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The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 Years: Overview

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and... DCCT/EDIC 30TH ANNIVERSARY Diabetes Care Volume 37, January 2014 9 David M. Nathan, for the DCCT/EDIC The Diabetes Control and Research Group* Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 Years: Overview OBJECTIVE The Diabetes Control and Complications Trial (DCCT) was designed to test the glucose hypothesis and determine whether the complications of type 1 diabetes (T1DM) could be prevented or delayed. The Epidemiology of Diabetes Interven- tions and Complications (EDIC) observational follow-up determined the durability of the DCCT effects on the more-advanced stages of diabetes complications in- cluding cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS The DCCT (1982–1993) was a controlled clinical trial in 1,441 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 Diabetes Control and Complications Trial/ glucose. EDIC (1994–present) is an observational study of the DCCT cohort. Epidemiology of Diabetes Interventions and Complications Data Coordinating Center, George RESULTS Washington University, Biostatistics Center, Bethesda, MD The DCCT followed >99% of the cohort for a mean of 6.5 years and demonstrated a Corresponding author: David M. Nathan, 35–76% reduction in the early stages of microvascular disease with INT, with a dnathan@mgh.harvard.edu. median HbA of 7%, compared with CONV, with a median HbA1c of 9%. The major 1c Received 7 September 2013 and accepted 25 adverse effect of INT was a threefold increased risk of hypoglycemia, which was September 2013. not associated with a decline in cognitive function or quality of life. EDIC showed a Clinical trial reg. nos. NCT00360815 and durable effect of initial assigned therapies despite a loss of the glycemic separa- NCT00360893, clinicaltrials.gov. tion (metabolic memory) and demonstrated that the reduction in early-stage *A complete list of participants in the DCCT/EDIC complications during the DCCT translated into substantial reductions in severe Research Group can be found in N Engl J Med complications and CVD. 2011;365:2366–2376. © 2014 by the American Diabetes Association. CONCLUSIONS See http://creativecommons.org/licenses/by- nc-nd/3.0/ for details. DCCT/EDIC has demonstrated the effectiveness of INT in reducing the long-term complications of T1DM and improving the prospects for a healthy life span. See accompanying articles, pp. 5, 8, Diabetes Care 2014;37:9–16 | DOI: 10.2337/dc13-2112 17, 24, 31, 39, and 44. 10 DCCT/EDIC at 30 Years: Overview Diabetes Care Volume 37, January 2014 The plight of people with type 1 Institutes of Health (NIH) to “initiate and recruitment began. Recruitment ended diabetes changed dramatically with the support a 5-year clinical study to assess in 1989, and the DCCT was halted by its introduction of insulin therapy in 1922 the effects of treatment of juvenile- independent oversight committee in (1). Type 1 diabetes was transformed onset diabetes on the development of 1993, approximately 1 year ahead of from a uniformly fatal disease in the microvascular and macrovascular schedule, owing to the uniform and preinsulin era, with mortality occurring complications.” conclusive results achieved (10). The either acutely from diabetic original CON group was taught INT, The advances necessary to perform a ketoacidosis or subsequently from and the entire cohort was invited to definitive clinical trial were finally in inanition owing to a chronic catabolic join a long-term observational study place by the early 1980s. These state, to a chronic degenerative disease. named the Epidemiology of Diabetes included: the ability to manage glucose In the first 15 to 20 years of insulin Interventions and Complications (EDIC) levels in the near-normal range using therapy, a host of complications that (11). EDIC is now in its 20th year. multiple daily injection (MDI) therapy or had never been seen before was continuous subcutaneous insulin discovered in people with long-term infusion (CSII) with external pumps, RESEARCH DESIGN AND METHODS diabetes (2). These complications, guided by self-monitoring of blood The eligibility criteria have been affecting the eyes, kidneys, and glucose (SMBG); the means of described in detail (8,10). Briefly, in peripheral nervous system, were measuring chronic glycemia objectively order to address the primary prevention collectively called microvascular and accurately with the glycated and secondary intervention questions, complications, to distinguish them from hemoglobin (HbA )assay;and 1c the following eligibility criteria were the less diabetes-specific but highly objective measures of long-term used: age 13–39 years with type 1 prevalent macrovascular disease complications. With these tools diabetes diagnosed based on clinically complications. Microvascular disease available and with generous support accepted criteria and with fasting and peripheral neuropathy resulted in from the National Institute of Arthritis, c-peptide concentrations ,0.2 nmol/L. blindness, kidney failure, and Diabetes, and Digestive and Kidney The subjects had to be generally healthy amputations (3); and macrovascular Diseases, which later became the with no history of cardiovascular disease disease, exacerbated by renal National Institute of Diabetes and (CVD) and without hypertension (blood dysfunction and autonomic neuropathy, Digestive and Kidney Diseases (NIDDK), pressure ,140/90 mmHg) or increased the risk for myocardial 21 centers were selected in 1982 to plan dyslipidemia (8), and those with infarctions and stroke to levels that and conduct a study that would test neuropathy requiring treatment were were 10-fold or more than in the age- what had become known as the excluded. Additionally, the primary matched nondiabetic population (2,3). “glucose hypothesis.” Practically stated, prevention cohort had to have a duration The pathoetiology of the microvascular the glucose hypothesis posited that of 1–5 years with no evidence of complications was vigorously debated achieving near-normal glucose