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Review Article

EP13471.RA

USE OF INCRETIN-BASED THERAPY IN HOSPITALIZED PATIENTS WITH HYPERGLYCEMIA Guillermo E. Umpierrez, MD1, and Stanley Schwartz, MD2 Running title: Incretin-based therapy in hospitals

From: 1Professor of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA; 2 Affiliate, Main Line Health System, and Clinical Associate Professor of Medicine, Emeritus, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Correspondence Address: Guillermo E. Umpierrez, MD Professor of Medicine, Emory University School of Medicine 49 Jesse Hill Jr. Drive, Atlanta, Georgia 30303 USA E-mail: [email protected]

DOI:10.4158/ EP13471.RA © 2014 AACE.

ABSTRACT Objective: Hyperglycemia is common in hospitalized patients with and without prior history of diabetes and is an independent marker of morbidity and mortality in critically and non-critically ill patients. Tight glycemic control using insulin has been shown to reduce cardiac

morbidity and mortality in hospitalized patients, but also results in hypoglycemic episodes, which have been linked to poor outcomes. Thus, alternative treatment options that can normalize blood glucose levels without undue hypoglycemia are being sought. Incretin-based therapies, such as glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors, may have this potential. Methods: A PubMed database was searched to find literature on the use of incretins in hospital settings. Title searches included the terms diabetes (care, management, treatment), hospital, inpatient, hypoglycemia, hyperglycemia, glycemic, incretin, dipeptidyl peptidase (DPP)-4 inhibitor, glucagon-like peptide (GLP)-1, and GLP-1 receptor agonist. Results: The preliminary research experience with native GLP-1 therapy has shown promise, achieving improved glycemic control with a low risk of hypoglycemia, counteracting the hyperglycemic effects of stress hormones, and improving cardiac function in patients with heart failure and acute ischemia. Large, randomized controlled clinical trials are necessary to show whether these favorable results will extend to the use of GLP-1 receptor agonists and DPP-4 inhibitors. Conclusions: This review offers hospitalist physicians and healthcare providers involved in inpatient diabetes care a pathophysiologic-based approach for the use of incretin agents in patients with hyperglycemia and diabetes, as well as a summary of benefits and concerns of insulin and incretin-based therapy in the hospital setting. Key words: incretin; DPP-4; GLP-1; inpatient; hospital; hyperglycemia DOI:10.4158/ EP13471.RA © 2014 AACE.

INTRODUCTION Hyperglycemia is a common and serious health care problem in hospitals, reported in approximately 30% of general medicine and surgery patients with and without a history of prior diabetes mellitus (1-3). Extensive evidence indicates that hyperglycemia is associated with an increased risk of complications, a longer hospital or intensive care unit (ICU) stay, and higher mortality (3,4). The results of observational and randomized controlled trials have also shown that improvement in glycemic control with insulin therapy in critically ill, general medicine, and surgery patients reduces hospital complications (4-7). Recent trials and meta-analyses, however, have shown that intensified insulin therapy increases the risk for severe hypoglycemia (8-10), which has been associated with increased morbidity and mortality (11). Thus, while an insulin-based approach is the current standard of care for achieving glycemic control in hospitalized patients (3,12), the concern about the risk of hypoglycemia as well as potential cardiovascular risks has led to a search of alternative treatment options, such as incretin-based therapy (13-15). Incretins are known to stimulate insulin secretion in a glucose-dependent fashion, thus not causing hypoglycemia when used as monotherapy. In addition, increasing evidence indicates that incretin therapy results in metabolic and cardiovascular benefits, including reduced inflammation and oxidative stress (12,14), improved endothelial function, and improved left ventricular (LV) function, which could benefit critically ill patients (16). This review offers hospitalist physicians and health care providers involved in inpatient diabetes care a pathophysiologic-based approach for the use of incretin agents in patients with hyperglycemia and diabetes, as well as a summary of benefits and concerns of insulin and incretin-based therapy in the hospital setting.

DOI:10.4158/ EP13471.RA © 2014 AACE.

