Emerging Therapies

The lungs have a large surface area and are highly vascularized, allowing for ideal insulin absorption. One form of inhaled insulin called Exubera® (insulin human [rDNA origin]) Inhalation Powder was approved by the FDA in January 2006, and current clinical trials are testing several aerosol devices for inhalation of insulin, either as a dry powder or in a solution. Inhaled insulin devices deliver a small amount of short- or rapid-acting insulin designed to be administered right before ingestion of meals. In studies testing inhaled insulin devices, basal insulin is still taken by conventional injection protocols. Absorption via the pulmonary route is similar to or faster than subcutaneous injection of rapid-acting insulin, and the duration is longer. Intercurrent respiratory conditions and smoking contribute to overall absorption variability of inhaled insulin.[1] Some examples of inhaled insulins are illustrated in Table 1.

Table 1. Inhaled insulins currently under investigation [1]

*FDA approved

**Delivery ensured only by releasing insulin when optimum flow rate and volume are achieved

Oral insulin

Over the last several decades, attempts have been made to develop an oral insulin product using various technologies, including liposome-encapsulated insulin and polymer-wrapped insulin. Neither of these technologies has provided an adequate shield against proteolytic digestion, nor do they provide appropriate absorption, resulting in low bioavailability. Recently, however, compounds using alkyl-polyethylene-glycol conjugated hexyl-insulin (HIM2) have been undergoing clinical trials. A phase 1/2 clinical trial investigated the safety and effectiveness of a single oral dose of HIM2 in controlling postprandial plasma glucose levels in 14 patients with type 1 diabetes who were receiving basal continuous subcutaneous insulin infusion therapy.[2] The study demonstrated that oral HIM2, when combined with a basal insulin regimen, appeared to be safe and was able to control postprandial hyperglycemia. In addition, results from an exploratory study involving 18 type 2 patients indicate single oral doses of HIM2 are safe and well tolerated.[3] The goal of this exploratory study was to determine the effectiveness of a single, oral dose of HIM2 for controlling postprandial glycemia among type 2 patients. The 4-hour postdose evaluation indicated that administration of 0.5 and 1.0 mg/kg of HIM2 30 minutes before a meal resulted in lower postprandial plasma glucose levels.

The long-acting oral insulin, intesulin-1 (unmodified regular insulin), recently underwent a proof-of-principle trial in patients with type 2 diabetes.[4] A total of 4 patients underwent treatment with intesulin 0.33 mg/kg dose in gel-capsule or subcutaneous Aspart analog insulin at 0.1 unit/kg dose. These preliminary data indicated that intesulin-1 data showed a long-acting efficacy, with a first insulin peak at 30 minutes, compared to 60 minutes with injected insulin. The biopotency of intesulin-1 was 64.6% of that seen with Aspart injection. Another similarly designed proof-of-principle study evaluated intesulin IVE (in-vivo encapsulation), a drug delivery system designed to overcome variables related to membrane permeability, enzymatic degradation, and other physical barriers within the gastrointestinal tract.[5] The study showed that the IVE formulation also had a positive efficacy, with rapid onset of action and a biopotency of 60-70% compared to that of the Aspart injection.

Buccal and nasal insulin

Insulin therapies absorbed through the buccal route of administration and currently in clinical development include Ora-Lyn^® (Generex), which uses the aerosol delivery system RapidMist^®. This permits the delivery of a fine spray directly onto the buccal mucosa in a manner similar to that of an angina spray. Ora-Lyn has recently demonstrated the ability to achieve stable glucose parameters in patients with type 1 diabetes as documented by improvements in 6-point glucose daily profiles and protein glycosylation parameters.[6] This agent has already been approved for clinical use in Ecuador.

