Hospital Practice: Volume 37: No.1

Review of the Outpatient Literature with Implications for Use in the Hospital and After Discharge

Bruce Bode, MD, FACE And Alpesh Amin, MD,FACP,FHM

Abstract: A large percentage of critically ill adult inpatients have type 2 diabetes, which may be undiagnosed or uncontrolled during hospitalization. Hyperglycemia complicates the therapeutic management of inpatients and leads to adverse outcomes, and intensive glycemic control with insulin reduces morbidity and mortality. Insulin therapy, however, is labor-intensive and time-consuming. More important, long-standing protocols such as the sliding scale do not provide adequate glucose control. Although more research is needed to determine the best methods for treating hyperglycemia in-hospital, the importance of achieving better glycemic control while reducing the risk of hypoglycemia has been demonstrated. Post-discharge diabetes care is equally important, as it is essential in improving long-term outcomes after a hospital stay. Hospital care providers can play an important role in effective antihyperglycemic regimens in patients with diabetes prior to discharge. Post-discharge management is a formidable challenge because of the availability of an array of oral antidiabetes agents, including metformin, sulfonylureas, and thiazolidinediones, each with distinct therapeutic and adverse event profiles. Incretin-based therapies offer a potentially useful option for post-discharge therapy, and possibly for inpatient diabetes treatment. Incretins are effective, safe, and well-tolerated; they are easier for patients to use compared with insulin injections (eg, continual glucose monitoring is not required); and they may provide long-term improvement of cardiovascular parameters and β-cell function. This review examines the challenges to achieving glycemic control in the hospital setting and summarizes clinical data on the efficacy and safety of incretin-based therapies in their use in the hospital and after discharge.

Keywords: type 2 diabetes; glucagon-like peptide-1 receptor agonists; dipeptidyl peptidase-4 inhibitors; critical care

A substantial proportion of critically ill adult inpatients have type 2 diabetes, which may remain undiagnosed or uncontrolled during their hospital stay.^1,2 Type 2 diabetes has a high and rising prevalence in the general population, and comorbidities and complications associated with diabetes—obesity, cardiovascular disease, renal dysfunction, neuropathy, and visual impairment—place patients at increased risk of hospitalization. In 2007, the total direct cost for diabetes in the United States was $116 billion, with 50% of the overall direct costs spent on hospitalizations.³ Both uncontrolled hyperglycemia and stress hyperglycemia in these hospitalized patients can lead to increased morbidity and mortality.

Observational studies have shown that previously diagnosed diabetes, newly diagnosed diabetes, and stress hyperglycemia are very common in the hospital. A retrospective review of records from a community teaching hospital found a history of diabetes prior to admission in 26% of admitted patients, and another 12% had newly diagnosed hyperglycemia, defined as an admission or in-hospital fasting plasma glucose (FPG) level > 126 mg/dL or a random blood glucose level > 200 mg/dL on ≥ 2 determinations.¹ A prospective cohort trial conducted at an acute care general hospital indicated that 19% (n = 136; 127 with type 2 diabetes) of newly admitted patients had previously diagnosed diabetes, and 18% (n = 123) had probable undiagnosed diabetes (ie, a glycated hemoglobin [HbA_1c] > 6.1% and no diagnosis or treatment before or during admission).² Of 1199 patients admitted to 1 of 2 Midwestern hospitals for acute coronary syndrome, 27% were previously diagnosed with diabetes. Among the remaining group (n = 878), 14% had an in-hospital FPG level (≥ 126 mg/dL) indicative of diabetes, and 29% met the criterion for impaired fasting glucose (FPG 100–125 mg/dL) during their stay. Only 35% of patients found to have diabetes during their hospital stay received a diabetes diagnosis at discharge, and no patient with newly discovered impaired fasting glucose received a corresponding diagnosis.⁴

The correct assessment and management of diabetes in the hospital is complicated by the fact that severe illness or trauma may exacerbate hyperglycemia in diabetes patients, or even induce hyper-glycemia in patients without diabetes (ie, stress hyperglycemia). The etiologic mechanisms underlying stress hyperglycemia are complex and are not fully characterized.⁵ Medications associated with the treatment of acute illness (eg, high-dose corticosteroids) are also known to increase the incidence of hyperglycemia.⁶ Nonetheless, the results of a recent study suggest that hyperglycemia at admission to the emergency department should warrant suspicion for diabetes. A prospective study of 541 emergency department admissions compared plasma glucose levels obtained for the purpose of clinical management with the results of HbA_1c testing, which provides a weighted average of glucose levels over several preceding months and is highly specific for identifying diabetes. Patients with a previous history or current symptoms of diabetes were excluded from the sample. The results yielded a significant correlation between plasma glucose and HbA_1c levels (r = 0.60; P < 0.001). Among patients with a plasma glucose level ≥ 110 mg/dL, 22.4% also had elevated HbA_1c (≥ 6.2%), whereas only 7.6% of those with plasma glucose < 110 mg/dL had elevated HbA_1c. Those with plasma glucose ≥ 200 mg/dL had a high risk (85%) for having HbA_1c ≥ 6.2%.⁷

