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Investigating Inhaled Insulin

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Published Online: Jun 6th 2011 US Endocrinology, 2006;(2): DOI:
Authors: Virginia Zamudio
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A Novel Delivery System
Inhaled human insulin (Exubera®) is the newest innovation in insulin therapy. The idea of delivering insulin via the pulmonary system, however, is not entirely new. In 1925, the German scientist Dr M Gänsslen published an article proposing the idea of inhaled insulin.1 Unfortunately, the science to accomplish this feat has eluded us until now. The limiting factors have been two-fold: developing a dry, powdered insulin of the right particle size; and manufacturing a mechanical device that will adequately deliver it into the deep lung.


In order for a particle to be inhaled into the deep lung for transport across the alveolar membrane, it must be of a certain size—between one and three micrometres (μm). Smaller than 1μm, the particle is so light in weight that it will be deposited in the upper airway or exit during exhalation; larger than 5μm, the particle is so heavy, it will settle into the mouth and throat.2,3 Exubera insulin has a particle size of about 3μm (see Figure 1).

In order for a particle to be inhaled into the deep lung for transport across the alveolar membrane, it must be of a certain size—between one and three micrometres (μm). Smaller than 1μm, the particle is so light in weight that it will be deposited in the upper airway or exit during exhalation; larger than 5μm, the particle is so heavy, it will settle into the mouth and throat.2,3 Exubera insulin has a particle size of about 3μm (see Figure 1).

Alveolar deposition is ideal because nearly the entire cardiac output circulates through the lungs at the level of the alveoli.The alveolar bed is an effective portal for systemic drug delivery because of its large surface area—about 150m2, approximately the size of a tennis court. In contrast, inhaled drugs targeted for the nasal bed only have an area smaller than the size of a bath towel in which to be absorbed. When a dry particle contacts the moist alveolar membrane, it immediately dissolves and is absorbed into the bloodstream.

The ideal device for delivering a dry particle to the deep lung must allow for consistent dosing with a normal breath. The rate of flow must be slow enough to limit particle turbulence, but not so slow that too many particles escape.The size of the chamber is a key factor in the particular flow rate.The Exubera powder is enclosed in blister packs, which are individually placed into the inhaler device. Ambient air is compressed into the system using a simple pump-action handle. On pressing the release button, the blister pack is pierced, the compressed air is forced through the powder and a standing cloud is formed in the chamber. One normal breath through the mouthpiece draws the insulin into the deep lung. Considering the average adult vital-lung capacity is about three litres, inhaling the 200 cubic centimetres (cc) of air within the chamber with a normal breath intake does not propose a challenge. After inhalation, the patient holds their breath for five seconds, then exhales. The used blister pack is removed and the process repeated until the dose is complete.4 In the clinical trials, patients experienced in the process were able to inhale up to five blister packs within one minute. A New Way of Dosing—A New Action Profile
As Exubera is a dry powder, the standard unit of measurement is milligrams (mg). After nearly a century of dosing insulin in units, this change naturally requires practitioners accustomed to dosing liquid insulin to think differently. Fortunately, most patients will not face this particular learning curve. Insulin-naïve adult patients with type-2 diabetes represent the largest group of candidates for Exubera therapy. Blister packs are currently available in two strengths—1mg and 3mg. Strengths should be combined to ensure that the least number of blisters are used in order to deliver the dose. One milligram of Exubera is equivalent to about three units of rapidacting insulin; 3mg is equivalent to about eight units (see Table 1).4

This is an important teaching point for patients because an incorrect combination of blister packs could lead to overdosage—if three 1mg blisters are taken, the net insulin intake would be about nine units, as opposed to the eight units delivered in one 3mg blister. Another safety point is to observe the colour difference between the two blister strengths, as well as the raised bumps on the packaging, which offer a tactile cue for differentiation.

Postprandial hyperglycemia is seen early on, and is progressive, in the natural history of type-2 diabetes.As such, most patients with type-2 diabetes will eventually need insulin therapy to control hyperglycemia.5 Prandial insulin is a useful tool in addressing this defect.

Figure 1: Alveolar Deposition Depends on Particle Size*

*To deliver drugs to the deep lung for maximum absorption through the alveoli, particles should be 1–3 μm in size. EXUBERA particle size is ~3 μm MMAD (mass median aerodynamic diameter)
Patton JS, et al., Clin Pharmacokinet. (2004);43:pp.781–801.
Byron JS., Proc Am Thorac Soc. (2004);1:pp.321–328.

Table 1: Exubera Approximate Equivalence to Regular Human SC Insulin

Exubera is a prandial insulin with a unique pharmacodynamic profile. The onset of action is within 10 to 20 minutes of inhalation; the maximum effect is observed approximately two hours postinhalation; duration is about six hours.4 Simply put, Exubera has an onset and peak much like other rapidacting insulin analogs, but tails off somewhere between the rapid-acting analogs and regular insulin. Exubera should be taken within 10 minutes prior to starting a meal.

