In addition to the hypoglycemia and weight gain associated with many treatments for type 2 diabetes, α-glucosidase inhibitors, thiazolidinediones, metformin, sulfonylureas, and the glinides do not address all of the multiple defects existing in the pathophysiology of the disease. Cumulatively, these oral agents address the influx of glucose from the gastrointestinal tract, impaired insulin activity, and acute β-cell dysfunction in type 2 diabetes; however, until recently, there were no means to deal with the inappropriate hyperglucagonemia or chronic β-cell-decline characteristic of the disease. The recently introduced incretinbased therapies serve to address some of the challenges associated with traditionally available oral antidiabetic agents. In addition to improving β-cell function, stimulating insulin secretion, and inhibiting glucagon secretion, these agents reduce appetite, thereby stabilizing weight and/or promoting weight loss in patients with type 2 diabetes. Of the incretin-based therapies, both the dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon-like peptide-1 (GLP-1) receptor agonists stimulate insulin secretion and inhibit glucagon secretion. The subsequent review outlines evidence from selected clinical trials of the currently available GLP-1 receptor agonists, exenatide and liraglutide, and DPP-4 inhibitors, sitagliptin and saxagliptin. Earlier and more frequent use of these incretin-based therapies is recommended in the treatment of type 2 diabetes, based on their overall safety and ability to achieve the glycosylated hemoglobin level goal. As such, both the American Diabetes Association and the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) treatment algorithms recommend the use of incretin-based therapy in both treatment-naive and previously treated patients. The AACE/ACE guidelines clearly state that these agents should not be limited to third- or fourth-line therapy.
(Am J Manag Care. 2010;16:S187-S194)
The pathophysiology of hyperglycemia in type 2 diabetes involves 3 main defects: insulin deficiency due to insufficient pancreatic insulin release, excess hepatic glucose output, and insulin resistance (decreased glucose uptake) in peripheral tissues (including muscle and fat) and the liver. Defects of the α- and β-cells in the pancreatic islet contribute to this pathology. While α-cells producing excess glucagon promote increased hepatic glucose output resulting in hyperglycemia, a decline in functional β-cell mass in type 2 diabetes causes insulin deficiency, which in turn also contributes to hyperglycemia. These complex processes culminate in a chronic progressive disease characterized by declining β-cell function, deterioration of glycemic control, and an increased risk of cardiovascular disease.
The multiple levels of dysmetabolism of both carbohydrates and lipids in type 2 diabetes-all brought about by the malregulation of insulin and glucagon in the diabetic islet-is further complicated by the multitude of therapies available for treating the disease. In targeting declining β-cell function in type 2 diabetes, there exists significant potential to create other problems for patients. Though employed in an attempt to improve glycemic control and reduce cardiovascular risk, many of these therapies may have a counterintuitive reverse effect. Care must be taken to avoid inducing hypoglycemia in patients with type 2 diabetes, and weight gain remains a concern with many available therapies. Furthermore, the characteristic progressive weight gain that typically comes with age and contributes to increased cardiovascular risk is accentuated in patients with type 2 diabetes when they are treated with these agents.
In addition to the hypoglycemia and weight gain associated with many treatments for type 2 diabetes, previous oral therapies did not address all of the multiple defects existing in the pathophysiology of the disease. A panoply of oral agents are available for the treatment of type 2 diabetes, including α-glucosidase inhibitors, thiazolidinediones (TZDs), metformin, sulfonylureas, and the glinides. The α-glucosidase inhibitors address the influx of glucose from the gastrointestinal (GI) tract by blocking absorption. Despite addressing a key defect in type 2 diabetes pathophysiology, these agents have serious limitations in terms of therapeutic convenience, as unabsorbed glucose is fermented in the GI tract by coliform bacteria, resulting in the production of gas in the intestines. The TZDs and metformin are essentially the only insulin sensitizers available for the treatment of type 2 diabetes.1 While these agents are effective in improving insulin resistance, each class of agents is associated with unique treatment-related adverse events. The TZDs tend to decrease bone density and increase fracture rates in postmenopausal women and may lead to retention of salt and water, making the use of these agents in patients with unstable class III or IV heart failure virtually unacceptable. Metformin, on the other hand, has reduced GI tolerability, with 5% to 10% of the US population completely intolerant to therapy. The acute b-cell dysfunction in type 2 diabetes can be effectively addressed in the short term with sulfonylureas and glinides, which promote insulin production by the b-cells. Still, use of these 2 classes of agents may contribute to a burnout in glucose control by the b-cells in the long term, although the data are unclear for glinides. Cumulatively, these oral agents address the influx of glucose from the GI tract, impaired insulin activity, and acute b-cell dysfunction in type 2 diabetes; however, until recently, there were no means to deal with the inappropriate hyperglucagonemia or chronic b-cell-decline characteristics of the disease ().1
The recently introduced incretin-based therapies serve to address some of the challenges associated with traditionally available oral antidiabetic agents. In addition to improving b-cell function, stimulating insulin secretion, and inhibiting glucagon secretion, these agents reduce appetite, thereby stabilizing weight and/or promoting weight loss in patients with type 2 diabetes. Of the incretin-based therapies, both the dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon-like peptide-1 (GLP-1) receptor agonists stimulate insulin secretion and inhibit glucagon secretion. In particular, the injectable GLP-1 receptor agonists assist in curbing the overactive appetite characteristic of patients with type 2 diabetes. As a result, incretin-based therapies are garnering more attention from physician organizations and have been integrated into the most recent treatment algorithms for type 2 diabetes. In addition, managed care organizations are now charged with the task of positioning these agents within their plans to maximize clinical and economic outcomes for patients with type 2 diabetes.
