrezza TI should be discontinued. (See 'Monitoring for safety' above.)

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Topic 1764 Version 18.0

References