Regardless of whether elevated blood glucose is attributable to undiagnosed diabetes or the stress of severe illness or injury, hyperglycemia in the critically ill has been associated with adverse outcomes. A retrospective study of a heterogeneous group of critically ill intensive care unit (ICU) patients (n = 1826) demonstrated increasing hospital mortality as mean glucose levels increased. In patients with mean glucose levels between 80 and 99 mg/dL (n = 264), mortality was 9.6% (n = 25); in those with mean glucose levels > 300 mg/dL (n = 40), mortality reached 42.5% (n = 17).⁸ Glycated hemoglobin predicted hospital mortality and length of stay in diabetes patients with sepsis,⁹ and postoperative hyperglycemia was associated with risk of nosocomial infection in diabetes patients who underwent major surgery.¹⁰ Compared with normoglycemic patients, those with in-hospital hyperglycemia (an FPG level > 126 mg/dL or a random blood glucose level > 200 mg/dL on ≥ 2 determinations) and no prior history of diabetes experienced significantly (P < 0.01) higher rates of ICU admission (29% vs 9%) and in-hospital mortality (16% vs 2%).¹ The correlation of higher glucose levels with worse outcomes has been demonstrated for several categories of hospitalized cardiovascular patients, including patients with acute myocardial infarction,^11-13 those undergoing coronary artery bypass grafting,¹⁴ those with congestive heart failure,¹⁵ and stroke patients.^16,17

Interventional studies have indicated that achieving intensive glycemic control with insulin during hospitalization reduces morbidity and mortality in critically ill patients with or without diabetes. In-hospital insulinization improved outcomes both before and after patient discharge.^18-24 Several recent studies, however, indicated no mortality benefit and an increased risk of hypoglycemic episodes with intensive insulin therapy.^25-28 In some of these studies, severe hypoglycemia (defined as a blood glucose < 40 mg/dL) has been an independent predictor of mortality.^8,21,22 The discrepancy between these results has produced uncertainty about optimal blood glucose-lowering regimens for hospitalized patients, with specific recommendations to avoid severe hypoglycemia. Attempts to explain the divergent results have focused on differences in study designs, including the glycemic targets used, methods of blood glucose monitoring, insulin infusion protocols, and rates of success in achieving glycemic goals.²⁹ Additionally, it has been pointed out that surgical and medical ICU patients may present with differing clinical histories and therapeutic needs.^30,31 Although more research is needed on the optimal methods of treating hyperglycemia in the hospital, the importance of achieving better glycemic control without hypoglycemia has been demonstrated.

As with the diabetes population in general, patients with diabetes discharged from the hospital after critical illness will benefit from long-term glycemic control. Well-designed, large-scale outpatient studies have demonstrated that the incidence of diabetic complications such as retinopathy, neuropathy, and renal dysfunction is decreased in patients who maintain HbA_1c-lowering targets over time.^32,33 Hospital care providers can play an important role in initiating diabetes patients on effective antihyperglycemic regimens before discharge.

In the hospital, insulin therapy is the standard for controlling hyperglycemia, but treatment protocols lag behind research in this area. Insulin has traditionally been initiated in a reactive manner (the “sliding scale”), only when blood glucose tests are indicative of extreme hyperglycemia (eg, > 400 mg/dL),³⁴ even though this approach has been demonstrated as ineffective in providing glucose control.^35,36 As recently as 2007, the sliding scale was still the most frequently used insulin regimen in hospitalized patients.³⁷ Regardless of the insulin protocol used, in-hospital management of patient glucose levels continues to be inadequate and is characterized by unacceptably high levels of glycemia.^38,39

Recommended insulin therapy in the hospital setting includes intravenous infusion, which provides the most rapid onset of effect and is indicated in several clinical situations, such as perioperative or critical care.⁴⁰ In less critical situations when the patient is able to eat, subcutaneous insulin therapy can be administered in a basal-bolus regimen with correction-dose injections of rapid-acting insulin.^40,41 Reluctance to adopt an aggressive, proactive approach to glucose control is due in part to the labor-intensive and time-consuming character of recommended insulin protocols, which require constant blood glucose testing and frequent dose adjustment. As the American College of Endocrinology/American Diabetes Association Task Force on Inpatient Diabetes acknowledged, instituting optimal insulin therapy necessitates hospital administrative support, multidisciplinary care, and provider education.⁴¹ Other obstacles to introducing effective insulin therapy include lack of familiarity among midlevel practitioners (physician assistants and nurse practitioners) on how to use insulin⁴² and a lack of time and resources available to nurses.⁴³ Tight glycemic control for a single patient may necessitate 2 hours of nursing time every 24 hours.⁴⁴

Inadequate therapy for hyperglycemia in the hospital may be followed by suboptimal diabetes care after discharge. The reluctance of hospital care providers to initiate patients on post-discharge antidiabetes regimens is attributable to several reasons. Insulin, in particular, has perceived disadvantages that may limit use, such as the need to teach patients at discharge how to administer treatment⁴⁵ and high outpatient medical resource use associated with insulin therapy without appropriate reimbusement.⁴⁶ Clinicians may perceive a potential for hypoglycemia and weight gain despite the availability of newer insulin formulations that mitigate these adverse effects. Providers may also be reluctant to confront the resistance of patients to initiating insulin because it is an injection that needs titration and follow-up.⁴⁷

Many patients with diabetes will not require insulin therapy after discharge. Determining optimal noninsulin regimens for patients after their hospital stay presents a formidable challenge to hospital-based providers because of the availability of an array of oral antidiabetes agents (eg, metformin, sulfonylureas, thiazolidinediones), each with distinct therapeutic profiles, and the newer incretin-based therapies. In addition, metformin is contraindicated in patients with certain levels of hepatic or renal impairment, sulfonylureas have a high risk of hypoglycemia and weight gain, and thiazolidinediones lead to weight gain and (as demonstrated by recent evidence) cause fluid retention, which may increase the risk of congestive heart failure and lead to a higher risk of fractures.⁴⁸

In view of these considerations, incretin therapies provide a potentially useful option for post-discharge therapy (and possibly also for inpatient diabetes treatment, although clinical studies in this context are needed). Incretins are effective at lowering blood glucose; have good safety and tolerability profiles; are relatively simple for patients compared with insulin injections; and may provide long-term benefits, such as improving cardiovascular parameters and β-cell function.

