The Diabetes Control and Complications Trial (DCCT) is a landmark multicenter trial designed to test the proposition that complications of diabetes mellitus are related to elevation of the plasma glucose concentration. The study design was simple. Two groups of patients were followed long-term, one treated conventionally (goal: clinical well-being; called standard treatment group) and another more intensively (goal: normalization of blood glucose; called intensive treatment group). The intensive treatment group was clearly distinguished from the control group in terms of glycated hemoglobin levels and measured capillary blood glucose values. Normalization of glucose values was not achieved in the intensively treated cohort as a group since mean glucose values were approximately 40% above normal limits. Nevertheless, there was an approximate 60% reduction in risk between the intensive treatment group and the standard treatment group in diabetic retinopathy, nephropathy, and neuropathy. The benefit of intensive therapy resulted in a delay in the onset and a major slowing of the progression of these three complications. Finally, the benefits of intensive therapy were seen in all categories of subjects regardless of age, sex or duration of diabetes.
American Diabetes Association
The Diabetes Control and Complications Trial
Approved by the Executive Committee of the Board of Directors, June 1993
The American Diabetes Association believes the study has both statistical and clinical significance. The DCCT is the longest and largest prospective study showing that lowering the blood glucose concentration slows or prevents the development of diabetic complications. As such, it has therapeutic implications for health-care providers and their patients. Many questions remain to be answered but the following conclusions appear warranted:
- A primary treatment goal in insulin-dependent diabetes mellitus should be blood glucose control at least equal to that achieved in the intensively treated cohort. This goal may not apply to all patients with IDDM (insulin-dependent diabetes mellitus) and must be based on clinical judgment. Of importance, intensively treated patients had a three-fold greater risk of hypoglycemia than did the patients in the control group. Because serious hypoglycemia is dangerous, "tight" control goals may have to be sacrificed in people in whom frequent or severe hypoglycemia cannot be avoided by treatment modification.
- It is not known for certain whether the results obtained in this study of people with insulin-dependent diabetes apply to people with non-insulin-dependent diabetes mellitus (NIDDM). Nonetheless, it seems reasonable to recommend more intensive therapy in many patients with non-insulin-dependent disease because it is presumed that the mechanisms by which glucose causes complications is the same in both forms of diabetes. However, because there may be other medical conditions in people with NIDDM, tight control may not be appropriate for all people with this type of diabetes.
- There is no favored form of treatment to achieve tight control blood glucose levels. The decision to use multiple injections of insulin versus an insulin pump depends on the preference of the patient with IDDM and the ability of the health care team to provide the necessary resources and support. In NIDDM, diet, exercise and oral drugs may achieve tight control, but insulin will often be required.
In order to expand on these conclusions, a list of pertinent questions and answers is provided in the accompanying pages.
The American Diabetes Association Response to the DCCT
- Are the results of the DCCT significant and reliable?
The DCCT was well designed and efficiently carried out. The results are statistically significant and are of major clinical importance. They convincingly demonstrate that blood glucose control significantly influences development of complications in subjects with IDDM. The study does not appear to have major flaws. As in all clinical trials, not every variable could be studied. In the DCCT, the age range was rather narrow and relatively few minority patients were included, but there is no reason to believe that the results do not apply in all persons with IDDM.
- What level of glucose control should be sought?
It appears that there is a direct relationship between blood glucose level and the risk of complications. However, there are other factors, such as genetics, that influence complications. Nevertheless, patients should aim for the best level of glucose control they can achieve without placing themselves at undue risk for hypoglycemia or other hazards associated with tight control (see question 3). As has always been the case, therapy for diabetes must be individualized in consultation between patient and primary health care provider. If the IDDM patient is intellectually, emotionally, physically and financially able to attempt tight control, and if a health care team is available to provide resources, guidance and support, a reasonable goal is the mean plasma glucose and hemoglobin A1c levels achieved in the intensive treatment group of the trial (i.e., mean blood glucose of 155 mg/dl and HbA1c of ~7.2%; normal average blood glucose ~110 mg/dl and HbA1c <=6.05%).
