women

A class of injectable type 2 meds gains ground

For decades, insulin was the only injectable diabetes medication. But in the past seven years, several more have come on the market, including three incretin mimetics: exenatide (Byette), long-acting exenatide (Bydureon), and liraglutide (Victoza). These medications are approved only for the treatment of type 2 diabetes, though they may someday be used by people with type 1 as well.

Description: For decades, insulin was the only injectable disbetes medication

For decades, insulin was the only injectable disbetes medication

Many have heralded this class of medications as a monumental advance in diabetes care, and indeed their attractive characterstics include promoting weight loss and carrying a low risk foe hypoglycemia (low blood glucose). Here’s the skinny on incretin mimetics: how they work, how they differ, and what to consider discussing with your doctor.

Inner workings

Incretins are a group of hormones, and all three U.S.-approved incretin mimetics mimic the same incretin hormone, GLP-1. This hormone is made by specialized cells in the small intestine, which release the incretin into the body when sense food from a meal passing through the intestines.

Description: This hormone is made by specialized cells in the small intestine

This hormone is made by specialized cells in the small intestine

Once in the bloodstream, incretins travel around the body, affecting several organs, including the pancreas. Incretins spur cells in the pancreas to make more insulin in response to a rise in blood glucose. The insulin brings blood glucose levels back down after eating. Incretins also suppress the production of glucagon, a hormone that signals the liver to release its glucose stores into the blood. When the liver holds back its stored glucose, blood glucose levels are more likely to remain in the normal range. “Glucagon suppression may account for 50 percent of the incretin effect.” Says Carol Wysham, MD, clinical associate professor of medicine at the University of Washington School of Medicine.

People with type 2 diabetes have depressed GLP-1 levels. However, GLP-1 itself would make a poor drug because it is quickly broken down in the body by an enzyme called DPP-4. (DPP-4 inhibitors are another class of type 2 medications; they increase GLP-1 levels by slowing the enzyme’s effects). A breakthrough came when researcherers discovered a protein in the saliva of the Gila monster, a Southwestern lizard. The protein, exenatide, looks similar to GLP-1 and works about the same, but it goes unrecognized by DPP-4. Later, protein engineers developed liraglutide by employing a subtle chemical trick that changes GLP-1 just a tiny bit, but enough to fool DPP-4. Because they are small proteins, incretin mimetics be injected so that they enter the bloodstream. If the proteins were taken orally, gastric juices would digest them.

When doctors talk about incretin mimetics, weight loss invariably comes up early in the conversation. “No other type 2 drug on the market results in [so much] weight loss,” says Filip Knop, MD, PhD, head of the Diabetes Research Divison at the University of Copenhagen. But results vary, and some people will lose little or no weight. Another bonus is that incretin mimetics aren’t likely to cause hypoglycemia. “they only exert their effects when glucose is relatively high,” says Knop. “When glucose is low, they have no effect on insulin secretion.”

Same difference

The three incretin mimetics differ in how often they’re taken. Exenatide needs to be injected twice a day, in the hour before a meal. Liraglutide is taken once daily, at any time and independent of meals. Long-acting exenatide is a week’s worth of regular exenatide that is designed to release gradually. It is injected every seven days, at any time of day, with or without meals.

Description: All the incretin mimetics sometimes cause discomfort

All the incretin mimetics sometimes cause discomfort

All the incretin mimetics sometimes cause discomfort. Gastrointestinal side effects, such as nausea, vomiting, and diarrhea, are not uncommon complaints. Many people experience mild nausea at first, which goes away with time, and slowly work up to taking a full dose as directed. Some of the medications may be tolerated better than others. “A general rule,” according to Wysham, “is that the longer the medicaiton works, the less severe the side effects.” Accordingly, once-weekly exenatide use is associated with the least stomach distress.

Researchers are also comparing the incretin mimetics’ results in lowering blood glucose and promoting weight loss. So far, they have found greater differences in A1C reduction (average blood glucose over the previous two to three months) than in weight loss.

A difference between exenatide and liraglutide is in how the body metabolizes the medications. Liraglutide is eventually broken down by enzymes in the body, while exenatide is excreted through the kidneys, which makes it unsuitable for people with kidney problems.

Other considerations

One of the biggest drawbacks of incretin mimetics is their cost. “The prices are extraordinarily hard to swallow,” says Wysham, ranging from around $300 a month for exenatide to over $400 for liraglutide. Incretin mimedics may not be covered as well by insurance plans as other diabetes medications. “The major barrier from my perspective is that my patients are willing, but insurers are not,” says Wysham.

Another concern is that because these drugs are relatively new, there may yet be safety issues. All incretin mimetics carry a black box warning about thyroid cancer. Stuides in rats showed that the drugs did increse the likelihood the animals would get thyroid cancer; the effects in humans are uncertain at this time. There have also been reporst of people developing pancreatitis after starting an incretin mimetic. “As doctors, we need to inform patients on these risks,” says Knop, “but the data are not the best. For now, it’s just a signal that we have to take seriously, but the exact connection is not well established.”

Incretin Mimetics and Type 1

Description: Diabates Care

Diabates Care

Some research ahs hinted that incretin mimetics may actually give the insulin-producing beta in the pancreas a boost. This opens the door to the possibility that those with type 1 might benefit from the drugs, as an add-on to insulin. A small July 2011 study, published in Diabates Care, found that liraglutide treatment in poeple with type 1 lowered blood glucose levels and reduced insulin doses. The researchers said that participants’ beta cell function appeared to improve, too. Filip Knop, MD, PhD, of the University of Copenhagen says that in an ongoing study in Denmark, liraglutide is being given to people with newly diagnosed type 1, who still maintain some beta sell function. Researchers are “hoping they can prevent the immune system from killing those beta cells by helping the beta cells preserve themselves,” he says.

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