would retinopathy on fundus photography and during the mid-20th century (4–6). ameliorate the long-term complications an albumin excretion rate (AER) ,40 mg Some practitioners considered the of diabetes. Over the course of more per 24 h. The secondary intervention complications a result of nonphysiologically than a year, the investigators planned cohort could have a longer duration of controlled hyperglycemia; others thought the Diabetes Control and diabetes (1–15 years) and had to have at that they were a glycemia-independent Complications Trial (DCCT) (8). The two least one microaneurysm in either eye. feature of diabetes. Perhaps the most primary aims of the DCCT consensus This cohort could have an AER as high as sensible opinion regarding the role protocol were to determine whether, 200 mg per 24 h. Subjects in the primary of glucose control, expressed by compared with conventional therapy prevention cohort and those in the R.D. Lawrence, the preeminent (CON), an intensive treatment program secondary intervention cohort with diabetologist of his time and who had designed to achieve glycemic control ,5 years duration could have 2-h type 1 diabetes himself, was as follows: as close to the nondiabetic range as stimulated c-peptide levels as high “The attempt to keep the blood sugar safely possible would prevent or delay as 0.5 nmol/L; otherwise, it had to be constantly normal may be ideal in the appearance of early background #0.2 nmol/L. theory, but in practice it is very difficult retinopathy (primary prevention) and to achieve and makes the diabetic life would prevent the progression of DCCT Interventions and Metabolic unnecessarily hard without adequate early retinopathy to more advanced Goals benefit” (7). forms of retinopathy (secondary The clinical goals for both treatment intervention). The devastating consequences of the groups included absence of frequent long-term complications led in part to After the successful completion of a symptoms of hyperglycemia or frequent the formation of the National Diabetes 1-year feasibility phase, during which a or severe hypoglycemia, defined as Commission by an Act of Congress (PL substantial separation of HbA levels requiring assistance from another 1c 93-354). In 1975, the Commission issued between the intensive therapy (INT) person. DCCT INT aimed to achieve The Long-Range Plan to Combat (“experimental”)and CON (“standard”) HbA levels that were ,2SDabove 1c Diabetes, which included the groups was achieved (9), an additional the mean value determined for recommendation for the National eight centers were added, and full-scale similarly aged nondiabetic volunteers care.diabetesjournals.org Nathan 11 (,6.05%, 42.6 mmol/mol). HbA was lente, and beef ultralente insulin for reading center (13), was the primary 1c measured monthly to aid adjustment basal delivery in MDI regimens. There outcome used for power and of INT and quarterly as a process was no single MDI or CSII regimen, sample-size calculations. Similarly outcome in both therapy groups. Only and clinic staff and participants important outcomes were the quarterly results were used for worked together to individualize the nephropathy and retinopathy. The study data. INT was adjusted based on regimens to match lifestyle factors measurements and their frequency four or more SMBG tests with the and achieve the SMBG and HbA and definitions of outcomes are 1c following self-monitored glucose goals (12). included in Table 1. targets: premeals 70–120 mg/dL (3.9– CON was consistent with standard 6.7 mmol/L) and 2-h postmeals ,180 EDIC Design and Outcomes care in the 1980s and usually included mg/dL (10 mmol/L). In addition, a weekly In the wake of the successful completion one or two daily injections of insulin 3:00 A.M. blood glucose was to be .65 of the DCCT (10), the DCCT investigators with daily urine or SMBG. The only mg/dL (3.6 mmol/L) in order to protect and the NIDDK decided that longer- numeric glycemic target was if HbA 1c against otherwise unappreciated term follow-up would provide exceeded 13.5%, the mean +2 SD of nocturnal hypoglycemia. To achieve important information regarding the the cohort’s baseline value, in which the glycemic goals, participants durability of the original DCCT INT case treatment was intensified randomly assigned to INT used at least effects and, in particular, the effects of independent of whether the subject three insulin injections per day (MDI) INT on the more-advanced stages of had symptoms. or CSII. The subjects and DCCT clinic complications and CVD (11). After the staff chose which modality to use. The end of the DCCT and before initiating Outcomes insulins used were those that were Retinopathy, which was measured the long-term follow-up called EDIC, all available at the time: clear zinc objectively with stereoscopic fundus of the CON participants were offered (regular) insulin for premeal boluses photography and graded with training in INT. In addition, diabetes care andinthe insulinpumpand NPH, standardized methods by a central was returned to the subjects’ own care Table 1—Major outcome measurements Frequency Complication DCCT EDIC Defined outcomes Retinopathy: 7-field stereoscopic 6 months 1/4 cohort/year, Three-step progression*, CSME, and fundus photography entire cohort year 4 severe NPDR, PDR Renal function Albumin excretion+ Annual Alternate years‡ Albuminuria: micro $40 mg/24 h, macro .300 mg/24 h Serum creatinine (eGFR@) Annual Annual eGFR: ,60 mL/min/1.73 m Neuropathy History, examination, and NCS Baseline, year 5, and/or study end Year 13/14 Confirmed clinical: abnormal exam and abnormal NCS or autonomic study Autonomic Cardiac Baseline, every 2 years, end Years 13/14 and 16/17 R-R variation ,15 or R-R ,20 and Valsalva ratio ,1.5 or orthostatic hypotension Urologic (ED) d Year 10 MNSI + monofilament d Annual Cardiovascular History Annual Annual Aggregate major#: fatal CVD, nonfatal MI, and stroke, hospitalized ECG Annual Annual Angina, vascular procedures Ankle-brachial index Annual Annual Carotid ultrasound d Years 1, 6, and 12 CT CAC d Year 8 Agatston score .200 Cardiac MRI d Year 15 Cardiac structure, function, scars