Comparison of extended release GLP-1 receptor agonist therapy versus sitagliptin in the management of type 2 diabetes

Introduction

Managing type 2 diabetes mellitus (T2DM) over the course of a patient’s lifetime has proven to be challenging, with less than half of patients at any given time achieving therapeutic goals.¹ This may be due to many factors, including the advanced state of pancreatic beta-cell dysfunction at the time of diagnosis, the relatively modest efficacy of therapeutic agents to lower blood glucose, and lack of agents that are not only glucose-lowering, but also intrinsically disease-modifying.^2–4 In addition, numerous challenges surround patient treatment adherence, including cost and tolerability issues.⁵ The discovery and clinical implementation of incretin-based therapies has offered health care providers the opportunity to address a number of intrinsic physiologic defects seen in diabetes and, in the case of glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) therapy, offer somewhat more efficacious glucose-lowering properties than oral therapeutic alternatives. The development of extended release GLP-1RA therapy may address some of the adherence and side effect issues that have proved to be barriers to therapy in the past.

Over 40 years ago, it was discovered that the human insulin response to intravenous glucose was only 30%–40% of that observed after an oral glucose load that raised blood glucose to the same level, indicating that not only blood sugar, but also alimentary mechanisms, regulated insulin secretion.^6,7 Subsequent studies found that this phenomenon, known as the incretin effect, was attributable in part to a 30-amino-acid hormone known as GLP-1, which is co-encoded with glucagon and is released into circulation from the distal small bowel and colon in response to nutrient ingestion.^8,9 Upon reaching pancreatic islets, GLP-1 binds to heptahelical G protein-coupled receptors on the membrane of beta cells and stimulates insulin secretion in a glucose-dependent fashion, accounting in large part for the observed incretin effect.⁸

Consistent with the wide expression of its receptors in diverse tissues,^8,9 GLP-1 exhibits biologic activities beyond insulinotropism. In published studies, GLP-1 also inhibited glucagon secretion from pancreatic alpha cells at glucose levels at or above normal fasting levels, reduced gastric motility, and induced feelings of satiety via hunger centers in the hypothalamus.^10,11 In other studies, direct infusion of GLP-1 modulated fluid intake and increased renal sodium excretion,^12,13 whereas incretin-based therapy has been associated with blood pressure lowering, beneficial changes in lipid profiles, and improvements in hepatic, myocardial, and endothelial function.^14,15

Two general classes of incretin therapies have been designed to capitalize on the antihyperglycemic effects of GLP-1. The first, the GLP-1RAs, act by increasing the level of systemic GLP-1 activity. Administered by subcutaneous injection, currently available GLP-1RAs include exenatide twice daily (EBID),¹⁶ liraglutide once daily,¹⁷ and exenatide once weekly (EQW).¹⁸ The dipeptidyl peptidase 4 (DPP-4) inhibitors increase the levels of native GLP-1 by a different mechanism, ie, by inhibiting DPP-4, a widely dispersed and promiscuous protease that normally turns over native GLP-1 rapidly in vivo.¹⁹ Administered orally, currently available DPP-4 inhibitors include sitagliptin,²⁰ saxagliptin,²¹ linagliptin,²² and vildagliptin.²³ All of the preceding incretin agents (GLP-1RAs and DPP-4 inhibitors) have been approved in the United States and the European Union for use in patients with T2DM, with the exception of vildagliptin, which has received marketing authorization in the European Union only.

The purpose of this review is to describe the properties of EQW, the most recently approved incretin therapy and the only antidiabetic agent administered one time per week. Included here will be a summary of the basic pharmacology, efficacy, and safety of this new long-acting agent, with a particular focus on its comparison to the DPP-4 inhibitor sitagliptin.

Pharmacology of EQW

Exenatide, the active ingredient in EQW, is a 39-amino-acid synthetic version of exendin-4, a peptide isolated from the lizard Heloderma suspectum that shares approximately 50% sequence identity with human GLP-1.²⁴ Exenatide binds with high affinity to GLP-1 receptors and has all of the known glucoregulatory activities of GLP-1.^25–27 However, it is more resistant than GLP-1 to degradation by DPP-4.²⁴ In the twice-daily formulation, median peak plasma concentrations of exenatide occurred 2.1 hours after administration, and the subsequent mean terminal half-life was 2.4 hours,¹⁶ pharmacokinetic parameters that permitted twice-daily administration before the two main meals of the day.