The 2 known incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are secreted by the lower gut in response to meal ingestion. Glucose-dependent insulinotropic polypeptide and GLP-1 play a key role in maintaining glucose homeostasis under normal physiologic conditions. It has been hypothesized that impairment of GLP-1 and GIP secretion and/or activity might play a role in the pathogenesis of type 2 diabetes. The glucoregulatory effects of endogenous GLP-1 are blunted but partially preserved in type 2 diabetes, whereas the effects of GIP are almost entirely abolished.⁴⁹ Accordingly, this discussion of the physiologic activity of the incretins and the potential of incretin therapies in type 2 diabetes will focus on GLP-1.

The activity of GLP-1 in healthy individuals and patients with type 2 diabetes has been characterized in exogenous infusion studies. Glucagon-like peptide-1 decreases glycemia by: 1) stimulating insulin secretion by pancreatic β-cells in a glucose-dependent manner; 2) inhibiting excessive secretion of glucagon during elevated glycemia as seen in type 2 diabetes; and 3) decreasing the rate of gastric emptying, thus, food absorption.^50-53 In a 3-month study, continuous subcutaneous infusion of GLP-1 reduced blood glucose levels to the same extent as oral antidiabetes therapies in elderly patients with type 2 diabetes and enhanced glucose-induced insulin secretion.⁵⁴ Glucagon-like peptide-1 infusion also restored a more normal temporal pattern of insulin secretion in this population.⁵⁵ The glucose dependence of GLP-1 effects on insulin release was demonstrated in clinical studies comparing GLP-1 and placebo infusions in healthy volunteers, in which GLP-1 stimulated insulin secretion only at elevated blood glucose levels.^56,57 Importantly, GLP-1 infusion also preserved the physiologic counterregulatory response to hypoglycemia in these studies. This property was evidenced by the observation that glucagon secretion, which stimulates hepatic glucose production during hypoglycemia, increased to a similar extent during GLP-1 or placebo infusion as blood glucose levels decreased. The ability of GLP-1 to stimulate insulin secretion in a glucose-dependent manner and preserve the glucagon response to hypoglycemia provides a rationale for the low potential of GLP-1-based therapies to induce hypoglycemic episodes.

The possible utility of GLP-1 in critically ill patients was suggested by a study in which a GLP-1 analogue prevented hyperglycemia in rats subjected to anesthesia and surgical manipulation.⁵⁸ Human data have also indicated therapeutic benefits. Glucagon-like peptide-1 infusion stimulated endogenous insulin secretion and controlled hyperglycemia in severely ill patients with no prior diagnosis of diabetes receiving total parenteral nutrition, reducing plasma glucose from 211 (during placebo treatment) to 150 mg/dL (P < 0.0001).⁵⁹ Glycemic response to enteral nutrient stimulation was attenuated with GLP-1 infusion (glucose area under the curve [AUC]_30–270 minutes = 2077 mmol/L minute) compared with placebo (AUC_30–270 minutes = 2568 mmol/L minute; P = 0.02) in mechanically ventilated critically ill patients not previously known to have diabetes.⁶⁰ In a randomized crossover pilot study done in 8 patients with type 2 diabetes in a clinical research center, intravenous GLP-1 infusion was shown to be superior and more practical than intravenous regular insulin in normalizing glucose levels.⁶¹ Glucagon-like peptide-1 may exert other benefits in hospitalized patients. In a small study conducted in patients with type 2 diabetes and congestive heart failure, GLP-1 infusion significantly improved glycemia and nonsignificantly improved parameters of left ventricular function.⁶² Glucagon-like peptide-1 therapy improved endothelial function in patients with type 2 diabetes and coronary artery disease.⁶³ More research is clearly needed, however, before GLP-1 or GLP-1-derived therapies could be recommended for glucose control in hospitalized patients. The occurrence of nausea in patients receiving GLP-1 infusion,^52,54 for example, suggests a need for caution in the use of GLP-1-based treatments in the hospital. As the next section of this review demonstrates, there are more efficacy and safety data for patients with type 2 diabetes in the community.

Native GIP and GLP-1 have very brief half-lives (~4 minutes and ~2 minutes, respectively) in vivo⁶⁴ because of their rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP-4). The therapeutic use of native GLP-1 requires continuous infusion, whereas the therapeutic use of GIP is limited because of its reduced insulinotropic effect in patients with type 2 diabetes.⁶⁵ Given that continuous infusion of GLP-1 is an impractical approach to long-term diabetes treatment, longer-acting agonists of the GLP-1 receptor and inhibitors of DPP-4 have been developed.

The GLP-1 receptor agonists act by stimulating the GLP-1 receptor while resisting the rapid inactivation that occurs with the circulating native hormone. Dipeptidyl peptidase-4 inhibitors decrease the rate of degradation of endogenous GLP-1 and GIP by the DPP-4 enzyme. Glucagon-like peptide-1 receptor agonists thus provide pharmacologic levels of GLP-1 receptor stimulation greater than those seen with the native hormone, whereas DPP-4 inhibitors preserve endogenous GLP-1 and GIP levels in the physiologic range.⁶⁶ This may be the reason why, in controlled trials, GLP-1 receptor agonists have generally achieved blood glucose reductions greater than those seen with DPP-4 inhibitors (although no clinical studies directly comparing agents from each drug class have been published). It may also account for why the GLP-1 receptor agonists are associated with weight reduction and improvement in surrogate markers of cardiovascular health (outcomes data are as yet unavailable) not seen with DPP-4 inhibitors. Conversely, DPP-4 inhibitors do not carry an increased risk of gastrointestinal symptoms as reported with the GLP-1 receptor agonists.