Incretins exert their effects in a variety of different target tissues, thereby addressing the complex pathophysiologic processes of type 2 diabetes. Glucose disposal is facilitated in peripheral tissues such as muscle tissue due to improved insulin secretion. Because incretin-based therapies are vasodilators, they increase cardiac output slightly by improving endothelial dysfunction in the arterial tree. As with all vasodilators, GLP-1 receptor agonists cause acute, significant drops in systolic pressure with some reflex increase in cardiac output. Incretins also affect the GI tract and b-cells, thereby directly reducing hepatic glucose production by decreasing glucagon, increasing insulin secretion, and eventually suppressing fasting hyperglycemia. Incretin-based therapies are also associated with direct inhibition of gastric emptying. In the central nervous system, these agents exert effects at the hypothalamus to reduce appetite and eliminate cravings.
Incretins augment the normal mealtime response, whereby intestinal hormones are released almost immediately as an individual begins eating. In part, this involves vaguely neurally mediated secretion of the 2 major incretins in the body: gastric inhibitory peptide (GIP) in the proximal small intestine and GLP-1 in the distal small intestine. Patients with diabetes generally become resistant to GI P action and demonstrate some resistance to GLP-1, but not nearly as much resistance as to GIP.
Incretin-based therapy may be administered in the form of a GLP-1 receptor agonist or DPP-4 inhibitor. Since GLP-1 is a protein, all GLP-1 agonists are proteins and must be delivered via injection. The other approach is to attack the DPP-4 enzyme that is responsible for the rapid degradation of GLP-1 with an oral DPP-4 inhibitor. The normal half-life of GLP-1 is 2 minutes, while the half-life of an analogue such as liraglutide is 13 hours. Conversely, administration of a DPP-4 inhibitor doubles the level of GLP-1 in circulation by interfering with the natural mechanism of GLP-1 metabolism.
GLP-1 agonists and DPP-4 inhibitors share several characteristics because they both ultimately increase or sustain the level of GLP-1 in circulation. However, these incretinbased therapies employ different mechanisms of action within the GLP-1 pathway, and a number of differences exist between the agents beyond their route of administration.2 While the DPP-4 inhibitors have a greater effect on postprandial hyperglycemia, they also have a lesser effect on fasting hyperglycemia because high, sustained levels of GLP-1 are required to improve fasting glycemia.2 The high levels of GLP-1 achieved with injections of GLP-1 agonist proteins have a greater effect on appetite and weight loss because of appetite suppression, but the GLP-1 agonists also have a more notable GI side-effect profile (ie, 35%-50% of patients experience GI adverse events vs very few patients with DPP-4 inhibitors).2
Even when considering the apparent clinical benefits of incretin-based therapies, cost remains a central factor in evaluating the use of these agents from a managed care perspective. Despite carrying higher drug acquisition costs than more conventional type 2 diabetes therapies, the incretins appear to confer advantages that contribute to lowering the total cost of care beyond that of traditional agents.3 In an administrative claims data analysis of adults diagnosed with type 2 diabetes by Misurski et al, annual diabetes-related drug costs were higher in patients treated with the GLP-1 agonist exenatide versus those treated with insulin glargine ($3160 vs $2422, respectively; P <.001).3 However, due to hidden costs associated with insulin therapy-such as educating patients on insulin administration, titrating the appropriate dose of insulin, and hypoglycemia complications arising from insulin use-annual diabetes-related medical costs and total direct medical costs were lower in patients treated with incretin-based therapy ($7833 vs $8536 and $19,293 vs $23,782, respectively; P <.001 for both).3 Although efficacy and safety should not be usurped as the primary components for evaluating type 2 diabetes therapies, analyses such as these demonstrate the value of incretins when there appears to be no clear-cut advantage in terms of clinical characteristics.
