Review of the Safety and Efficacy of Exenatide Once Weekly for the Treatment of Type 2 Diabetes Mellitus

Catherine E Murphy PharmD BCPS BCACP


The Annals of Pharmacotherapy. 2012;46(6):812-821. 

In This Article

Abstract and Introduction


Objective: To summarize and evaluate the available literature assessing the efficacy and safety of exenatide once weekly for the treatment of type 2 diabetes mellitus.
Data Sources: PubMed (1966-January 2012) and International Pharmaceutical Abstracts (1969-January 2012) were searched using the term exenatide once weekly. Abstracts presented at the European Association for the Study of Diabetes Annual Meeting in 2011 and reference citations from publications were reviewed for inclusion. Eli Lilly and Company and Amylin Pharmaceuticals were contacted for additional unpublished information.
Study Selection and Data Extraction: All English-language articles and abstracts were evaluated for inclusion. All randomized controlled trials were included in the review.
Data Synthesis: The efficacy and safety of exenatide once weekly has been evaluated as initial monotherapy and as add-on therapy to metformin, sulfonylureas, and thiazolidinediones in patients with uncontrolled type 2 diabetes for up to 3 years. Results from 6 randomized, comparator-controlled studies in over 3000 patients indicate that treatment with exenatide once weekly results in significant glycemic improvements and weight loss. Gastrointestinal adverse effects and injection site reactions are common, but rarely lead to drug discontinuation.
Conclusions: Exenatide once weekly holds promise as a convenient, efficacious, and well-tolerated antihyperglycemic agent for the treatment of type 2 diabetes. Studies evaluating outcomes such as cardiovascular events or all-cause mortality with exenatide once weekly are lacking.


There is an epidemic of diabetes in the US, with the disease affecting an estimated 25 million people.[1] Complications of diabetes contribute to excess morbidity and mortality and include cardiovascular disease, kidney disease, limb amputation, painful neuropathy, and blindness. Estimated total direct and indirect costs attributed to diabetes in the US were $174 billion in 2007 and are likely more than that now given the increasing prevalence of the disease.[2] The excess morbidity and mortality and staggering costs attributed to diabetes underline the need for effective prevention and treatment.

Although recent studies have questioned the clinical benefit of aggressive glycemic control, a hemoglobin A[1c] (A1C) less than 7.0% is an appropriate glycemic goal for most patients.[3–5] This should be targeted with lifestyle modifications and pharmacologic therapies while avoiding severe hypoglycemia and adverse effects. Unfortunately, despite the availability of multiple effective antihyperglycemic therapies, almost half of patients with diabetes continue to have suboptimal glycemic control.[6]

Modest weight loss can improve glycemic control and prevent progression or development of the disease, but most patients require pharmacologic therapy to manage hyperglycemia.[7,8] Guidelines for treatment of type 2 diabetes recommend metformin as the initial therapy for most patients because of its efficacy, safety, tolerability, and low cost.[9,10] Alternatives to metformin monotherapy include thiazolidinediones, sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) agonists. Advantages of GLP-1 agonists include the low incidence of hypoglycemia and associated weight loss; disadvantages include the need for administration via injection, frequent gastrointestinal adverse effects, and cost. Current guidelines do not recommend GLP-1 agonists as a first-line option, but they should be considered as monotherapy or adjunctive therapy when hypoglycemia or weight loss is of particular concern, or when postprandial hyperglycemia is the primary target. These recommendations were published before the approval of liraglutide, a long-acting GLP-1 agonist with a less pronounced effect on postprandial glucose (PPG) than exenatide twice daily.[11]

The first GLP-1 agonist, exenatide, was approved by the Food and Drug Administration (FDA) in 2005 as a twicedaily subcutaneous injection.[12] Multiple studies have demonstrated that treatment with exenatide twice daily results in reduction of both fasting and postprandial glucose and A1C lowering of up to 1.1% (generally about 0.6− 0.9%).[13–16] Advantages of exenatide twice daily include weight loss of approximately 2–3 kg and a low incidence of hypoglycemia. However, the usefulness of this formulation is limited by the high rate of gastrointestinal adverse effects, most notably nausea and vomiting, and the inconvenience of twice-daily injections that must be administered within 60 minutes before meals. Furthermore, the twice-daily formulation does not result in 24-hour glycemic coverage, and the rapid increase in exenatide serum concentrations after dosing may contribute to the high rate of gastrointestinal adverse effects.

Liraglutide was approved in 2010.[17] The longer half-life (12 hours vs 2.4 hours for exenatide) allows for once-daily dosing, which affords a more convenient administration schedule than exenatide twice daily. Additionally, liraglutide results in greater reductions in fasting plasma glucose (FPG) and an approximately 0.3% greater reduction in A1C than exenatide twice daily.[11] Reductions in PPG after breakfast and dinner are greater with exenatide twice daily. Weight loss and overall tolerability with liraglutide appear to be similar to exenatide twice daily, while the incidence of hypoglycemia is significantly lower with the longer acting GLP-1 agonist.[11] The incidence of nausea and vomiting with liraglutide is slightly lower than that seen with exenatide twice daily, and gastrointestinal adverse effects tend to be more transient with liraglutide.

The recent development of a once-weekly exenatide formulation may provide a more convenient antihyperglycemic option for many patients with uncontrolled type 2 diabetes. This new formulation uses biodegradable microsphere technology to encapsulate the active drug and slowly release exenatide into the systemic circulation after subcutaneous injection. The result is therapeutic drug concentrations over the entire dosing interval and a more gradual increase in serum drug concentrations after dosing, leading to the potential for greater efficacy and improved gastrointestinal tolerability. Exenatide extended-release was approved in January 2012 as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. This article reviews and evaluates the evidence for the use of exenatide once weekly in the treatment of type 2 diabetes and its potential place in therapy.


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