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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EThis article explains the medical need of \u201cwarp-speed\u201d (ultrarapid absorption) insulin. Also included are a review or slow-release insulins and new versus old delivery systems.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EInsulin\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EHyperglycemia\/Hypoglycemia\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EA great deal of progress is being made in the area of insulin therapy. The goal of these new therapeutic approaches is to address three distinct needs: 1) the need for so-called \u201cwarp-speed insulins\u201d as an improvement over rapid-acting formulations, 2) the need for a more efficient, long-acting basal insulin, and 3) the need to reduce or eliminate the use of needles.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EMichael Weiss, MD, PhD, Case Western Reserve University, Cleveland, OH, explained the medical need of \u201cwarp-speed\u201d (ultrarapid absorption) insulin. \u201cWarp-speed insulins\u201d may mimic first-phase insulin secretion more efficiently to prevent immediate postprandial hyperglycemia. Additionally, they may reduce late postprandial hypoglycemia and the pharmacokinetic (PK) variability that is currently observed within and between patients.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EThe technical hurdle to achieving these goals is to stabilize the aggregate form of insulin prior to administration while at the same time ensuring rapid dissociation of injected hexameric complex to the therapeutically active insulin monomer. Methods to achieve rapid absorption have included delivery systems (microneedle patch), chemical accelerants (EDTA\/citrate; VIAject), the use of an enzymatic environment (hyaluronidase co-injection), and protein engineering [Forst T et al. \u003Cem\u003EDiabetes Care\u003C\/em\u003E 2010; Muchmore DB et al. \u003Cem\u003EJ Diabetes Sci Technol\u003C\/em\u003E 2010; Weiss MA. \u003Cem\u003EVitam Horm\u003C\/em\u003E 2009].\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EDr. Weiss\u0027s work at Case Western focuses primarily on this last approach, with the practical aim of not only producing a more rapid onset of action but also developing a temperature-stable insulin molecule that could be distributed in areas that lack refrigeration, such as in underdeveloped nations. His work using an amino acid linker technology has yielded lead compounds that do not rely on zinc (contrary to other preparations) and are stable over several days at room temperature [Hua QX et al. \u003Cem\u003EJ Biol Chem\u003C\/em\u003E 2008]. Investigations that concern these types of compounds are ongoing.\u003C\/p\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003ESlow-Release Insulin\u003C\/h2\u003E\n         \u003Cp id=\u0022p-6\u0022\u003ESatish K. Garg, MD, University of Colorado, Denver, CO, reviewed pipeline candidates of slow-release insulin. While acknowledging the currently available treatment options of insulin glargine and insulin detemir as viable choices for long-acting basal coverage, the development of next-generation compounds is necessitated by the need for a \u201ctrue\u201d 24-hour therapeutic effect with less hypoglycemia and better A1C control and without the potential for weight gain. Novel candidates include degludec, basal insulin therapy, \u201csmart\u201d insulin, and the transdermal insulin patch.\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EDegludec is a recombinant human insulin with a single-base deletion and an added 16-carbon fatty acid moiety. Degludec forms soluble multihexamer assemblies after subcutaneous injection. In the first of three studies that were reported at the American Diabetes Association 70\u003Csup\u003Eth\u003C\/sup\u003E Annual Scientific Session 2010, degludec demonstrated equivalent duration with less glycemic variation compared with insulin glargine (IGlar) in a euglycemic clamp investigation [Jonassen IB et al. ADA 2010 Abstract #0039].\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EA second study that compared degludec and IGlar in combination with insulin aspart in type 1 diabetes mellitus (T1DM) patients showed that at 16 weeks, degludec was similar to IGlar with regard to glycemic control. However, degludec demonstrated superiority over IGlar for incidence of hypoglycemia (RR, 0.72; 95% CI, 0.52 to 0.99; n=177) [Luigi F et al. ADA 2010 Abstract #0559-P].\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EA similar study, looking at activity in T2DM patients with both comparators taken in combination with metformin (n=122), also showed similar glucose control. There was a nearly 50% reduction in hypoglycemic episodes for degludec versus IGlar (RR, 0.44; 95% CI, 0.15 to 1.25) [Zinman B et al. ADA 2010 Abstract #0040]. Phase III trials for this compound are ongoing.\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003ESmart insulin refers to ongoing efforts to develop a compound that is able to sense and respond to glycemic levels in the body. The molecular technique is based on insulin with built-in pairs of boronates and polyols that can produce soluble high-molecular-weight self-assemblies under control by carbohydrates [Hoeg-Jensen T et al. \u003Cem\u003EJ Am Chem Soc\u003C\/em\u003E 2005]. This approach is currently entering Phase I trials.