Risk factors HbA 3 months Annual 1c Fasting lipids Annual Alternate years‡ Blood pressure Annual Annual *Based on modified Airlie House criteria (13); +based on a 4-h timed collection; @ calculated based on Modification of Diet in Renal Disease equation, #adjudicated by reviewers masked to treatment assignment HbA ; ‡during EDIC, albumin excretion and fasting lipids were measured in alternate 1c years. CAC, coronary artery calcification; CSME, clinically significant macular edema; CT, computed tomography; ED, erectile dysfunction; eGFR, estimated GFR; MI, myocardial infarction; MNSI, Michigan neuropathy screening instrument; MRI, magnetic resonance imaging; NCS, nerve conduction study; NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy. 12 DCCT/EDIC at 30 Years: Overview Diabetes Care Volume 37, January 2014 Table 2—Clinical characteristics of DCCT/EDIC participants at DCCT baseline, DCCT closeout, and EDIC year 18 DCCT baseline (1983–1989) End of DCCT (1993) EDIC year 18 (2010–2012) (N =1,441) (N =1,422)* (N =1,284)* INT CON INT CON INT CON n 711 730 698 717 620 597 Demographics Age (years) 27.2 (7.1) 26.7 (7.1) 33.6 (7.0) 33.0 (7.0) 52.3 (6.9) 51.4 (6.9)† Female (%) 48.5 45.9 49.0 46.0 48.7 45.7 Diabetes duration (years) 5.8 (4.2) 5.5 (4.1) 12.3 (4.9) 11.9 (4.8) 30.7 (5.0) 30.2 (4.9) DCCT primary prevention cohort (%) 49.0 51.8 49.1 51.7 47.7 50.6 Hypertension (%)|| 3.1 2.1 4.4 3.9 66.6 68.8 Hyperlipidemia (%)** 22.8 23.4 25.6 29.7 68.6 68.2 Current cigarette smoking (%) 18.6 18.4 20.2 19.8 11.5 10.7 Medical treatment Glucose management Pump or multiple daily injections ($3) (%) 0 0 97.4 5.0‡ 97.6 97.7 Glucose monitoring $4 times a day (%) 0 0 52.7 3.8‡ 67.7 70.7 Use of antihypertensive medication (%)§ Any dd d d 60.3 62.7 ACE inhibitor or ARB 0 0 dd 56.8 59.8 Physical examination BMI (kg/m ) 23.4 (2.7) 23.5 (2.9) 26.6 (4.2) 25.0 (3.1)‡ 29.1 (5.7) 28.5 (5.1) Obese (BMI $30 kg/m ) (%) 1.3 1.9 18.6 5.6‡ 36.1 33.0 Systolic blood pressure (mmHg) 114.5 (11.3) 114.6 (11.4) 116.3 (11.7) 115.3 (12.0) 122.4 (15.4) 121.8 (15.1) Diastolic blood pressure (mmHg) 73.1 (8.2) 72.9 (8.7) 74.4 (8.8) 74.3 (8.8) 71.4 (9.0) 71.3 (8.8) Mean arterial pressure (mmHg) 86.9 (8.2) 86.8 (8.6) 88.3 (8.9) 88.0 (8.9) 88.4 (9.8) 88.2 (9.6) Laboratory values HbA (%)†† 9.1 (1.6) 9.1 (1.6) 7.2 (0.9) 9.1 (1.3)‡ 8.0 (1.0) 8.0 (1.0) 1c Plasma lipids (mg/dL) Total cholesterol 177.1 (32.8) 175.7 (33.6) 178.8 (31.2) 183.4 (36.6) 174.8 (35.4) 172.1 (36.4) HDL cholesterol 50.8 (12.3) 50.3 (12.3) 50.8 (12.8) 51.5 (12.9) 61.9 (19.4) 61.5 (17.7) LDL cholesterol 110.3 (28.7) 109.1 (29.4) 111.6 (27.2) 114.3 (31.4) 96.7 (29.2) 94.7 (29.5) Triglycerides 80.8 (43.3) 81.8 (51.3) 82.0 (51.6) 87.8 (54.0)† 81.1 (50.6) 80.6 (71.5) Complications Eye Retinopathy levels (%) ‡‡ No retinopathy (10/10) 49.0 51.8 28.3 17.3 10.7 4.7 Microaneurysm only (20/#20) 35.0 27.8 39.7 32.1 36.9 26.8 Mild NPDR (35/#35) 11.6 15.2 21.2 28.5 21.3 18.3 Moderate NPDR (43/#43–53/53) 4.5 5.1 8.2 14.3 16.5 19.6 Severe PDR or worse (53/,53+) 0 0.1 2.6 7.8 14.7 30.7 Renal* AER (%) ‡‡ 0to ,30 mg/24 h 88.3 90.0 89.8 82.2 81.5 75.1 30 to ,300 mg/24 h 11.7 10.1 8.8 14.6 14.2 17.0 $300 mg/24 h or ESRD 0 0 1.4 3.2 4.3 7.9 eGFR (mL/min/1.73 m ) 126.0 (13.9) 126.2 (14.6) 116.0 (13.0) 117.8 (13.7)‡ 93.3 (18.1) 91.7 (20.1) Sustained eGFR ,60 mL/min/1.73 m (%) 0 0 0.1 0.4 3.2 5.3 Neuropathy Confirmed clinical neuropathy (%) 6.8 5.6 9.3 17.5‡ 23.6 32.7‡ Data are mean (SD) unless otherwise indicated. *Renal measurements (AER or eGFR) were completed for 1,415 subjects at DCCT closeout and 1,217 subjects at EDIC year 17 or 18 (1,194 with AER at year 17 or 18 and 1,187 with eGFR at year 18). For EDIC year 18, clinical characteristic values were carried from measurements from the most recent visit if not measured at year 18. AER and lipid data were collected at year 17 or 18. †P, 0.05 by the 2 2 Wilcoxon rank sum test or the x test comparing CON and INT. ‡P, 0.01 by the Wilcoxon rank sum test or the x test comparing CON and INT for all categories. ||Hypertension was defined by a systolic blood pressure $140 mmHg, diastolic blood pressure $90 mmHg, or use of antihypertensive medications. ** Hyperlipidemia was defined by an LDL cholesterol level$130 mg/dL (3.4 mmol/L) or the use of lipid-lowering agents. ††End of DCCT HbA values are time-averaged mean HbA throughout the DCCT; EDIC year 17/18 HbA values are time-averaged mean EDIC HbA .Mean(SD) 1c 1c 1c 1c HbA levels time-averaged through DCCT/EDIC were 7.8% (0.9%) and 8.3% (1.0%) among participants assigned to INT and CON, respectively. 1c §Medication data were not collected during the DCCT. ACE inhibitors were prohibited during the DCCT. At EDIC year 1, ACE inhibitor use was 5.6% in the INT and 6.9% in the CON groups. ARBs were not available until later during EDIC. Antihypertensive use at EDIC year 1 was 8.7% in the INT and 10.1% in the CON groups. Primary prevention cohort = 1–5 years duration, ,30 mg albuminuria per 24 h, and no retinopathy in either eye at baseline. ARB, angiotensin II receptor blocker; eGFR, estimated GFR; ESRD, end-stage renal disease; NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy. care.diabetesjournals.org Nathan 13 provider, some of whom were DCCT/ than 99% (1,422 of 1,441) completed to include episodes that were EDIC investigators. the study. After another 20 years of recognized and treated by the patients. follow-up in EDIC, 88% of the original To qualify as severe hypoglycemia, an Whereas the DCCT was a controlled cohort (95% of the survivors) is being episode had to require assistance from clinical trial, EDIC was observational. actively followed in DCCT/EDIC clinical another and included coma or seizures The frequency of interactions with the centers. or episodes requiring glucagon, IV subjects and of the outcome dextrose, or oral carbohydrate measurements decreased substantially Glycemia administered by another person. (Table 1); however, the methods of The DCCT INT did not uniformly achieve Although the intent was to limit bias of measuring glycemia, other metabolic the goal HbA of ,6.05%; however, 1c ascertainment by collecting the outcomes, and complications 44% reached that level at least once hypoglycemia events at quarterly visits remained identical to those used during the trial (10). The median of the for both INT and CON subjects, INT during DCCT. Several procedures were quarterly measured HbA levels in INT 1c subjects were seen and contacted added to measure atherosclerosis was 7% compared with 9% in CON more frequently than those in the (Table 1). (Fig. 1). There was almost no crossover CON group, and some of the between INT and CON during the DCCT, differences in hypoglycemia may be RESULTS other than the protocol-dictated change attributable to differences in the to INT for women assigned to CON who Subjects frequency of ascertainment. The were planning pregnancy and during The characteristics of the DCCT cohort frequency of severe hypoglycemia pregnancy (14). 