The initial dose of Exubera is determined based on body weight and then titrated according to the individual’s blood-glucose levels and various other factors (e.g. time of day, physical-activity level, timing of meals and meal composition). The equation is: patient’s weight in kilograms (kg) x 0.05mg/kg/meal.For safety, the product is rounded down to the nearest whole number in milligrams (e.g. 4.6mg rounds down to 4mg).4

Candidates for Exubera?
Exubera is indicated for adults with type-1 diabetes, used along with a long-acting insulin, and for adults with type-2 diabetes as monotherapy, with oral agents or with a long-acting insulin. No indication exists for pediatric use because the long-term safety and effectiveness in this population has not been determined. A category-C indication is given for use during pregnancy in that no reproductive animal studies have been carried out with Exubera. Exubera can be given to a pregnant woman only if clearly indicated.4 Exubera use is contraindicated in those who currently smoke, or who have ceased smoking less than six months prior to beginning therapy. Patients with unstable or poorly controlled lung disease should not take Exubera because the absorption of the drug would be unpredictable, leading to the potential for hypoglycemia or hyperglycemia. Exubera use is not recommended in patients with underlying lung conditions such as chronic obstructive pulmonary disease or asthma, since safety and efficacy has not been established in this particular population. Lung function must be assessed for all patients prior to starting Exubera and at certain intervals thereafter.4

Safety First

Lung Function
During the Exubera clinical trials, more than 3,800 patients were evaluated for the effects on lung function. This represents the largest study to focus on the diabetic lung. In order to begin Exubera therapy, the forced expiratory volume in one second (FEV1) should be at least 70% of predicted volume. After six months of therapy, and annually thereafter, the FEV1 should be repeated, even if the patient has no pulmonary symptoms. If a >20% decline is observed in the FEV1, and then confirmed in a repeated FEV1, Exubera should be discontinued.4

A two-year study showed that changes in the FEV1 were small, early, and nonprogressive in type-2 patients on Exubera, compared with those on subcutaneous insulin. A decline of between 1% and 1.5% from baseline was noted in the Exubera group at three months.This decline in FEV1—about 40cc of volume—was reversible upon discontinuation of Exubera in patients with type-2 diabetes. A surprising finding in the study was that even those subjects on subcutaneous insulin experienced a progressive decline in FEV1 over time. To offer some perspective on the issue of FEV1 variation, a Dutch study showed that the average person experiences a 2.8% variation in FEV1 on a day-to-day basis.6 Cough and Dyspnoea
Patients in the Exubera clinical trials were asked to complete a questionnaire if they experienced any coughing. Cough was frequently reported but, in general, it tended to occur within seconds to minutes after inhalation, was predominantly mild, rarely productive, and rarely occurred at night.The incidence of cough decreased as use continued, and only 1.2% of patients discontinued Exubera due to cough. The incidence of dyspnoea was low and was described as mild to moderate.4

Chest Discomfort
A variety of chest symptoms—grouped under the nonspecific term ‘chest pain’—were reported as adverse events during the Exubera clinical trials. Over 90% of these events were described as mild or moderate, and they occurred in 4.7% of patients treated with Exubera compared with 3.2% of those in comparator groups. The incidence of adverse events of any cause related to coronary artery disease was comparable between treatment groups.4

Hypoglycemia was one of the most commonly reported adverse events in clinical trials.4 This is not surprising, as Exubera is insulin. The incidence of hypoglycemia was comparable between Exubera and those taking subcutaneous insulin; those taking Exubera experienced more hypoglycemia than those on oral agents.4,7,8 As with all insulin therapy, patients should be trained in the prevention, recognition, and treatment of hypoglycemia.

Efficacy—How Exubera Compares
Exubera provides superior glucose control when added to, or substituted for, therapy with two oral agents. In the clinical trials, the two oral agents consisted of one insulin secretagogue (sulfonylurea or repaglinide) and one insulin sensitizer (metformin or a thiazolidinedione).At baseline, blood-sugar (A1c) levels were comparable in all three treatment groups.After 12 weeks of therapy, the Exubera plus two oral-agents group showed the greatest reduction in A1c—1.9%, compared with 1.4% in the Exubera monotherapy group and 0.2% in the two oral-agents group (see Figure 2).8 Reduction of A1c is comparable between Exubera and subcutaneous insulin in both type-1- and type-2-diabetes patients.4

Figure 2: Exubera as Monotherapy and Add-on to Two Oral Agents— A1c Change from Baseline at 12 Weeks