Efficacy and Safety of the Incretins
Both classes of incretin-based therapies-GLP-1 receptor agonists and DPP-4 inhibitors-have demonstrated efficacy and safety in the treatment of type 2 diabetes. The subsequent review will outline evidence from selected clinical trials of the currently available GLP-1 receptor agonists, exenatide and liraglutide, and DPP-4 inhibitors, sitagliptin and saxagliptin.
Exenatide. As the first incretin-based therapy to be approved for use in the United States, a wealth of clinical trial data support the efficacy and safety of exenatide for the treatment of type 2 diabetes. Exenatide therapy, in combination with a previous sulfonylurea, in combination with prior metformin and sulfonylurea therapy, or in combination with prior metformin alone, clearly reduces glycosylated hemoglobin (A1C) levels compared with placebo (mean change from baseline in A1C levels for exenatide 10 μg + existing sulfonylurea, metformin and sulfonylurea, or metformin therapy vs placebo: -0.9% vs +0.1%; -0.8% vs +0.2%; -0.8% vs +0.1%, respectively; P <.005 for all).4-6 While A1C level reductions with exenatide are generally uniform regardless of existing treatments, weight loss differs depending on the baseline therapy to which the GLP-1 agonist is added.4-6 Since there is typically an increased incidence of hypoglycemia with an existing sulfonylurea, weight loss is generally less pronounced when adding exenatide to sulfonylurea therapy than when adding exenatide to other existing therapies.5,6 As such, sulfonylureas tend to undo some of the benefits of incretin-based therapies, leading many clinicians to avoid this traditional class of antihyperglycemic medications altogether. In terms of durability, open-label extension trials have demonstrated that the A1C level reductions and weight loss associated with exenatide therapy persist for 3 years.7 Furthermore, there appears to be no rebound in weight gain with exenatide, as there is with other agents, unless patients stop taking the medication.7 The incidence of treatment-related nausea with exenatide appears to be dose-dependent and slightly greater when the GLP-1 agonist is added to existing metformin therapy than when it is added to other therapies.4-6 While the incidence of nausea is slightly lower when exenatide is added to an existing sulfonylurea, the higher incidence of hypoglycemia and reduced weight loss benefit associated with this combination may negate the minimal nausea-related advantage. Exenatide has also been associated with cases of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis.8 While it is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while receiving exenatide, the US Food and Drug Administration (FDA) recommends that other antidiabetic therapies be considered in patients with a history of pancreatitis.8
Liraglutide. The latest GLP-1 agonist to come to the US market, liraglutide, featured an active comparator in all of its clinical trials (including one study vs exenatide and another vs sitagliptin) and demonstrated improved efficacy versus comparators in reducing A1C levels.9-15 Data from the phase 3 Liraglutide Effect and Action in Diabetes (LEAD) Program demonstrated that liraglutide monotherapy was more effective in reducing A1C levels than glimepiride monotherapy (LEAD 3).11 Furthermore, in combination with failed monotherapies or failed combination therapies in the 4 other LEAD trials (LEAD 1, 2, 4, and 5), liraglutide was generally at least as effective in reducing A1C levels as its active comparators-or even more effective, especially in combination with insulin glargine when compared with prior insulin glargine.9,10,12,13 Across all 5 trials of the LEAD Program, liraglutide monotherapy and combination therapy resulted in an average A1C level reduction of 1.18%.9-13 Similar results in favor of liraglutide were reported across the LEAD trials in terms of weight profile, with the GLP-1 agonist demonstrating consistent weight loss compared with all prior therapies.9-139-13
The average weight loss associated with liraglutide monotherapy or combination therapy in the 5 LEAD Program trials was 1.86 kg.