In the new once-weekly formulation, exenatide has been encapsulated in injectable microspheres that degrade in situ after administration and slowly release drug into circulation in a sustained fashion.²⁸ The structural matrix of the microsphere is composed of a medical-grade biodegradable polymer called poly-(d,l-lactide-co-glycolide) (PLG), which has been used in dissolvable surgical sutures, bone plates, and orthopedic implants for decades and in microsphere form as a long-acting drug-delivery system since 1984.^29–31 Degradation of the PLG polymer occurs by hydrolysis of the ester linkages into lactic acid and glycolic acid, which are easily eliminated as carbon dioxide and water. It is important to note that the encapsulated exenatide in EQW, as well as the active agent released into circulation, is identical to that in EBID.

In a pharmacokinetic study on patients with T2DM receiving a single dose of EQW, exposure increased with dose (2.5, 5, 7, or 10 mg), with measurable levels of exenatide lasting for up to 10 weeks.³² The same study evaluated exenatide exposure following once-weekly administrations of EQW 0.8 mg or EQW 2.0 mg in 45 patients with T2DM across a 15-week treatment period (Figure 1).³² In patients who received the 2.0 mg dose, the currently indicated dosage,¹⁸ plasma exenatide concentrations rose over time and reached steady-state levels by approximately 6–7 weeks. At steady state, overall plasma levels were roughly comparable to the maximum concentration reached after a single injection of EBID.

Efficacy of EQW versus sitagliptin

Six randomized controlled trials, known by the acronym DURATION for Diabetes Therapy Utilization: Researching Changes in A1c, Weight and Other Factors Through Intervention with Exenatide Once Weekly, have been conducted to determine the efficacy and safety profiles of EQW (Table 1).^33–38 DURATION-4³⁷ and DURATION-2³³ directly compared EQW with the DPP-4 inhibitor sitagliptin.

EQW versus other antidiabetic agents

EQW also compared favorably with other antidiabetic agents in its glucose-lowering and weight-sparing effects (Figure 3). For instance, compared with EBID in DURATION-1, patients on EQW exhibited a larger mean reduction from baseline in HbA_1c (−1.9% versus −1.5%; P=0.0023), a higher proportion of patients reaching target HbA_1c ≤7% (77% versus 61%; P=0.0039), and a larger mean reduction in FPG (−41.4 mg/dL versus −25.2 mg/dL; P<0.00001). Patients receiving EBID, on the other hand, had significantly greater improvements in 2-hour postprandial plasma glucose excursions (−124.2 mg/dL versus −95.4 mg/dL; P=0.00123).³⁶ Similar weight loss was observed with both agents.³⁶ DURATION-5 also compared EQW with EBID, and EQW was associated with significantly greater changes from baseline in HbA_1c (−1.6% versus −0.9%; P<0.0001) and FPG (−35 mg/dL versus −12 mg/dL; P<0.0008) and similar reductions in mean bodyweight (−2.3 and −1.4 kg).³⁴

Other comparators in the DURATION trials included metformin, pioglitazone, insulin glargine, and liraglutide. In patients on diet and exercise background therapy, EQW, metformin, and pioglitzaone reduced HbA_1c to similar extents, whereas in patients on metformin background therapy, EQW reduced HbA_1c (−1.5%) significantly more than pioglitazone (−1.2%; P=0.017).³³ In patients on oral antidiabetic agent combination therapy, EQW reduced HbA_1c significantly more than insulin glargine (−1.5% versus −1.3%; P<0.05),³⁵ but significantly less than liraglutide (−1.3% versus −1.5%; P<0.05).³⁸ EQW therapy was associated with moderate weight loss in all of the DURATION trials; pioglitazone and insulin glargine use were associated with weight gain (Figure 3).

