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New Developments in Insulin Therapy for Type 2 Diabetes Christopher Sorli, MD, FACE Department of Diabetes, Endocrinology and Metabolism, Billings Clinic, Billings, Mont. ABSTRACT Insulin has classically been considered a treatment of last resort for individuals with type 2 diabetes, delayed until all other efforts by the patient and healthcare provider have failed. Recent treatment guidelines recommend the use of insulin, in particular basal insulin, as part of a treatment regimen earlier in the disease process. Many patients are reticent about initiating insulin, so therapies that allow insulin treatment to be more tailored to individual needs are likely to result in greater acceptance and patient adherence with therapy. To meet this need, a range of insulin products are in development that aim to increase absorption rate or prolong the duration of action, reduce peak variability and weight gain associated with insulin treatment, and offer alternative delivery methods. This review describes insulin products in clinical development, new combination therapies, and new devices for insulin delivery. Ó 2014 Elsevier Inc. All rights reserved. The American Journal of Medicine (2014) 127, S39-S48 KEYWORDS: Basal insulin; Insulin; Type 2 diabetes Exogenous insulin is well established as the primary and lifesaving therapy for type 1 diabetes. Individuals with type 2 diabetes initially are treated with lifestyle changes including diet and exercise,1-3 but treatment intensification because of declining beta-cell function usually is required and blood glucose may become inadequately controlled with oral glucose-lowering treatments or incretin-based therapies only. At this stage, supplementary insulin therapy typically is added, but insulin has classically been considered the final treatment option for individuals with type 2 diabetes.1-3 As treatment guidelines and insulin products are refined, however, it is increasingly being recognized that insulin may be used at an earlier stage in the management of type 2 Funding: The publication of this manuscript was funded by Novo Nordisk Inc. Conflict of Interest: CS is a member speaker bureau for AstraZeneca, Novo Nordisk, Eli Lilly, and Bristol Meyers Squibb; has received research support from Eli Lilly, Novo Nordisk, Sanofi, MannKind, and GI Dynamics; and is on the advisory board for GI Dynamics and Novo Nordisk. Authorship: The author takes full responsibility for the content of this manuscript. Writing support was provided by Watermeadow Medical. Requests for reprints should be addressed to Christopher Sorli, MD, FACE, Department of Diabetes, Endocrinology and Metabolism, Billings Clinic, Billings, MT 59101. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2014.07.006 diabetes. Recent treatment guidelines emphasize individualized therapy, acknowledging the difficulties associated with lifestyle therapy and the progressive nature of the disease. Some patients are recommended to include insulin, in particular basal insulin, as a component of treatment earlier in the disease process. In this way, the role of basal insulin changes from one of damage control in an inevitably progressive disease to one of preventative care, with the ability to modify the disease process in a positive way.4 Because many patients are reluctant to initiate multiple daily injections of insulin, insulin initiation often involves basal-only therapy in conjunction with existing oral glucoselowering drugs. Used as supplementary therapy, insulin can rest beta-cells and facilitate recovery of the prandial response; however, early intensive therapy may offer advantages in beta-cell preservation in type 2 diabetes.5 Patient-friendly, effective, and safe therapies that allow insulin treatment to be fully tailored to individual needs will significantly influence adherence to therapy. This review describes insulin products in clinical development, new combination therapies, and new devices for insulin delivery. NEW BASAL INSULIN PRODUCTS The currently available basal insulin analogs, insulin glargine (Lantus; Sanofi, Paris, France) and insulin detemir (Levemir; Novo Nordisk Inc, Plainsboro, NJ), offer an S40 The American Journal of Medicine, Vol 127, No 10A, October 2014 improvement over neutral protamine Hagedorn insulin in terms of duration of action and reduced peak effect.6-8 However, they still demonstrate suboptimal/nonideal pharmacokinetic and pharmacodynamic properties.9 A basal insulin ideally will provide a continuous and flat glucoselowering effect over 24 hours in all