97% of study time was at baseline and at study end, which (62/100 patient-years) and the subset spent on assigned therapy. During EDIC, represents the EDIC baseline, and at of episodes involving coma or seizure the adoption of INT by the original CON the most recent EDIC annual (16/100 patient-years) were both group and the transition for all subjects examinationin2012are shownin threefold higher than in the CON group. to their own health care providers Table 2. The baseline characteristics Despite the increased frequency of resulted in a narrowing and then were well matched between the INT hypoglycemia, there were no adverse disappearance of the differences in and CON for the primary prevention effects of INT or of repeated severe HbA maintained during DCCT (Fig. 1). and secondary intervention cohorts. 1c episodes, on rigorously and repeatedly The changes over time largely reflect measured cognitive function in adults the effects of INT versus CON. Although Adverse Effects or adolescents, either during the DCCT in most long-term studies loss to The two major adverse events or after even longer-term follow-up follow-up may compromise the experienced by INT subjects were (18–20). Weight gain with INT resulted integrity and interpretation of study hypoglycemia and weight gain (15–17). in significantly more subjects becoming results, the follow-up in DCCT and The definition established for severe overweight or obese compared with subsequently in EDIC has been virtually hypoglycemia, which has subsequently CON (17). The 4.6 kg difference in complete. At the end of DCCT, after an been adopted by many studies, was weight during the DCCT largely average of 6.5 years (range 3–9), more meant to be relatively inclusive but not dissipated during the EDIC. Outcomes More detailed descriptions of the individual outcomes are presented in the subsequent articles in this series (21–25). In brief, DCCT INT reduced the early stages of microvascular complications by 35–76% compared with CON (Fig. 2) (10). 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. Analyses of the relationship between metabolic control, measured by the “updated mean” HbA and 1c including approximately 18,000 HbA 1c measurements for each therapy Figure 1—Median HbA concentrations during DCCT, the “training” period between DCCT and 1c group, revealed a strong association EDIC, and EDIC. P, 0.001 for INT vs. CON during entire DCCT and for the first 3 years during EDIC. with each of the three complications Reprinted and modified with permission from Nathan et al. Diabetes Control and Complications (26,27). The difference in updated Trial/Epidemiology of Diabetes Interventions and Complications study at 30 years: advances and contributions. Diabetes 2013;62:3976–3986. mean HbA levels between the 1c 14 DCCT/EDIC at 30 Years: Overview Diabetes Care Volume 37, January 2014 could be ameliorated by intensive glycemic therapy. The DCCT/EDIC convincingly demonstrated that the glucose hypothesis was correct and that an intervention that aimed to achieve glycemia as close to the nondiabetic range as safely possible reduced all of the microvascular and cardiovascular complications of diabetes. Translating the findings of the DCCT/EDIC into clinical care has substantially improved the long-term health of people with type 1 diabetes. Funding. The DCCT/EDIC has been supported by U01 Cooperative Agreement Grants (1982–1993, 2011–2016) and contracts (1982–2011) with the Division of Diabetes Figure 2—Summary of reduction in major complications with INT compared with CON during Endocrinology and Metabolic Diseases of the DCCT, EDIC, and combined study periods. 3+step devel, Prim: three-step or more development National Institute of Diabetes and Digestive of retinopathy based on Early Treatment of Diabetic Retinopathy scale (ref. 13) in the primary and Kidney Diseases (current grant numbers prevention group. Scnd: secondary intervention group. Microalb: microalbuminuria defined as U01 DK094176 and U01 DK094157), and albumin excretion $40 mg/24 h. Macroalb: macroalbuminuria defined as albumin excretion through support by the National Eye .300 mg/24 h. Reduced GFR: estimated GFR ,60 mL/min/1.73 m . CVD events: CVD including Institute, the National Institute of myocardial infarctions, stroke, and CVD death. Reprinted with permission from Nathan et al. Neurological Disorders and Stroke, the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Genetic Clinical Research Centers Program Complications study at 30 years: advances and contributions. Diabetes 2013;62:3976–3986. (1993–2007), and the Clinical Translational Science Center Program (2006–present), Bethesda, MD. therapy groups explained the vast mechanism, metabolic memory has lasted The following industry contributors have had no majority (.98%) of the difference in for at least 10 years. role in the DCCT/EDIC study but have provided free or discounted supplies or equipment to complications between the groups The long-term EDIC follow-up has support participants’ adherence to the study: (26), leaving little room for other allowed the study of the impact of INT Abbott Diabetes Care (Alameda, CA); Animas established or putative risk factors to (Westchester, PA); Bayer Diabetes Care (North versus CON on more advanced play a role in the trial’s differential America Headquarters, Tarrytown, NY); Becton, complications