COVID is an emerging, rapidly evolving situation. Get the latest public health information from CDC: www. The NIDDK funded the landmark Diabetes Control and Complications Trial DCCT to see if people with type 1 diabetes who kept their blood glucose levels as close to normal as safely possible with intensive diabetes treatment 3 or more shots of insulin per day or an insulin pump with self-monitoring of blood glucose at least 4 times per day could slow the development of eye, kidney, and nerve disease, compared to people who used the conventional treatment at the time of the study one or two shots of insulin per day with daily self-monitoring of urine or blood glucose. The DCCT ended after 10 years in —a year earlier than planned—when the study proved that participants who kept their blood glucose levels close to normal greatly lowered their chances of having eye, kidney, and nerve disease. EDIC has shown that there are long-term benefits of early and intensive blood glucose control on the future development of diabetes-related complications such as heart, eye, kidney, and nerve disease, and that early and intensive blood glucose control also lengthens life.
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The DCCT — was a controlled clinical trial in 1, subjects with T1DM comparing intensive therapy INT , aimed at achieving levels of glycemia as close to the nondiabetic range as safely possible, with conventional therapy CON , which aimed to maintain safe asymptomatic glucose control. INT utilized three or more daily insulin injections or insulin pump therapy guided by self-monitored glucose. The major adverse effect of INT was a threefold increased risk of hypoglycemia, which was not associated with a decline in cognitive function or quality of life.
EDIC showed a durable effect of initial assigned therapies despite a loss of the glycemic separation metabolic memory and demonstrated that the reduction in early-stage complications during the DCCT translated into substantial reductions in severe complications and CVD. The plight of people with type 1 diabetes changed dramatically with the introduction of insulin therapy in 1.
Type 1 diabetes was transformed from a uniformly fatal disease in the preinsulin era, with mortality occurring either acutely from diabetic ketoacidosis or subsequently from inanition owing to a chronic catabolic state, to a chronic degenerative disease. In the first 15 to 20 years of insulin therapy, a host of complications that had never been seen before was discovered in people with long-term diabetes 2. These complications, affecting the eyes, kidneys, and peripheral nervous system, were collectively called microvascular complications, to distinguish them from the less diabetes-specific but highly prevalent macrovascular disease complications.
Microvascular disease and peripheral neuropathy resulted in blindness, kidney failure, and amputations 3 ; and macrovascular disease, exacerbated by renal dysfunction and autonomic neuropathy, increased the risk for myocardial infarctions and stroke to levels that were fold or more than in the age-matched nondiabetic population 2 , 3. The pathoetiology of the microvascular complications was vigorously debated during the midth century 4 — 6.
Some practitioners considered the complications a result of nonphysiologically controlled hyperglycemia; others thought that they were a glycemia-independent feature of diabetes. Perhaps the most sensible opinion regarding the role of glucose control, expressed by R. The devastating consequences of the long-term complications led in part to the formation of the National Diabetes Commission by an Act of Congress PL The advances necessary to perform a definitive clinical trial were finally in place by the early s.
These included: the ability to manage glucose levels in the near-normal range using multiple daily injection MDI therapy or continuous subcutaneous insulin infusion CSII with external pumps, guided by self-monitoring of blood glucose SMBG ; the means of measuring chronic glycemia objectively and accurately with the glycated hemoglobin HbA 1c assay; and objective measures of long-term complications.
The two primary aims of the DCCT consensus protocol were to determine whether, compared with conventional therapy CON , an intensive treatment program designed to achieve glycemic control as close to the nondiabetic range as safely possible would prevent or delay the appearance of early background retinopathy primary prevention and would prevent the progression of early retinopathy to more advanced forms of retinopathy secondary intervention.
Recruitment ended in , and the DCCT was halted by its independent oversight committee in , approximately 1 year ahead of schedule, owing to the uniform and conclusive results achieved EDIC is now in its 20th year. The eligibility criteria have been described in detail 8 , The secondary intervention cohort could have a longer duration of diabetes 1—15 years and had to have at least one microaneurysm in either eye.
This cohort could have an AER as high as mg per 24 h. The clinical goals for both treatment groups included absence of frequent symptoms of hyperglycemia or frequent or severe hypoglycemia, defined as requiring assistance from another person.
HbA 1c was measured monthly to aid adjustment of INT and quarterly as a process outcome in both therapy groups. Only the quarterly results were used for study data. In addition, a weekly a. The subjects and DCCT clinic staff chose which modality to use. The insulins used were those that were available at the time: clear zinc regular insulin for premeal boluses and in the insulin pump and NPH, lente, and beef ultralente insulin for basal delivery in MDI regimens.
CON was consistent with standard care in the s and usually included one or two daily injections of insulin with daily urine or SMBG. The only numeric glycemic target was if HbA 1c exceeded Retinopathy, which was measured objectively with stereoscopic fundus photography and graded with standardized methods by a central reading center 13 , was the primary outcome used for power and sample-size calculations.
Similarly important outcomes were nephropathy and retinopathy. The measurements and their frequency and definitions of outcomes are included in Table 1.
The frequency of interactions with the subjects and of the outcome measurements decreased substantially Table 1 ; however, the methods of measuring glycemia, other metabolic outcomes, and complications remained identical to those used during DCCT. Several procedures were added to measure atherosclerosis Table 1. The baseline characteristics were well matched between the INT and CON for the primary prevention and secondary intervention cohorts.
