Incretin hormones, such as glucagon-like peptide-1 (GLP-1), play a crucial role in modulating insulin and glucagon secretion, as well as regulating appetite, gastric emptying, and pancreatic beta cell function. The pathophysiology of type 2 diabetes mellitus (T2DM) is complex and includes impaired incretin response, among other metabolic abnormalities. Incretin-based treatments for T2DM, such as GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, mimic or prolong the actions of incretin hormones and function in a glucose-dependent manner, thereby reducing hyperglycemia and avoiding hypoglycemia. There are important mechanistic differences between the GLP-1 receptor agonists and the DPP-4 inhibitors. DPP-4 inhibitors protect endogenous GLP-1 from DPP-4 degradation, thereby achieving a physiologic level of GLP-1. In contrast, GLP-1 receptor agonists act directly on the GLP-1 receptor, achieving a pharmacologic level of GLP-1 activity. These different mechanisms yield different effects on diabetes and weight loss. Incretin-based treatments may improve beta cell function, and, while not indicated for these effects, GLP-1 receptor agonists may also promote satiety, reduce weight, slow gastric emptying, and possibly improve hypertension and triglyceride levels; these characteristics are absent with DPP-4 inhibitors. Therefore, GLP-1 receptor agonists can be an appropriate clinical choice for glycemic control in patients with T2DM, especially in those who would benefit from weight loss or are prone to hypoglycemia.
(Am J Manag Care. 2011;17:S52-S58)
Pathophysiology of Type 2 Diabetes Mellitus
The pathophysiology of type 2 diabetes mellitus (T2DM) is complex and includes several metabolic abnormalities.
Abnormalities in T2DM include:1
Beta cell dysfunction, an important feature of T2DM pathophysiology, means impaired insulin secretion, which results in insulin deficiency.1 Additionally, beta cell failure and insulin resistance appear to be linked.1 Defective beta cell function progresses over decades, beginning many years before T2DM is diagnosed and continuing at an annual rate of decline of approximately 2%.3 By the time of T2DM diagnosis, 50% to 80% of beta cell function has been lost.3 Starting about 3 years after diagnosis, the rate of decline becomes 18% per year.3 This deterioration is a major part of T2DM progression and is one reason why glycemic control becomes more difficult over time.1 Medications that may act to preserve the remaining beta cell function could help secure long-term glycemic control2 and might have the potential to alter the natural history of T2DM.4
Alpha cells secrete more glucagon than normal in T2DM (hyperglucagonemia), both in the fasting state and in response to meals.1 These elevated plasma glucagon levels do not return to normal after meals. The elevated glucagon stimulates increased glucose production in the liver and therefore fasting hyperglycemia.1
Insulin resistance is present prior to the onset of hyperglycemia, and contributes to the development of T2DM. Insulin resistance is a condition in which the cellular response to insulin is impaired. To compensate, beta cells secrete more insulin, and blood glucose levels may remain normal. Over time, beta cells can no longer produce sufficient insulin to overcome insulin resistance, the result being increased glucose levels and clinical diagnosis of T2DM.1
The role of impaired incretin response in the pathophysiology of T2DM will be discussed in detail in the next section.