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003ENew (Old) Delivery Systems\u003C\/h2\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EWilliam Cefalu, MD, Pennington Biomedical Research Center, Baton Rouge, LA, reviewed recent findings for insulin formulas that are being tailored to perform in noninjection delivery systems. The rationale for such efforts is that alternative insulin delivery has the potential to increase compliance while inducing better metabolic control. The possible routes of administration are nasal, sublingual, buccal, oral, inhaled, and intraperitoneal.\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EThe challenges of the intranasal approach are the need for a permeability enhancer, low bioavailability, and nasal irritation. Benefits include rapid onset of action and a significant reduction in postprandial glycemia (p\u0026lt;0.001) [Coates PA et al. \u003Cem\u003EDiabet Med\u003C\/em\u003E 1995]. A recent study that evaluated the pharmacokinetics of nasal insulin demonstrated that an ultrarapid-acting intranasal insulin formulation was effective at varying concentrations (0.7% and 1% concentration) and that dose flexibility was feasible. A dose response was observed, as measured by baseline-adjusted maximum concentration C(max) of 22, 27, 56, 62, and 84 muU\/ml for the 25-, 35-, 50-, 70-, and 100-U doses (p\u0026lt;0.0001), respectively, and by baseline-adjusted area under the curve (AUC; 0\u201345 min) values of 491, 592, 1231, 1310, and 1894 muU\/ml\/min (p\u0026lt;0.0001) [Stote R et al. \u003Cem\u003EJ Diabetes Sci Technol\u003C\/em\u003E 2010].\u003C\/p\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EBiopotency for intranasal insulin was confirmed in a study that compared intranasal insulin and the oral insulin lispro in T1DM patients [Stote R. et al. ADA 2010 Abstract #520-P]. However, a Phase II investigation of intranasal insulin + oral therapy versus oral therapy alone in T2DM subjects failed to meet the primary endpoints of a 0.7% mean reduction in HbA1C and mean reduction in 2-hour postprandial blood glucose of at least 20 mg\/dL (n=90). A follow-up study that used CGM to control for uneven data contribution throughout the course of a day did show significant efficacy (p\u0026lt;0.001), though current development of this method awaits partnering [CPEX Pharmaceuticals. AACE Meeting 2010].\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EThe buccal route of administration takes advantage of the mucosal area in the back of the throat. Though this tissue is not amenable for peptide transport, buccal insulin uses a microfine preparation of encapsulated insulin micelles to overcome the barrier. Biopotency of buccal insulin therapy was demonstrated in 2005, and equivalence to subcutaneous insulin was shown in a small study in 2007 [Guevara-Aguirre B et al. \u003Cem\u003EDiabetes Technol Ther\u003C\/em\u003E 2007]. Phase III trials of this insulin strategy in T1DM are ongoing.\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003EOral insulin appears to be the most attractive to patients. However, this approach has the most physiological barriers to overcome, and multiple formulations with liposomes, protease inhibitors, and absorption promoters have been attempted [Dhawan S et al. \u003Cem\u003EPharmTech\u003C\/em\u003E 2009]. New formulations that have demonstrated proof of principle have recently emerged [Kapitza C et al. \u003Cem\u003EDiabetes Care\u003C\/em\u003E 2010; Heinemann L et al. \u003Cem\u003EJ Diabets Sci Technol\u003C\/em\u003E 2009]. An insulin conjugate molecule, IN-105, is currently in a Phase III study.\u003C\/p\u003E\n         \u003Cp id=\u0022p-16\u0022\u003EIn a small study that was highlighted at the ADA 2010, an oral insulin demonstrated proof of principle and the ability to be effective, irrespective of timing of meals, in T1DM [Eldor R et al. ADA 2010 Abstract #521]. Additionally, the development of a hepatic-directed vesicle oral insulin that targets the liver in an attempt to restore the liver\u0027s key function of storage\/release of glucose is currently underway. Proof of principle has been demonstrated, and a Phase IIB trial was recently completed [Schwartz S et al. \u003Cem\u003EDiabetes\u003C\/em\u003E 2009].\u003C\/p\u003E\n         \u003Cp id=\u0022p-17\u0022\u003EDr. Cefalu closed with a review of data for inhalable insulin therapies. Using an insulin particle of 2\u20135 microns, an inhaled insulin is able to penetrate deep into the lungs, where it is rapidly absorbed. In a large dataset that was presented at ADA 2010, T2DM subjects were randomized to either prandial inhaled insulin plus bedtime insulin glargine or twice-daily biaspart insulin for 1 year (n=667). The safety and tolerability profile was similar for both treatments. However, those who received inhaled insulin plus glargine demonstrated an increased occurrence of cough and change in pulmonary function [Rosenstock J et al. \u003Cem\u003ELancet\u003C\/em\u003E 2010].\u003C\/p\u003E\n         \u003Cp id=\u0022p-18\u0022\u003ERegarding safety, inhaled insulin was superior to biaspart insulin for total incidence of hypoglycemia (p\u0026lt;0.0001), and the formation of antibodies, though observed, did not appear to impact glucose control [Rosenstock J et al. \u003Cem\u003ELancet\u003C\/em\u003E 2010; Rosenstock J et al. \u003Cem\u003EDiabetes\u003C\/em\u003E 2006]. Effect on FEV\u003Csub\u003E1\u003C\/sub\u003E was reported as \u201cslight\u201d initially and nonprogressive over time [Petrucci R et al. \u003Cem\u003EDiabetologia\u003C\/em\u003E 2009]. Patients also exhibited less weight gain with inhaled insulin versus subcutaneous insulin [Rosenstock J et al. \u003Cem\u003EDiabetes\u003C\/em\u003E 2006].\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2010 MD Conference Express\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/10\/6\/33.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzmrld\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}