- Is tight control of the blood glucose dangerous?
It can be. The major danger is hypoglycemia. Serious hypoglycemia may result in altered consciousness, coma or convulsions resulting in injury to the patient or others. Hypoglycemia may also have harmful effects on neuropsychological and intellectual function in children, although in DCCT participants, these adverse affects were not observed. In older subjects low blood sugar may lead to strokes or heart attacks. The intensive treatment group in the DCCT had a three-fold greater risk of severe hypoglycemia than did the control group.
The risk of hypoglycemia must be recognized, although the danger may be reduced by frequent blood glucose monitoring; adjustment of insulin dosage; alteration of the timing, frequency, and content of meals and change in exercise/activity patterns. Thus comprehensive self-management training is essential.
The treatment group also experienced significant weight gain which might have adverse medical and emotional consequences.
- Do the results of the DCCT apply to persons with non-insulin- dependent diabetes mellitus?
Patients with NIDDM were not studied in the DCCT. However, there is no reason to believe that the effects of better control of the blood glucose levels would not apply in subjects with this form of diabetes. The eye, kidney and nerve abnormalities appear quite similar in IDDM and NIDDM, and it is likely that the same or similar underlying mechanisms of disease apply.
Universal recommendations for tight control may not be appropriate, however. The weight gain characteristic of intensive therapy may be greater in subjects with NIDDM since a high percentage are overweight or frankly obese. Since obesity is associated with resistance to insulin action, a vicious cycle of insulin->weight gain->more insulin is possible. Some investigators believe that the higher insulin concentrations required to overcome insulin resistance may be a factor in development of high blood pressure, abnormal lipid levels and artherosclerosis. Also, because of an increased prevalance of macrovascular disease, older patients with NIDDM may be more vulnerable to serious consequences of hypoglycemia including fainting, seizures, falls, stroke, ischemia, or sudden death. Thus, as is the case for everyone having diabetes, the treatment in NIDDM has to be individualized. But the results of the DCCT do suggest that many otherwise healthy patients with NIDDM should strive to achieve tight control. Advanced age or significant co-morbidity (e.g., cerebrovascular or coronary artery disease) should be considered a relative contraindication to tight control in NIDDM. Also, other factors important in the development of atherosclerosis in these patients, including smoking, elevated blood pressure, abnormal lipid values and obesity, must be addressed.
- Is tight control contraindicated in any group of patients?
Tight control should not be attempted by patients unable or unwilling to participate actively in their glucose management. Tight control is contraindicated in infants under 2 and should be undertaken with extreme caution in children between ages of 2 and 7, because hypoglycemia may impair normal brain development which is not complete until 7 years. The danger of hypoglycemia is greater in infants and children because food intake, activity and adherance to treatment schedules are less predictable than in adults. Because pre-adolescents appear to be relatively protected from micro-vascular complications, the need for tight control might be less than in post-pubertal subjects. Older patients with significant atherosclerosis may be vulnerable to permanent injury from hypoglycemia. Although there are few absolute contraindications to tight control, relative contraindications will be more frequent. Clinical judgment and common sense will be required in decision making under the latter circumstance. Given the above caveats, multiple insulin injections and frequent blood glucose monitoring from the onset of IDDM should be standard therapy.
- Should tight control be the goal for patients with established complications?
Again, clinical judgment is required. Unless patients have advanced, severe complications, the answer would often be yes. Tight control may not be indicated for patients who already have marked visual loss, are blind, or have end-stage renal disease. Patients with advanced complications were not entered in the trial so no direct evidence is available to indicate that tight control in such patients is beneficial.
- Should intensive therapy be offered to patients with longstanding diabetes and no evidence of microvascular disease?
If a person has had diabetes for 20-25 years without signs of retinal, nerve or kidney disease, or if complications are minimal (e.g., one or two microaneurysms in the retina), standard rather than tight control may be reasonable.
- Will tight control prevent macrovascular complications?
Atherosclerosis occurs earlier in subjects with diabetes than it does in persons without elevated blood glucose, and it is reasonable to suppose that better control might slow macrovascular as in addition to microvascular complications.