than were studied during Dickinson and Company (Franklin Lakes, NJ); outcomes. the DCCT. Major beneficial effects of INT CanAm (Atlanta, GA); Eli Lilly (Indianapolis, IN); on advanced complications (34), LifeScan (Milpitas, CA); Medtronic Diabetes including retinopathy (35), nephropathy (Minneapolis, MI); Nova Diabetes Care EDIC/Metabolic Memory (Billerica, MA); Omron (Shelton, CT); OmniPod (reduced glomerular filtration rate Considering the powerful effect that Insulin Management System (Bedford, MA); [GFR]) (36), and autonomic mani- glycemic separation had on the outcomes Roche Diabetes Care (Indianapolis, IN); and festations of neuropathy (37), have Sanofi (Bridgewater, NJ). during DCCT, the subsequent narrowing been demonstrated (Fig. 2). Finally, and then disappearance of the difference Duality of Interest. No potential conflicts of measurements of atherosclerosis in interest relevant to this article were reported. in HbA levels between the two original 1c several macrovascular beds, including Author Contributions. D.M.N. researched the therapy groups during EDIC could carotid intima media thickness (38) and data and wrote the manuscript. D.M.N. is the logically have been expected to result in computed tomography–measured guarantor of this work and, as such, had full the subsequent parallel development of access to all the data in the study and takes coronary artery calcification (39), have complications. However, the first 4 years responsibility for the integrity of the data and revealed less atherosclerosis in the INT the accuracy of the data analysis. of the EDIC follow-up demonstrated a group. The clinical expression of these further widening of the differences in changes, fatal and nonfatal myocardial outcomes, after adjusting for EDIC infarctions and stroke, were also reduced References baseline outcomes (28). This pheno- 1. Banting FG, Best CH. The internal secretion by INT, with a 58% reduction in CVD menon of a durable effect on complica- of the pancreas: 1922. 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Nathan DM, Zinman B, Cleary PA, et al.; Group. The Diabetes Control and modified Airlie House classification. ETDRS Diabetes Control and Complications Trial/ Complications Trial/Epidemiology of report number 10. Ophthalmology 1991;98 Epidemiology of Diabetes Interventions Diabetes Interventions and Complications (Suppl.):786–806 and Complications (DCCT/EDIC) Research study at 30 years: summary and future 14. The Diabetes Control and Complications Group. Modern-day clinical course of type 1 directions. Diabetes Care 2014;37:44–49 diabetes mellitus after 30 years’ duration: Trial Research Group. Pregnancy outcomes 26. The Diabetes Control and Complications in the Diabetes Control and Complications the Diabetes Control and Complications Trial Research Group. The relationship of Trial/Epidemiology of Diabetes Trial. Am J Obstet Gynecol 1996;174:1343– glycemic exposure (HbA ) to the risk of 1c Interventions and Complications and development and progression of Pittsburgh Epidemiology of Diabetes 15. The DCCT Research Group. Epidemiology of retinopathy in the Diabetes Control and Complications Experience (1983-2005). severe hypoglycemia in the Diabetes Complications Trial. Diabetes 1995;44:968– Arch Intern Med 2009;169:1307–1316 Control and Complications Trial. Am J Med 35. Aiello LP, Sun W, Cleary P, Lachin SM, 1991;90:450–459 27. Lachin JM, Genuth S, Nathan DM, Zinman B, Gangaputra S, Davis MD, Klein R, Das A, Kiss 16. The Diabetes Control and Complications Rutledge BN; DCCT/EDIC Research Group. S, Domalpally A, Danis R; DCCT/EDIC Trial Research Group. Hypoglycemia in the Effect of glycemic exposure on the risk of Research Group. Intensive diabetes therapy Diabetes Control and Complications Trial. microvascular complications in the reduces ocular surgeries in patients with Diabetes 1997;46:271–286 Diabetes Control and Complications type 1 diabetes: twenty-eight year follow- Trialdrevisited. Diabetes 2008;57:995– 17. The Diabetes Control and Complications up of the Diabetes Control and Trial Research Group. Adverse events and Complications Trial/Epidemiology of their association with treatment regimens 28. Lachin J, Genuth S, Nathan D, Davis M; The Diabetes Interventions and Complications in the Diabetes Control and Complications Diabetes Control and Complications Trial/ (DCCT/EDIC) Study (Abstract). ARVO Trial. Diabetes Care 1995;18:1415–1427 Epidemiology of Diabetes Interventions Meeting Abstracts 2013;54:4024 16 DCCT/EDIC at 30 Years: Overview Diabetes Care Volume 37, January 2014 36. de Boer IH, Sun W, Cleary PA, et al.; DCCT/ Epidemiology of Diabetes Interventions Diabetes Interventions and Complications EDIC Research Group. Intensive diabetes and Complications Research Group. (DCCT/EDIC) Study. Diabetes 2006;55: therapy and glomerular filtration rate in Intensive diabetes therapy and carotid 3556–3565 type 1 diabetes. N Engl J Med 2011;365: intima-media thickness in type 1 diabetes 40. Nathan DM, Cleary PA, Backlund JY, et al.; 2366–2376 mellitus. N Engl J Med 2003;348:2294– Diabetes Control and Complications 37. Wessells H, Penson DF, Cleary P, et al.; the Trial/Epidemiology of Diabetes DCCT/EDIC Research Group: effect of 39. Cleary PA, Orchard TJ, Genuth S, et al.; Interventions and Complications intensive glycemic therapy on erectile DCCT/EDIC Research Group. The effect of (DCCT/EDIC) Study Research Group. function in men with type 1 diabetes. J Urol intensive glycemic treatment on coronary Intensive diabetes treatment and 2011;185:1828–1836 artery calcification in type 1 diabetic cardiovascular disease in patients with type 38. Nathan DM, Lachin J, Cleary P, et al.; participants of the Diabetes Control and 1 diabetes. N Engl J Med 2005;353:2643– Diabetes Control and Complications Trial; Complications Trial/Epidemiology of 2653 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diabetes Care Pubmed Central

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 Years: Overview

Diabetes Care , Volume 37 (1) – Dec 11, 2013

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© 2014 by the American Diabetes Association.
