Exenatide Acetate: A Multifaceted Antidiabetic with Established Efficacy and Evolving Formulations

Exenatide acetate is available in a short-acting formulation for administration twice daily (BID) before meals and a long-acting formulation, containing the same parent drug as exenatide BID, for administration once weekly (QW). Alternative formulations of exenatide are currently being investigated, including a QW suspension for autoinjection.

Exenatide acetate as adjunctive therapy in patients with type 2 diabetes

Incretin glucagon-like peptide-1 (GLP-1) is a hormone released from cells in the gastrointestinal tract (GI), leading to glucose-dependent insulin release from the pancreas. It also suppresses postprandial hyperglycemia, glucagon secretion and slows gastric emptying. Exenatide acetate (EXE), a functional analog of human GLP-1, was approved by the US FDA in April 2005. The treatment of type 2 DM consists of life-style changes (diet and exercise) and the use of oral hypoglycemic agents, insulin sensitizers, oral agents that impede hepatic production of glucose, and exogenous insulin. However, hypoglycemia, gastrointestinal (GI) side effects, weight gain, and lack of optimal control of postprandial glucose are limitations that may present with the use of these type 2 DM treatments, preventing patients from reaching glycemic control. As a result, there is an interest in therapies that control blood glucose by alternative physiological mechanisms that do not significantly change patients weight, induce hypoglycemia or GI side effects, In April of 2005, the FDA approved Exenatide acetate (EXE) as the first incretin mimetic injection formulation to treat type 2 DM. This article compiles results of recently published primary literature on the efficacy and safety of Exenatide acetate injection. Additional topics discussed in this article include dosing, administration, drug interactions, pharmacokinetics, and pharmacodynamics of Exenatide acetate injection.[1]

Exenatide acetate reaches median peak plasma concentrations in 2.1 hours after subcutaneous injection. The mean peak EXE concentration (Cmax) is 211 pg/mL and the mean area under the plasma concentration-time curve from time zero to infinity (AUC0–inf) is 1036 pg*h/mL following subcutaneous administration of a 10 μg dose of Exenatide acetate. The EXE exposure (AUC) increases proportionally over the therapeutic dose range of 5 μg to 10μg unlike the Cmax values that increase less proportionally over the same dose range. No differences in Exenatide acetate exposure are found at the different sites of subcutaneous administration (abdomen, thigh, or arm). EXE is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The t1/2 of EXE is 2.4 hours. These pharmacokinetic characteristics of EXE are independent of the dose. Exenatide acetate slows gastric emptying and therefore may reduce the rate of absorption of certain oral medications. Patients should be advised to take medications that depend on threshold concentrations for efficacy (ie, oral contraceptives and antibiotics) at least 1 hour before injecting EXE. Additionally, caution should be exercised when taking medications that require rapid GI absorption while using Exenatide acetate. In a randomized, single-blind, placebo-controlled, 6-way crossover study by Blase et al the effects of EXE 10 μg on the pharmacokinetics of acetaminophen 1000 mg were assessed (N = 39 healthy subjects). Acetaminophen AUC0–12 h levels were reduced by 11% to 24% and acetaminophen Cmax were reduced by 37% to 56% depending on the coadministration times with EXE (−1, 0, +1, +2 and +4 hours).

As a result, Exenatide acetate dose escalation from 5 μg SC BID for a month to 10 μg SC BID is recommended. While being treated with EXE, patients that experience severe abdominal pain with or without nausea/vomiting, should seek immediate medical attention to rule out hemorrhagic/necrotizing pancreatitis. Exenatide acetate can be safely added to metformin therapy, sulfonylurea therapy or metformin and sulfonylurea therapy combination to effectively target glycemic goals in patients with type 2 DM. A new formulation of EXE 2 mg sustained release SC once weekly for the treatment of type 2 diabetes is being study. This new formulation has shown to reduce HbA1c by 1.9% and body weight by 3.7 kg at week 30. This formulation seems to share a similar tolerability profile that Exenatide acetate SC BID with nausea and vomiting being the most commonly reported adverse events.