patients, with low day-to-day variability (reducing the risk of hypoglycemia) and once-daily dosing for all. Both insulin glargine and insulin detemir need to be injected at the same time each day; this can make adherence difficult for patients who have varying daily schedules. As discussed by Tibaldi,10 insulin degludec (Tresiba; Novo Nordisk Inc) is a novel basal insulin comprising recombinant DesB30 human insulin acylated at the LysB29 residue with a hexadecandioyl-g-L-Glu side-chain that has a unique mode of protraction.11,12 The pharmacokinetic/pharmacodynamic profile of insulin degludec confers reduced variability at similar efficacy to insulin glargine, with a lower risk of nocturnal hypoglycemia and the ability to dose more flexibly.13-18 Insulin degludec is approved for use in several regions, including Europe, Japan, and Mexico, and regulatory filings in several other countries have been submitted. Approval in the United States is conditional on a satisfactory outcome in a dedicated cardiovascular safety trial.19 The molecular structure of insulin degludec permits the production of a co-formulation containing 70% insulin degludec and 30% insulin aspart (Ryzodeg; Novo Nordisk Inc), which has been approved in Europe, Japan, and Mexico, with product availability anticipated during 2014. In combining the long duration of action of insulin degludec with the rapid-acting insulin analog, insulin aspart (NovoRapid/NovoLog; Novo Nordisk Inc), this product aims to provide 24 hours of basal insulin coverage with additional post-prandial blood glucose control for 1 meal per day. Several new insulin products are in clinical development. PEGYLATED INSULIN LISPRO (LY2605541) Exogenously administered insulin is prone to glomerular filtration and therefore to significant renal clearance. PEGylated insulin lispro (PEG-lispro; Eli Lilly and Company, Indianapolis, Ind) is a novel basal insulin comprising lispro covalently bound to a 20 kDa polyethylene glycol chain (PEG) at lysine B28, resulting in a large hydrodynamic size. PEGylation appears to alter the tissue distribution of this insulin, delay absorption, and reduce renal clearance as incorporation of water molecules into hydrophilic structures increases the effective size of the molecule beyond the filtration potential of the kidney. These effects increase the duration of action to >36 hours.20,21 Endogenous insulin is secreted into the portal vein and travels directly to the liver, where approximately 80% is extracted.22 Exogenous insulin is absorbed into the systemic circulation, leading to high concentrations in peripheral tissue, which may account for weight gain associated with insulin treatment.23 It is proposed that the large size of PEGlispro may reduce transport into peripheral tissue, such as adipose tissue.24 Moore et al25 have postulated that the fenestrated sinusoidal endothelium of the liver may allow preferential transport of PEG-lispro into the liver relative to peripheral tissues, and a clamp study in dogs suggested that PEG-lispro had a preferential hepatic versus peripheral effect on glucose metabolism. Clamp studies have shown that PEG-lispro has a longer duration of action and less variability compared with insulin glargine.21,26 In phase II trials, once-daily PEG-lispro (administered in the morning) provided similar blood glucose levels to insulin glargine, with less variability. In one study, the overall percentage of patients with type 2 diabetes reporting nocturnal hypoglycemia was similar with PEG-lispro and insulin glargine (25.6% vs 34.4%, P ¼ .127); however, there was a rate reduction of 48% in favor of PEG-lispro when data were adjusted for baseline differences (P ¼ .021).24 Furthermore, patients receiving PEGlispro lost weight (mean [standard deviation {SD}] weight loss, 0.6 [0.2] kg, P ¼ .007), whereas patients receiving insulin glargine gained weight (mean [SD] weight gain, 0.3 [0.2] kg, P ¼ .662; treatment difference: 0.8 kg, P ¼ .001). In a phase II study in patients with type 1 diabetes, the overall hypoglycemia rate was 12% higher with PEG-lispro than insulin glargine (mean [SD] events/patient/30-day period: 8.74 [7.70] vs 7.36 [6.80]; P ¼ .037).27 However, the nocturnal hypoglycemia rate was 25% lower with PEGlispro in this study (0.88 [1.22] vs 1.13 [1.42] events/patient/ 30-day period; P ¼ .012). Consistent with the study in patients with type 2 diabetes, PEG-lispro was associated with a mean weight loss of 1.20 kg (P < .0001), whereas insulin glargine was associated with a mean weight gain of 0.69 kg (P ¼ .0007) (least-squares mean difference, e1.89 kg) (P < .0001).27 In both studies, enzyme levels used for liver function tests (alanine aminotransferase and aspartate aminotransferase) were increased in the PEG-lispro versus the insulin glargine treatment groups.24,27 Larger phase III clinical trials with PEG-lispro are ongoing, including a randomized clinical trial of PEG-lispro used in basalebolus therapy in type 2 diabetes (NCT 0146898728), which was completed in August 2013, and publication of data is awaited. HIGH-DOSE FORMULATIONS Many patients with type 2 diabetes are obese and may display insulin resistance, requiring high doses of insulin. Increasing the insulin concentration reduces the injection volume and potentially reduces the number of injections needed to deliver the required dose. However, changing the concentration may alter the pharmacodynamic profile because the surface area of the depot in contact with the interstitial fluid is reduced, which may slow absorption. A 500 U/mL formulation of human insulin was shown to have significantly delayed absorption in pigs when compared with a 100 U/mL formulation.29 Clinical studies of a 300 U/mL formulation of insulin glargine (U300) by Sanofi are under way, and phase I and II Sorli Insulin Developments for Type 2 Diabetes trials are complete. In a single-dose clamp study the U300 formulation had a flatter profile, with less fluctuation in individual glucose infusion rates, than U100 insulin glargine, and full blood glucose control was maintained until the end of the clamp (36 hours).30 Exposure and bioactivity after injection of U300 were reduced approximately 40% compared with exposure and bioactivity after administration of the same amount (0.4 U/kg) of insulin glargine U100.31 Likewise, in a study conducted at steady state, the U300 insulin glargine formulation had a flatter profile and longer duration of action compared with the U100 insulin glargine formulation.32 The first insulin glargine U300 phase III results in patients with type 2 diabetes using basalebolus therapy were recently presented (EDITION I [NCT0149908233] and EDITION II [NCT0149909534]). In EDITION I, insulin glargine U300 was noninferior in terms of glycated hemoglobin (HbA1c) reduction and associated with a 21% reduction in the incidence rate of confirmed (>70 mg/dL) and severe nocturnal hypoglycemia from months 3 to 6 compared with insulin glargine U100.35 EDITION II showed similar reductions in HbA1c (e0.57% and 0.56%) with insulin glargine U300 versus insulin glargine U100, but the rate of severe hypoglycemia was significantly 23% lower with U300 from months 3 to 6.36 Additional phase III studies (EDITION III [NCT0167622037]) in patients with type 2 diabetes comparing insulin glargine U300 with U100 are ongoing, whereas other phase III studies are currently recruiting patients (EDITION I Japan [NCT0168912938] and EDITION IV [NCT0168326639]). A 400 U/mL formulation of recombinant human insulin (BIOD-530; Biodel Inc, Danbury, Conn) is in development for patients with insulin resistance. BIOD-530 has a faster rate of absorption and onset of action compared with 500 U/mL human insulin.40 The formulation contains disodium ethylenediaminetetraacetic acid, as well as citrate and magnesium sulfate, which have been shown in multiple clinical studies to mitigate injection site pain associated with ethylenediaminetetraacetic acid. Insulin degludec is manufactured in a high-dose formulation (200 U/mL), as well as the 100 U/mL formulation, but this insulin is unique in that the 2 formulations do not show different pharmacodynamic profiles.41 Insulin degludec forms soluble multi-hexamers on subcutaneous injection, resulting in a depot from which monomers are slowly and continuously absorbed to provide an ultra-long action profile in which the monomer release rate is the limiting factor.11,42,43 A 26-week randomized, controlled trial in insulin-naïve patients with type 2 diabetes reported similar HbA1c reductions with insulin degludec U200 compared with insulin glargine U100.44 The fasting plasma glucose reduction was slightly, but significantly, greater with insulin degludec (e67 vs e61 mg/dL, P ¼ .02), whereas hypoglycemia occurred at lower rates with insulin degludec versus insulin glargine (not significant). S41 ULTRAeRAPID-ACTING INSULINS In contrast to basal insulins, rapid-acting insulins are designed to be absorbed quickly over a short interval and are taken before meals to limit postprandial hyperglycemia; thus, they attempt to mimic the physiologic prandial insulin response. Current rapid-acting insulin analogs (aspart, lispro, and glulisine [Apidra; Sanofi]) offer