Incretin Hormones and T2DM
An important factor in T2DM pathophysiology is the incretin response.1 Peptide hormones, including glucosedependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are secreted in the small intestine into the circulation in response to meals.2,5,6 These hormones stimulate glucose-induced insulin secretion; at higher glucose levels the effect of GLP-1 is dominant.6 In healthy individuals, oral glucose ingestion results in 2- to 3-fold higher insulin secretion than intravenous glucose infusion, a phenomenon called the incretin effect.6,7,8 Early studies found that incretin hormones contributed up to 70% of normal postprandial insulin response.6,8 However, in T2DM, the incretin response was found to be impaired, reduced, or in some patients, even absent,6-9 which might contribute to abnormalities in insulin regulation and glucagon secretion.6 This led to preclinical studies of the incretin hormones as possible contributors to T2DM. Investigators found that GLP-1 was essential to normal glucose homeostasis.7,10
Actions of GLP-1
Endogenous GLP-1 acts on alpha and beta cells1 in the pancreatic islets in ways that are critical for glycemic control (Table).11 It stimulates secretion of insulin in a glucosedependent manner (ie, only during hyperglycemia) by activating receptors on beta cells and via the vagus nerve.2,5,10 GLP-1 also suppresses elevated postprandial glucagon secretion in a glucose-dependent manner by activating receptors on alpha cells.2,5,10 These actions result in reduced hepatic glucose production.5
In addition, GLP-1 improves beta cell function10 by promoting beta cell proliferation and differentiation (in animal models) and inhibiting apoptosis (in animal models and in vitro).2,4,5,12 GLP-1 also delays gastric emptying2,5,10 and acts centrally to promote satiety,2,5,10 actions that result in reduced caloric intake and weight loss.10,13
Animal and human studies have shown that GLP-1 has beneficial cardiovascular effects.6 GLP-1 has improved endothelial function in coronary heart disease and several measures including left ventricular ejection fraction in heart failure and after myocardial infarction.6 GLP-1 has also shown neuroprotective effects in animals and humans.6
In T2DM, if GLP-1 actions could be restored or enhanced to pharmacologic levels, they might restore the sensitivity of alpha and beta cells to glucose6 and the insulinotropic actions of the incretin system.2 Incretin-based treatments might help normalize diabetes-associated abnormalities including hyperglycemia, obesity, hypertension, and dyslipidemia.14 These metabolic abnormalities increase the risk for vascular complications5 and also are difficult to reverse. In the United States, only 1 in 8 patients with T2DM reaches standard targets for blood pressure and LDL cholesterol as well as glycosylated hemoglobin (A1C) levels.14,15
Progression of Treatment
Because T2DM is a progressive disease, standard therapy for glycemic control in T2DM typically progresses in intensity, including changes in dose and/or number of antidiabetic agents.16,17 These drugs either increase sensitivity to insulin or increase secretion of endogenous insulin.16 Although achieving glycemic control may slow disease progression, exogenous insulin will be needed once beta cell capacity becomes limiting.2,16
Upon diagnosis, diet and lifestyle changes are prescribed along with metformin unless contraindicated.16,17 If normoglycemia is not achieved, additional antidiabetic medications are used as recommended by the American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE).17,18 Patients taking oral antidiabetic drugs (OADs) may experience common adverse effects (AEs). Gastrointestinal symptoms can occur with metformin and alpha-glucosidase inhibitors, drug-drug interactions with sulfonylureas and glinides, edema, and fractures with thiazolidinediones (TZDs).9,16 Two of the more troublesome AEs of some OADs are weight gain and hypoglycemia. Weight gain, which contributes to insulin resistance,10 occurs frequently with sulfonylureas9,16,12,13 and TZDs.9,12 Episodes of hypoglycemia occur commonly with sulfonylureas9,16,12,13 and can occur with glinides.16 Because weight gain and hypoglycemia are undesirable to patients with diabetes, these effects can contribute to medication nonadherence.19 Managing these adverse effects and the patient’s reactions to them can become obstacles to achieving normoglycemia with OADs. Moreover, as T2DM progresses, most OADs begin to fail in glycemic control.4,5,10,20
Prior to the introduction of the incretin-based therapies, typical clinical practice involved the addition of insulin replacement therapy, if glycemic control did not improve despite lifestyle changes and OADs.5,10,20 This is because most OADs are dependent on sufficient beta cell capacity to secrete endogenous insulin. Once this is lost, insulin therapy is needed.2 However, patients initiating insulin therapy face a variety of challenges. The treatment requires daily blood glucose monitoring and insulin titration.5,10,20 Insulin can also be associated with weight gain and hypoglycemia,5,9,10,20 which may contribute to poor adherence and resulting suboptimal glycemic control.9,19 The risk of these and other adverse effects increases with any combination therapy.13 Thus, the addition of insulin can increase the chance of achieving glycemic targets but also pose new challenges for patients.
