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FDA Approvals: Once-Weekly Exenatide for Type 2 Diabetes

Clinical Context

The US Food and Drug Administration (FDA) has approved an extended-release formulation of exenatide injection as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. This is the first approved medication administered once weekly for type 2 diabetes.
The FDA has required the manufacturer to perform a randomized, double-blind, placebo-controlled trial of effects of the drug on the incidence of major adverse cardiovascular events, pancreatic cancer, kidney disease, serious hypoglycemia, and on potential biomarkers of medullary thyroid carcinoma (MTC). An MTC case series registry and Risk Evaluation and Mitigation Strategy (REMS) are also mandated.

Study Synopsis and Perspective

The US FDA approved a once-weekly extended-release formulation of exenatide injection (Bydureon, Amylin Pharmaceuticals) as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.
It is the first once-a-week medication for type 2 diabetes on the market.
The approval comes roughly 2 and a half years after Amylin applied for FDA approval of the extended-release version of its twice-daily exenatide injection (Byetta). During that time, the manufacturer endured 2 rejections, with the agency asking it to supply more data on efficacy and safety — in particular, the drug's effect on heart rate.
The agency still has its safety concerns. In approving the once-weekly medication, the FDA ordered Amylin to conduct a randomized, double-blind, placebo- controlled trial evaluating the drug's effect on the incidence of major adverse cardiovascular events among patients with type 2 diabetes. The trial also must assess the risk for certain other adverse events, such as pancreatic cancer, renal disorders, and serious hypoglycemia, and the long-term effects on potential biomarkers of MTC.
In addition, the company must conduct a number of studies with mice — and one that also includes mice, rat, and human thyroid C cells — that focus on MTC.
Two other precautionary strings are attached to the drug's approval. The FDA required Amylin to create an MTC case series registry to monitor the annual incidence of the cancer in the United States for at least 15 years and identify any increase related to the introduction of extended-release exenatide. And Amylin must carry out a risk evaluation and mitigation strategy (REMS) "to ensure the benefits of the drug outweigh the risks of [MTC] and acute pancreatitis, including hemorrhagic and necrotizing pancreatitis."
A boxed warning on the drug's label explains why the FDA is worried about MTC. Extended-release exenatide "causes thyroid C-cell tumors at clinically relevant exposures in rats," according to the boxed warning. "It is unknown whether Bydureon causes thyroid C-cell tumors, including ...MTC, in humans, as human relevance could not be determined by clinical or nonclinical studies."
The boxed warning also states that the drug is contraindicated in patients with a personal or family history of MTC and in patients with multiple endocrine neoplasia syndrome type 2.
Extended-Release Exenatide Outperforms Twice-Daily Version
A clinical trial showed that after 24 weeks of treatment, patients taking extended-release exenatide lowered their hemoglobin A1c levels by 1.6 percentage points from baseline compared with a 0.9-percentage point reduction for patients taking the twice-daily version, Amylin stated in a press release.
The most common adverse effects that emerged in clinical trials were nausea (which usually decreased with time), hypoglycemia, vomiting, diarrhea, jittery feeling, dizziness, headache, dyspepsia, constipation, and asthenia.
Amylin stated that its newly approved drug will be available in pharmacies in February.
Other Warnings, Precautions, and Adverse Reactions
Postmarketing reports with exenatide indicate some cases of fatal and nonfatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, exenatide should be discontinued, and it should not be restarted if pancreatitis is confirmed.
There is an increased risk for hypoglycemia when extended-release exenatide is used in combination with a sulfonylurea. In these cases, clinicians should consider reducing the sulfonylurea dose.
There have been some postmarketing reports of renal impairment with exenatide, sometimes requiring hemodialysis and kidney transplantation. Use of the drug is not recommended in patients with severe renal impairment or end-stage renal disease, and caution is warranted in patients with renal transplantation or moderate renal impairment.
Extended-release exenatide is not recommended in patients with gastroparesis or other severe gastrointestinal tract disease.
Patients in whom serious hypersensitivity reactions develop should discontinue extended-release exenatide and other suspect medications and promptly seek medical attention.
Nausea, diarrhea, headache, vomiting, constipation, injection site itching or nodule, and dyspepsia are the most common adverse reactions, occurring in at least 5% of patients and more often than with the comparator in clinical trials.
Limitations of Use
Because of the uncertain relevance of the rat thyroid C-cell tumor findings to humans, clinicians should prescribe extended-release exenatide only to patients in whom the potential benefits are thought to outweigh the potential risk.
It should not be used first-line in patients who have inadequate glycemic control with diet and exercise, nor is it a substitute for insulin. Also, it is ineffective in patients with type 1 diabetes and in patients with diabetic ketoacidosis. Concurrent use with insulin has not been studied and cannot be recommended, nor should it be used with exenatide injection.
Other antidiabetic agents should be considered in patients with a history of pancreatitis.
Use in Special Populations
Animal data suggest that extended-release exenatide may cause fetal harm, and it should therefore be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Caution is warranted when the drug is given to a breast-feeding mother.
More information about the approval of extended-release exenatide is available at the FDA Web site.
Laurie Barclay, MD, contributed to this synopsis.

Clinical Implications


  • The FDA has approved a once-weekly extended-release formulation of exenatide injection to improve glycemic control in adults with type 2 diabetes, used as an adjunct to diet and exercise.
  • Exenatide has been linked to some cases of fatal and nonfatal hemorrhagic or necrotizing pancreatitis. The risk for hypoglycemia is increased when extended-release exenatide is used concurrently with a sulfonylurea. The drug is not recommended in patients with severe renal impairment or end-stage renal disease and is not recommended in patients with gastroparesis or other severe gastrointestinal tract disease.
  • Clinicians should prescribe extended-release exenatide only to patients in whom the potential benefits are thought to outweigh the potential risk, because it is unclear whether findings of thyroid C-cell tumors in rats are relevant to humans. It is not intended as first-line therapy in patients who have inadequate glycemic control with diet and exercise, is not a substitute for insulin, and is not effective in patients with type 1 diabetes. In patients with a history of pancreatitis, other antidiabetic agents should be considered.

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