an improvement over soluble human insulin in terms of faster onset, shorter duration of action, and greater predictability. Faster-acting insulin aspart is a new ultraerapid-acting formulation of insulin aspart being developed by Novo Nordisk that has entered phase III trials. These trials will compare fasteracting insulin aspart with insulin aspart in basalebolus therapy in patients with type 1 diabetes (onset 1 NCT0183176545) and in basalebolus therapy plus metformin in patients with type 2 diabetes (onset 2 NC T0181912946). A further trial will compare basalebolus therapy with faster-acting insulin aspart with a basal-only regimen, both with metformin (NCT0185061547) in patients with type 2 diabetes. Compared with current prandial insulins, the faster onset of action is expected to better mimic the immediate prandial insulin response seen in people without diabetes. Another ultraerapid-acting bolus insulin in development is BIOD-123 (Biodel Inc, NCT0190889448 and NCT0 168662049), which is a formulation of recombinant human insulin. Magnesium sulfate is added to BIOD-123 as an excipient, accelerating absorption and reducing injection site reactions.50 In an ongoing phase II trial, this formulation demonstrated significantly faster absorption rates compared with insulin lispro (NCT0168662049). ADDITION OF HYALURONIDASE A further approach to increasing the speed of insulin absorption is to combine it with human recombinant hyaluronidase.51 Hyaluronidase enzymes speed up the dispersion and absorption of co-administered molecules by momentarily breaking down the interstitial barrier. Clamp studies investigating human recombinant hyaluronidase with insulin lispro or human insulin51 or insulin aspart, glulisine, and lispro52 showed that the addition of hyaluronidase accelerated insulin exposure, producing an ultraerapid-action profile in healthy subjects.51,52 Data consistent with these healthy volunteer studies also were obtained in patients with type 1 diabetes.53 Addition of hyaluronidase has been shown to result in decreased intra-subject variability of pharmacokinetic end points.54 NEW TREATMENT COMBINATIONS: COMBINING INSULIN AND INCRETIN THERAPY At the time of diagnosis, beta-cell function is compromised by up to 50% in patients with type 2 diabetes.55 Glycemic targets may be achieved in 50% to 60% of patients with type 2 diabetes using basal insulin alone.56 For those unable to achieve glycemic targets, further intensification is required S42 The American Journal of Medicine, Vol 127, No 10A, October 2014 to reduce post-prandial glucose levels,57,58 and prandial insulin injections often are added to basal insulin. Although highly efficacious, multiple daily injections of insulin therapy are associated with an increased risk of hypoglycemia,59 weight gain, and the need for frequent blood-glucose monitoring. The American Diabetes Association/European Association for the Study of Diabetes and American Association of Clinical Endocrinologists position statements consider incretin-based therapies a possible alternative to insulin initiation after failure of lifestyle changes and metformin in patients with type 2 diabetes,60,61 and there is increasing interest in the use of these drugs in combination with insulin. The incretin hormone glucagon-like peptide-1 is secreted into the circulation by intestinal cells in response to caloric intake. Glucagon-like peptide-1 has multiple effects, including glucose-dependent stimulation of insulin secretion and suppression of glucagon secretion, reduced gastric emptying, and increased satiety.62 Incretin-based therapies include dipeptidyl peptidase-4 inhibitors, such as sitagliptin, linagliptin, and saxagliptin, and glucagon-like peptide-1 receptor agonists, such as exenatide, liraglutide, and lixisenatide. Incretin-based therapies tend to augment the prandial insulin response and induce independent mechanisms to reduce postprandial hyperglycemia, and they have an advantage over prandial insulin analogs in that they incur a lower risk of hypoglycemia and are not associated with weight gain. In the case of glucagon-like peptide-1 receptor agonists, there is typically a degree of weight loss, and they may slow disease progression by helping to preserve residual beta-cell function.63 Long-acting glucagon-like peptide-1 receptor agonists have been associated with gastrointestinal side effects, including nausea, vomiting, and diarrhea, but the side effects typically diminish over time and can be avoided by gradual escalation of the dose. The combination of insulin and incretin-based therapies is an