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0149-5992
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1935-5548
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10.2337/dc13-2112
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Abstract

DCCT/EDIC 30TH ANNIVERSARY Diabetes Care Volume 37, January 2014 9 David M. Nathan, for the DCCT/EDIC The Diabetes Control and Research Group* Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 Years: Overview OBJECTIVE The Diabetes Control and Complications Trial (DCCT) was designed to test the glucose hypothesis and determine whether the complications of type 1 diabetes (T1DM) could be prevented or delayed. The Epidemiology of Diabetes Interven- tions and Complications (EDIC) observational follow-up determined the durability of the DCCT effects on the more-advanced stages of diabetes complications in- cluding cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS The DCCT (1982–1993) was a controlled clinical trial in 1,441 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 Diabetes Control and Complications Trial/ glucose. EDIC (1994–present) is an observational study of the DCCT cohort. Epidemiology of Diabetes Interventions and Complications Data Coordinating Center, George RESULTS Washington University, Biostatistics Center, Bethesda, MD The DCCT followed >99% of the cohort for a mean of 6.5 years and demonstrated a Corresponding author: David M. Nathan, 35–76% reduction in the early stages of microvascular disease with INT, with a dnathan@mgh.harvard.edu. median HbA of 7%, compared with CONV, with a median HbA1c of 9%. The major 1c Received 7 September 2013 and accepted 25 adverse effect of INT was a threefold increased risk of hypoglycemia, which was September 2013. not associated with a decline in cognitive function or quality of life. EDIC showed a Clinical trial reg. nos. NCT00360815 and durable effect of initial assigned therapies despite a loss of the glycemic separa- NCT00360893, clinicaltrials.gov. tion (metabolic memory) and demonstrated that the reduction in early-stage *A complete list of participants in the DCCT/EDIC complications during the DCCT translated into substantial reductions in severe Research Group can be found in N Engl J Med complications and CVD. 2011;365:2366–2376. © 2014 by the American Diabetes Association. CONCLUSIONS See http://creativecommons.org/licenses/by- nc-nd/3.0/ for details. DCCT/EDIC has demonstrated the effectiveness of INT in reducing the long-term complications of T1DM and improving the prospects for a healthy life span. See accompanying articles, pp. 5, 8, Diabetes Care 2014;37:9–16 | DOI: 10.2337/dc13-2112 17, 24, 31, 39, and 44. 10 DCCT/EDIC at 30 Years: Overview Diabetes Care Volume 37, January 2014 The plight of people with type 1 Institutes of Health (NIH) to “initiate and recruitment began. Recruitment ended diabetes changed dramatically with the support a 5-year clinical study to assess in 1989, and the DCCT was halted by its introduction of insulin therapy in 1922 the effects of treatment of juvenile- independent oversight committee in (1). Type 1 diabetes was transformed onset diabetes on the development of 1993, approximately 1 year ahead of from a uniformly fatal disease in the microvascular and macrovascular schedule, owing to the uniform and preinsulin era, with mortality occurring complications.” conclusive results achieved (10). The either acutely from diabetic original CON group was taught INT, The advances necessary to perform a ketoacidosis or subsequently from and the entire cohort was invited to definitive clinical trial were finally in inanition owing to a chronic catabolic join a long-term observational study place by the early 1980s. These state, to a chronic degenerative disease. named the Epidemiology of Diabetes included: the ability to manage glucose In the first 15 to 20 years of insulin Interventions and Complications (EDIC) levels in the near-normal range using therapy, a host of complications that (11). EDIC is now in its 20th year. multiple daily injection (MDI) therapy or had never been seen before was continuous subcutaneous insulin discovered in people with long-term infusion (CSII) with external pumps, RESEARCH DESIGN AND METHODS diabetes (2). These complications, guided by self-monitoring of blood The eligibility criteria have been affecting the eyes, kidneys, and glucose (SMBG); the means of described in detail (8,10). Briefly, in peripheral nervous system, were measuring chronic glycemia objectively order to address the primary prevention collectively called microvascular and accurately with the glycated and secondary intervention questions, complications, to distinguish them from hemoglobin (HbA )assay;and 1c the following eligibility criteria were the less diabetes-specific but highly objective measures of long-term used: age 13–39 years with type 1 prevalent macrovascular disease complications. With these tools diabetes diagnosed based on clinically complications. Microvascular disease available and with generous support accepted criteria and with fasting and peripheral neuropathy resulted in from the National Institute of Arthritis, c-peptide concentrations ,0.2 nmol/L. blindness, kidney failure, and