Optimizing Glycemic Control:The Search for Feasible Noninvasive Insulin Delivery Systems

Address for correspondence: William T. Cefalu Department of Medicine University of Vermont, College of Medicine UHC Campus,Arnold 3433 One South Prospect Street Burlington,Vermont 05401 United States Telephone: (802) 847-8901 E-mail: william.cefalu@ uvm.edu 43 noninvasive insulin delivery systems INTRODUCTION Since its discovery, insulin has been the mainstay of treatment for patients with type 1 diabetes. For patients with type 2 diabetes, clinicians have traditionally relied on oral antihyperglycemic agents, as their mechanisms of action are designed to overcome the pathophysiological abnormalities recognized to be present (1,2). However, with observations acquired from long-term, prospective trials, it is now recognized that patients with type 2 diabetes undergo various stages of clinical management as beta cell dysfunction progresses and insulin secretory capacity declines, necessitating the use of multiple oral therapies to achieve glycemic control (3,4). Thus, therapeutic combinations of different classes of oral agents have been shown to have additional glycemic benefit, and combination oral therapy is now routine (3,4). Due to continued progression of the disease, however, even combination oral antihyperglycemic therapy may prove inadequate to control hyperglycemia, as determined by failure to achieve target HbA1c levels. In this regard, for patients with type 2 diabetes, exogenous insulin therapy may be appropriate to achieve glycemic control, either as monotherapy or in combination with oral agents (4,5). As such, the use of insulin earlier in the management of type 2 diabetes has received considerable attention (6). Although an estimated 40% of patients with type 2 diabetes in the United States (US) currently receive exogenous insulin therapy, this use of insulin appears to be more widely accepted in Europe than in the US (7,8). For example, the European Diabetes Policy Group has suggested guidelines for diabetes care that recommend using insulin in patients with type 2 diabetes who have HbA1c levels >7.5% (7). In attempts to achieve good glycemic control, exogenous insulin therapy can be considered the gold standard, as the dose can be titrated to achieve the desired glycemic target. Thus, insulin has emerged as a more viable treatment option much earlier in the disease process in patients with type 2 diabetes. In addition, it is well documented that, in patients with type 1 diabetes, multiple daily injection therapy (i.e. intensive insulin therapy [IIT]) achieves tight glycemic control and reduces complications associated with diabetes (9). Nevertheless, despite the demonstrated benefits of IIT, this approach has not gained widespread acceptance in clinical practice (10) due to barriers regarding the initiation of insulin therapy (for patients with type 2 diabetes) and in advancing to IIT (for patients with type 1 and type 2 diabetes). BARRIERS TO IIT Patient compliance IIT requires a substantial commitment from the patient, who must administer multiple daily injections, check blood glucose (BG) levels frequently and carry insulin and supplies at work and play.The inconvenience of these factors alone may discourage patients from advancing to more intensive insulin therapy. Patients with type 2 diabetes may also perceive that advancing to insulin therapy is related to a serious progression of their disease state or may feel anxiety about injections. In a recent survey of insulin-treated patients with either type 1 or type 2 diabetes, 14% of respondents avoided injections because of anxiety and 42% refused to increase their number of injections. Of the 28% who considered themselves “highly anxious,” approximately 45% avoided injections and were extremely troubled by the idea of giving themselves multiple injections (11). Weight gain/hypoglycemia Both clinicians and patients may be concerned about the potential side effects of weight gain and hypoglycemia with insulin therapy (12). Clinical observations suggest that weight gain may be associated with the large doses of insulin required to achieve a reduction in hyperglycemia and overcome insulin resistance in patients with type 2 diabetes. Furthermore, the pharmacokinetic (PK) profile of regular subcutaneous (SC) insulin is not ideal for physiological insulin replacement, as it is absorbed slowly and has a delayed onset of action, thus predisposing the patient to hypoglycemia. However, newer insulin formulations and dosing regimens provide a more physiological approach to insulin therapy and have helped to ameliorate these side effects. Cardiovascular risk The issue of whether exogenous insulin therapy increases cardiovascular (CV) risk in patients with type 2 diabetes is much debated. Results from the United Kingdom Prospective Diabetes Study (UKPDS) suggest that exogenous insulin treatment does not worsen cardiovascular disease (CVD) and probably has favourable effects (13). These findings are supported by an observed 16% reduction in the risk of combined fatal and nonfatal myocardial infarction (MI) and sudden death in those who received intensive therapy in the UKPDS, a figure that approached statistical significance (13). Additional evidence supporting the favourable effects of insulin therapy on the CV system was provided by the Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study, which demonstrated that IIT in the setting of acute CV events improved longterm survival in patients with diabetes (14). Healthcare practitioner limitations A time commitment is required by healthcare practitioners to successfully implement IIT (15). In addition, the practitioner must have access to resources to educate patients about insulin formulations, home BG monitoring, carbohydrate counting and treatment of hypoglycemia. Therefore, lack of ready access to diabetes educators and nutritionists may limit patients’ successful implementation of insulin therapy. Insulin formulation limitations The PK and pharmacodynamic (PD) shortcomings of previous insulin preparations have also limited widespread acceptance 44 CANADIAN JOURNAL OF DIABETES Table 1. Research approaches to noninvasive insulin delivery of IIT. The time-action profile of regular SC insulin (i.e. slower onset and more prolonged duration of action) does not mirror normal physiology by failing to provide early insulin release in response to a meal (16,17). The patient with type 2 diabetes lacks the first phase of insulin release and will require replacement of the meal-related bolus in insulin secretion in addition to basal control (18).As a result, insulin doses large enough to lower postprandial increases in BG levels often predispose patients to later episodes of hypoglycemia, as well as hyperinsulinemia and weight gain. Lower doses, which decrease the risk of hypoglycemia, fail to provide adequate control of postprandial blood glucose (PPG) levels, leading to inadequate HbA1c control (15). In addition, optimal timing of injections 30 to 60 minutes before meals may require inconvenient delays. The new long-acting formulations (insulin glargine [Lantus]), in addition to the new rapid-acting insulin analogues (lispro [Humalog] and aspart [NovoRapid]), have addressed these concerns. Lispro and aspart have a more rapid onset and shorter duration of action than regular insulin (19,20). Thus, regimens that combine prandial rapid-acting lispro or aspart with a longer-acting insulin (e.g. glargine) for basal insulin better mimic a normal and more physiological insulin profile. It is apparent that practical and psychological hurdles contribute to resistance to insulin therapy in patients with type 2 diabetes and to IIT in patients with type 1 and 2 diabetes.The inertia in advancing to more aggressive therapy may adversely influence compliance and greatly interfere with the clinical goal of achieving BG control. NONINVASIVE INSULIN DELIVERY SYSTEMS The major goals when considering a practical, noninvasive insulin delivery system are to overcome the primary limitation associated with conventional insulin regimens by eliminating injections and to preserve a more physiological insulin profile. Innovations have made self-injection easier; for example, the insulin pen injector is small, convenient, disposable and allows the desired dose of insulin to be selected with precision (21). It uses smaller-gauge needles that may result in less painful injections than conventional needles (22). Elucidation of insulin’s structure has allowed for development of newer analogues that provide a more physiological insulin PK profile (19,20,23). Achieving the above-stated goals for noninvasive insulin delivery (i.e. eliminating injections and providing a more physiological insulin secretory profile) will allow for more intensive insulin delivery with a regimen clinically proven to significantly improve BG levels and reduce complications, while enhancing patient compliance. Such goals are lofty, but several research approaches are undergoing evaluation to achieve them (Table 1). Jet injectors Jet injectors administer insulin without needles by delivering a high-pressure stream of insulin into SC tissues. These devices, first developed 40 years ago, have limited use in the treatment of diabetes (21,24). The advantage initially suggested for jet injectors was that the insulin dose delivered was more precise and more quickly absorbed than with SC needle delivery; however, it appears that the duration of intermediate-acting insulin may be decreased with the use of these devices, which can defeat glycemic control (24). Moreover, although the absence of needles is appealing, the discomfort associated with jet injectors is reported to be comparable to that associated with injections (21). These devices, however, can potentially benefit a patient who has severe anxiety regarding needles. Iontophoresis Transdermal delivery of insulin by direct electrical current, a process referred to as iontophoresis, has been tested in laboratory animals. Iontophoresis is similar to the transdermal patches currently used to deliver nicotine for smoking cessation programs or hormone replacement therapy (HRT) for postmenopausal women. However, iontophoresis uses lowlevel electrical current to accelerate delivery of drug ions into the skin and surrounding tissues. In a study of rats with diabetes, iontophoretic delivery of bovine insulin produced a concentration-dependent reduction in BG levels (25). The method did not appear to be as effective in rats that had not been depilated, suggesting that either the depilation was effective in reducing the skin’s barrier function or the creams used with the iontophoretic device acted as a penetration enhancer only in animals that had been treated in advance with a depilatory cream instead of having their hair removed with scissors. In contrast, iontophoretic delivery of a Device Method of delivery Jet injectors Devices that administer insulin by delivering a high-pressure stream of insulin into tissues Iontophoresis Transdermal delivery of insulin by a direct electrical current Ultrasound Process by which sound waves increase, by several fold, the permeability of human skin to macromolecules Transfersomes Composites of pharmaceutically accepted ingredients flexible enough to pass through pores in the skin; transfersomes are much smaller than their components Intranasal Use of nasal membranes as absorptive surface for insulin Oral Uptake of insulin occurring within the gastrointestinal tract or buccal mucosa Pulmonary Insulin uptake occurring in the highly vascularized alveoli of the lung Figure 1. Average change in systemic insulin/ C-peptide molar ratio as a function of time after epicutaneous Transfersulin administrations (6 experiments) in an individual without diabetes (27) 45 noninvasive insulin delivery systems