Safety and tolerability of EQW

Other investigational approaches for reducing the frequency of exenatide administration

Given the positive outcomes of EQW studies, it is of interest to assess the clinical utility of even longer-acting preparations. Two other investigational agents have been described that allow for lower frequency of exenatide dosing. The first was a new once-monthly formulation, consisting of EQW microspheres reconstituted in a triglyceride-based diluent.⁵² Improved patient adherence may be a potential benefit of exenatide once monthly (EQM), owing to greater convenience of administration,^53,54 although this advantage remains unproven and will require prospective Phase III trials for confirmation. A preliminary open-label controlled study evaluated the safety and efficacy of EQM (5, 8, or 11 mg) versus EQW in 121 patients with T2DM on diet/exercise, metformin, pioglitazone, or metformin plus pioglitazone.⁵² Across a 20-week treatment period, HbA_1c decreased in the EQM 5, 8, and 11 mg groups by −1.3%, −1.3%, and −1.5%, respectively (EQW control, −1.5%), and the percentages of patients achieving HbA_1c <7% were 50%, 57%, and 70%, respectively (EQW control, 48%). EQM therapy was also associated with improvements in FPG (−25, −30, and −49 mg/dL, respectively) and weight (−1.1, −0.4, and −1.1 kg, respectively). No unique safety findings were observed with EQM relative to EQW. The most frequent adverse events for EQM were headache (17%–27%) and nausea (17%–23%). No major or minor hypoglycemia was observed in any treatment group.

Another form of exenatide delivery was evaluated in a Phase II study with ITCA 650, a subcutaneous osmotic delivery system that provides for continuous delivery of exenatide at specified doses for 3 months. A 48-week study evaluated ITCA 650 at 4 doses (20, 40, 60, and 80 μg per day) in patients with T2DM.⁵⁵ After 48 weeks at the chronic dose selected for further Phase III studies (60 μg per day), mean HbA_1c levels decreased from baseline by 1.5%, 78% of patients had HbA_1c levels ≤7%, and mean weight declined by 3.5 kg. Overall, the treatment appeared to be well tolerated.

Conclusion

EQW is the first approved medication for T2DM that is administered one time per week. In direct head-to-head comparisons, EQW resulted in better glucose control (HbA_1c), higher proportions of patients reaching treatment goals, greater reductions in FPG, and more significant weight loss than the DPP-4 inhibitor sitagliptin. To date, the primary limiting factor for GLP-1RA use has been gastrointestinal adverse events, notably nausea, vomiting, diarrhea, and constipation. EQW, however, was associated with less nausea than either EBID or liraglutide, but more than sitagliptin. The incidence of mild hypoglycemia in patients who received EQW as monotherapy or in combination with metformin or thiazolidinediones was low, although it was higher in patients who received concomitant treatment with a sulfonylurea.

A recent position statement from the American Diabetes Association and the European Association for the Study of Diabetes recommended maintaining HbA_1c below 7% as a general treatment goal in patients with T2DM, but emphasized individualization of therapy rather than a rigid step-care approach.⁵⁶ The clinical utility of EQW is intriguing when looked at from the perspective of this new treatment paradigm in that it allows for earlier use of EQW in patients with diabetes, significant obesity, and issues with both dietary compliance and postprandial glycemic control.

Although many physicians may still view DPP-4 inhibitors as equivalent to injectable GLP-1RAs, both postprandial and overall glycemic control was significantly better on EQW therapy in clinical trials. Time and teaching barriers to any injectable therapy may lead many patients to favor an oral therapy, but it should be noted that administration of EQW requires only one additional step than other common injectable diabetes medications, ie, suspension of the microspheres before administration, and that a published study showed a majority of patients were capable of independently self-administering a microsphere preparation.⁵⁷

Regarding other therapies, early use of EQW may be hindered by the impending availability of less costly generic thiazolidinediones, as well as metformin and sulfonylureas. However, exenatide in combination with metformin or with metformin plus pioglitazone, as suggested by DeFronzo,³ may possibly address physiologic defects seen in diabetes more effectively than alternative combinations. The ability to modify postprandial glycemic excursions with a once-weekly shot rather than multiple doses of insulin may also have added benefits in patient compliance and reduced hypoglycemia.