Clinical use, and future directions of Exenatide acetate

Exenatide acetate is a first-in-class glucagon-like peptide-1 receptor agonist (GLP-1RA), initially approved for treatment of type 2 diabetes (T2D) in 2005. In patients with T2D, GLP-1RAs improve glycemic control through mechanisms including glucose-dependent insulinotropic and glucagonostatic effects, delayed gastric emptying, and decreased food intake. Exenatide acetate is available in a short-acting formulation for administration twice daily (BID) before meals and a long-acting formulation, containing the same parent drug as exenatide BID, for administration once weekly (QW). Alternative formulations of exenatide are currently being investigated, including a QW suspension for autoinjection. In clinical trials of patients with T2D, exenatide BID reduced postprandial glucose and glycated hemoglobin (HbA1c), promoted weight loss, and decreased markers of cardiovascular (CV) disease risk. Exenatide acetate QW also reduced HbA1c, fasting glucose (FG), weight, and CV risk factors in patients with T2D in randomized clinical trials, with benefit observed in patients followed for up to 7 years in open-label extensions. Several studies are ongoing to explore the efficacy of exenatide QW in new combination therapies for the treatment of T2D, in special patient populations, and for patient benefits beyond glycemic control.[2]

Exenatide BID was the first of the GLP-1RA class to reach the markets in 2006. Exenatide acetate QW was approved by the EMA and the US FDA in 2011 and 2012, respectively. Until the approvals of albiglutide and dulaglutide in 2014, exenatide QW was the only QW GLP-1RA accessible to clinicians and patients with T2D. So, given the rising competition, is exenatide still relevant today? Overall, exenatide acetate QW and BID have been demonstrated to be well tolerated. Nonetheless, the most common short-term AEs were the well-known gastrointestinal AEs, which, along with injection-site-related AEs, were reported more often after treatment with exenatide compared with non-GLP-1RA drug classes. In DURATION-6, the exenatide QW group reported fewer gastrointestinal AEs than the liraglutide-treated group, whereas subcutaneous nodules were more frequent with Exenatide acetate QW. In contrast, the LEAD-6 trial reported very similar rates of these various AEs following treatment with exenatide BID and liraglutide QD. Exenatide acetate BID was associated with higher frequencies of nausea, vomiting, and diarrhea, but fewer injection-site reactions than lixisenatide QD in the GetGoal-X trial.

Exenatide acetate: A New Promising Antidiabetic Agent

Exenatide acetate is a unique agent which can effectively control blood glucose levels in type 2 diabetes mellitus without producing dangerous adverse effects. In addition, it can lower body weight which is very essential for the treatment of obese type 2 diabetes mellitus patients. Since it can delay the destruction of islet beta-cells, type 2 diabetes mellitus patients are not rapidly converted to type 1 diabetes mellitus and ultimately appearance of complications of the disease is halted or delayed. Its long-acting-release formula, which would be used once per week, simultaneously retaining all the properties of twice-daily subcutaneous administration, is undergoing clinical trial. This drug is considered as an adjunct to metformin/sulfonylureas/insulin. One unique and exceptional property of Exenatide acetate has been demonstrated by several study groups, where the drug has been found to halt the progression of degeneration of insulin secreting islet beta-cells as well as stimulates their regeneration, both on T2DM and T1DM. Convincing study reports in this respect are awaited. If proved, this action of Exenatide acetate would eliminate or reduce the major progressive pathology of diabetes mellitus, thereby bringing great relief to many diabetes mellitus patients as well as physicians, who are facing a tremendous challenge daily to treat the most complicated disease, diabetes mellitus, both type 1 and 2.[3]

References

[1]Robles GI, Singh-Franco D. A review of exenatide as adjunctive therapy in patients with type 2 diabetes. Drug Des Devel Ther. 2009 Sep 21;3:219-40.

[2]Knop FK, Brønden A, Vilsbøll T. Exenatide: pharmacokinetics, clinical use, and future directions. Expert Opin Pharmacother. 2017 Apr;18(6):555-571.

[3]Chakraborti CK. Exenatide: a new promising antidiabetic agent. Indian J Pharm Sci. 2010 Jan;72(1):1-11.

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