attractive option because it is likely to increase the number of patients reaching glycemic target compared with a glucagon-like peptide-1 receptor agonist or basal insulin alone, while having a lower risk of hypoglycemia and weight gain than basal insulin alone or multiple daily injections of insulin.64,65 The glucose-dependent effect of a glucagon-like peptide-1 receptor agonist is expected to augment the prandial insulin response and limit postprandial hyperglycemia. Supplementary basal insulin also would help to control fasting plasma glucose and rest the betacell to allow for a better post-prandial response. CO-ADMINISTRATION OF INCRETIN AND INSULIN THERAPY Studies show that the combination of incretin-based therapies with basal insulin is a viable alternative to introducing prandial insulin injections in patients with inadequately controlled diabetes by either therapy alone. In addition to the benefits associated with incretin-based therapies discussed previously, the synergistic nature of the combination allows the administration of a lower dose of insulin, contributing to reductions in risk of hypoglycemia and weight gain. Retrospective analyses of patients with inadequately controlled type 2 diabetes who were co-prescribed insulin glargine and exenatide suggest that regardless of treatment order, long-term combined therapy with insulin glargine and exenatide reduces HbA1c without significant weight gain or increased hypoglycemia risk.66,67 Similar outcomes have been demonstrated in patients receiving once-daily lixisenatide as an add-on to basal insulin.68,69 Saxagliptin as an addition to metformin and basal insulin was shown to improve HbA1c (difference in adjusted mean HbA1c: e0.41%, P < .0001) and post-prandial blood glucose (difference in 120minute post-prandial glucose: e23.0 mg/dL, P ¼ .0016) at 24 weeks compared with placebo without increasing the rate of hypoglycemia.70 Rosenstock et al71 recently published results from a 52-week study showing that the addition of insulin detemir to liraglutide and metformin led to significant further improvements in glycemic control in patients who had failed to reach target using liraglutide and metformin alone. Compared with continuation on liraglutide and metformin alone, the addition of insulin detemir significantly reduced HbA1c (e0.51%; 95% confidence interval [CI], 0.70 to 0.31; P < .0001) and fasting plasma glucose (e1.77 mg/dL; 95% CI, e2.24 to e1.30; P < .0001) by the end of the study. Weight loss observed during the run-in period with liraglutide and metformin (e3.5 kg) was maintained over 52 weeks in patients adding insulin detemir (weight change: e0.05 kg in this period). In the control group randomly assigned to continue on liraglutide and metformin alone, weight decreased further over the same period (1.02 kg, estimated treatment difference: 0.97 kg; 95% CI, 0.04-1.91; P ¼ .04). The rate of hypoglycemia was higher in patients adding insulin detemir than in the control patients (0.23 events/patient-year vs 0.03 events/patientyear, respectively), but these rates are nevertheless both low.71 The study of basal insulin plus incretin therapy recently has been extended to investigate the feasibility of using a glucagon-like peptide-1 receptor agonist as an alternative to prandial insulin. One such study, of 26 weeks’ duration, randomized patients whose type 2 diabetes remained inadequately controlled (HbA1c 7.0%) after 2 years of treatment with insulin degludec plus metformin to receive additional once-daily liraglutide or once-daily insulin aspart (taken with the largest meal).72 In this study, addition of liraglutide resulted in a significantly greater improvement in HbA1c compared with insulin aspart (estimated treatment difference: 0.32%; 95% CI, 0.53 to 0.12; P ¼ .0024) and an 87% reduction in the rate of total hyperglycemia (1.00 vs 8.15 episodes/patient-y of exposure, respectively, P < .0001). In addition, patients adding liraglutide benefited from a mean weight loss of 2.8 kg, whereas those adding Sorli Insulin Developments for Type 2 Diabetes S43 insulin aspart gained on average 0.9 kg (estimated treatment difference: 3.8 kg; 95% CI, 4.7 to 2.8; P < .0001).72 controlled with metformin and glucagon-like peptide-1 receptor agonist therapy. COMBINATION INSULIN/INCRETIN THERAPY: INSULIN DEGLUDEC/LIRAGLUTIDE INSULIN GLARGINE/LIXISENATIDE FIXED COMBINATION Given the promising outcomes of studies in which basal insulin and incretin therapies have been used together, products are now being developed in which the 2 components are combined in a single pharmaceutical formulation for