Story of Discovery: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions And Complications Study
Thirty Years of Research That Has Improved the Lives of People with Type 1 Diabetes
Diabetes slowly damages major organs in the body, such as the eyes, kidneys, and heart. Impressive research progress toward combating diabetes complications was achieved through a large clinical trial launched by the NIDDK in 1983. The Diabetes Control and Complications Trial (DCCT) was a multi-center clinical trial in 1,441 people ages 13 to 39 years with type 1 diabetes. It compared the effects of intensive versus conventional treatment of blood glucose levels on the development of microvascular complications (those affecting the small blood vessels in the eyes, kidneys, and nerves). Participants in the intensive treatment group kept their blood glucose levels and hemoglobin A1C (HbA1c) levels—which reflect average blood glucose levels over a two- to three-month period—as close to normal as safely possible through a regimen that included frequent monitoring of blood glucose and at least three insulin injections per day or use of an insulin pump. The study’s conventional treatment, based on what was standard practice at the time the DCCT began, consisted of one or two insulin injections per day, with once-a-day urine or blood glucose testing.
The two treatment groups achieved markedly different average HbA1c levels over the course of the trial, and strikingly different rates of microvascular complications. The DCCT proved conclusively that intensive therapy reduces the risk of microvascular complications, such as diabetic eye, kidney, and nerve damage, by 35 to 76 percent compared with what was then conventional treatment. It also demonstrated that HbA1c measurements could be used by health care providers and patients to monitor disease management by assessing blood glucose control and predicting risk of developing complications. The DCCT findings had a profound impact on clinical practice for the management of type 1 diabetes by leading to the development of clinical guidelines to recommend HbA1c targets for people with the disease; it also spurred the creation of the National Diabetes Education Program, co-led by the NIDDK and the Centers for Disease Control and Prevention (CDC), to disseminate the findings to patients and health care providers (www.ndep.nih.gov).
Long-term Benefits of Intensive Blood Glucose Control
Upon completion of the DCCT, participants who had received conventional treatment were taught the intensive treatment methods, and all were encouraged to use intensive treatment on their own, although the intervention itself stopped. Nearly all people who participated in the DCCT volunteered for the follow-on Epidemiology of Diabetes Interventions and Complications (EDIC) study, which began in 1994. EDIC was established to determine the long-term outcomes of reducing exposure of the body’s tissues and organs to high blood glucose levels.
About five years after the transition to EDIC, blood glucose control (as measured by HbA1c levels) in the former intensive and conventional treatment groups converged to a similar level. This convergence occurred because of changes in glucose control in both groups. The level of blood glucose control in the participants from the former intensive treatment group was not quite as tight as it was during the DCCT, when they had the advantages of the clinical trial setting—although they were still able to achieve better glucose control on their own after the DCCT than they had before the trial. At the same time, those who were in the conventional treatment group during the DCCT began implementing a more intensive control regimen afterward, and thus improved their glucose control. With both groups now striving for intensive control on their own, the net result was that blood glucose control became nearly identical in the two groups during EDIC.
In 2002 and 2003, DCCT/EDIC investigators reported that, even though the two treatment groups had similar blood glucose control during EDIC, the former intensive treatment group had long-term health benefits from the finite period (averaging six and a half years) of intensive glucose control during DCCT: they continued to have reduced risk for microvascular complications seven to eight years after the end of DCCT compared to the former conventional treatment group. The phenomenon of long-lasting effects of a period of intensive or non-intensive glucose control has been termed “metabolic memory.” More recent observations show that the differences in new cases of diabetic eye disease between participants who received the intensive treatment and those who received conventional treatment are beginning to narrow.
Nonetheless, three decades after the start of DCCT, the two former treatment groups have substantially different rates of complications, suggesting that people with type 1 diabetes implement intensive glucose control as early in the course of the disease as possible. An important unanswered research question after the DCCT ended was the effect of glucose control on cardiovascular disease (CVD), as CVD can take a long time to develop and the participants were too young to examine this complication during the DCCT. That question was answered in 2005—over 20 years from the start of the trial—when the DCCT/EDIC research group reported that intensive blood glucose control reduced the risk of nonfatal heart attack, stroke, or death due to CVD by 57 percent. These results showed for the first time that intensive control of blood glucose levels has long-term beneficial effects on CVD risk in people with type 1 diabetes. These findings are particularly significant because people with type 1 diabetes face a 10-fold increased risk of CVD death compared to the general age-matched population.1,2
Insights continue to emerge regarding the long-term benefits of early and intensive blood glucose control. In 2009, DCCT/EDIC researchers found that, after 30 years of diabetes, DCCT participants in the former intensive treatment group had about half the rate of eye damage compared to those in the former conventional treatment group (21 percent versus 50 percent). They also had lower rates of kidney damage (9 percent versus 25 percent) and cardiovascular events (9 percent versus 14 percent) compared to those in the former conventional treatment group. These findings suggest that with early intensive therapy to control blood glucose levels, the outlook for people with type 1 diabetes is better than ever.