The following section summarizes glucose-lowering efficacy, safety, and tolerability from large-scale (> 100 patients), randomized, controlled clinical trials of incretin therapies. The review includes agents currently available in the United States or under Food and Drug Administration (FDA) review.

Glucagon-like peptide-1 receptor agonists have demonstrated efficacy as monotherapy and in combination with oral agents (Table 1).^67-93 Hospitalists may consider initiating GLP-1 receptor agonists as post-discharge treatment for diabetes. Glucose-lowering efficacy and the subcutaneous mode of administration are potentially useful in the hospital setting, given that critically ill patients may be unable to ingest medication orally. Moreover, the continual glucose monitoring and subsequent dose adjustment required with insulin are not necessary with GLP-1 receptor agonists, thereby reducing caregiver treatment burden. Research on inpatient use is needed.

Exenatide, which is a synthetic version of a peptide originally obtained from the saliva of the Gila monster, has a 53% amino acid sequence overlap with mammalian GLP-1.⁹⁴ Exena-tide has been shown to share the glucose-lowering effects of endogenous GLP-1 in humans. As with native GLP-1, the agent enhances glucose-dependent insulin secretion while preserving counterregulatory response to decreased glycemia.⁹⁵ Exenatide has also been shown to restore a more normal pattern of insulin secretion in type 2 diabetes.⁹⁶ This drug is currently available for use in the United States. Exenatide has a 2.4-hour half-life; dosing is 5 or 10 μg twice daily, with the requirement that each dose be administered within 60 minutes prior to mealtime.⁹⁷

Exenatide monotherapy in drug-naïve patients with type 2 diabetes decreased HbA_1c at 26 weeks by 0.7% at a dose of 5 μg twice daily and 0.9% at 10 μg twice daily. Reductions in fasting serum glucose were 18 to 19 mg/dL. Daily mean postprandial glucose levels were lowered significantly with exenatide 5 μg and 10 μg twice daily compared with placebo (−21.3 mg/dL and −24.7 mg/dL vs −8.3 mg/dL).⁶⁷ Exenatide appears to have a low potential to induce mild or moderate hypoglycemia (incidence of 4%–5% with 5–10 μg twice daily and no severe events). Transient gastrointestinal symptoms (eg, nausea, 3%–13% incidence) were the most common adverse events.⁶⁷ Exenatide is not indicated for diabetes monotherapy.⁹⁷

In combination with oral antihyperglycemic agents (met-formin, a sulfonylurea, or a thiazolidinedione, used singly or as multiple oral therapies), exenatide 5 or 10 μg twice daily was associated with HbA_1c decreases of 0.4% to 1.5% in randomized controlled studies of 16 to 30 weeks. The decrease in FPG ranged from 5 to 29 mg/dL. Hypoglycemia, minor to moderate in character with the exception of 1 case, occurred in 4.5% to 36% of patients and was most frequent with concomitant sulfonylurea therapy, which is known to increase the risk of hypoglycemia. Nausea was reported by 34% to 51% of patients and generally subsided within the first 8 weeks of treatment.^68-71,93

Improvements in glycemia observed in three 30-week, randomized controlled studies of exenatide added to metformin and/or a sulfonylurea were sustained over 3 years of open-label follow-up.^68,70,93 Reductions from baseline to year 3 were 1% for HbA_1c and 23.5 mg/dL for FPG in patients who continued their randomized treatment.⁹⁸

Regarding patient selection, it should be remembered that exenatide is cleared renally and as such is not recommended for use in severe or end-stage renal impairment.⁹⁷ Exenatide has exhibited a favorable drug interaction profile in relation to statins,⁹⁹ warfarin,¹⁰⁰ digoxin,¹⁰¹ and acetaminophen.¹⁰²

Glucagon-like peptide-1 receptor agonists, as protein-based therapies, can potentially induce the formation of antibodies. Antiexenatide antibodies appeared in 27% to 49% of patients who received exenatide in clinical trials.^67-71,93 The prescribing information notes that glucose-lowering efficacy may be attenuated in patients who exhibit high-titer antibody levels. High-titer antibody levels were reported in 6% of patients in a study of exenatide added to metformin and/or a sulfonylurea, and 9% of those in a study of exenatide added to thiazolidinediones, with or without metformin.⁹⁷

Post-marketing adverse event reports have stimulated the investigation of a possible association of GLP-1 agonists with acute pancreatitis. A recent health insurance database analysis (~28 000 patients), however, yielded no evidence of an increase in risk with exenatide compared with metfor-min or sulfonylureas.¹⁰³ It should be noted that patients with type 2 diabetes have a 3-fold higher likelihood of developing acute pancreatitis than the general population, and cases of pancreatitis in patients taking GLP-1 receptor agonists may be attributable to this background risk.¹⁰⁴

A new once-weekly formulation of exenatide is currently under FDA review.¹⁰⁵ Published data are limited. In one study, 2-mg exenatide once weekly, as monotherapy or in combination with 1 or 2 oral agents, achieved an HbA_1c reduction of 1.9% and a 41 mg/dL decrease in FPG at 30 weeks. Minor hypoglycemia occurred in 6% of patients, and nausea incidence was 26%. Among patients who received exenatide once weekly, 74% tested positive for antiexenatide antibodies, and 24% had high-titer levels.⁶⁹ Significant improvements from baseline in blood glucose levels continued during an extension period; HbA_1c decreased by 1.8% and FPG decreased by 37 mg/dL at 2 years.¹⁰⁶

