Some of the oldest, most widely used type 2 diabetes medications still have their secrets—here’s looking at you, metformin—scientists just don’t know exactly how they work. It’s different with GLP-1 agonists, a relatively recent injectable form of medication, because scientists have a pretty good idea what molecular switch the medication flips to lower blood glucose levels. On top of that, GLP-1 agonists can spur weight loss (2 to 10 pounds on average within three months), don’t cause lows (hypoglycemia), and can, in some cases, be taken only once a week. That’s a first for diabetes medications, which typically require at least daily doses. Less frequent dosing may make it easier for people to take their medication as directed.
Though GLP-1 agonists are still considered “new” diabetes drugs, it’s already been nine years since the first member of this class, exenatide (Byetta), came to market. Exenatide was initially discovered in the venom of the Gila monster, a large lizard from the U.S. Southwest. The ingredient happens to be a good imitation of a human hormone, glucagon-like peptide 1 (GLP-1).
The hormone is released by the small intestine moments after eating and travels rapidly through the bloodstream until connecting with specialized molecules called receptors. GLP-1 receptors are found throughout the body—in the brain, heart, liver, fat, kidney, blood vessels, and pancreas—giving the hormone a variety of places to connect and do its various jobs, including controlling hunger.
When GLP-1 activates its receptors on cells in the pancreas, they release insulin and withhold glucagon. “This is how the body lowers blood glucose,” says David Drucker*, MD, senior investigator at the Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital in Toronto. “If we have diabetes and need more help, we can pharmacologically enhance this normal response.” GLP-1 agonist medications are designed to activate the GLP-1 receptor, triggering some of the body’s natural mechanisms for lowering blood glucose.
There are now four GLP-1 agonists on the U.S. market. When comparing the medications, preliminary evidence suggests that longer-acting GLP-1 agonists are associated with fewer side effects (nausea, vomiting) and lower average blood glucose levels than shorter-acting versions. Head-to-head comparisons are few, however. “I don’t think we have enough information about the differences between these drugs,” says Drucker. “There is a great complexity in determining which drug will work for which patient.”
The reason GLP-1 agonists must be injected is that they, like insulin, are proteins. If taken orally, they would be digested in the stomach, like the protein in food. Exenatide is injected twice daily. The latest trend in GLP-1 agonists is toward fewer injections. “We think—we don’t know—that patients would be happier with fewer injections,” says Alan Garber**, MD, PhD, FACE, professor of medicine at the Baylor College of Medicine in Houston. If nothing else, Garber expects longer-acting GLP-1 agonists to work better because they’re easier to take, which makes users more likely to take the medication as directed.
“Treatment is challenging for patients,” says Molly Carr***, MD, a global medical affairs leader at the pharmaceutical company GlaxoSmithKline (GSK), who helped develop once-weekly albiglutide (Tanzeum), approved in April. “When GSK was developing Tanzeum, the No. 1 goal was to make it user friendly.” To make a GLP-1 agonist friendlier, that meant making it last longer in the body to reduce the number of injections needed.
GLP-1 and exenatide are peptides—mini proteins—and, because of their petite size, get cleared rapidly by the kidneys, says Drucker, which means they have less time in the body to lower blood glucose levels. So developers sought ways to increase the size of the proteins and help them stick around. “The larger the protein, the less likely that the kidney is going to chew it up,” he says. To create albiglutide, GSK stitched together two GLP-1 agonist molecules and attached them to a large protein called albumin that has an impressively long life span in the body. “Normal healthy kidneys will filter but reabsorb albumin,” says Drucker. “It’s not a big leap of faith that if I have a drug bound to albumin, it may also … be reabsorbed.” (You may have heard of albumin; when found in the urine, albumin is a sign of declining kidney health.)
Once-daily liraglutide also uses albumin to prolong its tenure in the body, but its maker, Novo Nordisk, followed a somewhat different strategy: the addition of a fatty acid chain. Once injected, liraglutide’s fatty extension binds to the albumin that’s already in the body. Like a little kid clinging to an older sibling, albumin allows liraglutide to stick around. Novo Nordisk used the same trick on insulin; insulin detemir (Levemir) also carries an albumin-loving fatty acid, which increases the molecule’s size and how long it’s effective in the body.
Size isn’t everything, though. The exenatide in the once-weekly GLP-1 agonist is the same size (and the same in every way) as that used in the twice-daily version. But, in once-weekly exenatide, the peptide is embedded in tiny biodegradable spheres. “They’re like Dippin’ Dots,” says Drucker, referring to the ice cream snack, and they slowly dissolve to release the medication bit by bit over a week.
But why stop at a week? Intarcia Therapeutics is testing a matchstick-sized implantable device (ITCA 650) that continuously delivers exenatide. Only one or two implants a year—each would take only five minutes to insert in an office procedure—are needed. Scientists await results from a large global study that, at press time, was expected to finish in July.
We know a lot about how GLP-1 agonists work to lower blood glucose, but these young drugs still have their secrets. For example, scientists continue to debate how GLP-1 agonists lower body weight; they suspect it may have something to do with the brain. GLP-1 agonists may have unexpected benefits for neurological function, too. A recent small study found that twice-daily exenatide improved physical and cognitive function in people with Parkinson’s disease. That means what we don’t know about GLP-1 agonists may turn out to be a good thing.
Meet the GLP-1 Agonists
GLP-1 agonists are on the expensive end of the diabetes medication spectrum, typically costing hundreds of dollars for a month’s supply. All but Bydureon are currently on the market in injectable pen form, and Bydureon is expected to be so later in 2014. These drugs tend to be considered after and as an add-on to metformin, though some experts are exploring GLP-1 agonists as a first medication to try.
|Medication||Brand Name||Injection Schedule|
|Exenatide Once Weekly||Bydureon||1x Weekly|
Talk Like a Doc:
An agonist is any molecule that activates a receptor in the body.
SOURCES:*David Drucker has served as an advisor or consultant within the past 12 months as of May to Arisaph Pharmaceuticals Inc., Intarcia Therapeutics, Merck Research Laboratories, MedImmune, Novo Nordisk Inc., NPS Pharmaceuticals Inc., Receptos, Sanofi, Takeda, and Transition Pharmaceuticals Inc. Neither Drucker nor his family members hold stock directly or indirectly in any of these companies. **Alan Garber has served as an advisor, consultant, or speaker with Amarin, Eisai, Halozyme, Janssen, Lexicon, Merck, Novo Nordisk, Salix, Viking Therapeutics, and Vivus. ***Molly Carr is an employee of GlaxoSmithKline.