More good news was reported in 2011 related to the long-term risk of developing kidney disease. During the DCCT, the participants were too young for researchers to examine the effect of glucose control on actual kidney disease, which (like CVD) can take a long time to develop. The researchers did find that at the end of DCCT, intensive therapy reduced a condition associated with kidney damage, called albuminuria. However, following the participants for longer timeframes in EDIC allowed the researchers to examine the development of kidney disease. In 2011, after an average 22-year follow up, DCCT/EDIC demonstrated that controlling blood glucose early in the course of disease not only continued to reduce albuminuria, but also decreased participants’ long-term risk of developing kidney disease by 50 percent. This important finding showed that controlling blood glucose early in the course of type 1 diabetes yields huge dividends, preserving kidney function for decades.
In 2013, the DCCT/EDIC researchers and patient volunteers celebrated a remarkable 30 years of participation in research since the launch of the DCCT in 1983. To date, 95 percent of living DCCT patient volunteers continue to participate in EDIC. This unwavering dedication to research has transformed how type 1 diabetes is treated: when people with the disease visit their doctors today, the advice that they receive stems directly from DCCT/EDIC research findings—a testament to the impact that DCCT/EDIC research has had on a public health level.
Research To Combat Hypoglycemia and To Help People Achieve Recommended Levels of Blood Glucose Control
Even though the results of DCCT/EDIC show that intensive glucose control is beneficial for long-term prevention of complications, type 1 diabetes is a burdensome disease to manage. It requires patients (or parents of young children) to check their blood glucose levels with finger sticks, monitor food intake and physical activity levels, and administer insulin. In addition, a severe limitation to the practice of intensive therapy is the potential for acute episodes of hypoglycemia, or low blood glucose. The immediate effects of hypoglycemia can be severe, including changes in cardiovascular and central nervous system function, cognitive impairment, increased risk for unintentional injury, coma, and death. Therefore, the DCCT/EDIC findings underscore the importance of research to develop new tools to help patients achieve recommended levels of glucose control with less risk of hypoglycemia.
NIDDK-supported researchers have already been successful in contributing to the development of U.S. Food and Drug Administration (FDA)-approved continuous glucose monitoring technology, which may enable better glucose control by providing patients with real-time measurements of glucose levels every few minutes and sounding alarms when glucose levels are too high or too low. The NIDDK also supports research to develop artificial pancreas technology, which would integrate continuous glucose monitoring with automated insulin delivery based on the glucose data, representing an important current opportunity to help people with diabetes implement intensive blood glucose control. Other research is pursuing strategies to develop approaches to replace or regenerate the body’s insulin-producing beta cells, which are lost in type 1 diabetes, as a potential cure for the disease. Through these multi-faceted approaches, the NIDDK remains committed to helping people with type 1 diabetes safely achieve good blood glucose control with less burden, to realize the full benefits of the DCCT/EDIC findings.
Benefits for Type 1 Diabetes and Beyond
Findings from the DCCT/EDIC have transformed the management of type 1 diabetes, but have also benefited people with type 2 diabetes. For example, the results of DCCT/EDIC stimulated the conduct of trials assessing the role of blood glucose control in type 2 diabetes. These trials have informed clinical guidelines developed by the American Diabetes Association and other groups, which now include HbA1c targets for most people with diabetes.
However, lack of standardization of HbA1c tests made it dificult to utilize these targets in medical practice. In other words, there were many different types of HbA1c tests being used that gave varied results, so results were not comparable from one laboratory to another. To address this gap, the NIDDK and the CDC launched the National Glycohemoglobin Standardization Program in 1996 to improve the standardization and reliability in measures of HbA1c. The standardization effort has been a great success: variability of HbA1c test results has steadily reduced, and the availability of a standardized testing method has allowed international experts to recommend expanding the use of HbA1c beyond monitoring of blood glucose control during treatment to use it as a more convenient test to diagnose type 2 diabetes. Thus, standardization of the HbA1c test has not only benefitted management of type 1 and type 2 diabetes by enabling health care providers and patients to accurately and meaningfully assess blood glucose control and risk for complications, but has expanded the utility of the HbA1c test to be used for diagnosis of type 2 diabetes. In addition, the DCCT established the value of HbA1c as an outcome measure for clinical trials in both type 1 and type 2 diabetes. This has dramatically shortened the cost and duration of trials for new therapies because improvements in HbA1c levels are detected long before changes in complications become apparent. The use of HbA1c as an outcome measure was the basis for FDA approval of approximately 10 new classes of drugs for type 2 diabetes, as well as for improved forms of insulin. These are just a few examples of the far-reaching benefits that have stemmed from DCCT/EDIC research.
A Long-term Investment in Research Improves the Lives of People with Type 1 Diabetes
The DCCT/EDIC demonstrates how a long-term investment in research has had a profound impact on the health of people with type 1 diabetes. Thirty years after the beginning of the DCCT, researchers are still demonstrating significant findings that continue to improve the care of people with type 1 diabetes and also have implications for people with type 2 diabetes. Because the cohort of DCCT patients was too young for examination of cardiovascular complications and kidney disease when the study began, the long-term follow up was necessary to assess the effect of intensive glucose control on these devastating and life-threatening diabetic complications. The research shows that the full benefits of treatment may not be seen for decades, especially for complications of diabetes, which can progress slowly but have devastating consequences. It has only been through 30 years of steadfast dedication of the DCCT/EDIC research group and patient volunteers that these benefits continue to emerge. They are a key reason why people with type 1 diabetes are living longer, healthier lives than ever before.