Some T2DM treatments that work early in the course of the disease do not sustain glycemic control over the long term, in part because they do not address the progressive decline in beta cell function and the cumulative effects of hyperglycemia (glucotoxicity).4,9,10,21,22 With this decline and intensification to double or triple therapy, patients can find adherence more and more difficult while agents and doses that once controlled hyperglycemia begin to fail. Patients with T2DM need therapies that will address both fasting and postprandial glucose control over the long term without introducing treatmentlimiting adverse effects such as weight gain and hypoglycemia.23 Optimal control during the early stages of T2DM may slow disease progression and the need for insulin therapy.2
Two Classes of Incretin-Based Therapies
The practical results of the incretin investigations are welcome in medical progress for T2DM. They have led to development of pharmaceutical agents that can mimic or assist the antidiabetic actions of native GLP-1.10
In the research and development of incretin-based drugs, investigators needed to overcome a problem inherent to native GLP-1. The enzyme dipeptidyl peptidase-4 (DPP-4) rapidly degrades endogenous active GLP-1 to the biologically inactive GLP-1.2,21 As a result, native GLP-1 has a half-life of 1 to 2 minutes and short-lived activity.2,10,19,21 Researchers developed 2 different solutions to this problem.2
GLP-1 receptor agonists resemble GLP-1 structurally but resist degradation by DPP-4, for longer action.2 Exenatide is a synthetic form of exendin-4, a hormone in the saliva of the Gila monster (Heloderma suspectum) that shares 53% amino acid sequence identity with human GLP-1 and resists degradation by DPP-4.5,16 The half-life of exenatide is 2.4 hours; therefore, dosing is twice daily (0-60 minutes before breakfast and dinner).5,12 The predominant effect of exenatide is reduced postprandial glucose (PPG), especially following the meals before which it is administered.5 A longer-acting form has been developed but has not received Food and Drug Administration (FDA) approval.24
Liraglutide, an analog of human GLP-1, shares 97% amino acid sequence identity with human GLP-1.4,12,13,21 For liraglutide, the GLP-1 molecule was modified with 1 amino acid substitution and a C-16 palmitic-acid side chain attached via a glutamyl spacer.5 These modifications enable slower absorption from subcutaneous tissue, reversible albumin binding, and stability against DPP-4 degradation,5,12 for a half-life of 13 hours and once-daily administration.4,5,13,21
DPP-4 inhibitors (sitagliptin and saxagliptin) preserve and prolong the physiologic actions of native GLP-1.2 DPP-4 inhibitors act by reducing enzyme degradation to preserve endogenous GLP-1 in its intact, biologically active form.16 These inhibitors extend the half-life and increase the pool of endogenous active GLP-1, thereby enhancing its action.16 GLP-1 receptor agonists, on the other hand, produce significantly higher pharmacologic levels of GLP-1 activity relative to the endogenous GLP-1 levels preserved with DPP-4 inhibitors; thus GLP-1 receptor agonists have greater glucose lowering and weight loss effects than DDP-4 inhibitors.2
Actions of Incretin-Based Therapies
The GLP-1 receptor agonists and DPP-4 inhibitors share several important actions:
However, there are also major differences:
GLP-1 receptor agonists and DPP-4 inhibitors also improve pancreatic beta cell function, as assessed by C-peptide secretion and homeostasis model of assessment (HOMA-B).2
Because incretin-based agents stimulate insulin secretion and suppress glucagon secretion in a glucose-dependent manner, both the incidence and severity of hypoglycemia are low, an advantage over some other antidiabetic medications.25,28 A panel of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) has recommended GLP-1 receptor agonists for patients who do manual labor, drive vehicles, or operate dangerous machinery, or others for whom hypoglycemia is of particular concern.26 An American Association of Clinical Endocrinologists (AACE) consensus panel recommends a GLP-1 receptor agonist second only to metformin, because of the safety of GLP-1 receptor agonists, with nearly complete absence of hypoglycemia.16 Note that at the time the AACE recommendations were published, liraglutide had not yet received approval from the FDA, and exenatide was the only available GLP-1 receptor agonist. The Federal Aviation Administration lists both classes of incretin-based medications as acceptable for aviators.28 However, for patients receiving an incretin-based agent in combination therapy, the exact combination is important: the risk of hypoglycemia increases if a GLP-1 receptor agonist or DPP-4 inhibitor is used concomitantly with sulfonylureas.25,28
Differential Efficacy of Incretin-Based Agents
The two classes of pharmaceutical solutions to the problem of impaired incretin response have important mechanistic differences. DPP-4 inhibitors protect endogenous GLP-1 from DPP-4 degradation, thereby achieving a physiologic level of GLP-1 activity limited by the amount of endogenous GLP-1 in the circulation.2,25,27 In contrast, GLP-1 receptor agonists act directly on the GLP-1 receptor, achieving a pharmacologic level of GLP-1 activity.2,25,27 These different mechanisms yield certain different effects that can enter into clinical decision making for individual patients.
