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GLP-1 Agonists

Derived from a compound found in the saliva of the Gila monster, a lizard that lives in the southwestern US, Byetta (exenatide), was approved by the FDA in May, 2005. It is an injectable drug that reduces the glucose level in people with Type 2 diabetes. It is the first of a new class of drugs called incretin mimetics that mimic the effects of incretins. Incretins are hormones that are produced and released into the blood by the intestine in response to food intake. Byetta is a synthetic (man-made) version of one of the incretins called glucagon-like peptide-1 (GLP-1) which works longer than human GLP-1 because the slight modifications found in the Gila monster version cause it to be broken down more slowly by the enzyme DPP-4.

GLP-1 increases insulin secretion from the pancreas when the blood sugar is high, slows glucose absorption from the gut, and decreases the release of glucagon, a hormone that increases glucose production by the liver. These three actions reduce glucose levels in the blood. GLP-1 also reduces appetite and may assist weight loss in some users.

By the time diabetes is diagnosed, people with Type 2 diabetes already have defective insulin production, so any medication that improves insulin production and lowers glucose levels could be very helpful. In contrast with sulfonylureas that increase insulin production regardless of the glucose level and often lead to hypoglycemia, the insulin production seen with Byetta shuts off in a normal manner as the glucose level approaches normal.

Byetta's overall action appears to be beneficial. Although injections are required, many people with Type 2 diabetes like this drug because it lowers A1c levels and often weight as well. It is unclear what its long-term effects may be for preventing the gradual loss of insulin production that forces most people with Type 2 diabetes to eventually require insulin. Amylin, a startup drug company, risked a small fortune on simultaneous testing and production of two first-of-class drugs (Byetta and Symlin).

The name glucagon-like peptide 1 (GLP-1) is actually something of a misnomer. GLP-1 does not act like glucagon which raises glucose levels. Instead, it lowers both glucagon and glucose levels. Although their actions are quite different, both GLP-1 and glucagon are derived from the same parent compound called proglucagon, hence the name.

Approved For Some Type 2s

Byetta is approved by the FDA for use in patients with type 2 diabetes who have not achieved adequate blood glucose control while taking metformin (Glucophage) or a combination of metformin (Glucophage) and a sulfonylurea (glyburide, glipizide etc). Byetta is not approved for use in patients with type 1 diabetes.

Although it increases beta cell mass and first phase insulin release, it is not yet approved as a substitute for insulin in patients who require insulin. It is unclear whether GLP-1 agonists will offer any benefit for maintaining insulin production in early Type 1 diabetes or in Type 1.5 diabetes, where an antibody attack by the immune system causes destruction of the beta cells that make insulin.

Dosing

Byetta is injected from a pre-filled pen into the thigh, abdomen or upper arm. An initial dose of 5 mcg of Byetta is injected an hour before breakfast and dinner. It should not be taken after a meal. The starting dose can be increased to 10 mcg twice daily after 1 month of therapy.

Byetta slows down the transit of drugs through the intestine, so any oral medications should be taken one hour before it is injected. Medications that need to be taken with food can be taken with a light snack. Byetta requires refrigeration between 36-46°F (2-8°C), protection from light, and should not be used once frozen. The pen should be discarded 30 days after first use.

There are not adequate studies of Byetta for use in pregnant women or nursing mothers, and its effects on a fetus are unknown. It is not known whether Byetta is excreted in breast milk.

Side Effects

The most common side effect of Byetta is nausea. Nausea from Byetta is more common with higher doses and tends to decrease over time. Other common side effects include hypoglycemia when used with sulfonylureas, vomiting, diarrhea, headache, nervousness and stomach discomfort. Patients may also experience decreased appetite, acid reflux and increased sweating.

Results

One 30 week study of Byetta that was extended to 82 weeks showed a reduction in the A1c by 1% at 30 weeks and another reduction of 0.2% at 82 weeks. Weight loss averaged 6.6 lbs (3kg) after 30 weeks and 10.66 lbs (5.3kg) after 82 weeks. However, some people lost little or no weight and others lost as much as 20 to 25 pounds. Those who were heavier at the beginning of the study tended to lose the most weight. Even in those who lost little or no weight, the A1c came down significantly. Blood pressure came down on average about 3 mmHg in the systolic reading and 4 mmHg in the diastolic. Also the lipid profile improved with an average rise of 7.4 mg/dl in HDL ("good cholesterol") and a fall of about 92 mg/dl in triglycerides.

Other companies are actively seeking related compounds and easier methods to deliver them. The Gila monster has yet to offer its opinion on what humans have done with this derivative from its toxic spit.

Meanwhile, visit www.byetta.com for more information.

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