GLP-1 agonist, like Byetta and Bydureon can help treat Type 2 Diabetes.

GLP-1 or glucagon-like peptide 1 is one of several naturally occurring incretin compounds that possess biologic activity when released from the gut during digestion. Because of its name, GLP-1 would seem to act like glucagon, which is a hormone that increases glucose production by the liver and raises glucose levels. Rather, GLP-1 lowers both glucagon and glucose levels. Though their actions differ, GLP-1 and glucagon are both derived from the same parent compound called proglucagon, hence the similarity in name.

GLP-1 naturally works on several deficient organs to lower blood sugar levels. It slows glucose absorption from the gut, increases insulin secretion from the pancreas when the blood sugar is high, and lowers high levels of glucagon that are found in people with diabetes after meals. Its action to reduce glucagon levels causes the liver’s production of excess glucose to fall and makes fasting and after meal glucose levels easier to control. GLP-1 also increases beta cell mass and improves first phase insulin release.

In the brain, GLP-1 attaches to an appetite receptor in the hypothalamus which often decreases appetite and gradually reduces weight over time.

The combination of these actions reduces glucose levels in the blood and reduces weight, which puts drugs that mimic GLP-1 actions into a unique category of being able to significantly delay the progression of Type 2 diabetes. Unlike glitazone medications which directly reduce insulin resistance, GLP-1 does not have any effect on the insulin resistance that is characteristic of Type 2 Diabetes.

Unfortunately, GLP-1 as a drug is not useful because it is broken down within minutes by an enzyme called DPP-4 which is present throughout the body. Instead, a class of medications called GLP-1 agonists, or drugs that act like GLP-1, but are not broken down as quickly, have been developed.

Insulin production in the pancreas in people with Type 2 diabetes is greatly reduced by the time diabetes is diagnosed, so a medication that improves insulin production and lowers glucose levels is very helpful. GLP-1 agonists cause insulin production to shut off as the glucose level approaches normal, in contrast with sulfonylureas that increase insulin production regardless of the glucose level and can cause hypoglycemia. No hypoglycemia is seen with use of a GLP-1 agonist but hypoglycemia can occur if its glucose-lowering effects are combined with an excess of a sulfonylurea or insulin (Byetta has not been approved for use by those who take insulin).

Byetta

Byetta (exenatide) was the first GLP-1 agonist to receive FDA approval in May 2005 for the new class of drugs called incretins. It is similar to a compound found in the saliva of the Gila monster, a lizard that lives in the southwestern US. Byetta 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.

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 those with Type 1 diabetes or Type 2s who are on insulin.

Although two daily injections are required, many people with Type 2 diabetes like this drug because it lowers glucose levels and helps with weight loss. And, although they do it by very different actions, both Byetta and the glitazones have been shown to slow loss of insulin production that results in a persistent rise in the glucose over time and that forces most people with Type 2 diabetes to eventually require insulin. In his 2008 Banting Lecture to the American Diabetes Association, Dr. Ralph DeFronzo, a renowned diabetes clinician and researcher at the University of Texas Health and Science Center in San Antonio, recommended that these two types of medication be considered first for Type 2 diabetes to preserve beta cell function and that they might also be considered for pre-diabetes due to this ability.

It is not clear whether the increase in beta cell mass and improved first phase insulin release seen with GLP-1 agonists will offer any benefit for maintaining insulin production in early Type 1 diabetes or in Type 1.5 diabetes. These types of diabetes are caused by an antibody attack by the immune system that gradually destroys the beta cells that make insulin, so little or no benefit is likely.

Dosing

Byetta is injected from a pre-filled pen into the abdomen, thigh or upper arm. An initial set 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 a set 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.

Byetta is not approved 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 effects of Byetta is a feeling of fullness and nausea. Nausea from Byetta does not appear to be related to the size of the dose and usually disappears after a couple of weeks. 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.

Byetta was under close scrutiny, with a warning by the FDA in August 2008, for a possible association with hemorrhagic or necrotizing pancreatitis, a serious illness caused by destruction of the pancreas, that occurs in people with Type 2 diabetes and who take Byetta. Because of the large number of people who take Byetta, and the relatively large number who are overweight which increases the risk of pancreatitis, it was never made clear whether Byetta causes pancreatitis or is randomly associated with it.

Bydureon, The Once A Week Form Of Byetta

Amylin, the drug company that developed Byetta, is currently working on a time-released version of Byetta, now called Bydureon, that would only need to be injected once a week. The newest report from Amylin shows that it outperforms it's rival, Januvia, but remains inline with Actos and Metformin when comparing A1C levels. The 26 week trial participants were not achieving good A1c control using diet and exercise alone and they were under no diabetes therapy. After 26 weeks, users of Bydureon showed a 1.5% reduction in their A1cs, compared to 1.2% from Januvia. Users of metformin and actos showed 1.5% and 1.6% reductions, respectively.

Dosing

Bydureon is set up to be taken once weekly. This is a benefit when compared to Januvia, Actos, Metformin, and Byetta which are all taken more frequently. Convenience goes a long way towards helping improve managment.

Side Effects

Side effects of Bydureon include nausea, itching or discomfort at injection site, diarrhea, vomiting, constipation and injection site bruising. Bydureon may also influence digestion and effectiveness of other medications you are currently taking.

Bydureon was submitted to the FDA for approval in 2011. The FDA came back with a complete response letter, simply meaning the drug was not approved in its current form. Amylin replied to the FDA and received approval in January of 2012.