Liraglutide was developed by making structural modifications to the native GLP-1 peptide. Arginine has been substituted for lysine at position 34, and a C16 fatty acid chain has been attached to lysine at position 26 using a glutamoyl spacer.¹⁰⁷ The half-life of liraglutide in humans is 13 hours; the peptide retains a 97% amino acid sequence homology to the endogenous hormone.^107,108 Liraglutide is thus suitable for once-daily dosing, regardless of mealtimes.⁷³ Consistent with native GLP-1 and other GLP-1 receptor agonists, liraglutide increases insulin secretion in a glucose-dependent manner.¹⁰⁹ Liraglutide has been approved in Europe and is in late-stage review by the FDA.¹¹⁰

In a 52-week monotherapy study in patients with type 2 diabetes who were either drug-naïve or previously treated with a single oral antidiabetes drug, liraglutide was associated with HbA_1c reduction of 0.84% at a dose of 1.2 mg once daily and 1.14% at a dose of 1.8 mg once daily. Fasting plasma glucose decreased by 15 and 26 mg/dL, respectively.⁷³ These effects were maintained during a 52-week, open-label extension period. Among 440 patients who continued the same treatment assigned during the double-blind phase, liraglutide 1.2 mg and 1.8 mg, compared with glimepiride, produced significantly greater reductions in HbA_1c (−0.9% and −1.1% vs −0.6%; P = 0.0376) and FPG (−24 and −27 vs −6 mg/dL; P = 0.0016).¹¹¹

Liraglutide exhibits a low potential for hypoglycemia (8%–12% of patients experienced minor hypoglycemia, with no severe adverse events reported). Transient gastrointestinal symptoms (eg, nausea incidence 28%–29%) were the most common adverse events. Most nausea subsided within the first 4 weeks after initiating treatment.⁷³

In randomized controlled trials, liraglutide 0.6, 1.2, or 1.8 mg once daily in combination with oral agents (metfor-min, a sulfonylurea, or a thiazolidinedione, used singly or as multiple oral therapies) was associated with HbA_1c reductions of 0.6% to 1.5% at 26 weeks. Fasting plasma glucose decreased by 13 to 44 mg/dL. Hypoglycemia occurred in 3% to 27% of patients and was minor in nature, with the exception of 6 major episodes reported by patients taking concomitant sulfonylureas in the combined study populations. Nausea incidence ranged from 5% to 40%, and nausea generally subsided after 4 weeks.^74-76,112

A head-to-head study compared liraglutide 1.8 mg and exenatide 10 μg twice daily for 26 weeks. Liraglutide was associated with a significantly (P < 0.0001) greater reduction in HbA_1c (−1.12% vs −0.79%) and FPG (−29 vs −11 mg/dL) compared with exenatide. Liraglutide-treated patients also had a significantly (P = 0.0131) lower rate of minor hypoglycemia (1.9 vs 2.6 events/subject-year). Nausea was transient with liraglutide, markedly subsiding within 2 weeks of treatment initiation.⁷²

Of 386 patients enrolled in a 14-week extension period, 200 patients continued liraglutide treatment, and 186 were switched from exenatide to liraglutide 1.8 mg once daily. Patients who switched experienced additional improvements in HbA_1c (−0.3%) and FPG levels (−16.2 mg/dL).¹¹³

There is no single major route of liraglutide elimination,¹¹⁴ so pharmacokinetics are not substantially affected by renal¹¹⁵ or hepatic¹¹⁶ impairment. Data in patients with end-stage renal disease requiring hemodialysis are limited; currently, European labeling does not recommend liraglutide for use in these patients.¹¹⁷ As a consequence, a need for dosage adjustment in these patient groups appears unlikely. Liraglutide has a benign drug interaction profile, including cardiovascular drugs such as atorvastatin, lisinopril, digoxin,¹¹⁷ griseofulvin,¹¹⁸ and acetaminophen.¹¹⁹

Compared with studies of exenatide, studies of liraglutide yielded a smaller proportion of patients who developed antibodies (4%–13%),^74-76 possibly because of the greater amino acid sequence homology of liraglutide to native GLP-1. The incidence of acute pancreatitis among subjects taking liraglutide appears to be similar to that of patients with type 2 diabetes treated with other medications, although the number of cases reported during the liraglutide clinical development program was too low to draw statistical conclusions.^73-76

Dipeptidyl peptidase-4 inhibitors can be considered as post-discharge therapy but would probably be less suitable for use during the hospital stay than GLP-1 receptor agonists, given the oral route of administration. There appear to be no data on inpatient use. In general, gastrointestinal adverse events are less frequent with DPP-4 inhibitors than with GLP-1 receptor agonists, although the degree of HbA_1c reduction is more modest. Dipeptidyl peptidase-4 is widely expressed in different tissue types, and the long-term safety of DPP-4 inhibition requires further study.⁶⁶ Further clinical characteristics of GLP-1 receptor agonists and DPP-4 inhibitors, such as effects on weight and cardiovascular parameters, will be discussed in later sections.