The different levels of GLP-1 activity enable glycemic control that tends to be greater with GLP-1 receptor agonists than DPP-4 inhibitors.2,27 In combination trials with metformin, A1C level reduction has been greater with GLP-1 receptor agonists (eg, liraglutide, exenatide) than DPP-4 inhibitors (eg, saxagliptin, sitagliptin).12,27,29 Note that these results were not from head-to-head trials comparing a DPP-4 inhibitor versus a GLP-1 receptor agonist.12,27,29 Monotherapy trials have shown greater reduction in FPG with GLP-1 receptor agonists than DPP-4 inhibitors.27 GLP-1 receptor agonists have greater efficacy in reducing PPG than DPP-4 inhibitors, which is important to patients who have achieved an A1C level of less than 8%.16,27 PPG level contributes more at A1C levels less than 8% and FPG level contributes more at A1C levels greater than 8.5%.27 However, at any A1C level, both PPG and FPG are important; therefore, patients with A1C levels less than 8% require therapy that reduces PPG as well as FPG levels to meet the ADA glycemic goal of an A1C level of 7% or less.27 DeFronzo et al compared the effects of the GLP-1 receptor agonist exenatide with the DDP-4 inhibitor sitagliptin on PPG in a double-blind, randomized crossover trial. In 61 evaluable patients, switching from exenatide to sitagliptin increased 2-hour PPG by 73 ± 11 mg/dL and switching from sitagliptin to exenatide further decreased 2-hour PPG by -76 ± 10 mg/dL.9 GLP-1 receptor agonists have also been shown to reduce glucagon secretion significantly more than DPP-4 inhibitors.2 DeFronzo et al also compared the effects of exenatide and sitagliptin on glucagon secretion, and determined that compared with sitagliptin, exenatide significantly reduced postprandial glucagon area under the curve (AUC) ratio (0.88 ± 0.03, P = .0011).9
Pharmacologic levels of GLP-1 activity can promote weight loss.2,25 Unlike DPP-4 inhibitors, GLP-1 receptor agonists promote satiety and decelerate gastric emptying, contributing to reduced food intake.9,16,25,28 The DeFronzo trial previously mentioned showed reduced caloric intake with exenatide and increased intake with sitagliptin.9,28 With slowed gastric emptying and increased satiety, GLP-1 receptor agonists may promote weight loss of up to 1 to 4 kg, whereas DPP-4s tend to be weight neutral.28 Weight loss with GLP-1 receptor agonists has been maintained for at least 52 weeks and is independent of nausea.4,7,28 In a liraglutide study, patients who experienced nausea had no significant difference in weight loss versus those who did not.21,28 The effects of GLP-1 receptor agonists on gastric emptying and satiety may occur because they act directly on the GLP-1 receptor, effecting stimulation, whereas DPP-4 inhibitors slow the clearance of endogenous GLP-1, a less direct action.25,28 Regardless of the mechanism, for many patients the potential for weight loss might give GLP-1 receptor agonists an advantage over DPP-4 inhibitors.16
Because patients with T2DM are at risk for cardiovascular disease (CVD), positive effects on cardiovascular risk factors would increase the value of T2DM therapy. Solid CVD health outcomes data is not yet available for incretin-based therapies; however, GLP-1 receptor agonists have been associated with small but significant decreases in systolic blood pressure.4,13,16,19,28,29 In a placebo-controlled trial of liraglutide as monotherapy, for example, systolic blood pressure was significantly reduced by -7.9 mm Hg (P = .0023).29 In contrast, insufficient evidence exists to draw conclusions about DPP-4 inhibitors and blood pressure.28 GLP-1 receptor agonists have shown consistent decreases in triglyceride levels, whereas DPP-4 inhibitors have been associated with both decreases and increases.5,16,28,30 The changes in blood pressure and lipid levels with GLP-1 receptor agonists are not enough to replace other therapies for those risk factors, but are an added benefit to consider, especially for patients at high cardiovascular risk.28 Long-term outcome trials in patients with T2DM and CVD risk factors are ongoing with liraglutide (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results - A Long Term Evaluation [LEADER])31 and other incretin-based therapies.
Differential Safety and Tolerability of Incretin-Based Agents
GLP-1 receptor agonists are administered by injection, whereas DPP-4 inhibitors are orally administered. Liraglutide is injected once daily, while the approved version of exenatide is injected twice daily.32,33 Injection is less convenient, but is not a safety issue and has for decades been used by patients with T2DM for administration of insulin. Pen devices and fine teflon-coated needles have improved patient acceptance of injections. Given the generalized T2DM disease process, the implementation of GLP-1 receptor agonist therapy has also been viewed by some as a bridge to insulin therapy.
