New Medications for People With Type 1?
It's easy to forget that insulin entered the medical world like a miracle, pulling sick children back from the brink of death. But why did we stop at insulin? "We've had one form of therapy for 90 years—insulin monotherapy. While it is miraculous … no insulin-treated [person with type 1 diabetes] has ever been restored to normal glucose regulation," says Roger Unger, MD, professor at the University of Texas Southwestern Medical Center. "Normal glucose regulation means you can drink a gallon of Coca-Cola and your glucose won't go over 150 [mg/dl]. Or you can run a marathon and you won't go [low]."
While people with type 2 diabetes can choose from a variety of medications to improve blood glucose control, the list for those with type 1 is short. Researchers are exploring new options for people with type 1 diabetes to help them target tighter blood glucose levels and reduce insulin doses. In the body, insulin doesn't have a monopoly on metabolism, so scientists are trying to develop alternative medications that fine-tune blood glucose. One such medication, pramlintide (Symlin), is already available, while others are being studied for use in type 1 diabetes.
In 2005, the Food and Drug Administration (FDA) approved pramlintide, an injectable medication for people with type 1 diabetes and insulin-treated people with type 2. Pramlintide is a synthetic version of a natural hormone called amylin. Like insulin, amylin is produced by the beta cells in the pancreas. In type 1 diabetes, the beta cells are attacked by the immune system, cutting the supply of insulin and amylin.
"Pramlintide lowers the glucose rise after meals," says W. Kenneth Ward, MD, associate professor of medicine at Oregon Health and Science University, resulting in modestly lower A1C levels (a measure of average blood glucose over the previous two to three months). "It slows down the stomach emptying into the intestine, so food gets held longer in the stomach," says Ward. That leaves a person feeling full after a meal, which helps promote weight loss, as well as keeping blood glucose low. Pramlintide also works by suppressing the release of yet another hormone, glucagon.
The Glucagon Problem
You are probably familiar with glucagon as a lifesaving medication, injected to rapidly raise blood glucose levels if a severe low should strike. Now, scientists are studying whether medications that suppress glucagon production or block its action can improve blood glucose control in people with type 1.
Glucagon is a natural hormone that, among other functions, causes the liver to release glucose into the blood. That helps keep blood glucose levels up to fuel the body. The hormone is produced by the alpha cells, which live in the pancreas directly next to the beta cells. That closeness is important. "Insulin is a powerful glucagon repressor," says Unger. "The minute the insulin leaves the beta cell, it hits the alpha cell, suppressing glucagon release."
In people with type 1, the beta cells are few, but the alpha cells remain and continue to produce glucagon. Insulin taken as a medication may not be enough to effectively shut down glucagon because, unlike the insulin made by beta cells, it is delivered through the skin, far from the alpha cells. That may be one reason, according to Unger, why the medication insulin doesn't fully normalize blood glucose levels in people with type 1. "In order to be able to eat a meal that contains glucose, you have to have your liver primed to store glucose," he says. With too much glucagon around, this doesn't happen.
Scientists are tackling the glucagon challenge from a few different angles. Other hormones besides insulin and pramlintide are believed to suppress glucagon. Leptin, for example, is produced by fat cells and triggers a feeling of satisfaction after eating. Amylin Pharmaceuticals has developed a synthetic version of leptin (metreleptin) and is testing it in a small study of people with type 1 diabetes. Preliminary data suggest metreleptin may lower blood glucose levels and reduce insulin doses in people with diabetes. "Leptin suppresses glucagon," says Unger, and "virtually takes care of the diabetes without any insulin at all."
Another hormone that is being studied in people with type 1 diabetes is GLP-1, the incretin hormone imitated by the medications exenatide (Byetta, Bydureon) and liraglutide (Victoza), all approved to treat type 2 diabetes. "GLP-1 comes from the same gene as glucagon," says Unger. "It stimulates insulin and it suppresses glucagon … almost as well as leptin." A 2010 study in Diabetes Care reported that giving exenatide to adolescents with type 1 diabetes reduced blood glucose after meals, even with a lower insulin dose. A 2013 study in Diabetes Research and Clinical Practice found that people with type 1 needed less insulin while taking exenatide or sitagliptin (Januvia), a medication that works by keeping levels of GLP-1 in the body high.
Michael Roth, PhD, a colleague of Unger's, is developing small molecules, which are easier to turn into drugs than are large-molecule hormones, to suppress glucagon. "We are very early," says Roth. "We've looked through hundreds of drug-like molecules that could block the production of glucagon, and we found a few." He adds that the pharmaceutical company Merck is also developing small-molecule drugs that target glucagon. Instead of suppressing glucagon in the alpha cell, though, they work at the other end, blocking glucagon from interacting with cells. "The approach Merck is taking has an obvious side effect," says Unger, which is that some glucagon will still be in the bloodstream, capable of raising blood glucose levels.
Not every scientist working on glucagon is trying to block it. Some are just trying to make it play nice. Glucagon is unstable in liquid form so it comes in kits for treating lows as a powder that must be dissolved in the provided liquid just before injecting. But that situation is far from ideal. "If your spouse is [having a seizure], it can be hard to mix the water and the powder," says Ward. "If you had a pen that was always available—you'd just smack it in. At the very least it would save time and be more reliable."
Some scientists who are developing the artificial pancreas—a device that could measure glucose levels and automatically dose the appropriate amount of insulin—hope it will be able to deliver glucagon as well as insulin. "If you are giving insulin by a pump and you are getting low … well, you can just turn the insulin off. The problem is the insulin lasts too long once it gets in the system," says Ward. "If you give glucagon, you get action within 10 minutes. It really can prevent most cases of hypoglycemia."
But getting glucagon into an artificial pancreas will require liquid glucagon. "Glucagon is a very unstable protein," says Ward. "If you look at it wrong, it [forms useless clumps] within hours at room temperature. We want liquid glucagon in a portable pump for days." Ward discovered in a series of experiments that increasing the pH helps keep glucagon stable in solution and that adding certain compounds, such as the spice turmeric, stabilizes the hormone. "We are getting close," he says. "I hope to apply to the FDA within six to eight months to try it in people."
Not all alternative type 1 medications in the pipeline are fancy hormones. The humble type 2 medication metformin may do the trick. Unlike most oral meds for type 2, metformin doesn't work by increasing insulin levels. Instead, it improves glucose metabolism in the muscles and liver. A 2010 review in Diabetologia that analyzed 197 studies of metformin in type 1 diabetes concluded that metformin can reduce insulin-dose requirements. It's still unclear though if the benefits last in the long term.
Finally, SGLT-2 inhibitors, the newest class of type 2 diabetes medications, have the potential to benefit people with type 1, says Unger. SGLT-2 inhibitors encourage the body to shunt excess glucose to the urine for excretion. A study in rats with type 1 diabetes published last year suggested that an SGLT-2 inhibitor, alone, could normalize blood glucose levels without insulin.
As of now, besides pramlintide and insulin, no other medications have been approved for the treatment of type 1 diabetes. Insulin isn't going away any time soon; that would take a cure. While the medications described above may not replace insulin, they could make useful sidekicks to a superhero.
SOURCES: Roger Unger, MD, receives funding from Amylin for his leptin studies. W. Kenneth Ward, MD, obtained a patent on a method of stabilizing glucagon, which was assigned to Oregon Health and Science University.
For more information on type 1 diabetes treatments and cure research, check out the new e-book Targeting a Cure for Type 1 Diabetes: How Long Will We Have to Wait? Published by the American Diabetes Association, it is available at shopdiabetes.org.