convenient administration in a single injection. One product combining insulin degludec and liraglutide (IDegLira; Novo Nordisk Inc) contains a fixed ratio of 1 unit of degludec and 0.036 mg of liraglutide per unit drug. Data have been reported from a 26-week trial (DUAL I) involving patients with type 2 diabetes, which compared IDegLira with insulin degludec alone and liraglutide alone, each as an addition to metformin with or without pioglitazone.73 The IDegLira combination product showed superior HbA1c reductions compared with insulin degludec or liraglutide alone, and fasting plasma glucose reductions were significantly greater with IDegLira than with liraglutide. Post-prandial glucose control was significantly better with IDegLira compared with insulin degludec alone, and similar to that achieved with liraglutide alone.73 The risk of hypoglycemia was significantly lower with IDegLira versus insulin degludec alone (rate ratio, 0.68) but significantly higher compared with liraglutide alone (rate ratio, 7.61) (both P < .0001)73; however, compared with liraglutide alone there were fewer gastrointestinal adverse events in patients receiving IDegLira. In a second 26-week, double-blind trial (DUAL II) in patients with inadequately controlled diabetes who were taking basal insulin and oral antidiabetic agents, superior HbA1c (estimated treatment difference: 1.1%, P < .0001) and fasting plasma glucose reductions (63 mg/dL vs 47 mg/dL, P ¼ .0019) were observed with IDegLira compared with insulin degludec. Moreover, mean 9-point glucose profiles were significantly (P < .0001) lower with IDegLira (135.2 mg/dL) than with insulin degludec (157 mg/dL), as was the mean prandial increment across meals (IDegLira: 40 mg/dL vs insulin degludec: 43 mg/dL, P ¼ .026).74 These results suggest that the IDegLira combination may result in a substantial improvement in glycemic control with a low risk of hypoglycemia and weight gain, providing a convenient way for patients to intensify their therapy with a low injection frequency. A marketing authorization application for this product was submitted to the European Medicines Agency, who have recently adopted a positive opinion, recommending marketing authorization for IDegLira for the treatment of adults with type 2 diabetes. Two further trials of IDegLira are currently under way or recently completed: NCT0161816275 (DUAL IV) is a placebocontrolled trial investigating the addition of IDegLira to oral therapies in poorly controlled type 2 diabetes, and NCT0167611676 (DUAL III) compares IDegLira with liraglutide or exenatide in patients with type 2 diabetes poorly Another basal insulin/glucagon-like peptide-1 receptor agonist fixed-dose combination product, namely, insulin glargine/lixisenatide, is in clinical development by Sanofi. A 24-week phase II trial (NCT0147647577), which compared this combination with insulin glargine alone and with metformin in patients with type 2 diabetes, has been completed, but the results have not been presented. Sanofi has been developing a combination product of insulin glargine and lixisenatide in which each of the 2 components can be dosed flexibly, because it may be an advantage if the dose of one component is not “controlled” by the dose of the other. However, because of technical difficulties, Sanofi has suspended the development of the “flex-dose” product at the present time. DEVELOPMENTS IN INSULIN ADMINISTRATION For many patients, administering insulin by subcutaneous injection seems like a daunting therapy option, and as a result there may be procrastination over insulin initiation. Consequently, research is being undertaken on alternative methods for administering insulin. Oral insulin may offer a welcome alternative by facilitating insulin initiation and increasing patient adherence to treatment. A potential advantage of oral insulin is that insulin absorbed via the gut will undergo hepatic first-pass metabolism with reduced peripheral exposure, thereby replicating the physiologic route of insulin distribution.78 Oral insulin is particularly indicated for the early stages of type 2 diabetes, when slowing disease progression may be possible by providing the pancreas with some respite. However, the reduced bioavailability and low reproducibility that result when insulin is required to cross the gastrointestinal tract mucosa have hampered efforts in this field.79 A liquid spray of recombinant human insulin (Oral-lyn; Generex Biotechnology Corp, Toronto, Ontario, Canada) is currently in phase III trials (NCT00948493,80 NCT0066885081). Delivered transbuccally using a “RapidMist” device