The most common AEs of GLP-1 receptor agonists reported in 5% or more of patients in clinical trials and more commonly than with placebo include headache, nausea, diarrhea, and anti-liraglutide antibodies for liraglutide, while for exenatide, nausea, vomiting, diarrhea, feeling jittery, dizziness, headache, and dyspepsia were reported.28,32,33 In clinical trials, nausea occurred in up to 57% of patients treated with exenatide and 29% of patients treated with liraglutide.28 However, nausea was largely transient16,28,30 and can be minimized withgradual dose escalation of the GLP-1 receptor agonists.6,16,28 Probably because of lower GLP-1 activity, DPP-4 inhibitors do not ordinarily cause nausea (<5% of patients in clinical trials).25,28 Thus the pharmacologic level of GLP-1 activity may be associated with both the benefit of weight loss and the AE of transient gastrointestinal symptoms.7
The most common AEs with DPP-4 inhibitors include upper respiratory tract infection and headache.26,34,35 Nasopharyngitis is also common with sitagliptin, and urinary tract infection with saxagliptin.28,34,35
More rarely, hypersensitivity reactions have been reported with all 4 approved incretin-based agents, but may be more likely with DDP-4 inhibitors.28 The reactions have included anaphylaxis, urticaria, angioedema, dermatitis, and facial edema; none were life-threatening or required hospitalization.28
Acute pancreatitis has been reported with both GLP-1 receptor agonists and DPP-4 inhibitors.28 However, patients with T2DM already have increased risk of acute pancreatitis,16 up to 2.8-fold greater than persons without T2DM.11,28 A large insurance claims database study showed no statistical difference in risk of pancreatitis with exenatide compared with sitagliptin, metformin, and glyburide.36 Nevertheless, patient education about the signs and symptoms of pancreatitis is critical,28 and patients with a history of pancreatitis should not use these agents.16 Animal studies have suggested a risk of thyroid C cell cancer with native GLP-1 and the GLP-1 receptor agonists.28 The FDA concluded that the incidence of carcinomas among rodents translated into low risk for humans.37 Further, the FDA has required surveillance studies, which are ongoing.28 The prescribing information for liraglutide includes a black box warning regarding the risk of thyroid C-cell tumors and contraindication of the medication in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2) or a family history of medullary thyroid cancer.33
Because the submission of liraglutide and saxagliptin data occurred before the FDA cardiovascular safety standards were issued in December 2008, the FDA required the manufacturers to conduct postapproval clinical trials of cardiovascular safety.28 The FDA also required the manufacturer of exenatide to perform cardiovascular safety trials before reconsideration of the long-acting form.24
Expert Guidelines and Incretin-Based Treatment for the Individual Patient
Official statements of the ADA and EASD recommend initial treatment with comprehensive lifestyle management combined with metformin.26 For patients with A1C values above 7%, the guidelines recommend treatment intensification with additional agents to achieve and maintain glycemic targets.5,17 GLP-1 receptor agonists are specifically mentioned as options when hypoglycemic risk or weight loss are major considerations.5,26 DPP-4 inhibitors are described among therapeutic alternatives, but are not included in the treatment algorithm.26 The 2009 consensus statement of the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) panel on T2DM recommends specific strategies and medication classes depending on the A1C level after lifestyle modification.16 For patients with an A1C level between 6.5% and 7.5%, AACE/ACE recommends initial monotherapy, for A1C levels between 7.6% and 9.0%, dual therapy, and for A1C levels greater than 9.0%, dual or triple therapy.16,27 All of these therapeutic strategies include GLP-1 receptor agonists and DPP-4 inhibitors as options, except combinations with insulin.16
In the AACE/ACE treatment algorithm, the GLP-1 receptor agonists are preferred options as part of dual and triple therapy. AACE and ACE state that their treatment algorithm “favors the use of GLP-1 agonists and DPP-4 inhibitors with higher priority because of their effectiveness and overall safety profiles.”16 Because of the incretin-based medications’ “excellent performance…in combination with the growing literature indicating the serious risks of hypoglycemia, these agents are increasingly preferred for most patients in place of sulfonylureas and glinides.”16 GLP-1 receptor agonists are preferred because of their greater efficacy in reducing PPG compared with DPP-4 inhibitors and their potential to induce weight loss.16