Nasal epithelium provides a very low bioavailability of insulin and is sensitive to intercurrent local infections and irritation. Surfactants and other absorption enhancers increase bioavailability, but have not led to a viable delivery system due to disturbances to the integrity of the nasal epithelium.[7] The use of bioadhesive nasal gel containing insulin may enhance contact between the drug and the absorptive sites in the nasal cavity as well as direct absorption of medicament through the nasal mucosa, and is currently being investigated.[8]

Implanted peritoneal insulin infusion pumps

The goal of implanted peritoneal infusion pumps is to develop a closed-loop system to re-create normal physiologic patterns, thus reducing the risk of hypoglycemia, preventing complications, and improving quality of life.[9] The intraperitoneal route has been found to deliver reliable and reproducible insulin levels. Insulin is absorbed more rapidly through the intraperitoneal route with lower peripheral insulin levels. An implanted device now approved for use in the US is produced by Medtronic, Inc. This device allows programming of basal rates and telemetry control of bolus delivery. In addition, recent advances linking subcutaneous glucose sensors and external insulin pumps combined with insulin delivery algorithms are beginning to facilitate a fully automated closed-loop system.[10]

Glucagon-like peptide-1 (GLP-1)

GLP-1 is a potent glucose-dependent insulinotropic hormone that is secreted by the intestinal L-cells in response to carbohydrate and fat consumption. It has important effects on gastric motility, satiety, suppression of plasma glucose levels, and possibly on the stimulation of glucose disposal in peripheral tissues.[11] The actions of GLP-1 are mediated by GLP-1 receptors, which are located in the pancreatic islet, the stomach, lung, and neural tissue. GLP-1 regulates glucose concentrations by stimulating the β-islet cells as well as by influencing gastric emptying and more directly by inhibition of glucagon secretion. Table 2 summarizes the currently accepted mechanisms of GLP-1 regulated glucose homeostasis.

Table 2. Mechanism of GLP-1 regulated glucose homeostasis [11]

GLP-1 is rapidly inactivated in a matter of minutes by the enzyme dipeptidyl peptidase IV (DPP-IV), limiting the therapeutic use of naturally-occurring GLP-1.[12,13] Two approaches have been taken to use the insulinotropic and glucose-lowering effects of GLP-1 for the treatment of diabetes: the development of DPP-IV-resistant incretin mimetics and the inhibition of DPP-IV.¹³

GLP-receptor agonists

Exenatide has been approved for use in patients with type 2 diabetes whose hyperglycemia was not adequately controlled by their present therapies.[14,15] Other GLP-receptor agonists currently in development include liraglutide (NN2211) a long-acting GLP-receptor analog designed for once-daily injection; CJC-1134, a modified analog of exendin-4 conjugated to recombinant human albumin that is in early stage clinical trials;  AVE0010 (formerly known as ZP-10), which has completed phase 2a clinical trials[16]; and LY548806, a GLP-1 derivative designed to avoid rapid proteolysis by DPP-IV.[17] Other GLP-receptor agonists entering into or currently in early stage in clinical development include GSK716155 (albumin-glucagon-like peptide-1, GLP-1, formerly known as Albugon), R1583 (BIM 51077), and GLP1-I.N.T.  

DPP-IV inhibitors

No DPP-IV inhibitors have been approved in the US, but DPP-IV inhibitors currently in clinical trials include sitagliptin[18], vildagliptin[19], saxagliptin (BMS-477118)[20], and PHX1149.[21] Sitagliptin is an orally active and selective DPP-IV inhibitor in phase 3 development for the treatment of type 2 diabetes. A recent trial in healthy male volunteers demonstrated that sitagliptin inhibits plasma DPP-IV activity and increases active GLP-1 concentrations in a dose-dependent manner without producing hypoglycemia and was well tolerated at multiple doses.¹⁸ Vildagliptin is a competitive and reversible inhibitor of DPP-IV and has been shown to improve glycemic control both as monotherapy and in combination with metformin for periods of up to 52 weeks in subjects with type 2 diabetes.[19] Saxagliptin (BMS-477118) is a highly potent, long-acting, orally active DPP-IV inhibitor currently in clinical trials for treatment of type 2 diabetes.[20] PHX1149 is currently in phase 1b trials for type 2 diabetes.[21]

Islet cell transplantation

Islet cell transplantation has been attempted since the beginning of the 20th century. Islet cell transplantation initially was believed to be a simple process and expected to rapidly replace whole pancreas transplantation. The applicability of islet cell transplantation was hampered by a variety of technical and biological obstacles.[22] Reports from the International Islet Registry indicate that of the 267 islet allografts performed on patients with type 1 diabetes, only 12% achieve insulin-independence and only 8% remain insulin-independent beyond 1 year.[23] Successful islet transplantation depends on the infusion of sufficiently large quantities of islets, of which approximately 30% become stably engrafted. Rapid and adequate revascularization of transplanted islets is important for islet survival and function.