Although in most long-term studies loss to follow-up may compromise the integrity and interpretation of study results, the follow-up in DCCT and subsequently in EDIC has been virtually complete. At the end of DCCT, after an average of 6. Reprinted and modified with permission from Nathan et al. Diabetes ;— The two major adverse events experienced by INT subjects were hypoglycemia and weight gain 15 — The definition established for severe hypoglycemia, which has subsequently been adopted by many studies, was meant to be relatively inclusive but not to include episodes that were recognized and treated by the patients.
To qualify as severe hypoglycemia, an episode had to require assistance from another and included coma or seizures or episodes requiring glucagon, IV dextrose, or oral carbohydrate administered by another person.
Although the intent was to limit bias of ascertainment by collecting the hypoglycemia events at quarterly visits for both INT and CON subjects, INT subjects were seen and contacted more frequently than those in the CON group, and some of the differences in hypoglycemia may be attributable to differences in the frequency of ascertainment. Despite the increased frequency of hypoglycemia, there were no adverse effects of INT or of repeated severe episodes, on rigorously and repeatedly measured cognitive function in adults or adolescents, either during the DCCT or after even longer-term follow-up 18 — The 4.
More detailed descriptions of the individual outcomes are presented in the subsequent articles in this series 21 — The magnitude and consistent direction of the effects on retinopathy, neuropathy, and nephropathy led to the termination of the study 1 year ahead of schedule by the independent oversight group.
Scnd: secondary intervention group. Reprinted with permission from Nathan et al. Considering the powerful effect that glycemic separation had on the outcomes during DCCT, the subsequent narrowing and then disappearance of the difference in HbA 1c levels between the two original therapy groups during EDIC could logically have been expected to result in the subsequent parallel development of complications.
However, the first 4 years of the EDIC follow-up demonstrated a further widening of the differences in outcomes, after adjusting for EDIC baseline outcomes Studies during EDIC suggested that glycation of long-lived proteins, such as dermal collagen, might account for this persistent effect Regardless of the mechanism, metabolic memory has lasted for at least 10 years.
Major beneficial effects of INT on advanced complications 34 , including retinopathy 35 , nephropathy reduced glomerular filtration rate [GFR] 36 , and autonomic manifestations of neuropathy 37 , have been demonstrated Fig. Finally, measurements of atherosclerosis in several macrovascular beds, including carotid intima media thickness 38 and computed tomography—measured coronary artery calcification 39 , have revealed less atherosclerosis in the INT group.
The DCCT and its observational EDIC follow-up were designed to determine whether the long-term complications that affect people with type 1 diabetes could be ameliorated by intensive glycemic therapy. Duality of Interest. No potential conflicts of interest relevant to this article were reported.
Author Contributions. Clinical trial reg. See accompanying articles, pp. National Center for Biotechnology Information , U. Journal List Diabetes Care v.
Diabetes Care. Published online Dec David M. Author information Article notes Copyright and License information Disclaimer. Corresponding author: David M. Nathan, ude. Received Sep 7; Accepted Sep Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
This article has been cited by other articles in PMC. Introduction The plight of people with type 1 diabetes changed dramatically with the introduction of insulin therapy in 1. Research Design and Methods The eligibility criteria have been described in detail 8 , DCCT Interventions and Metabolic Goals The clinical goals for both treatment groups included absence of frequent symptoms of hyperglycemia or frequent or severe hypoglycemia, defined as requiring assistance from another person.
Outcomes Retinopathy, which was measured objectively with stereoscopic fundus photography and graded with standardized methods by a central reading center 13 , was the primary outcome used for power and sample-size calculations. Table 1 Major outcome measurements.
Open in a separate window. Figure 1. Adverse Effects The two major adverse events experienced by INT subjects were hypoglycemia and weight gain 15 — Outcomes More detailed descriptions of the individual outcomes are presented in the subsequent articles in this series 21 — Figure 2. Conclusions The DCCT and its observational EDIC follow-up were designed to determine whether the long-term complications that affect people with type 1 diabetes could be ameliorated by intensive glycemic therapy.
Article Information Funding. Footnotes Clinical trial reg. References 1. The internal secretion of the pancreas: Nathan DM. Long-term complications of diabetes mellitus. Prognosis of diabetes with diabetes onset before the age of thirty-one. Diabetologia ; 14 — [ PubMed ] [ Google Scholar ]. Control of blood glucose and diabetic vascular disease. Avoidance of degenerative lesions in diabetes mellitus. Dolger H. Clinical evaluation of vascular damage in diabetes mellitus.
Lawrence RD. Diabetes ; 35 — [ PubMed ] [ Google Scholar ]. The Diabetes Control and Complications Trial Research Group The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. Early Treatment Diabetic Retinopathy Study Research Group Grading diabetic retinopathy from stereoscopic color fundus photographs—an extension of the modified Airlie House classification.
Blood Glucose Control Studies for Type 1 Diabetes: DCCT and EDIC
In patients with T1DM, how does strict glycemic control with intensive therapy compare with conventional therapy in preventing microvascular complications? The Diabetes Control and Complications Trial DCCT demonstrated that strict glycemic control targeting lower HbA1c goals among patients with T1DM can both delay the onset of retinopathy, nephropathy, and neuropathy and slow the progression of existing microvascular complications. This came at the expense of a threefold higher risk of hypoglycemia, underlying the fact that HbA1c goals should be tailored to the individual. DCCT was unable to demonstrate a reduction in CV events, likely because the study population was relatively young at the time. However, EDIC and other follow-up studies did demonstrate such benefits. Jump to: navigation , search.