A. M. Deane

Deane

M. Horowitz

Schwartz

Umpierrez

Diabetes Care

English

Deane, A.

Horowitz, M.

Adelaide Research & Scholarship

ACCEPTED VERSION Deane, Adam Matthew; Horowitz, Michael  Comment. Is incretin-based therapy ready for the care of hospitalized patients with type 2 diabetes? Diabetes Care, 2014; 37(2):e40-e41 “This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes Care. The American Diabetes Association (ADA), publisher of Diabetes Care, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes Care in print and online at http://care.diabetesjournals.org ”   © 2014 by the American Diabetes Association                       http://hdl.handle.net/2440/82068  PERMISSIONS http://care.diabetesjournals.org/site/misc/PoliciesCare.pdf  From Publication Policies and Procedures for Diabetes Care (Last updated 30 January 2014). 13-14  Reuse, Post-Prints, and Public Access  Authors are permitted to reuse portions of their ADA-copyrighted work, including tables and figures, in their own work, and to reuse portions or all of their ADA-copyrighted work for educational purposes, without submitting a request to ADA, provided that the proper citation and copyright information is given.   Authors are permitted to submit the final, accepted version of their manuscript to their funding body or institution for inclusion in their funding body or institution's database, archive, or repository, or to post the final, accepted version on their personal website. These manuscripts may be made freely accessible to the public upon acceptance, provided that the following two conditions are observed:  First, post-prints must include the following statement of provenance and, once the final version has been published in the journal, a link to the final published version of the paper on the journal's website:  “This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes Care. The American Diabetes Association (ADA), publisher of Diabetes Care, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes Care in print and online at http://care.diabetesjournals.org.”   Second, the version of the manuscript deposited or posted must be identical to the final accepted version, with the exception of the addition of the above statement and any changes necessary to correct errors. Authors may make changes to the posted version to correct mistakes or may issue an erratum at any time. However, the final published version of the manuscript may not be deposited, posted, or later substituted for the post-print.      Title  Comment on: Is Incretin-Based Therapy Ready for the Care of Hospitalized Patients With Type 2 Diabetes?  Running Title Incretin-Based Therapy & Hospitalized Patients   Authors Adam M Deane1,2 MBBS PhD Michael Horowitz3 MBBS PhD  1 Discipline of Acute Care Medicine, University of Adelaide, North Terrace, Adelaide, South Australia, Australia 5000. 2 Intensive Care Unit, Level 4, Emergency Services Building, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia 5000. 3 Discipline of Medicine, University of Adelaide, Royal Adelaide Hospital Level 6 Eleanor Harrald Building, North Terrace, Adelaide, South Australia Australia 5000.  Corresponding Author: Adam M Deane Email: adam.deane@adelaide.edu.au Phone: +61 8 8222 2818 Intensive Care Unit, Level 4, Emergency Services Building, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia 5000 Word Count: 490 Number of tables and figures: 0     Dear Sir, We read with interest the narratives by Schwartz and DeFronzo (1) and Umpierrez and Korytkowski (2) relating to the use of incretin-based therapy in the care of hospitalized patients with hyperglycemia. We have performed a number of mechanistic studies to evaluate incretin-based therapies in the critically ill that were not referred to (3-5). In these exogenous glucagon-like peptide-1 (GLP-1) was shown to attenuate the glycaemic response to enteral nutrient in mechanically-ventilated critically ill patients both with, and without, pre-existing type 2 diabetes, and associated with stimulation of serum insulin and suppression of plasma glucagon (3; 5). Enteral nutrition can be administered directly into the stomach or small intestine, and the route of feeding is a major determinant of glucose-lowering that occurs with GLP-1. We observed that GLP-1 slows gastric emptying when the emptying rate is relatively ‘normal’, but not when emptying is already abnormally slow, which is often the case in the critically ill (4).    It is recognized that the use of insulin has substantial limitations, particularly as excess dosing precipitates hypoglycemia and, despite sophisticated algorithms, glycemic variability remains a major problem (1; 6). GLP-1 also has potential advantages over insulin, including putative beneficial cardiac effects, and its use has the capacity to reduce nursing workloads (1; 2). Neither narrative, however, discussed the concept that hyperglycemia is not the same insult in every patient, rather, that patients with critical illness-induced hyperglycemia should potentially be treated differently to those patients with pre-existing hyperglycemia, associated with diabetes, that is exacerbated by critical illness (6). Rapid glucose-lowering with, or without, overt hypoglycemia may indeed be harmful in the latter group, and the capacity of GLP-1 to lower glycemia more gradually may lead to improved outcomes (6). Another potential advantage is that there is no impediment to intravenous administration of an agent in the critically ill. Nauck and colleagues have recently summarized the evidence that intravenous administration of GLP-1 or its agonists may be more effective, with less adverse events, than subcutaneous administration (7). While the ‘normalization’ of glycemia did not occur in all critically ill patients we studied, we have not observed hypoglycemia or vomiting following intravenous administration of GLP-1 in this group (3-5).  While we agree with Schwartz and DeFronzo (1) that the use of incretin-based therapies in hospitalized patients is appealing, our experience would support the view of Umpierrez and Korytkowski (2) that insulin is a proven therapy, albeit one with major limitations, and should currently remain the treatment of choice. We suggest that additional data relating to: (i) optimizing incretin-based regimens - such as whether the intact peptide, agonists, dipeptyl-peptidase 4 (DPP-4) inhibitors and/or glucose-dependent insulinotropic polypeptide should be used; (ii) whether GLP-1/agonists are effective as monotherapy (which we would favour) and, if so, which patients will respond, or which are more appropriately treated using GLP-1/agonists in combination with insulin; and (iii) cardiovascular safety, should be sought promptly, as this information is important prior to wide-spread use of incretin-based regimens in hospitalized patients.     References 1. Schwartz S, Defronzo RA: Is Incretin-Based Therapy Ready for the Care of Hospitalized Patients With Type 2 Diabetes?: The time has come for GLP-1 receptor agonists! Diabetes Care 2013;36:2107-2111 2. Umpierrez GE, Korytkowski M: Is Incretin-Based Therapy Ready for the Care of Hospitalized Patients With Type 2 Diabetes?: Insulin therapy has proven itself and is considered the mainstay of treatment. Diabetes Care 2013;36:2112-2117 3. Deane AM, Chapman MJ, Fraser RJ, Burgstad CM, Besanko LK, Horowitz M: The effect of exogenous glucagon-like peptide-1 on the glycaemic response to small intestinal nutrient in the critically ill: a randomised double-blind placebo-controlled cross over study. Crit Care 2009;13:R67 4. Deane AM, Chapman MJ, Fraser RJ, Summers MJ, Zaknic AV, Storey JP, Jones KL, Rayner CK, Horowitz M: Effects of exogenous glucagon-like peptide-1 on gastric emptying and glucose absorption in the critically ill: relationship to glycemia. Crit Care Med 2010;38:1261-1269 5. Deane AM, Summers MJ, Zaknic AV, Chapman MJ, Fraser RJ, Di Bartolomeo AE, Wishart JM, Horowitz M: Exogenous glucagon-like peptide-1 attenuates the glycaemic response to postpyloric nutrient infusion in critically ill patients with type-2 diabetes. Crit Care 2011;15:R35 6. Deane AM, Horowitz M: Dysglycaemia in the critically ill - significance and management. Diabetes, Obesity & Metabolism 2013; in press 7. Nauck MA, Baranov O, Ritzel RA, Meier JJ: Do current incretin mimetics exploit the full therapeutic potential inherent in GLP-1 receptor stimulation? Diabetologia 2013; in press  