Sitagliptin, an oral DPP-4 inhibitor, is available for use in the United States. The recommended sitagliptin dosage is 100 mg once daily and can be taken without regard to meals.¹²⁰

In doses of 25 to 100 mg/day, sitagliptin monotherapy was associated with a decrease in HbA_1c of 0.28% to 0.61% over 12 to 24 weeks. The range of reduction was 11 to 17 mg/dL for FPG.^78,79,92 Decreases in HbA_1c of 0.36% to 0.76% occurred with 200 mg/day,^79,92 which exceeds the recommended dose. At 200 mg/day, FPG decreased by 11 to 16 mg/dL.^79,92 Hypoglycemia incidence ranged from 0.8% to 1.8% in monotherapy studies. Common adverse events included nasopharyngitis (3%–9%), upper respiratory tract infection (3%–9%), and headache (2%–5%).^78,79,92

In studies of 18 to 52 weeks, sitagliptin 100 mg/day, added to other oral diabetes therapies (metformin, a sulfonylurea, or a thiazolidinedione, used singly or in combination regimens), was associated with HbA_1c reductions of 0.45% to 1%. Fasting plasma glucose decreased by 4 to 29 mg/dL, and the incidence of hypoglycemia was 1% to 12.2%. Adverse events included nasopharyngitis (4%–11%), respiratory tract infection (0%–7%), and headache (3%–6%).^80,82-85

Pooled data from studies of sitagliptin monotherapy indicated an HbA_1c reduction of 1.4% from baseline to 2 years. Pooled data from studies of sitagliptin added to metformin yielded an HbA_1c decrease of 0.8% from baseline to 2 years.¹²¹

Sitagliptin is primarily (70%–80%) renally cleared.^122,123 Dosage adjustment is thus recommended in patients with renal impairment. Reduction of the recommended 100-mg dose to 50 mg should be made for patients with moderate impairment (creatinine clearance [CrCl] 30–50 mL/min) and to 25 mg for patients with severe impairment (CrCl < 30 mL/min) or end-stage renal disease.¹²⁰ Sitagliptin has a favorable drug interaction profile. No clinically significant interactions have been observed with simvastatin,¹²⁴ rosiglitazone,¹²⁵ a sulfonylurea (glyburide),¹²⁶ or warfarin.¹²⁷ Based on post-marketing reports, the FDA has required that the prescribing information for sita-gliptin include a warning on the potential for acute pancreatitis in patients receiving this drug.¹²⁸

Saxagliptin was recently approved by the FDA. The recommended dosages are 2.5 or 5 mg once daily and can be taken without regard to meals.¹²⁹

Published clinical data on the use of saxagliptin as monotherapy are limited to a brief (12-week) dose-ranging study.¹³⁰ Saxagliptin 2.5 to 10 mg/day in combination with a single oral therapy (metformin, a sulfonylurea, or a thiazolidinedione) was associated with HbA_1c reductions of 0.54% to 0.94% at 24 weeks. Fasting plasma glucose decreased by 7 to 22 mg/dL. The incidence of hypoglycemia was 2.7% to 4.1% when saxagliptin was added to a thiazolidinedione, 0.5% to 0.6% when added to metformin, and 13.3% to 14.6% when added to a sulfonylurea. Common adverse events included nasopharyngitis (6%–10%), headache (6%–9%), and urinary tract infection (5%–8%).^87,88

Saxagliptin is subject to hepatic metabolism. A clinical pharmacokinetic study in patients with normal or impaired hepatic function, however, did not suggest a need for dosage adjustment in patients with hepatic dysfunction.¹³¹ No dosage adjustment is recommended for patients with mild renal impairment (CrCl > 50 mL/min). In patients with moderate-to-severe renal impairment or with end-stage renal disease requiring hemodialysis (CrCl > 50 mL/min), the dose of saxagliptin is 2.5 mg/day.¹²⁹ No clinically relevant drug interactions have been found between saxagliptin and such medications as metformin, glyburide, pioglitazone, simvas-tatin, or digoxin.¹³²

Metabolism of saxagliptin is primarily mediated by the cytochrome P450 3A4/5 (CYP3A4/5) system. The major metabolite of saxagliptin is also a DPP-4 inhibitor (with ~50% potency as saxagliptin); thus, the pharmacokinetics of saxagliptin will be altered by strong inhibitors of the CYP3A4/5 system. Therefore, dosage adjustment to saxagliptin 2.5 mg is advised when coadministered with strong inhibitors of CYP3A4/5, such as ketoconazole.¹²⁹

A New Drug Application for alogliptin was submitted to the FDA, which has requested that an additional cardiovascular safety trial be conducted before issuing a decision.¹³³

In a 26-week monotherapy study, HbA_1c decreased by 0.56% with alogliptin 12.5 mg/day and 0.59% with alogliptin 25 mg/day. The reduction in FPG was 11 mg/dL at 12.5 mg/day and 16 mg/dL at 25 mg/day. A low incidence of hypoglycemia (1.5%–3% across all treatment groups) was reported. Adverse events included headache (7%–8%).⁸⁹

Alogliptin 12.5 to 25 mg/day as combination therapy with oral agents (metformin, a sulfonylurea, or a thiazolidinedione, used singly or as multiple oral therapies) was associated with a decrease in HbA_1c of 0.38% to 0.86% at 26 weeks. Change in FPG ranged from 5 to 20 mg/dL.^77,90,91 Hypoglycemia occurred in 0% to 15.8% of patients; 2 patients in a study of alogliptin combined with a sulfonylurea experienced severe hypoglycemia.^77,91,134 Adverse events included nasopharyngitis (4%–12%) and headache (2%–8%).^77,91