- Is there any way to predict genetic susceptibility to diabetic complications?
As mentioned earlier, susceptibility to complications and damage from elevated blood glucose is influenced by one's genes. Unfortunately, we do not have measurable genetic markers of susceptibility.
- For those choosing tight control, is life-time treatment required?
In general, tight control for subjects beyond puberty should be maintained for life. Alteration of therapy may be required by advanced age or other changes in clinical circumstances; e.g., following a stroke or heart attack signalling more serious risks from hypoglycemia.
- Are the results of the DCCT achievable in the general population of subjects with diabetes?
In theory the answer is yes. However, in the real world, great effort will be required to reproduce the results of DCCT. Practically it must be recognized that the study group was young, generally healthy and highly motivated. The professional personnel carrying out the study were trained endocrinologists and diabetes educators in academic centers who were highly motivated and meticulous in management of the study subjects. The intensively treated group received far more attention and medical services than are routinely available in clinical practice. In many cases, participants and professionals became "family." Broad implementation of intensive therapy will require expanded health care teams (knowledgeable physicians, diabetes educators, nutritionists and social workers), major professional and patient educational efforts, and an enhanced partnership between specialists and primary care providers. The costs of these services and reimbursement mechanisms will have to be adressed (see Question 13).
- What form of intensive treatment is recommended?
Improved glucose control in IDDM had beneficial effects whether delivered by multiple daily injections or programmable insulin infusion pumps. The choice of treatment depends on the wishes of the individual patient and the comfort/competence of the health care team with a given technique.
- Will the postulated benefits of better control be worth the increased costs?
It is recognized that there will be increased costs of widely applying the recommendations of this study in the United States. There will also need to be additional efforts to insure professional education, so that health practitioners are able to effectively and safely implement the therapy employed in the DCCT. It is hoped that the long term benefits of healthier, more productive lives with fewer complications would offset the costs of tight control. This issue is being studied. Ultimately, this will be a societal decision.
- Insulin-dependent diabetes mellitus (IDDM)
- The form of diabetes commonly developing in persons under the age of 25, which was the study group in this trial. Insulin is required in all patients and its omission results in life-threatening diabetic ketoacidosis ("diabetic coma"). It is also called type I diabetes.
- Non-insulin-dependent diabetes mellitus (NIDDM)
- By far the most common form of diabetes, NIDDM usually begins in middle age but can occur earlier or later. It is called non-insulin-dependent to indicate resistance to diabetic ketoacidosis. Patients may be treated by diet or oral drugs ("sulfonylureas") but many are best managed by insulin. NIDDM is also called Type 2 diabetes.
- Diabetes of both types may result in tissue damaging complications. One set of complications is designated microvascular. Microvascular means small blood vessel, but this is simply a traditional terminology and does not imply that the complications are due to blood vessel disease. The microvascular complications affect three organ systems: the eyes ("retinopathy"), the kidneys ("nephropathy") and the nerves ("neuropathy"). These complications lead to visual loss, kidney failure and multiple neurologic symptoms in some patients. The purpose of the DCCT was to test the hypothesis that these complications could be prevented or their progress slowed by better control of blood glucose. Macrovascular means large blood vessel. Macrovascular complications are due to atherosclerosis of the blood vessels which results in narrowing or clotting such that blood flow to tissues is impaired. Complications include angina, heart attacks, strokes, and amputations. In addition to hyperglycemia, other factors are important in the pathogenesis of atherosclerosis in diabetes. These include known risk factors in persons without diabetes such as smoking, high blood pressure and abnormal lipids.
- Tight control
- This term will be used to indicate blood glucose equal to or better than those achieved in the intensively treated group in the DCCT.
- Hemoglobin A1c, or glycated hemoglobin
- This is a form of hemoglobin (the oxygen-carrying molecule of the blood) that reflects the average blood glucose concentration over a three month period. A high percentage of hemoglobin A1c indicates poor control while a low percentage indicates good control.
For Additional Information
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- The Diabetes Control and Complications Trial -- Implications for Policy and Practice, editorial in the New England Journal of Medicine.
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