In a 26-week, open-label, parallel-group, multinational trial comparing liraglutide with exenatide, liraglutide once daily provided greater improvements in glycemic control over exenatide twice daily (mean change in A1C levels: -1.12% vs -0.79%; P <.0001).1414 In another trial, estimated mean treatment differences in A1C level reduction for liraglutide 1.8 mg versus the DPP-4 inhibitor sitagliptin were -0.60% (95% CI, -0.77 to -0.43; P <.0001).15
Weight loss was also greater with liraglutide once daily compared with exenatide twice daily (3.24 vs 2.87 kg), but this difference was not significant.
As is the case with exenatide, the most prominent adverse events associated with liraglutide are GI-related. In the LEAD Program trials, nausea was more common in the liraglutide treatment groups relative to comparators. However, withdrawal rates due to nausea were very low with liraglutide, and much less than those observed with metformin (5%-10% in US multicenter trials) for an equivalent number of patients.9-13 Other potential safety concerns with liraglutide include the production of antibodies, its cardiovascular profile, the injection route of administration, and potential for acute pancreatitis.9-13 Like all injectable proteins, GLP-1 receptor agonists induce the production of some antibodies. In the liraglutide clinical trials, there was no evidence of neutralizing antibodies and no antibodies that had an impact on glycemic control.9-13 Liraglutide was associated with benefits in regard to cardiovascular profiles. Most patients lost weight, had decreasing systolic pressures, had significant A1C level reductions, and experienced vasodilation, and among those who lost weight, most had improved lipid profiles.9-13 Some transient increases in heart rate were observed, but they did not appear to be clinically meaningful in most studies. The injection route of administration was typically viewed as worthwhile if patients lost weight as a result of the therapy. Although there were too few cases in clinical trials to know if liraglutide causes pancreatitis, the FDA wants clinicians and patients to be aware of this potential risk and know that some common side effects of liraglutide may be similar to the symptoms of pancreatitis. Furthermore, animal studies showed that a rare type of thyroid cancer known as medullary thyroid cancer (MTC) was associated with liraglutide in mice and rats, although the relevance of this finding to humans remains unknown. Still, the FDA has stipulated that liraglutide be contraindicated in patients with a personal or family history of MTC and in patients with multiple endocrine neoplasia syndrome type 2.16
Sitagliptin. Among the DPP-4 inhibitors, sitagliptin is associated with the most clinical experience. This incretin-based therapy produces a slight reduction in A1C levels compared with the GLP-1 receptor agonists when it is added to metformin or a TZD. In a study by Ahren et al, the addition of sitagliptin to metformin was associated with a sustained reduction in A1C levels.17 In another study, sitagliptin 100 mg or placebo was added to metformin plus rosiglitazone therapy; the addition of sitagliptin was associated with a -0.7% improvement in A1C levels (P <.001), and more than twice the number of patients achieved an A1C goal of less than 7% (22 vs 10 with placebo).18 No significant weight loss benefit is expected from incretins in the DPP-4 inhibitor class, nor was it observed in clinical trials with sitagliptin.18
Saxagliptin. The latest DPP-4 inhibitor to come to market, saxagliptin, is very similar to sitagliptin in terms of clinical efficacy. As monotherapy, the agent produces placebo-adjusted A1C level reductions of 0.45% to 0.63% and produces the greatest A1C level reductions in combination with metformin (-2.53%).19,20 Similar to sitagliptin, the agent is administered orally and is not associated with weight loss in patients with type 2 diabetes. A brief synopsis of the clinical characteristics of all the aforementioned incretinbased therapies can be found in the .21-24
Incorporating Incretins Into Current Diabetes Treatment Algorithms
Treatment guidelines for type 2 diabetes recommend selecting drug therapy based on overall safety and the ability of a drug to achieve the A1C goal. Consequently, earlier and more frequent use of incretin-based therapies is recommended, since these agents meet the necessary criteria. As such, both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) treatment algorithms recommend the use of incretin-based therapy in both treatment-naïve and previously treated patients.25,26 Specifically, the AACE/ACE guidelines clearly state that these agents should not be limited to third- or fourth-line therapy.26 Patients with increased cardiometabolic risk-including those who are overweight or obese, have hypertension, and/or have dyslipidemia-may also benefit from incretin-based therapy.25,26 It should be noted, however, that only the GLP-1 receptor agonist exenatide and the DPP-4 inhibitors sitagliptin and saxagliptin were available when the current guidelines were published. Since then, the GLP-1 agonist liraglutide was approved (in January 2010), necessitating a revision of the guidelines.
