30 Years Later, a Landmark Study Lives On
The Diabetes Control and Complications Trial supported intensive therapy
Tracy Waters was one of 1,441 study volunteers. Today, she is a registered nurse.
Photo credit: Chris Bohnhoff
|The People Behind the Numbers|
Before we ask a person to take on the daily tasks of intensive insulin therapy to manage blood glucose—the finger pricks, the dosing, the advanced carbohydrate counting—there's an important question. Is all that effort worth it?
The answer was decades in the making. In 1922, beef pancreas "extract" saved the life of 14-year-old Leonard Thompson. Even with insulin injections, people with diabetes—if they lived long enough—often developed serious complications, such as blindness, amputations, and kidney failure.
But maybe that destiny could be altered. "Solving the riddle of what was responsible for these complications, and whether we could prevent or delay them, was the key question," recalls David M. Nathan, MD, professor of medicine at Harvard Medical School.
The Diabetes Control and Complications Trial (DCCT) launched in 21 medical centers across the United States and Canada and later expanded to 28 centers.
Intensive therapy, aimed at mimicking the way the body secretes insulin, began to emerge around 1980. It included multiple daily insulin injections or brick-size insulin pumps, blood glucose meters, and the A1C test (a measure of average blood glucose for the previous two to three months).
These brave new approaches were far from standard practice. Conventional treatment had tried to make insulin injections more convenient, meaning fewer of them—just one or two shots a day. "You'd have fair blood glucose control throughout the day, but nowhere near normal control," Nathan says.
Intensive insulin therapy was difficult, demanding multiple daily ministrations from the patient trying to imitate a pancreas. And there was no substantial evidence that it was better than conventional care at preventing complications. Many people "believed that you got the complications of diabetes independent of your glucose control," says Bernard Zinman, CM, MD, FRCPC, FACP, professor of medicine at the University of Toronto. "They believed that there was an independent underlying cause, possibly related to genetic susceptibility."
Perhaps all the work of intensive therapy was pointless—except for all those extra needles and lancets, of course.
|The epic Diabetes Control and Complications Trial is an example of research that then can be translated into a new approach to managing a condition. It helped to establish:
An A1C target of less than 7%. It's a useful cut point, safely achievable by some patients, but not by others, which is why the American Diabetes Association's Standards of Medical Care in Diabetes cautions that the target should be individualized. Because complications that affect the eyes, kidneys, and nerves are likely to follow a similar response to high glucose levels in all people, DCCT findings may have implications for type 2 diabetes as well.
Intensive therapy. The best regimen for people with type 1 diabetes includes multiple daily insulin injections (at least three) or insulin pump therapy and blood glucose testing at least four times daily.
The best evidence would come from a randomized controlled trial (RCT), the most respected type of medical study. In 1983, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) launched the Diabetes Control and Complications Trial (DCCT). Study cochair Saul Genuth, MD, professor of medicine at Case Western Reserve University, says the trial aimed to settle this question: "If glucose levels could be lowered close to normal—or better, to normal—would that eliminate the risk of complications to the eyes, kidneys, nerves, and cardiovascular system?" It would require 10 years, $150 million, and a complex study design to tease out the answers.
One of the most challenging parts of any RCT is to identify, recruit, and retain enough eligible subjects to make the findings statistically significant. Fortunately, many people heeded the call to join DCCT—7,304 individuals were screened for eligibility. Of those, 1,441 volunteers were selected and would be studied day in, day out for years.
Eligibility. The researchers recruited two groups of individuals. The first had been diagnosed with type 1 diabetes for no more than five years and had no detectable complications. They would show whether intensive therapy could prevent complications. Another group included people with diabetes of one to 15 years' duration, minimal to moderate retinopathy (eye damage), and low insulin production (measured with a C-peptide test). This group would show whether intensive insulin therapy could delay or even reverse the progression of complications.
Age. The study enrolled participants as young as 13. The oldest were under 40 at enrollment (See Fred Gaede, opposite).
Randomization. Participants were randomly assigned, as with a flip of a coin, to one of two groups: intensive therapy or conventional treatment. Neither the researchers nor participants had any say. "People had to accept randomization and stick to that treatment for years and years, until we had an answer," Genuth says.
The Study Design
Conventional therapy participants would use two insulin shots a day and whatever diet and exercise plan they were using at the start of the study. Home blood glucose testing wasn't standard practice then. The intensive therapy group was hospitalized for several days for the plunge into tight glucose control training. The treatment goal was ambitious—to achieve blood sugar control as close to the nondiabetic range as safely possible.