Diabetes, and Digestive and Kidney The subjects had to be generally healthy amputations (3); and macrovascular Diseases, which later became the with no history of cardiovascular disease disease, exacerbated by renal National Institute of Diabetes and (CVD) and without hypertension (blood dysfunction and autonomic neuropathy, Digestive and Kidney Diseases (NIDDK), pressure ,140/90 mmHg) or increased the risk for myocardial 21 centers were selected in 1982 to plan dyslipidemia (8), and those with infarctions and stroke to levels that and conduct a study that would test neuropathy requiring treatment were were 10-fold or more than in the age- what had become known as the excluded. Additionally, the primary matched nondiabetic population (2,3). “glucose hypothesis.” Practically stated, prevention cohort had to have a duration The pathoetiology of the microvascular the glucose hypothesis posited that of 1–5 years with no evidence of complications was vigorously debated achieving near-normal glucose would retinopathy on fundus photography and during the mid-20th century (4–6). ameliorate the long-term complications an albumin excretion rate (AER) ,40 mg Some practitioners considered the of diabetes. Over the course of more per 24 h. The secondary intervention complications a result of nonphysiologically than a year, the investigators planned cohort could have a longer duration of controlled hyperglycemia; others thought the Diabetes Control and diabetes (1–15 years) and had to have at that they were a glycemia-independent Complications Trial (DCCT) (8). The two least one microaneurysm in either eye. feature of diabetes. Perhaps the most primary aims of the DCCT consensus This cohort could have an AER as high as sensible opinion regarding the role protocol were to determine whether, 200 mg per 24 h. Subjects in the primary of glucose control, expressed by compared with conventional therapy prevention cohort and those in the R.D. Lawrence, the preeminent (CON), an intensive treatment program secondary intervention cohort with diabetologist of his time and who had designed to achieve glycemic control ,5 years duration could have 2-h type 1 diabetes himself, was as follows: as close to the nondiabetic range as stimulated c-peptide levels as high “The attempt to keep the blood sugar safely possible would prevent or delay as 0.5 nmol/L; otherwise, it had to be constantly normal may be ideal in the appearance of early background #0.2 nmol/L. theory, but in practice it is very difficult retinopathy (primary prevention) and to achieve and makes the diabetic life would prevent the progression of DCCT Interventions and Metabolic unnecessarily hard without adequate early retinopathy to more advanced Goals benefit” (7). forms of retinopathy (secondary The clinical goals for both treatment intervention). The devastating consequences of the groups included absence of frequent long-term complications led in part to After the successful completion of a symptoms of hyperglycemia or frequent the formation of the National Diabetes 1-year feasibility phase, during which a or severe hypoglycemia, defined as Commission by an Act of Congress (PL substantial separation of HbA levels requiring assistance from another 1c 93-354). In 1975, the Commission issued between the intensive therapy (INT) person. DCCT INT aimed to achieve The Long-Range Plan to Combat (“experimental”)and CON (“standard”) HbA levels that were ,2SDabove 1c Diabetes, which included the groups was achieved (9), an additional the mean value determined for recommendation for the National eight centers were added, and full-scale similarly aged nondiabetic volunteers care.diabetesjournals.org Nathan 11 (,6.05%, 42.6 mmol/mol). HbA was lente, and beef ultralente insulin for reading center (13), was the primary 1c measured monthly to aid adjustment basal delivery in MDI regimens. There outcome used for power and of INT and quarterly as a process was no single MDI or CSII regimen, sample-size calculations. Similarly outcome in both therapy groups. Only and clinic staff and participants important outcomes were the quarterly results were used for worked together to individualize the nephropathy and retinopathy. The study data. INT was adjusted based on regimens to match lifestyle factors measurements and their frequency four or more SMBG tests with the and achieve the SMBG and HbA and definitions of outcomes are 1c following self-monitored glucose goals (12). included in Table 1. targets: premeals 70–120 mg/dL (3.9– CON was consistent with standard 6.7 mmol/L) and 2-h postmeals ,180 EDIC Design and Outcomes care in the 1980s and usually included mg/dL (10 mmol/L). In addition, a weekly In the wake of the successful completion one or two daily injections of insulin 3:00 A.M. blood glucose was to be .65 of the DCCT (10), the DCCT investigators with daily urine or SMBG. The only mg/dL (3.6 mmol/L) in order to protect and the NIDDK decided that longer- numeric glycemic target was if HbA 1c against otherwise unappreciated term follow-up would provide exceeded 13.5%, the mean +2 SD of nocturnal hypoglycemia. To achieve important information regarding the the cohort’s baseline value, in which the glycemic goals, participants