New Options in Exogenous Insulin Therapy
William Cefalu, MD

Diabetes—The Increasing Mortality Rate

Diabetes is one of the world's most common noncommunicable diseases, and in most developed countries, it ranks as the fourth or fifth leading cause of death.1 In the United States, age-adjusted deaths from cancer, cardiovascular disease, and stroke are reported to have decreased since 1980; however, the age-adjusted rate of mortality from diabetes is reported to have increased by 30%2,3 (Figure 1).

Figure 1. Deaths from chronic diseases: US Data 1980-1996.2,3

The World Health Organization (WHO) recognizes type 2 diabetes and obesity as global health problems that have reached epidemic proportions expected to increase by as much as 45% between the years 2000 and 20101 (Figure 2). Increasing mortality rates are not due to lack of new developments in diabetes therapy; indeed, the past decade has seen the release of about 17 new diabetes drugs, including new formulations, new combinations, insulin analogs, and new delivery systems. This suggests that the state of diabetes treatment suffers not from a lack of effective tools but rather from a lack of effective management strategies.

Figure 2. Estimated number of people with diabetes worldwide.1

Natural Progression of Type 2 Diabetes

Insulin has always been the treatment mainstay for type 1 diabetes, but there is growing recognition that the natural development of type 2 diabetes (Figure 3)—metabolic syndrome, progressive hyperglycemia, and decreasing β-cell function—leaves the majority of patients unable to maintain healthy levels of blood glucose with oral agents alone.4 Most patients eventually require insulin therapy, alone or in combination.5 The UK Prospective Diabetes Study4 (UKPDS) estimated that at diagnosis, β-cell function may already be at 50% of normal in most patients, and will affect the way oral antidiabetic (OA) agents are used (Figures 3 and 4).

Figure 3. Natural history of type 2 diabetes.1

Figure 4. Progressive ß-cell failure in type 2 diabetes.4

A typical pattern of progression from dietary control to one OA agent, and the addition of other OAs, with diminishing glycemic control, is illustrated in Figure 5.

Figure 5. Stages of type 2 diabetes: criteria for advancing to next stage.

There are now a variety of OAs available to treat type 2 diabetes. As shown in Figure 6, these agents have various therapeutic targets. Newer agents, such as the thiazolidinediones, address insulin resistance at the skeletal muscle. Metformin inhibits gluconeogenesis in the liver and reduces hepatic glucose production. Acarbose and miglitol decrease glucose absorption from the gut. The UKPDS highlighted the importance of ß-cell dysfunction in type 2 diabetes, which needs to be addressed with insulin secretagogues or insulin.

Figure 6. Oral agents for type 2 diabetes mellitus: primary sites of action.

Even when glycemic control is at unacceptable levels, barriers to intensive insulin therapy are well documented from the perspective of both the patient and the physician6:

Overcoming the Skin Barrier

Insulin Pens
Insulin pens help to overcome skin barrier issues and are well liked by most patients. They can be easily titrated, are convenient, and use a smaller, less-painful needle.6

Other Dermal Delivery Methods
Other concepts for insulin delivery through the skin have been researched and show proof of concept: the high-pressure jet injector (drawbacks include injection discomfort and alteration in insulin absorption rate); iontophoresis (transdermal delivery facilitated by electrical current); and low-frequency ultrasound to transport insulin across the dermal barrier. Another noninvasive skin delivery method in the experimental stage uses phosphatidylcholine-based carriers (called Transferomes™) to transport insulin into the body between the intact skin cells; early studies suggest that this concept may prove feasible.6,7

Other Potential Routes of Insulin Delivery

Intranasal
Another promising concept is that of intranasal insulin for preprandial dosing. While intranasal insulin has been shown to achieve significant decreases in plasma glucose concentrations,8 its bioavailability is poor, and the dose needed to reach glycemic control markers is significantly higher than for insulin that is administered subcutaneously.6,9