People in the intensive therapy group had a monthly office visit with the study treatment team and usually weekly phone calls. Providers and patients focused on frequent adjustments to insulin based on food, exercise, and other factors. Conventional group participants visited the study care providers every three months.
"Initially, we really didn't appreciate what intensive therapy meant for the individal on a day-to-day basis," recalls Meg Bayless, BSN, RN, CDE, a study coordinator from the University of Iowa Department of Internal Medicine. She wore an insulin pump (with saline) and used a meter for a week to get a better sense of how people would have to manage a pump and check blood sugars.
Bayless says that the study team initially thought that with the right data, making tweaks was a matter of just doing the math. They all learned, however, that "diabetes is not just a numbers game."
The treatment teams helped people in intensive therapy go after one goal at a time to reach targets. "People accomplished the most changes in the first six months," she says. Then they settled into a routine and started to mold intensive therapy into their lives, whether figuring out how to carb count for a potluck meal or adjust overnight pump basal rates to avoid nighttime lows. A farmer might have one regimen for the heavy workdays of planting season and a different plan for the winter months.
Other care team members, including dietitians and behavioral therapists, were involved in individualizing intensive therapy. For an average of 6 1/2 years of intensive therapy, participants had access to team support to reach goals ("DCCT Blood Glucose Goals," right). Conventional group participants could access the care team if necessary to maintain safe diabetes control.
Members of the study committee presented findings from the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) study at the American Diabetes Association's 73rd Scientific Sessions in Chicago.
|DCCT Start||At 6 Months||For 6 1/2 Years|
|All Participants||Intensive Group||Conventional Group||Intensive Group||Conventional Group|
|Note: These are averages for the groups; individuals in either group may have had higher or lower A1Cs.|
The trial ended about a year early because the results were so clear-cut. The risk of the development and progression of complications was significantly lower in the intensive therapy group; members had less than half the risk of developing retinopathy, nephropathy (kidney disease), and neuropathy (nerve damage).
Almost all of the benefit was accounted for by the difference in A1C levels between the two treatment groups. "You didn't have to get to a magic number to see benefit," says Gayle Lorenzi, RN, CDE, study coordinator at the University of California–San Diego. "Any improvement in glucose control resulted in risk lowering. If you went from an A1C of 10 percent to an 8, risk was still reduced."
The benefits weren't limited to those in perfect health at the study's start. The thinking used to be that once a patient had signs of complications, the damage would inevitably worsen, says Rose Gubitosi-Klug, MD, PhD, principal investigator at Case Western Reserve University. But DCCT showed that "even if you have complications, you can slow the progression," she says.
For the diabetes community, the DCCT news was the equivalent of celebrating the first man on the moon. The September 1993 cover of Diabetes Forecast proclaimed in bold type: "The just-concluded Diabetes Control and Complications Trial (DCCT) has shown once and for all that controlling diabetes does matter—to you."
|DCCT Blood Glucose Goals|
|As part of intensive insulin therapy in the Diabetes Control and Complications Trial, participants were encouraged to check blood glucose levels from four to as many as seven times a day: before each meal, about 1 1/2 hours after each meal, and before bed. Once a week, they'd set their alarm clocks for a 3 a.m. check. They used the information to make changes to insulin, food, and activity as needed to try to reach these goals safely:
Fasting glucose: 70 to 120 mg/dl
After meals: less than 180 mg/dl, 1 to 2 hours after eating
Weekly, at 3 a.m.: 65 mg/dl or higher
A1C: as close to nondiabetic range (less than 6 percent)
as safely possible
The Next Phase: EDIC
At that point the study could have disbanded. But there was more to come. The study group asked NIDDK for funding to offer intensive therapy training to the people in the conventional treatment group. "We owed it to the other half to be sure that they were the first people to get the benefit of what we had learned," says Genuth.
So began the Epidemiology of Diabetes Interventions and Complications (EDIC) phase—an observational study that looks at even longer-term results of the original DCCT interventions and the factors associated with complications in type 1 diabetes over time. DCCT/EDIC is the Energizer Bunny of diabetes trials, and a whopping 96 percent of surviving original DCCT participants take part.
William Tamborlane, MD, DCCT/EDIC principal investigator at the Yale School of Medicine, says most clinical trials experience a 10 percent drop-out rate every six months. He credits the study coordinators for the world-renowned retention rate.
