A Review of Exenatide (BYETTA) for Type-2 Diabetes

Patients should wait to use exenatide (BYETTA), an injectable Type-2 diabetes drug, until 2012, seven years after the drug’s approval.

The Food and Drug Administration (FDA) approved exenatide in April 2005 to improve blood sugar control in patients with Type-2 diabetes.

Exenatide is recommended for use in patients with Type-2 diabetes mellitus who are already receiving metformin (GLUCOPHAGE), a sulfonylurea (see Table 1), a thiazolidinedione (see Table 1), a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione, and who have suboptimal glycemic control.

When exenatide is added to metformin or a thiazolidinedione, the current dose of metformin or thiazolidinedione can be continued as it is unlikely that the dose of metformin or thiazolidinedione will require adjustment due to hypoglycemia when used with exenatide. When exenatide is added to a sulfonylurea, a reduction in the dose of sulfonylurea may be considered to reduce the risk of hypoglycemia.

Exenatide should not be used in patients with Type-1 diabetes or patients with a serious acute complication of diabetes known as ketoacidosis.

Clinical studies have not yet determined whether exenatide is safe for children.

What evidence did the FDA use to approve exenatide?

The drug’s 2005 approval was based on clinical trials with very few patients (100 or 200 per group) and relatively short-term treatment (seven months). Patients are expected to take these drugs for many years.

The original approval of exenatide was based on three clinical trials, each of which lasted seven months.

In these three trials, conducted by the drug’s manufacturer, Amylin Pharmaceuticals, Inc., 480 patients were given 10 micrograms a day and 484 patients were given 20 micrograms a day. In these studies, the 483 patients in the control groups were assigned to take metformin (GLUCOPHAGE; study #1); a sulfonylurea (see Table 1; study #2); or both (study #3) without exenatide. The treatment groups in the three studies took these drugs in addition to their exenatide dose.

In the clinical trials submitted to the FDA, a laboratory test that measures how well exenatide controls blood sugar levels over time was used as the main measure of exenatide’s effectiveness. This test, hemoglobin A1c (HgbA1c), measures the percentage of hemoglobin (blood’s oxygen carrier) that has glucose. But HgbA1c levels are a substitute endpoint and do not necessarily predict a drug’s ability to reduce the serious complications of diabetes such as stroke and heart, kidney, nerve and eye disease.

The FDA medical officer for exenatide who recommended approval wrote that exenatide lowered HbgA1c between 0.46 percent and 0.66 percent in patients taking five micrograms, twice daily and between 0.86 percent and 0.91 percent in patients taking 10 micrograms, twice daily. Results for patients taking a placebo ranged from no change to an increase of 0.12 percent.

The American Diabetes Association (ADA) recommends that patients maintain an HgbA1c target level of 7 percent or lower. The normal range for HgbA1c is about 4 to 6 percent. About 9 percent of placebo patients, 30 percent of the patients taking 5 micrograms twice a day and 40 percent of the patients taking 10 micrograms twice a day achieved the ADA target HgbA1c level at week 30.

The studies that looked at exenatide were too short and too small to answer any questions about whether or not the drug improves the overall health or quality of life for patients with Type-2 diabetes. Exenatide has not been shown to reduce any meaningful endpoints, including, but not limited to, the risk of death, neuropathy, vision loss, heart disease or any of the other major complications of Type-2 diabetes.

In December 2006, FDA also approved the use of exenatide with either pioglitazone (ACTOS) or rosiglitazone (AVANDIA). This approval was based on a four-month study of 233 patients (of whom 121 took exenatide). The study was published in April 2007 along with an editorial criticizing its small size, short duration, high dropout rate (26 percent), lack of lifestyle (diet and exercise) intervention and lack of adequate dosing with conventional comparator drugs.

What are the most common side effects seen with exenatide?

Table 2 lists the most common side effects associated with exenatide that were seen in the clinical trials conducted prior to the drug’s approval. The table lists only those side effects in which the frequency of the side effect was at least two percent higher than in the control/placebo group.

What are the more serious side effects seen with exenatide?

Exenatide is the first in a new family of drugs. Because of this, it is possible that unknown and unpredictable side effects will occur if the drug continues to be used in large numbers of patients. More safety information can be expected to emerge as more patients take the drug. This is the reason we have designated exenatide as Do Not Use Until 2012, seven years after the drug has been released on the market.