For individual patients, cautious management of glycemic control might suggest a gradual increase in intensity from lifestyle modification to oral and perhaps to injected therapies, given the natural disease course of T2DM. However, the positive attributes of GLP-1 receptor agonists, including the potential to delay progression of beta cell dysfunction, should be considered when more intensive treatment is required, as should the attributes of other available therapies. The potential effects of GLP-1 receptor agonists on other metabolic abnormalities and risk factors should be considered in patients with advancing diabetes. Some data exist supporting positive effects of GLP-1 receptor agonists on blood pressure, dyslipidemia, obesity, and CVD risk.4,16,19,28,30
Effective individualization of T2DM therapy includes consideration of patient concerns, motivations, and likelihood of adherence. Some patients may not want to begin therapy with TZDs, insulin, and sulfonylureas because of concerns about weight gain.28 Others may adhere poorly to treatments because of weight gain effects, with resulting poor glycemic control. On the other hand, the potential for weight loss with GLP-1 receptor agonists can be a strong motivator for adherence.28 Patient satisfaction and physical and emotional domains of quality of life measures have improved with liraglutide-associated weight loss.21,25,28
Summary and Conclusions
Most T2DM treatments do not sustain efficacy in glycemic control over the long term. Some treatments also have AEs including hypoglycemia and weight gain, which can inhibit adherence. Research into new ways of treating T2DM has led to the development of antidiabetic agents that can help address these concerns.
The incretin hormones play a crucial role in insulin and glucagon secretion, appetite regulation, gastric emptying, and pancreatic beta cell function. Investigators found that the incretin response is impaired in T2DM, which raised the possibility of a new kind of treatment. The incretin hormone GLP-1 has several important actions in maintaining glucose homeostasis. Incretin-based pharmaceutical agents, GLP-1 receptor agonists and DPP-4 inhibitors, combat T2DM with these same actions, modulating insulin and glucagon secretion in a glucose-dependent manner, thus reducing hyperglycemia while avoiding hypoglycemia. Incretin-based medications also may improve beta cell function, the decline of which is an important factor in T2DM progression. In addition, GLP-1 receptor agonists have other actions that are absent with DPP-4 inhibitors, including promoting satiety and slowing gastric emptying, with resulting weight loss. GLP-1 receptor agonists also modestly improve cardiovascular risk factors including hypertension and high triglyceride levels.
Incretin-based medications have been endorsed in treatment practice guidelines of the principal diabetes organizations. Expert guidelines from the ADA/EASD and AACE/ACE list GLP-1 receptor agonists and DPP-4 inhibitors as treatment options for glycemic control in T2DM. AACE/ACE recommends the incretin-based treatments because of their safety and efficacy and prefers GLP-1 receptor agonists over DPP-4 inhibitors when weight loss is an objective. GLP-1 receptor agonists can be an appropriate clinical choice for glycemic control in individual patients, especially when weight loss is beneficial or hypoglycemia is a clinical concern.
Author Affiliation: MedMetrics Health Partners and Bouvé College of Pharmacy and Allied Health Sciences, Northeastern University, Boston, MA.
Funding Source: Financial support for this supplement was provided by Novo Nordisk.
Author Disclosure: Mr Calabrese reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.
Authorship Information: Concept and design; analysis and interpretation of data; drafting of the manuscript; and critical revision of the manuscript for
important intellectual content.
Address correspondence to: David Calabrese, RPh, MHP, MedMetrics Health Partners, 100 Century Dr, Worcester, MA 01606. E-mail: email@example.com.
1. Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, eds. Williams Textbook of Endocrinology. 11th ed. Philadelphia, PA: Saunders Elsevier; 2008:1331-1357.
2. Campbell RK, Cobble ME, Reid TS, Shomali ME. Distinguishing among incretin-based therapies. Pathophysiology of type 2 diabetes mellitus: potential role of incretin-based therapies. J Fam Pract. 2010;59(9 suppl 1):S5-S9.
3. Bagust A, Beale S. Deteriorating beta-cell function in type 2 diabetes: a long-term model. QJM. 2003;96(4):281-288.
4. Russell-Jones D, Vaag A, Schmitz O, et al; Liraglutide Effect and Action in Diabetes 5 (LEAD-5) met SU Study Group. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met SU): a randomised controlled trial. Diabetologia. 2009;52(1):2046-2055.
