Editor’s Note: This is the sixth post in our miniseries about diabetes drugs. Tune in on September 18 for the next installment.
A curious fact that has been known almost since the discovery of insulin is that glucose taken by mouth stimulates insulin secretion to a greater degree than glucose that is injected straight into the bloodstream. Researchers theorized that a hormone might be released by the gastrointestinal tract in response to glucose that could stimulate insulin secretion above and beyond that stimulated by glucose alone. This then-undiscovered hormone was called “incretin.”
The search for “incretin” was not fruitful until the DNA sequence of gastrin (an important hormone that helps regulate stomach acid secretion) was found to contain the DNA of a hormone called GLP-1, for glucagon-like peptide-1. The incretin GLP-1 was found to have a profound effect on stimulating the release of insulin from the pancreas. Unfortunately for researchers interested in diabetes treatments, GLP-1 was also found to be active for only a very short time because it was broken down by an enzyme called dipeptidyl peptidase-4, or DPP-4.
A solution to the issue of GLP-1’s short action time came from an unusual source. Scientists working on toxins in the saliva of the lizard Heloderma suspectum, otherwise known as the Gila monster, found a protein that activated GLP-1 receptors. This protein, named exendin-4, originates in the salivary glands but has endocrine effects.
Exendin-4 is a protein composed of 39 amino acids that mimics many of the actions of GLP-1 but that, unlike GLP-1, has a prolonged half-life in the bloodstream (meaning it remains in the blood for longer). Exendin-4 has several properties that mimic those of GLP-1. These include the stimulation of insulin secretion, the suppression of glucagon (a hormone that signals the liver to release glucose when blood glucose levels drop) secretion, and the slowing of stomach emptying.
In a study involving people with Type 2 diabetes and a synthetic form of exendin-4 known as exenatide (brand name Byetta), those taking the exenatide showed significantly reduced blood glucose, insulin, and glucagon levels after meals compared to people taking placebo (an inactive treatment). These results highlight some of the differences between exendin-4 and insulin: With insulin therapy, a person obtains lower blood glucose levels with high insulin levels, while exenatide therapy decreases blood glucose levels with a much lower level of insulin. This is most likely due to exenatide’s slowing of stomach emptying after a meal, which delays the introduction of glucose into the bloodstream, thus reducing a major source of stimulation for insulin secretion. Exenatide also inhibits glucagon secretion and stimulates insulin secretion, which additionally helps to drive blood glucose levels down.
Exenatide, which is administered via injection, is approved for use in people with Type 2 diabetes as an addition to the oral medicines metformin (brand name Glucophage and others) and sulfonylureas (Diabinese, Diabeta, Glynase, Micronase, Glucotrol, Glucotrol XL, Amaryl). It is not approved for people with Type 1 diabetes, because pancreatic function is required for exenatide’s insulin-stimulating effects to work. Nonetheless, the delayed stomach emptying and suppression of glucagon caused by this medicine may prove to be useful in people with Type 1 diabetes, and it is currently being studied in this population.
In clinical trials lasting six months, average reductions in HbA1c (an indicator of blood glucose control over the previous 2–3 months) in people with Type 2 diabetes have been between roughly 0.4% and 0.8% when exenatide is used along with metformin, a sulfonylurea, or both. Additionally, a small group of people taking exenatide who had an HbA1c reduction of 1.1% sustained the HbA1c reduction with continued use of the medicine over a year. Studies have shown that exenatide therapy also results in reductions in fasting blood glucose levels and reductions in weight (the greatest weight loss, of roughly 5 pounds, has been shown to occur when exenatide is taken with metformin), and that between a quarter and a third of people using this medicine achieve an HbA1c level of less than 7%.
Exenatide is injected under the skin twice daily, within one hour before the morning and evening meals, respectively. (This medicine should not be administered after a meal.) The typical starting dose is 5 micrograms taken twice a day, which can be increased up to 10 micrograms twice a day after four weeks on the 5-microgram dose. When exenatide is added to metformin, no change in the metformin dose is recommended, but when it is given with a sulfonylurea, the dose of the sulfonylurea may sometimes need to be changed to reduce the risk of hypoglycemia (low blood glucose).
Exenatide is associated with some side effects. The most frequent are gastrointestinal and include nausea, vomiting, and diarrhea, with nausea occurring most frequently. These side effects are reduced with the continued use of the drug, however, and in trials, only 3% of people stopped taking exenatide due to nausea. Hypoglycemia can occur when exenatide is taken with a sulfonylurea. Pancreatitis, inflammation of the pancreas, is a rare but serious condition that can occur with use of this medicine. Pancreatitis often requires hospitalization, and it may sometimes necessitate surgery and treatment in an intensive care setting.
Liraglitude, another type of GLP-1 agonist, is approved in Europe and is currently awaiting a ruling by the U.S. Food and Drug Administration. A longer-acting version of exenatide and several other new GLP-1 agonists are also under development.
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