However, two types of serious adverse events have already been reported with the use of this drug since its approval four years ago.

Pancreas

Exenatide has been linked to pancreatitis since its 2005 approval. This serious side effect was not discovered in clinical trials because of the small numbers of patients and short treatment times. In fact, it was not until the drug had been on the market for two years that the FDA issued a warning that the agency had received reports of pancreatitis.

In October 2007, based on the first 20 months the drug was on the market, the FDA issued its first warning, noting that it had received 30 reports of acute pancreatitis as a result of the use of exenatide. The FDA instructed health care professionals to tell their patients to seek prompt medical care if they had unexplained persistent severe abdominal pain, with or without vomiting, and to discontinue taking exenatide.

In August 2008, the FDA issued a second warning with six additional cases of massive bleeding or tissue injury in the pancreas in patients taking exenatide. All six patients were hospitalized; two died.

As a result of the FDA warnings, Public Citizen initiated its own analysis based on a longer reporting period (47 months on the market) in the FDA’s adverse event database (from April 2005 through March 2009), which included all reports considered by the person reporting the side effect to be due to exenatide.

Public Citizen’s analysis uncovered a total of 181 reports of acute pancreatitis related to the use of exenatide, of which 142 required hospitalization. Public Citizen is still evaluating these reports.

The National Institutes for Health and Clinical Excellence, an independent British organization that publishes guidances on drug use, states (as of July 2008), that "exenatide is not recommended for routine use."

Kidneys

In May 2008, the European Medicines Agency (Europe’s equivalent to the FDA) issued a warning that 86 cases of kidney failure or increases in blood creatinine levels (an indicator of kidney malfunction) had been reported in patients taking exenatide.

Because exenatide is removed from the body primarily by the kidneys, any impairment of kidney function could lead to elevated blood levels of the drug. Thus, FDA-approved labeling says exenatide is "not recommended" for patients with end-stage renal disease or renal impairment.

There also have been reports of altered kidney function in patients taking this drug including worsened chronic renal failure and acute renal failure, which sometimes has required dialysis.

How is exenatide taken?

Exenatide comes as a clear solution in an injection pen containing a 30-day supply of the drug. It is injected twice a day within a 60-minute period before two main meals, usually breakfast and dinner, but at least 6 hours apart.

Needles are bought separately, require a prescription, and are not reused. The pen is discarded at the end of 30 days, even if it is not empty.

A nine-page instruction manual comes with the pen and emphasizes the need for good vision in order to use the system correctly.

Are there other treatments available to treat Type-2 diabetes?

Yes. Other FDA-approved drug treatments for Type-2 diabetes include insulin and eight other families of drugs. These drugs are listed in Table 3.

Newly marketed drugs such as exenatide are generally no more potent, and in some cases less effective, in lowering blood sugar levels than the three oldest families of drugs: insulin, the sulfonylureas and the biguanides.

What You Can Do

The editors of Worst Pills, Best Pills News urge people to refrain from using exenatide until 2012, seven years from the date of approval.

In general, people should wait at least seven years from the date of FDA approval to take any new drug unless it is one of those rare "breakthrough" drugs that offers a documented therapeutic advantage over older, proven drugs.

We call this our "Seven Year Rule," and it is based on a study we co-authored in the May 1, 2002, Journal of the American Medical Association. This study found that one-half of all new drug safety withdrawals occurred within two years of their FDA approval. One-half of all black box warnings, the strongest type of safety warning the FDA can request, and drug safety withdrawals combined occurred within seven years of new drug approvals – thus the Seven Year Rule.

New drugs are tested in a relatively small number of people before being released, and serious side effects or life-threatening drug interactions may not be detected until the new drug has been taken by hundreds of thousands of people.

Table 1. Examples of Sulfonylureas and Thiazolidiniones

* Do Not Use in Worst Pills, Best Pills
** Limited Use in Worst Pills, Best Pills

Table 2. Side Effects Seen in Clinical Trials with Exenatide

Table 3. Drugs Approved for Type-2 Diabetes

* Do Not Use in Worst Pills, Best Pills
** Limited Use in Worst Pills, Best Pills
*** Do Not Use for Seven Years in Worst Pills, Best Pills; 2012 and 2014, respectively.