How Drug Combination Helps Control Type 1 Diabetes

Emily Raies, of Canton, Ohio, was a star soccer player in high school. But during her sophomore year, she started to lose a lot of weight and felt fatigued on the field. "My husband and I were watching her, and I said to him, 'It's like she's running in quicksand,'" says Emily's mother, Beth Raies.

Emily was often too lethargic to get out of bed in the morning, and she was moody. "[The doctors] kept saying, 'She's a teenage girl. She's just broken up with her boyfriend. It must be depression,'" Beth Raies recalls. But Emily's bloodwork came back with an oddly high sugar level, and eventually she was diagnosed with Type 1 diabetes, a condition that didn't run in the family and was a "total shocker" for everyone, Beth Raies says.

Like many people newly diagnosed with Type 1 diabetes, Emily's initial goal was to get accustomed to giving herself insulin shots to regulate her blood sugar. The condition occurs when so-called beta cells -- insulin-producing cells housed within the pancreas -- either stop working or die off altogether, leaving people with Type 1 diabetes wholly dependent on outside insulin injections for the rest of their lives. If blood sugar levels aren't controlled, complications such as kidney and heart disease, blindness and nerve damage can develop.

But research labs throughout the country are racing to change that outlook. Type I diabetes is essentially an immunological disorder in which the body's own immune system attacks the pancreas due to a miscommunication among cells, says Michael Haller, a pediatric endocrinologist at the University of Florida. Because the pancreas controls insulin, the condition throws off the body's insulin levels, requiring patients to take shots of the vital hormone. Some researchers are focusing their attention on stem cell therapy to replace the dysfunctional cells, while others are engineering smarter insulin pumps, for example, designed to act as a faux pancreas.

Another area of inquiry, which Haller is pursuing, focuses on interrupting the immune system's misdirected attack on the pancreas to see if Type 1 diabetes patients can continue producing insulin on their own. To do this, researchers have focused on combining drugs that both suppress and stimulate the immune system. Haller recently led a study that, for the first time, benefited type 1 patients undergoing this approach. The study, published earlier this month in the Journal of Clinical Investigation, found that combining two drugs not normally used for diabetes helped preserve the function of insulin-producing beta cells in chronic Type 1 diabetes patients.

Haller says this drug combination appears to have long-term effects on patients' blood sugar levels, allowing them to continue making some insulin on their own. "As soon as we get to a point where we believe these benefits are durable, we'd love to say immunotherapy is the standard of care for newly diagnosed patients," Haller says. "This particular [drug] combination may be headed toward that route. We're getting close."

Patients were given a low dose of anti-thymocyte globulin, or ATG, normally used to prevent rejection in organ transplant patients, followed by pegylated G-CSF, used in cancer patients to boost immune cells. ATG, commercially known as thymoglobulin, was delivered through an IV drip over two days, followed by bimonthly injections of pegylated G-CSF, or Neulasta, for 12 weeks. This combination restored homeostasis among two types of cells that are vital to a healthy immune system: regulatory T-cells and killer T-cells. Killer T-cells are the first line of defense against viruses and tumors, but in Type 1 diabetes, they go haywire, launching an attack on beta cells, explains Desmond Schatz, president-elect of the American Diabetes Association and medical director of the UF Diabetes Institute. That's why killer T-cells must be kept in check by regulatory T-cells, which police all cells of the immune system.

After receiving these drugs, patients in the study were able to retain a functional balance between their killer and regulatory T-cells, Schatz says. They also experienced fewer side effects than typically experienced with ATG, since it was given in smaller dosages than patients generally require. Combined drug therapy has also been used to treat diseases such as cancer, tuberculosis and AIDS, Schatz adds.

"Our viewpoint is that there are likely combinations of drugs that are already on the market and [Food and Drug Administration]-approved that might actually achieve what we are looking for," Haller says.

Improved Quality of Life for Patients

Study participants, like Emily Raies, continue to enjoy quality-of-life improvements. Eighteen months after her diagnosis, Emily's mother found out about the study through an acquaintance whose son had Type 1 diabetes. Most trials for the condition only enroll patients within the first 100 days of their diagnosis -- a narrow window in which many people are still digesting the diagnosis. So when Beth Raies learned that the UF study accepted patients who had been living with the disease for anywhere from four months to two years, she quickly enrolled Emily.

The study's generous enrollment criteria is significant because while a few thousand people are diagnosed with Type 1 diabetes each year in the United States, a few million are already living with it, Haller says. "Many diabetes patients lose total function of beta cells, so they have to go on insulin the rest of their lives. This would slow down that process."

Emily Raies says the combined drug therapy practically knocked out her diabetes. "I feel like I don't have it most of the time," she says. Although she still takes insulin -- the study did not aim to take people off insulin altogether -- she takes much smaller doses than she used to, and her condition hasn't prevented her from enjoying college.

"My goal as a parent was to hopefully make it so she could get through her college years without having to deal with full-blown diabetes," Beth Raies adds. "She only takes a fraction of the insulin that other diabetics would take."

Andrew Holcomb, another study participant, agrees that this treatment has made a significant impact. "I tend to have fewer highs and lows than most diabetic patients," Holcomb says. "But I still play the game just like the rest of them. So, the game isn't any easier, but it isn't lost as often."

Winning the Diabetes Game

By "game," Holcomb means keeping his blood sugar levels in check. For example, an indulgent pleasure for most people -- eating at restaurants -- is a nightmare for Holcomb, since nutritional information is notably absent from menus.

"When I eat at those kinds of places, it's like playing the most unrewarding guessing game imaginable," says Holcomb, a Ph.D. student in nuclear engineering at the Georgia Institute of Technology. "I not only have to estimate how many carbs are in a meal, but also guess at how the fat and protein will affect how it gets digested, and then give myself insulin accordingly. You get better at it over time, but it is still discouraging every time you get it wrong."

And that battle with the body -- in which the patient bears so much responsibility for the outcome -- is what makes Type 1 diabetes particularly burdensome for patients, Haller says. "Managing Type 1 diabetes effectively is a 24/7 job," Haller adds. "If something doesn't go right, [patients think], 'It's not the doctor's fault. It's my fault.'"

This combined drug therapy gives patients more of a cushion for regulating their own blood sugar, he adds. "I believe this has given me better overall diabetes management," Holcomb says.

Schatz adds that the short-term goal of the study was to allow people to continue to produce their own insulin, which leads to an easier disease course -- less hypoglycemia and fewer complications -- than exclusively relying on insulin injections.

The long-term goal, however, is to use the combined drug approach to actually prevent Type 1 diabetes.

"We hope this is the start of our efforts to prevent Type 1 diabetes," Schatz says. It's now possible to detect people at risk for Type 1 diabetes through genetic and metabolic markers; those whose risk is greater than 50 percent could be pre-emptively treated, for example.

Meanwhile, another multicenter study of this drug combination will soon begin on Type 1 diabetes patients on newly diagnosed Type 1 diabetes patients. The study, funded by the National Institutes of Health, is the first one to be offered to newly diagnosed patients in a few years, Haller says. The trial, which opened Dec. 17, 2014, screened the first prospective patient that same day, he adds. "We certainly want to encourage people to call" to see if they are eligible to participate, he says. They might just contribute to helping find a cure.

Kristine Crane is a Patient Advice reporter at U.S. News. You can follow her on Twitter, connect with her on LinkedIn or email her at kcrane@usnews.com.