Defronzo RA: Is Incretin-Based Therapy Ready for the Care of Hospitalized Patients With Type 2 Diabetes?: The time has come for GLP-1 receptor agonists! Diabetes Care

Do current incretin mimetics exploit the full therapeutic potential inherent in GLP-1 receptor stimulation? Diabetologia

Dysglycaemia in the critically ill - significance and management.

Effects of exogenous glucagon-like peptide-1 on gastric emptying and glucose absorption in the critically ill: relationship to glycemia. Crit Care Med

Exogenous glucagon-like peptide-1 attenuates the glycaemic response to postpyloric nutrient infusion in critically ill patients with type-2 diabetes. Crit Care

Is Incretin-Based Therapy Ready for the Care of Hospitalized Patients With Type 2 Diabetes?: Insulin therapy has proven itself and is considered the mainstay of treatment.

The effect of exogenous glucagon-like peptide-1 on the glycaemic response to small intestinal nutrient in the critically ill: a randomised double-blind placebo-controlled cross over study. Crit Care

Comment. Is incretin-based therapy ready for the care of hospitalized patients with type 2 diabetes?

Adam M. Deane

Michael Horowitz

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Comment. Is Incretin-Based Therapy Ready for the Care of Hospitalized Patients With Type 2 Diabetes?

http://digital.library.adelaide.edu.au/dspace/bitstream/2440/82068/1/hdl_82068.pdf

Comment. Is incretin-based therapy ready for the care of hospitalized patients with type 2 diabetes?

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