HYPERGLYCEMIA IN HOSPITALIZED PATIENTS — A MAJOR MEDICAL ISSUE IRRESPECTIVE OF DIABETES STATUS Patients with diabetes have a 3-fold greater chance of hospitalization than those without diabetes (3,17). An estimated 20% of adult patients admitted to the hospital have a diagnosis of diabetes, with 30% requiring 2 or more hospitalizations in any given year (17). The exact prevalence of hyperglycemia in hospitalized patients with or without diabetes is unknown, but has been reported to be 32% to 38% in community hospitals (3,18) and 60% to 80% in critically ill and cardiac surgery patients (7,19). There is a strong association between hyperglycemia and complications occurring in hospitalized patients with or without a history of diabetes (4,20,21). This association is well documented for the glucose level upon hospital admission and also for the mean glucose level during the hospital stay (4). Cross-sectional studies have shown that the risk of complications and mortality relates to the severity of hyperglycemia, with a higher risk observed in patients without a history of diabetes (new onset and stress-induced hyperglycemia) than in those with a known diagnosis of diabetes. It is estimated that each 18-mg/dL rise in admission fasting plasma glucose is associated with a 33% increase in mortality (22). In studies of patients undergoing cardiac surgeries, it was reported that those with hospital blood glucose values >200 mg/dL had higher mortality, more wound infections, and longer hospital stays than those with lower values, irrespective of pre-existing diabetes (23,24). A variety of biochemical mechanisms are thought to contribute to the detrimental effects of hyperglycemia in the context of acute illness. The development of hyperglycemia leads to generation of reactive oxygen species (ROS), lipid peroxidation, and elevated cardiovascular inflammatory markers. It also increased pro-inflammatory cytokine such as tumor necrosis factor- α (TNFα), interleukin (IL)-6, and IL-1, which ultimately alter the immune system (25,26). TNFα mediates insulin resistance DOI:10.4158/ EP13471.RA © 2014 AACE.

by interfering with insulin receptor signaling (27) or synthesis and/or translocation of the glucose transporter GLUT-4 to the plasma membrane (28). Acute hyperglycemia may also induce cardiac myocyte death through apoptosis or by exaggerating ischemia-reperfusion cellular injury (29). In addition, hyperglycemia-induced abnormalities in hemostasis including increased platelet activation, adhesion, and aggregation (30), reduced plasma fibrinolytic activity, and increased plasminogen activator inhibitor-1 activity (31). Many of these processes are thought to contribute to the increase in mortality observed in hospitalized patients experiencing hyperglycemia (32).

CURRENT STANDARD THERAPY Insulin, given intravenously or subcutaneously, is the preferred therapeutic agent for blood glucose control in the hospital setting. Intravenously (IV) administered insulin is most beneficial to critically ill patients with or without a history of diabetes (12,15). Because of the short half-life of circulating insulin, IV delivery allows rapid dosing adjustments to address alterations in patient status. Insulin infusion is ideally administered via validated written or computerized protocols that allow for predefined adjustments to the insulin infusion rate according to glycemic fluctuations and insulin dose (12). For most critically ill patients, a starting threshold of no higher than 180 mg/dL is recommended. Once IV insulin is started, the glucose level should be maintained between 140 and 180 mg/dL (12). Target levels less than 110 mg/dL are not recommended due to the risk of hypoglycemia. Clinical guidelines stress that patients should be monitored closely for hypoglycemia and that insulin protocols should undergo modification, as necessary, to prevent hypoglycemia (Table 1).

DOI:10.4158/ EP13471.RA © 2014 AACE.

In non-ICU settings, scheduled subcutaneous insulin therapy with basal analogues (glargine or detemir) or intermediate acting insulin (NPH) given once or twice a day in combination with regular or rapid-acting insulin analogues (lispro, aspart or glulisine) administered prior to meals is preferred as an effective strategy for glucose control in patients with T2DM. The practice of using sliding scale regular insulin, as a single regimen, to correct hyperglycemia should be avoided as it results in poor control, increased glycemic variability, and increased risk of hospital complications. In insulin-naïve patients, a starting insulin dose of 0.3 to 0.5 units per kg/day is recommended. Elderly patients or those with renal insufficiency (eGFR < 60 ml/min) should be started on a total daily dose ≤ 0.3 units per kg/day. Patients with adequate oral intake should receive a basal bolus regimen divided half as basal and half as prandial insulin. Patients with inadequate oral intake or who will be kept NPO should receive a daily dose of basal insulin (0.15 0.25 units/kg/day) and rapid-acting insulin analogues as correctional insulin coverage for glucose >140 180 mg/dl. Clinical guidelines recommend targeting a glucose level

Use of incretin-based therapy in hospitalized patients with hyperglycemia.

Hyperglycemia is common in hospitalized patients with and without prior history of diabetes and is an independent marker of morbidity and mortality in...
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