that delivers 10 U of insulin per spray, Orallyn is rapidly absorbed (15 minutes), reaching a maximum concentration after approximately 30 minutes and returning to baseline after 2 hours. The large size of the micelle spray particles (>10 mm) prevents entry into the lungs.82 Therefore, the exact mechanism of absorption is not fully elucidated, and only approximately 10% of the dose is absorbed; rates of absorption are expected to differ in different regions of the oral cavity. Pre-prandial oral insulin capsules (ORMD-0801; Oramed Pharmaceuticals Inc, Jerusalem, Israel) are being investigated. A recent pilot study showed that the addition of oral insulin to stable insulin treatment was well tolerated in S44 The American Journal of Medicine, Vol 127, No 10A, October 2014 8 patients with poorly controlled type 1 diabetes. Overall glucose exposure was reduced by 16.6% (vs pretreatment records) during continuous glucose monitoring.83 A small study in healthy individuals showed an inverse correlation between blood glucose levels and 2 doses of the oral insulin capsule.84 In 2013, the Food and Drug Administration (FDA) granted clearance for Oramed to proceed with phase II trials of the drug in the United States. INHALED INSULIN Inhaled human insulin (rDNA origin) (Afrezza; MannKind Corp, Valencia, Calif) is an ultraerapid-acting insulin that uses Technosphere drug delivery technology whereby regular human insulin molecules are absorbed onto Technosphere (powder) particles as charge-masked monomers. The particles are inhaled using breath-activated inhalers containing pre-metered unit doses of insulin and become a liquid on contact with the neutral pH of the alveolar epithelium. Afrezza onset of action is faster than that of recombinant human insulin; maximum concentration is achieved after 15 minutes, approximately 2 hours earlier than for recombinant human insulin and approaching the timing of physiologic prandial insulin release.85,86 Maximum post-prandial plasma glucose concentration is approximately 40% lower with Afrezza than with recombinant human insulin.85,86 Rosenstock et al87 have published results from a study comparing twice-daily premixed (biphasic) insulin aspart (70% insulin aspart protamine suspension and 30% insulin aspart of rDNA origin) with prandial Afrezza inhaled insulin plus bedtime insulin glargine. Similar HbA1c reductions (between-group difference: 0.07%; 95% CI, e0.13 to 0.27), a reduced incidence of hypoglycemia (47.99% vs 68.88%; odds ratio, 0.417; 95% CI, 0.303-0.573; P < .0001), and less weight gain (treatment difference: e1.6 kg; 95% CI, e2.4 to e0.7; P ¼ .0002) were reported with Afrezza/insulin glargine than with the premix regimen. No major safety issues were identified in the 302 patients using Afrezza; however, an increased incidence of cough and respiratory events was observed; these were described as nonprogressive and unlikely to be clinically meaningful. The pulmonary safety of Afrezza was investigated over 2 years and compared with regular clinical practice. No significant differences in pulmonary function were detected between groups, but there was a decline in function in both groups over the treatment period.88 Transient mild cough was reported with Afrezza, likely due to airway irritation from the powder. Afrezza was denied US FDA approval in 2011, but resubmission is expected. A rapid-acting inhaled human insulin (Exubera; Pfizer, New York, NY) has been used to treat type 1 and type 2 diabetes in adults, was withdrawn in 2007 because of disappointing global sales. A warning was subsequently issued to include information about lung cancer cases observed in patients who used Exubera. Over the course of a clinical trial, 6 of 4740 Exubera-treated patients developed lung cancer, compared with 1 of 4292 patients not treated with Exubera. An additional case of lung cancer in an Exubera-treated patient was discovered after approval of the drug by the FDA. All patients who developed lung cancer had a history of cigarette smoking, and there were insufficient cases to determine a causal relationship between the use of Exubera and the development of lung cancer; however, concern over these data led to the termination of all further development of the drug. PUMP THERAPY Continuous subcutaneous insulin infusion pumps currently are used by 20% of 25% of patients with type 1 diabetes in the United States,89 and they offer a reduction in hypoglycemia and modest improvements in HbA1c compared with multiple daily injections.90 Patch pumps are new-generation insulin infusion pumps that deliver continuous insulin, with