Choosing the appropriate incretin-based therapy for patients is really a matter of which algorithm is selected. The ADA algorithm emphasizes the use of GLP-1 receptor agonists due to the weight loss benefits. Sulfonylureas or insulin remain first-line therapies in this algorithm, but if weight loss is one of the primary foci of treatment, GLP-1 receptor agonists are indicated ().25
The AACE/ACE algorithm does not favor either the GLP-1 receptor agonists or the DPP-4 inhibitors. This more liberal approach allows for all therapeutic options to be considered, thus enabling clinicians to choose the therapy that best meets a patient's needs ().26 For example, if a patient unequivocally will not accept an injectable therapy, then DPP-4 inhibitors become the default choice of incretin. The AACE/ACE algorithm also ascribes to the notion that most patients failing metformin need to be considered as candidates for incretin therapy. Many clinicians believe that prescribing secretagogues (eg, sulfonylureas, glinides) at the present time is a disservice to patients, and the AACE/ACE algorithm reflects this concept, allowing for more liberal use of incretin-based therapies as first- and second-line treatment.26
Ultimately, when an incretin-based therapy is recommended, selection of an agent is at the clinician's discretion. Choice of therapy should be based on a patient's profile and preference, with consideration given to the unique characteristics of the GLP-1 receptor agonists and DPP-4 inhibitors. GLP-1 receptor agonists offer more robust A1C level reductions and the potential for weight loss. The use of these agents should be tempered by patients' willingness to receive a once- or twice-daily injection and their tolerability to GI adverse events. The DPP-4 inhibitors provide a simple oral route of administration and fewer GI adverse events, making them an ideal choice for patients who place high value on convenience and/or those who are intolerant to side effects.
In managed care, treatment algorithms such as these can be adapted to influence outcomes and manage costs. In order for an algorithm to successfully achieve the desired outcomes in the managed care setting, it should meet the following criteria27:
Related to the rationale for treatment algorithms is the concept of step therapy in managed care. Step therapy is intended to control costs by encouraging generic use without compromising the quality of care.28 It requires first-line use of medication(s) within a drug class (usually a generic) prior to receiving coverage for a second-line agent (usually a branded agent).28 This managed care initiative is promoted through the use of online claims edits, prior authorization, or implementation of approved guidelines.28 For the latter, step therapy should incorporate treatment algorithms to guide appropriate use that is evidence-based rather than authoritarian and restrictive.
GLP-1 receptor agonists and DPP-4 inhibitors increase insulin secretion, decrease glucagon secretion, and enhance β-cell function. As monotherapy, GLP-1 receptor agonists elicit an average A1C level reduction of 0.5% to 1.5%, and average A1C level reductions with DPP-4 inhibitors are between 0.5% and 0.8%. When one of these incretin-based therapies is added to existing glucose-lowering treatment with oral agents or insulin, further improvements in glycemic control are observed. In addition, the GLP-1 receptor agonist incretins promote weight loss, while the DPP-4 inhibitors are weight-neutral or may cause slight gains in weight. These factors, in addition to the injection route of administration and the potential for GI adverse events with the GLP-1 receptor agonists, should be considered when selecting a therapy. It should be noted, however, that incretin-based therapies generally exhibit a good safety profile with a low incidence of mostly mild-to-moderate adverse events.
Current diabetes treatment guidelines emphasize early diagnosis and intensification of therapy to achieve and maintain A1C level control. Furthermore, guidelines must reflect the most recent advances in medical therapy to be clinically relevant. These core concepts have led to the inclusion of incretin-based therapies in the ADA and AACE/ACE treatment algorithms, although another revision of these guidelines is warranted in response to the recent approval of the GLP-1 receptor agonist liraglutide. In managed care, these evidence-based guidelines should be applied as the basis for treatment algorithms and step-therapy initiatives to ensure the quality of care and control costs in a sustainable manner.
Author Affiliations: Division of Diabetes, Endocrinology, & Metabolism, Baylor College of Medicine, Houston, TX.
Funding Source: Financial support for this work was provided by Novo Nordisk.
Author Disclosure: Dr Garber reports consultancy/advisory board assignments, grants/honoraria/lecturer fees received, and meeting or conference attendance with Merck and Novo Nordisk, as well as expert testimony for Novo Nordisk. Dr Garber also received payment for involvement in the preparation of this manuscript from Novo Nordisk.
Authorship Information: Concept and design; analysis and interpretation of data; and critical revision of the manuscript for important intellectual content.
Address correspondence to: Alan J. Garber, MD, PhD, FACE, Baylor College of Medicine, 1709 Dryden Rd, Suite 1000, Houston, TX 77030. E-mail: firstname.lastname@example.org.
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