Most (60%–70%) of an alogliptin dose is excreted unchanged by the kidneys.^135,136 A clinical pharmacokinetic study found that exposure was increased in patients with renal impairment; relative to total exposure (AUC_0–tlqc) in normal patients, total exposure was higher by ~1.7-fold in patients with mild impairment (CrCl = ^51-80 mL/min), ~2.1-fold in those with moderate impairment (CrCl = 30–50 mL/min), ~3.2-fold in those with severe impairment (CrCl < 30 mL/min), and ~3.8-fold in those with end-stage renal disease (need for dialysis). Dosage reduction in patients with moderate or greater renal impairment is therefore advisable.¹³⁷ A clinical study found no clinically meaningful interaction between alogliptin and metformin.¹³⁵

Vildagliptin is available in the European Union (EU), but, due to safety concerns, the FDA required additional clinical trials after a New Drug Application was submitted for this agent. A resubmission of the application is not planned.¹³⁸ A discussion of clinical data on vildagliptin is therefore omitted.

In addition to glucose-lowering efficacy, incretin therapies provide benefits such as weight reduction or weight neutrality and improvement in surrogate markers of cardiovascular risk (Table 2).^{67-93,112,139} Given the close relationships among diabetes, obesity, and cardiovascular disease, such effects are important considerations, although long-term outcomes data are needed. Established antihyperglycemic pharmacotherapies such as sulfonylureas, thiazolidinediones, or insulin may exert deleterious effects on weight,⁴⁸ and thiazolidinediones have received warning labels because of their potential to cause or exacerbate congestive heart failure.^140,141 The extraglycemic benefits of the incretin-based therapies thus represent an advantage compared with earlier therapies. Glucagon-like peptide-1 receptor agonists and DPP-4 inhibitors have also been associated with enhanced function of insulin-secreting β-cells, and long-term data would be desirable to evaluate whether the incretin therapies, like the thiazolidinediones, may affect the course of type 2 diabetes. Further research is needed before conclusions can be drawn regarding the ability of incretin therapeutics to decrease mortality, long-term morbidity, or the progression of diabetes, but the available data suggest that these agents are promising additions to the type 2 diabetes therapeutic armamentarium.

Unlike several antihyperglycemic drug classes, which are associated with weight gain, GLP-1 receptor agonists achieve weight loss, whereas DPP-4 inhibitors exhibit weight neutrality. This is an important consideration in choice of therapy, as weight loss has been demonstrated to result in improved glycemia, blood pressure (BP), insulin sensitivity, and β-cell function.^142,143

In randomized controlled trials of 16 to 30 weeks, exenatide 5 or 10 μg twice daily was associated with weight loss from baseline ranging from 0.9 to 3.6 kg.^67-72,93 Exenatide 2 mg once weekly was associated with a decrease of 3.7 kg at 30 weeks.⁶⁹ Randomized controlled trials of liraglutide 0.6 to 1.8 mg once daily yielded reductions of 1 to 3.2 kg at 26 to 52 weeks.^{72,73,75,76,112} Liraglutide 0.6 mg was associated with a small increase (+0.7 kg) in 1 study, likely due to the concomitant use of a sulfonylurea.⁷⁴

Sitagliptin treatment generally resulted in modest (< ±1 kg) weight changes relative to baseline.^{78-81,83,85,92} Patients who received sitagliptin and a thiazolidinedione in a 24-week study experienced a weight gain of 1.8 kg, but this was similar to the gain observed with placebo (1.5 kg).⁸⁴ Weight decreased by 1.5 kg from baseline in a 52-week study of sitagliptin added to metformin.⁸² Similarly, alogliptin was associated with minor (< ±1 kg) weight changes at 26 weeks.^77,88,90,91 In 24-week studies of saxagliptin, weight change from baseline ranged from −1.4 to +0.8 kg.^87,88

Glucagon-like peptide-1 receptor agonists exert beneficial BP-lowering effects. Systolic BP (SBP) decreased by 2 to 3.7 mm Hg and diastolic BP (DBP) decreased by 0.8 to 2.3 mm Hg with exenatide 5 or 10 μg twice daily.^67,69,72 Blood pressure was lowered by 4.7/1.7 mm Hg with exenatide 2 mg once weekly.⁶⁹ Systolic blood pressure decreased by 0.6 to 6.7 mm Hg with liraglutide 0.6 to 1.8 mg. Diastolic blood pressure was unchanged in most studies of liraglutide, with a reduction of 1 to 2.3 mm Hg reported in 2 studies.^72-76,112

Studies of DPP-4 inhibitors do not report BP outcomes, although some note that there were no significant changes in vital signs.^{77-85,88,91,92} A single study of saxagliptin 2.5 and 5 mg/day reported decreases ranging from 3 to 4 mm Hg for SBP and 2 to 3 mm Hg for DBP.⁸⁷

Lipid parameters, including total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides, were unchanged in 2 studies of exenatide twice daily, although low-density lipoprotein cholesterol (LDL-C) improved significantly versus placebo in 1 of the studies.^67,68 In another study, exenatide twice daily produced a significant improvement (−11%) in triglyceride levels from baseline but also significantly decreased beneficial HDL-C (−1 mg/dL).⁶⁹ Exenatide once weekly has been associated with significant improvements from baseline in total cholesterol (−12 mg/dL), LDL-C (−5 mg/dL), and triglycerides (−15%).⁶⁹ Triglyceride levels decreased significantly with liraglutide versus exenatide (−36 mg/dL vs −20 mg/dL; P = 0.0485) in a head-to-head study.⁷² A meta-analysis of pooled data from 6 randomized, controlled, phase 3 studies of liraglutide indicated significant decreases from baseline to week 26 in such cardiovascular risk markers as total cholesterol (−5 mg/dL), LDL-C (−8 mg/dL), triglycerides (−18 mg/dL), free fatty acids (−0.09 mmol/L), brain natriuretic peptide (−11.9%), and high-sensitivity C-reactive protein (−23.1%).¹³⁹