the possibility of adding bolus mealtime doses. A middle ground between syringe/insulin pens and a full pump system, patch pumps are smaller and, in general, easier to operate than conventional pumps. Pump therapy can be coupled to continuous glucose monitoring, enabling minuteby-minute adjustment of insulin dose. By improving delivery and simplifying treatment regimens for patients, patch pumps may offer an option for those who struggle to control their blood glucose or who have recurrent hypoglycemia with injections of insulin analogs. Several patch pumps are currently marketed, including the OmniPod (Insulet Corp, Bedford, Mass) and V-Go (Valeritas Inc, Bridgewater, NJ) (as reviewed by Ramchandani and Heptulla91). Potential drawbacks to pump therapy include high costs, patient training requirements, and reliability concerns. In a 30-day study of the OmniPod system in 20 patients with type 1 diabetes, 18 of 20 patients (90%) stated a preference for the OmniPod over their current infusion set. HbA1C values at day 30 were significantly lower (mean, 6.8%; range, 5.4-7.6; P < .002) than at baseline.92 In a subsequent 1-year, proof-of-concept trial in 21 patients with type 2 diabetes requiring insulin treatment, HbA1c level 7.0%, and severe insulin resistance, it was demonstrated that treatment with insulin U500 via the OmniPod system significantly reduced HbA1c by 1.23% (P < .001) and significantly increased the percentage of time spent in the blood glucose target range (70e180 mg/dL) by 70.75% as assessed by continuous glucose monitoring (P < .001) without a significant increase in hypoglycemia. At the end of the study period, 14 of 20 patients who completed the study elected to remain on treatment.93 The V-Go system is aimed at a type 2 diabetes population requiring basal and bolus insulin. In a retrospective analysis of glycemic control in 23 patients who used the V-Go system for 12 weeks, the mean patient rating of the overall experience at 12 weeks was 9.1 (on a scale from 1 to Sorli Insulin Developments for Type 2 Diabetes 10, where 10 is most positive).94 Mean HbA1c decreased from baseline (from 8.8% to 7.6%; P ¼ .005) while using the V-Go system and increased to 8.2% 12 weeks after the end of the trial.94 FUTURE IDEAS The “holy grail” for treatment of advanced type 2 diabetes requiring insulin treatment or type 1 diabetes is to create a closed loop system, or “artificial pancreas,” that releases insulin according to the patient’s needs, as reviewed by Hovorka89 (Figure 1). Such a device would comprise a continuous glucose monitoring system, an insulin pump, and a control algorithm that facilitates the delivery of the correct amount of insulin. Initially, these systems will be aimed at those with recurrent hypoglycemia and children who struggle to manage their diabetes; however, they have the potential to benefit all patients. The Medtronic 530G with Enlite technology system (Medtronic, Northridge, Calif) has recently launched in the United States after FDA approval.95 The system provides a threshold suspend feature that will automatically stop insulin delivery when a preset low blood glucose value is detected by the continuous glucose monitor. More complex systems are still being tested in vivo and are several years from clinical use. In addition, ultraerapid-acting insulins may be better suited to closedloop systems than currently available insulins. Several studies have investigated glucose-sensitive insulin, which uses a gel-based system to control the release of insulin. The preparation contains glucose oxidase, catalase, Figure 1 Depiction of a closed-loop insulin delivery system. A sensor (black rectangle) identifies and transmits interstitial glucose data to a controller (red box), which runs a control algorithm and interacts with the user. An insulin pump (blue box) subcutaneously delivers a rapid-acting insulin analogue. Insulin delivery is modulated in real-time by the control algorithm. Communication between system components is wireless. Reproduced with permission from Hovorka.89 S45 and insulin.96 Glucose diffuses into the gel and is converted to gluconic acid, leading to swelling of the gel and the release of insulin. An in vivo rodent model study showed that the gel-based insulin delivery provided glucose control and was well tolerated; however, a mechanism for refill is required for future models.97 CONCLUSIONS Because of the increasing prevalence of type 2 diabetes and the earlier age of onset, the need to intensify treatment to manage glycemia is expanding. 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