In a landmark study published in 2000, Shapiro et al reported 7 consecutive patients treated with islet transplants under the Edmonton protocol, all of whom maintained insulin independence out to 1 year.[24] The key points present by the Edmonton group are presented in Table 3.

Table 3. Key points from Edmonton protocol [24]

Since that seminal experiment, progress has been made in transplant techniques related to pancreas procurement, transportation (with the oxygenated 2-layer method) and in isolation of islets (with controlled enzymatic perfusion and subsequent digestion in the Ricordi chamber). Several new pharmacologic agents that promise to promote islet cell survival and growth are in development.[22]

One study evaluated whether the addition of vascular endothelial growth factor (VEGF) to murine islets can cause angiogenesis and vascularization.[25] This trial determined that VEGF given to mice along with anti-insulin and anti-CD31 antibodies revealed a relatively higher insulin content and greater degree of microvasculature in the VEGF vector-transduced islet grafts. The overall outcome appeared to be improved blood glucose profiles and enhanced insulin secretion in response to glucose challenge. The results of this trial suggest that angiogenic growth factors may be explored further as a strategy to accelerate islet revascularization and improve long-term survival of functional islet mass posttransplantation.

Rimonabant

Rimonabant is a cannabinoid-1 receptor antagonist and represents a novel class of agents that may have efficacy in the treatment of factors associated with the metabolic syndrome. Rimonabant is currently in clinical development for the treatment of metabolic risk factors, weight reduction, and smoking cessation.[26,27]

At the 2005 annual meeting of the American Diabetes Association, investigators reported the results the RIO-Diabetes clinical trial.[28] In this trial, 1045 individuals with type 2 diabetes were randomized to receive 5 mg of rimonabant, 20 mg of rimonabant, or placebo. All patients were on noninsulin diabetic therapy (metformin or a sulfonylurea drug). After 1 year, the 20 mg group demonstrated significant reductions in weight and waist circumference. Body weight decreased by 1.4 kg in the placebo group, 2.3 kg in the 5 mg group, and 5.3 kg in the 20 mg group. A1C decreased by 0.7% more in the 20 mg group compared to the placebo group. In addition, a goal A1C of <6.5 % was achieved in 20% of patients on placebo and 43% of those who received 20 mg of rimonabant.

In a subsequent analysis of the RIO-Diabetes data, researchers evaluated the efficacy of rimonabant therapy in patients taking either metformin (65%) or sulfonylureas (35%).[29] Rimonabant 20 mg/day was found to significantly improve cardiometabolic risk factors independent of whether patients were receiving metformin or sulfonylureas.

In addition, in nondiabetic overweight/obese patients, rimonabant 20 mg/day has been found to significantly improve oral glucose tolerance compared with placebo.[30] Of the patients with normal glucose tolerance at baseline, fewer progressed to impaired or diabetic glucose tolerance at 1 year in the rimonabant 20 mg/day group than in the placebo group (P = .019), suggesting that rimonabant may also be useful in preventing the development of type 2 diabetes.

Diabetic microvascular complications

Protein kinase C β (PKC β)

Hyperglycemia activates several pathways leading to the development of diabetic microvascular complications. One hypothesis examines the role of PKC β in the development and progression of diabetic microvascular complications. PKC β overactivation is expressed in all 3 diabetic microvascular complications (retinopathy, nephropathy, neuropathy). PKC β activation is believed to stimulate the activation of several enzymes also resulting in the development of diabetic microvascular complications. Inhibition of these pathways could possibly slow or halt the progression of complications. One PKC β inhibitor, ruboxistaurin (Lilly), is currently in phase 3 clinical trials. Ruboxistaurin is a specific inhibitor of PKC β1 and PKC β2 and has been shown to prevent and reverse microvascular complications.[31] Results from recent clinical trials involving ruboxistaurin are highlighted in Table 4.

Table 4. Ruboxistaurin clinical trial results

References

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21. Guler H-P, Juarez JC, Van Vliet A, et al. PHX1149, an orally available, potent and selective dipeptidyldipeptidase 4 (dpp4) inhibitor: two week dosing study in normal volunteers. American Diabetes Association 66th Scientific Sessions. June 9-13, 2006. Washington, DC. Abstract 2017-PO.
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