Sitagliptin exerted no significant effects on lipid levels in several trials.^79,81,83,92 Some significant but small changes were noted in other studies, although the changes were neither consistently beneficial nor detrimental.^78,80,84,85 Lipid parameters were mainly unchanged in 4 studies of alogliptin, with the exceptions of a decrease in total cholesterol in 2 of the studies and a decrease in triglycerides in 1 of the studies (both changes were significant vs placebo).^77,88,91 Lipid changes with saxagliptin were reported to be minor in 2 studies.^87,88

Glucagon-like peptide-1 receptor agonists and DPP-4 inhibitors have both demonstrated improvements on measures of pancreatic β-cell function, such as homeostasis model assessment (HOMA)-B or proinsulin:insulin ratio.^{67-69,71,72,74-76,78-86,88,89,91-93,112} Additional in vivo research is desirable to assess whether the improvements are associated with long-term modification of the course of type 2 diabetes, which is characterized by a progressive decline in β-cell mass and function.¹⁴⁴

Evidence from animal and in vitro models has demonstrated that liraglutide and sitagliptin enhance β-cell survival and restore a balanced distribution of α- and β-cells. In several preclinical and rodent studies, liraglutide inhibited β-cell apoptosis¹⁴⁵ and increased β-cell mass.^146-148 Progressively higher doses of sitagliptin in a nongenetic rodent model of type 2 diabetes significantly reduced the number of α-cells in the islet core and increased β-cell mass.¹⁴⁹ Given the difficulty in assessing changes in β-cell mass in humans, it is not currently known if the effects observed in preclinical models are therapeutically relevant.

In view of the critical importance of patient adherence to the success of long-term type 2 diabetes therapy, the simplicity of dosage and administration of the incretins should be noted. The DPP-4 inhibitors sitagliptin and saxagliptin are dosed orally once daily with or without food,^120,129 and alogliptin was dosed orally once daily in clinical trials.^77,89-91 Sitagliptin has a single recommended dosage (100 mg/day), and saxagliptin may be dosed at 2.5 or 5 mg/day; dosages for these drugs should be reduced if moderate or greater renal impairment is present. Exenatide and liraglutide are administered subcutaneously via a prefilled pen. Exenatide is dosed twice daily, within 60 minutes prior to meals,⁹⁷ and liraglutide is dosed once daily regardless of meals.⁷³ The initial dosage of exenatide, 5 μg twice daily, may be increased to 10 μg twice daily after 1 month.⁹⁷ Under EU labeling, liraglutide is initiated at a dose of 0.6 mg/day and increased to 1.2 mg/day after 1 week, and may be further increased to 1.8 mg/day after another week.¹¹⁷ Few details are available regarding the device or dosing regimen used with exenatide once weekly.

Type 2 diabetes is present in a high proportion of patients admitted to the hospital, posing a complex challenge to adequate therapeutic management. Diabetes may be undiagnosed at admission, and hyperglycemia may be attributable to the stress of critical illness or injury rather than preexisting disease. Regardless of etiology, hyperglycemia is associated with poor patient outcomes and requires intensive management based on blood glucose monitoring and insulinization.

Post-discharge diabetes care is essential to improve long-term outcomes after a hospital stay. The development of an optimal, long-term antidiabetes pharmacotherapy regimen must occur as part of the patient’s regular health management, but hospital care providers can play a key role by initiating effective and tolerable therapy prior to discharge. The data reviewed in this paper suggest that incretin therapies provide a simple-to-use, efficacious glucose-lowering option that may minimize some of the known drawbacks of traditional antihyperglycemic agents, such as hypoglycemia and weight gain.

The incretin hormone GLP-1 maintains glucose homeostasis via several pathways, including glucose-dependent stimulation of insulin secretion, suppression of excessive glucagon secretion, and inhibition of gastric emptying and appetite. Incretin-based therapies appear to exhibit similar effects, decreasing excessive blood glucose levels without substantially increasing the risk of hypoglycemic episodes. The distinct clinical profiles of the 2 incretin classes may be due to differing levels of GLP-1 or GLP-1-like activity, which GLP-1 receptor agonists increase to pharmacologic levels, whereas DPP-4 inhibitors preserve endogenous GLP-1 within the physiologic range. Although no direct comparative studies have been published, these clinical profiles can be broadly described. Glucagon-like peptide-1 receptor agonists achieve substantial blood glucose reductions, are associated with weight loss, and improve some markers of cardiovascular risk. Dipeptidyl peptidase-4 inhibitors provide a more modest glucose reduction, are weight-neutral, and are less likely to induce gastrointestinal adverse effects than the GLP-1 receptor agonists. Both drug classes exert beneficial effects on indices of β-cell function and are simple to use for long-term therapy.

Data from outpatient studies suggest that incretin therapies provide a potentially useful option for hospital care providers who are selecting post-discharge treatment. Clinical studies conducted in post-hospital patients would enable treatment recommendations regarding incretin agents to be made specifically for this population. The incretin therapies might also play a useful role in inpatient glucose control, although such a conclusion must remain speculative in the absence of data.

The authors would like to thank Andrew Horgan, PhD, of AdelphiEden Health Communications, for providing medical writing and editorial services, supported by Novo Nordisk.
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