At the launch of the EDIC phase, conventional group subjects were trained in multiple daily injection or insulin pump therapy. To this day, most EDIC participants are using intensive therapy. Now all participants are seen by the study team once a year for various tests and to keep tabs on complications, including heart disease.
Within the first couple of years of EDIC, the A1C average for the original intensive therapy group rose while it fell for the conventional treatment group, meeting in the middle at about 8 percent. And that average has persisted for 20 years.
|More to Come|
|There is more to learn from the DCCT/EDIC study, including:
Do glucose swings matter? Based on blood samples collected, day-to-day variability seems to have little effect. But researchers are interested in using continuous glucose monitoring technology in EDIC to see if minute-to-minute fluctuations influence complications.
Joint and tendon woes. People with type 1 diabetes are more likely to have frozen shoulder and trigger finger (66 percent of all DCCT/EDIC participants have some form of limited joint mobility and thickened skin, known as cheiroarthropathy). These painful complications affect daily life.
Gastroparesis. High blood glucose can damage stomach nerves, which can affect digestion. EDIC researchers are testing better, noninvasive assessment methods to help measure this hard-to-study condition.
Beta cell function. Not everyone with type 1 diabetes loses all insulin-producing beta cells. Researchers want to determine how many people with long-term diabetes can still make tiny amounts of insulin—and if and how it makes a difference.
Heart disease. DCCT showed that glucose control prevents or slows small blood vessel (microvascular) complications to the eyes, kidneys, and nerves. Now EDIC is investigating whether such control also guards against large-vessel (macrovascular) complications to the heart.
Metabolic memory. EDIC will provide answers about the pathways involved in the long-term protection that intensive glucose management provides. "That's the hope of the future, that somehow we can understand metabolic memory and develop novel therapies to sustain the good effects and inhibit the bad effects," says Rose Gubitosi-Klug, MD, PhD, director of the EDIC Clinical Coordinating Center.
Even though the original intensive therapy group's average A1C rose a bit, there was one surprise. "Those exposed to intensive therapy … continued to do better," Zinman, a principal investigator and chair of the study's publications committee, says. "We call that metabolic memory."
The protection of intensive glucose control lasts for years, if not decades. "Even if A1C drifts up, benefit continues as if the body remembers that it used to have good control," study cochair Nathan says. And that finding contains some useful advice for people new to diabetes. "If you are going to implement intensive therapy, it's important to do it at diagnosis. If you start early, you get this long-term benefit," adds Zinman.
Intensive insulin therapy dramatically increases the risk of severe hypoglycemia (requiring assistance from another person). Of the first 817 to enter DCCT, 216 reported a total of 714 severe hypos. Of those, about 550 episodes occurred in the intensive group, a threefold increase compared to episodes in the conventional group. "It came at a clinical cost, a safety cost," Genuth says. "And it still does." He adds, however: "I've seen too many devastating results from complications to think it isn't worth hypoglycemia." And despite the immediate and serious dangers of severe hypoglycemic episodes, DCCT/EDIC found that such episodes do not lead to a long-term loss of cognitive function.
Although its findings are universally accepted, DCCT/EDIC has had its fair share of criticism. For example, its motivated group of participants may not reflect the majority of people living with type 1 diabetes. They volunteered for research, were a certain age, and had no high blood pressure or cholesterol problems to begin with. "I think less of this argument than I used to," Genuth says. "We compared their baseline characteristics to the general type 1 population. There wasn't much difference."
And though we now know intensive glucose control reduces the risk of complications, the health care system doesn't provide free, high-level care like the intensive group received. Many people see just a single provider for two to four visits a year.
Facing the Future
The trial fostered a legacy of team care that is found at diabetes centers nationwide. "Before the DCCT set the standard, there wasn't a multidisciplinary approach to diabetes," says Debra Counts, MD, principal investigator at the University of Maryland. Counts credits the team of physicians, dietitians, educators, and mental health professionals with helping participants to adapt their lifestyle to intensive management and vice versa.
EDIC funding extends to 2017. As long as the participants are willing to continue and new data are generated, the study group will apply for more funding support. "This population is so incredibly well described," says Tamborlane. "We have generated new and exciting information; it's an incredible resource."
Adds Genuth: "We should continue the study with our wonderful research partners—the participants—so long as there are people with type 1 diabetes who can benefit from additional findings, or until we can cure or prevent type 1 diabetes."