*Insulin secretagogue+metformin(Met) or TZD

The Challenge
The evidence for targeting near-normal glucose levels is overwhelming. Landmark studies such as the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study have unequivocally proven that microvascular and macrovascular diabetes complications are reduced with improved glycemic control.9,10 Both studies pointed to the role of insulin in achieving glycemic control. More recently, the Epidemiology of Diabetes Interventions and Complications study has shown that early intensive diabetes management is associated with a 42% reduction in the risk of cardiovascular disease events in patients with type-1 diabetes.11Yet a paradox exists in the current US diabetes landscape: despite the strong evidence that should be driving practice, a majority of patients with type-2 diabetes are still not meeting target A1c levels. A study comparing data from two National Health and Nutrition Examination Survey (NHANES) periods shows that glycemic control has worsened over the past 20 years. Forty-five per cent of adult patients with type-2 diabetes had an A1c below 7% in the earlier NHANES data period (1988–1994).12 Bearing in mind that this was before the advent of insulin analogues, thiazolidinediones, alpha-glucosidase inhibitors, and biguanides, the only oral-agent class available at the time was the sulfonylureas. In the later NHANES data period (1999–2000), only 36% of patients achieved an A1c less than 7%. Between the two data periods, the use of insulin therapy remained constant.12

A 2004 study clearly demonstrates this clinical inertia.13 In this prospective, population-based study, more than 7,000 complete courses of diabetes treatment were studied among members of the Kaiser Permanente Northwest Region health plan. Each course of treatment was measured in terms of how long the patient stayed at one level of therapy before being advanced to a more intensive regimen: from diet and exercise, to one oral agent, to combination oral-agent therapy, to insulin. At initiation of insulin, the average patient had accumulated more than five years with an A1c of greater than 8%, and more than 10 years with an A1c over 7%.13 Other studies focus on the factors that drive the resistance to initiating injected-insulin therapy. Reasons for this resistance are numerous and exist on the part of both the patient and the practitioner. The recently published Diabetes Attitudes, Wishes and Needs study looked at the barriers to the use of insulin. Barriers included a fear by the patient that his or her diabetes was getting worse, fears of injection and a perception that they would not be able to handle the complexities involved in taking insulin. Physicians cited a lack of office resources to adequately train and monitor the patient starting on insulin, and in issues such as weight gain and hypoglycaemia.14 A 2005 study found that many patients also felt a deep personal failure at having to begin insulin therapy, internalising the idea that they had not done a good job in managing their diabetes.15 In some ethnic groups, there is a prevalent health belief that insulin use is associated with certain diabetes complications or even death.15-17

New diabetes treatments such as Exubera may help to overcome some of the barriers associated with initiating insulin therapy. Clearly, the fear of injection is eliminated with inhaled insulin as there are no needles to consider. In clinical trials, subjects completed a diabetes quality-oflife survey as well as a comprehensive survey looking at 12 categories of satisfaction. Inhaled insulin was the most frequently chosen treatment, preferred over oral agents and subcutaneous insulin in both type-1 and type-2 patients. Those in the Exubera group rated an overall greater level of satisfaction than those on subcutaneous insulin or on oral agents alone. Exubera significantly improved the quality of life in both type-1 and type-2 diabetes patients.18-20

Perception is Reality
Although the A1c reduction was comparable between those on subcutaneous insulin and those on inhaled insulin, there was a perception among Exubera users that their treatment was more efficacious. A1c may not be a good indicator of glucose control from the patient’s perspective in that it does not reflect the day-to-day fluctuations in glucose and how the patient feels. The Exubera group also reported less hassle involved in their treatment regimen than the subcutaneous insulin group. In another study, perceptions related to the difficulty of regimen predicted A1c control. The patients who perceived their treatment regimens to be less difficult had significantly better A1c outcomes.21 In long-term extension trials, when given a choice of therapies, 75% of those on subcutaneous insulin chose to go on Exubera. For those already on Exubera, 85% chose to continue this form of therapy rather than revert to injections.20 Another perception that bears examination is the perception of insulin as the end of the line, a treatment to be feared, a threat to be used to motivate lifestyle efforts. Practitioners would do well to emphasize to patients early on that the natural progression of diabetes involves a steady decline in endogenous insulin.The use of insulin should therefore be positioned as a likely treatment at some point, a necessary strategy if the patient is
o achieve target blood-glucose levels and reduce the risk of complication. Linking the words ‘insulin’ to ‘failure’ in our collective vocabulary should cease, in that it perpetuates the idea among patients that they are personally responsible for their lack of endogenous insulin.Moving Forward
With each new diabetes treatment option, there are many challenges for the provider to consider. While there are not enough diabetes educators in some communities, it is also true that diabetes educators are generally under-utilized. For example, only about onethird of eligible Medicare patients in the US with diabetes have received diabetes education, even though it is a covered benefit.22 Most health plans today offer some coverage for this education. Referring out to a diabetes educator can help to reduce the in-office burden associated with starting a patient on insulin, whether inhaled or injected.The American Association of Diabetes Educators has a national hotline and website to help providers to locate a local educator.23 Any strategy that eliminates barriers or helps to simplify patients’ self-care regimens is likely to increase the chances that the patient will adhere to the regimen. Inhaled insulin is a treatment option that may be more palatable to patients who need insulin, and offers the hope that those patients may achieve the glycemic control that has eluded them thus far.


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