Oral
Oral insulin has always been an attractive but untenable concept, because insulin (a protein) is broken down in the digestive system. Research has focused on overcoming this limitation by stabilizing the degradation, improving the permeability, and adding absorption promoters to protect the insulin as it passes through the stomach. In a recent study, oral insulin was combined with an oral delivery agent (DA); plasma glucose levels of volunteers receiving the escalating doses of insulin/DA combination were compared with groups receiving subcutaneous insulin and placebo. Following oral administration of the insulin/DA capsules, insulin was rapidly absorbed, with peak plasma concentrations occurring within 25 minutes. No serious adverse events were reported, and all doses were well tolerated. Researchers concluded that oral dosing of the insulin/DA combination provided clinically significant levels of insulin absorption.10

Buccal/sublingual
The buccal inhaler delivers a high-pressure stream of insulin to the back of the throat. Like the nasal mucosa, the buccal mucosa offers limited surface area. Because the mucosa has low permeability, many puffs may be required for effective dosing.11 One study demonstrated efficacy for buccal insulin used as an add-on therapy for postprandial control in patients who were failing on oral therapy,12 but research overall has been limited to a very small number of subjects.

Pulmonary
Perhaps the most promising of the alternate routes for insulin delivery is pulmonary, because the lung has anatomic advantages over the upper airway. With each branching of the bronchi, the mucosa becomes thinner (Figure 7). By the time the honeycomb-like structures of the alveoli are reached, the surface area available for uptake is tremendous (Figure 8).


Figure 7. Airway branching in the human lung.

Figure 8. Epithelial comparison.

Several different pulmonary inhalation devices are currently in development, some using liquid-air aerosol insulin and some using dry insulin powder.

Efficacy of inhaled insulin
One study compared the time-action profiles of inhaled insulin, rapid-acting insulin lispro, and regular insulin in healthy volunteers. Onset of action following insulin inhalation was faster than onset of action after subcutaneous (SC) injection.14 A trial in patients with type 2 diabetes demonstrated improved glycemic control following administration of inhaled insulin. Further, it was well tolerated, with no adverse pulmonary effects.15 The time-concentration profile of inhaled insulin appears to mimic normal physiological insulin secretion, overcoming one of the limitations of conventional insulin.15 In the Inhaled Insulin Phase II Study, a group of patients with type 1 diabetes was treated with inhaled insulin and demonstrated glycemic control over 3 months as measured by hemoglobin A1C, matching that of a group of control patients treated with SC insulin.16

Treatment satisfaction with inhaled insulin
The Inhaled Insulin Phase II Study also measured overall satisfaction with treatment. The group treated with inhaled insulin showed a greater percentage change from baseline in treatment satisfaction (35% change) compared to patients treated with SC insulin (11% change), and 82% elected to continue an extension study of inhaled insulin. In particular, six factors were cited as contributing to satisfaction: ease of administration, comfort, convenience, time with regard to dosing, flexibility of eating schedule, and ease of administering multiple daily doses.17

Inhaled insulin in special populations: URTI
Because upper respiratory tract infections (URTIs) are common in the diabetic and nondiabetic population, a group of researchers looked at absorption of pulmonary insulin during and after an uncomplicated URTI in volunteers without diabetes. They found no significant change in insulin absorption during and after the URTI and no statistically significant difference in Cmax for insulin between the two periods. Tmax was significantly shorter during the active URTI, but no differences were seen in peak insulin concentrations. They concluded that inhaled insulin can be administered during a URTI without significantly affecting the pharmacodynamics and pharmacokinetics of the insulin.18

Inhaled insulin in special populations: smokers
Inhaled insulin is more readily absorbed by smokers. The influence of smoking on insulin absorption warrants further investigation.19

Discussion

The rising incidence and mortality rate of diabetes worldwide calls for aggressive treatment utilizing effective strategies and tools. Although most patients with type 2 diabetes eventually fail on oral agents and require insulin to maintain glycemic control, resistance to initiating insulin therapy persists among physicians and patients. A major reason for this is that the only currently available means of insulin delivery is via injection. Tests of alternate insulin delivery routes, including dermal absorption and intranasal, buccal, and pulmonary inhalation, have yielded promising results. Pulmonary insulin is perhaps the most feasible of these methods, and several different systems are in development to deliver insulin in this way. Inhaled insulin's ease of use could lead to improved compliance and glycemic control in all patients with diabetes.

References

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