5. Buse JB, Rosenstock J, Sesti G, et al; LEAD-6 Study Group. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374(9683):39-47.
6. Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol. 2009;297(1-2): 127-136.
7. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):1696-1705.
8. Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29(1):46-52.
9. DeFronzo RA, Okerson T, Viswanathan P, Guan X, Holcombe JH, MacConell L. Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study. Curr Med Res Opin. 2008;24(10):2943-2952.
10. Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG; GWAA Study Group. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005;143(8):559-569.
11. Deacon CF. Potential of liraglutide in the treatment of patients with type 2 diabetes. Vasc Health Risk Manag. 2009;5(1):199-211.
12. Nauck M, Frid A, Hermansen K, et al; LEAD-2 Study Group. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009;32(1):84-90.
13. Marre M, Shaw J, Brandle M, et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med. 2009;26(3):268-278.
14. Bergenstal RM, Wysham C, MacConell L, et al; DURATION-2 Study Group. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet. 2010;376(9739):431-439.
15. Cheung BM, Ong KL, Cherny SS, Sham PC, Tso AW, Lam KS. Diabetes prevalence and therapeutic target achievement in the United States, 1999 to 2006. Am J Med. 2009;122(5):443-453.
16. Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009;15(6):540-559.
17. Standards of medical care in diabetes—2011. Diabetes Care. 2011;34(suppl 1):S11-S61.
18. Rodbard HW, Blonde L, Braithwaite SS, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2007;13(suppl 1):1-68.
19. Zinman B, Gerich J, Buse JB, et al. LEAD-4 Study Investigators. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met TZD). Diabetes Care. 2009;32(7):1224-1230.
20. Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther. 2007;29(11):2333-2348.
21. Garber A, Henry R, Ratner R, et al; LEAD-3 (Mono) Study Group. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373(9662):473-481.
22. Stolar M. Glycemic control and complications in type 2 diabetes mellitus. Am J Med. 2010;123(3 suppl):S3-S11.
23. Diamant M, Van GL, Stranks S, et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet. 2010;375(9733):2234-2243.
24. Amylin, Lilly and Alkermes announce receipt of complete response letter from FDA for Bydureon [press release]. San Diego, CA: Amylin Pharmaceuticals, Inc, Indianapolis, IN: Eli Lilly and Co, and Waltham, MA: Alkermes, Inc; October 19, 2010. Available at: http://newsroom.lilly.com/releasedetail.cfm?releaseid=520521. Accessed March 8, 2011.
25. Pratley RE, Nauck M, Bailey T, et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trial. Lancet. 2010;375(9724):1447-1456.
26. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193-203.
27. Campbell RK, Cobble ME, Reid TS, Shomali ME. Distinguishing among incretin-based therapies. Glucose-lowering effects of incretin-based therapies. J Fam Pract. 2010;59(9 suppl 1):S10-S19.
28. Campbell RK, Cobble ME, Reid TS, Shomali ME. Distinguishing among incretin-based therapies. Safety, tolerability, and nonglycemic effects of incretin-based therapies. J Fam Pract. 2010;59(9 suppl 1):S20-S27.
29. DeFronzo RA, Hissa MN, Garber AJ, et al. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care. 2009;32(9):1649-1655.
30. Vilsboll T, Zdravkovic M, Le-Thi T, et al. Liraglutide, a longacting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care. 2007;30(6):1608-1610.
31. Novo Nordisk. Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results - A Long Term Evaluation (LEADER). http://novonordisk-trials.com/website/search/trial-registry-details.aspx?id=15076. Updated February 8, 2011. Accessed February 23, 2011.
32. Byetta [prescribing information]. San Diego, CA: Amylin Pharmaceuticals; 2010.
33. Victoza [prescribing information]. Princeton, NJ: Novo Nordisk, Inc; 2010.
34. Onglyza [prescribing information]. Princeton, NJ: Bristol- Myers Squibb; 2011.
35. Januvia [prescribing information]. Whitehouse Station, NJ: Merck & Co, Inc; 2011.
36. Dore DD, Seeger JD, Arnold Chan K. Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide. Curr Med Res Opin. 2009;25(4):1019-1027.
37. Parks M, Rosebraugh C. Weighing risks and benefits of liraglutide — the FDA’s review of a new antidiabetic therapy. N Engl J Med. 2010;362(9):774-777.