Diabetes Forecast

Incretins and Diabetes Medications

How a class of meds got from lizard to lab to you

By Erika Gebel, PhD ,

Every time you eat, an unseen drama unfolds inside your body: Hormones called incretins race from the gut to the pancreas and tell that organ to produce more insulin. But just as soon as an incretin goes to work, a killer enzyme gives chase, bent on its annihilation.

Understanding that natural process—plus a timely discovery about lizard venom (more on that later)—has led scientists to develop some of the newest diabetes medications. These meds, including exenatide (Byetta), sitagliptin (Januvia), and, most recently, saxagliptin (Onglyza), all use the incretin system to lower blood glucose in people with diabetes.

And they may be just the beginning. At least half a dozen more incretin-based medications are in line to seek Food and Drug Administration approval. Here's a look at the inner workings of the body that make these meds possible.

The Incretin System

Even before food hits the stomach, incretins are released from specialized cells in the small intestine into the bloodstream. As a meal is broken down and blood glucose levels increase, the incretins stimulate the pancreas to produce insulin, which brings blood glucose back down.

Researchers used to believe that insulin was released in direct response to increasing blood glucose levels. But then they noticed an odd thing: Injecting glucose into the bloodstream doesn't raise insulin levels as much as giving the same amount of glucose by mouth. The scientists reasoned that some messenger—an incretin—must go between the digestive tract and the pancreas to tell it to step up insulin production.

There isn't just one type of incretin, but the most significant for people with diabetes is called glucagon-like peptide-1. GLP-1 should not be confused with glucagon itself; they have very different functions (glucagon is a hormone that increases blood glucose). "GLP-1 is your natural anti-diabetic hormone," explains Patricia Brubaker, PhD, a professor at the University of Toronto who studies incretins.

Research has shown that people with type 2 diabetes don't have enough incretins, which could exacerbate the problem of high blood glucose. Studies suggest that one reason bariatric surgery may help people with diabetes is that, in addition to causing weight loss, it seems to stimulate incretin production.

GLP-1 has more responsibilities in the body than simply facilitating insulin release. "GLP-1 suppresses glucagon and it reduces appetite, which is associated with weight loss," says Brubaker, adding that the incretin may also improve heart health by lowering cholesterol and triglyceride levels in the blood.

An Aggressive Enzyme

So, why not just give people with diabetes more GLP-1? After all, doctors prescribe insulin to supplement or replace natural insulin all the time. As it turns out, though, GLP-1 is treated differently in the body than insulin. Just as soon as an incretin is made, an enzyme called DPP-4 starts after it and, like a minuscule Pac-Man, chomps on the ill-fated hormone. These attacks quickly reduce the levels of GLP-1 circulating in the body, until the next meal triggers the production of more. While this process is part of a healthy metabolism, in people with diabetes whose GLP-1 levels may already be low, DPP-4 is a hurdle to overcome.

Two classes of incretin-based diabetes medications have been developed to tackle the DPP-4 problem: incretin mimetics, which look like incretins but are not broken down by DPP-4, and DPP-4 inhibitors, which boost the amount of natural incretin in the body by disabling the incretin-destroying enzyme.

Here's where the lizard comes in. Exenatide (Byetta), the original incretin mimetic, is a synthetic version of a protein derived from the venom of the Gila monster, a lizard found in the Southwest. Thanks to a decades-long research project that probed reptiles for their medicinal properties, scientists discovered in the 1990s that Gila monster venom contains a substance that shares much of its chemistry with human GLP-1, yet is different enough to go unnoticed by DPP-4. Like insulin, incretin mimetics are made out of protein, and so they need to be injected, not taken as pills, to avoid being digested.

Exenatide, approved in 2005, has about an eight-hour life span in the body and is taken twice a day around mealtimes. There is a big push to come up with even longer-acting incretin mimetics, to reduce needle pricks and prolong the medications' benefits. Liraglutide, another incretin mimetic that is not yet available in the United States, is almost identical to human GLP-1, but with a couple of differences that confuse DPP-4 and throw it off the medication's trail. Liraglutide sticks around in the body longer than exenatide; it needs administration only once a day. The medication, which is sold in Europe as Victoza, is at this writing awaiting FDA approval.

A recent study compared liraglutide and exenatide head to head. Liraglutide outperformed exenatide on several blood glucose measures, and both medications caused similar weight loss. Also, liraglutide was associated with less hypoglycemia (low blood glucose) and nausea than exenatide, perhaps because of its longer presence in the body with fewer peaks and valleys in blood concentration.

According to Brubaker, the longer an incretin mimetic remains active, the better. For that reason, the makers of exenatide are working on a version that would be taken just once a week. "The once-weekly Byetta seems to be better than both [the original exenatide and liraglutide]," Brubaker says. There's even an implanted device being tested in clinical trials that would continuously deliver exenatide, over the course of a year.

Going After DPP-4

The other approach is to enhance the effects of the natural incretins, like GLP-1, by sabotaging their predator, DPP-4. That is what drugs called DPP-4 inhibitors do. The first member of this medication class was sitagliptin (Januvia), which won the FDA's OK in 2006; in July, the FDA approved a second DPP-4 inhibitor, saxagliptin (Onglyza). Takeda Pharmaceuticals is developing a third DPP-4 inhibitor, alogliptin.

These inhibitors employ different chemical tricks to stifle the DPP-4 enzyme, gagging that Pac-Man so GLP-1 can keep doing its job of spurring insulin production. "Blocking the binding site of a natural enzyme … is a very common form of enzyme inhibition," says Steve Gwaltney, PhD, of Takeda. "This approach is used in many of today's medicines." Researchers have yet to compare directly the efficacy of different DPP-4 inhibitors in diabetes patients, but both sitagliptin and saxagliptin lower A1C (estimated average blood glucose over the past two to three months) by similar amounts with few side effects. DPP-4 inhibitors appear not to affect body weight.

A third class of incretin-based therapies may be just over the horizon, says Brubaker: "I think the next wave of incretin therapy, potentially, is finding ways to enhance the release of GLP-1.… There are some leads in the data that suggest this is going to be possible. It's tricky, finding something that only stimulates GLP-1, but I think that is where things are going right now."

Your doctor is the best judge of whether an incretin-based therapy is right for you. An incretin mimetic may be just the ticket for people who want weight loss with their blood glucose control. For others, a simple daily oral medicine that is well tolerated, like a DPP-4 inhibitor, is a good choice. Yet these meds are still quite new; in rare cases, pancreatitis has been reported with their use, but it's not clear they cause the condition. What is clear, though, is that incretin medications are already a valuable tool in managing type 2 diabetes.

For a guide to incretin-based medicines, click here.



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