durability of the original DCCT INT case treatment was intensified randomly assigned to INT used at least effects and, in particular, the effects of independent of whether the subject three insulin injections per day (MDI) INT on the more-advanced stages of had symptoms. or CSII. The subjects and DCCT clinic complications and CVD (11). After the staff chose which modality to use. The end of the DCCT and before initiating Outcomes insulins used were those that were Retinopathy, which was measured the long-term follow-up called EDIC, all available at the time: clear zinc objectively with stereoscopic fundus of the CON participants were offered (regular) insulin for premeal boluses photography and graded with training in INT. In addition, diabetes care andinthe insulinpumpand NPH, standardized methods by a central was returned to the subjects’ own care Table 1—Major outcome measurements Frequency Complication DCCT EDIC Defined outcomes Retinopathy: 7-field stereoscopic 6 months 1/4 cohort/year, Three-step progression*, CSME, and fundus photography entire cohort year 4 severe NPDR, PDR Renal function Albumin excretion+ Annual Alternate years‡ Albuminuria: micro $40 mg/24 h, macro .300 mg/24 h Serum creatinine (eGFR@) Annual Annual eGFR: ,60 mL/min/1.73 m Neuropathy History, examination, and NCS Baseline, year 5, and/or study end Year 13/14 Confirmed clinical: abnormal exam and abnormal NCS or autonomic study Autonomic Cardiac Baseline, every 2 years, end Years 13/14 and 16/17 R-R variation ,15 or R-R ,20 and Valsalva ratio ,1.5 or orthostatic hypotension Urologic (ED) d Year 10 MNSI + monofilament d Annual Cardiovascular History Annual Annual Aggregate major#: fatal CVD, nonfatal MI, and stroke, hospitalized ECG Annual Annual Angina, vascular procedures Ankle-brachial index Annual Annual Carotid ultrasound d Years 1, 6, and 12 CT CAC d Year 8 Agatston score .200 Cardiac MRI d Year 15 Cardiac structure, function, scars Risk factors HbA 3 months Annual 1c Fasting lipids Annual Alternate years‡ Blood pressure Annual Annual *Based on modified Airlie House criteria (13); +based on a 4-h timed collection; @ calculated based on Modification of Diet in Renal Disease equation, #adjudicated by reviewers masked to treatment assignment HbA ; ‡during EDIC, albumin excretion and fasting lipids were measured in alternate 1c years. CAC, coronary artery calcification; CSME, clinically significant macular edema; CT, computed tomography; ED, erectile dysfunction; eGFR, estimated GFR; MI, myocardial infarction; MNSI, Michigan neuropathy screening instrument; MRI, magnetic resonance imaging; NCS, nerve conduction study; NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy. 12 DCCT/EDIC at 30 Years: Overview Diabetes Care Volume 37, January 2014 Table 2—Clinical characteristics of DCCT/EDIC participants at DCCT baseline, DCCT closeout, and EDIC year 18 DCCT baseline (1983–1989) End of DCCT (1993) EDIC year 18 (2010–2012) (N =1,441) (N =1,422)* (N =1,284)* INT CON INT CON INT CON n 711 730 698 717 620 597 Demographics Age (years) 27.2 (7.1) 26.7 (7.1) 33.6 (7.0) 33.0 (7.0) 52.3 (6.9) 51.4 (6.9)† Female (%) 48.5 45.9 49.0 46.0 48.7 45.7 Diabetes duration (years) 5.8 (4.2) 5.5 (4.1) 12.3 (4.9) 11.9 (4.8) 30.7 (5.0) 30.2 (4.9) DCCT primary prevention cohort (%) 49.0 51.8 49.1 51.7 47.7 50.6 Hypertension (%)|| 3.1 2.1 4.4 3.9 66.6 68.8 Hyperlipidemia (%)** 22.8 23.4 25.6 29.7 68.6 68.2 Current cigarette smoking (%) 18.6 18.4 20.2 19.8 11.5 10.7 Medical treatment Glucose management Pump or multiple daily injections ($3) (%) 0 0 97.4 5.0‡ 97.6 97.7 Glucose monitoring $4 times a day (%) 0 0 52.7 3.8‡ 67.7 70.7 Use of antihypertensive medication (%)§ Any dd d d 60.3 62.7 ACE inhibitor or ARB 0 0 dd 56.8 59.8 Physical examination BMI (kg/m ) 23.4 (2.7) 23.5 (2.9) 26.6 (4.2) 25.0 (3.1)‡ 29.1 (5.7) 28.5 (5.1) Obese (BMI $30 kg/m ) (%) 1.3 1.9 18.6 5.6‡ 36.1 33.0 Systolic blood pressure (mmHg) 114.5 (11.3) 114.6 (11.4) 116.3 (11.7) 115.3 (12.0) 122.4 (15.4) 121.8 (15.1) Diastolic blood pressure (mmHg) 73.1 (8.2) 72.9 (8.7) 74.4 (8.8) 74.3 (8.8) 71.4 (9.0) 71.3 (8.8) Mean arterial pressure (mmHg) 86.9 (8.2) 86.8 (8.6) 88.3 (8.9) 88.0 (8.9) 88.4 (9.8) 88.2 (9.6) Laboratory values HbA (%)†† 9.1 (1.6) 9.1 (1.6) 7.2 (0.9) 9.1 (1.3)‡ 8.0 (1.0) 8.0 (1.0) 1c Plasma lipids (mg/dL) Total cholesterol 177.1 (32.8) 175.7 (33.6) 178.8 (31.2) 183.4 (36.6) 174.8 (35.4) 172.1 (36.4) HDL cholesterol 50.8 (12.3) 50.3 (12.3) 50.8 (12.8) 51.5 (12.9) 61.9 (19.4) 61.5 (17.7) LDL cholesterol 110.3 (28.7) 109.1 (29.4) 111.6 (27.2) 114.3 (31.4) 96.7 (29.2) 94.7 (29.5) Triglycerides 80.8 (43.3) 81.8 (51.3) 82.0 (51.6) 87.8 (54.0)† 81.1 (50.6) 80.6 (71.5) Complications Eye Retinopathy levels (%) ‡‡ No retinopathy (10/10) 49.0 51.8 28.3 17.3 10.7 4.7 Microaneurysm only (20/#20) 35.0 27.8 39.7 32.1 36.9 26.8 Mild NPDR (35/#35) 11.6 15.2 21.2 28.5 21.3 18.3 Moderate NPDR (43/#43–53/53) 4.5 5.1 8.2 14.3 16.5 19.6 Severe PDR or worse (53/,53+) 0 0.1 2.6 7.8 14.7 30.7 Renal* AER (%) ‡‡ 0to ,30 mg/24 h 88.3 90.0 89.8 82.2 81.5 75.1 30 to ,300 mg/24 h 11.7 10.1 8.8 14.6 14.2 17.0 $300 mg/24 h or ESRD 0 0 1.4 3.2 4.3 7.9 eGFR (mL/min/1.73 m ) 126.0 (13.9) 126.2 (14.6) 116.0 (13.0) 117.8 (13.7)‡ 93.3 (18.1) 91.7 (20.1) Sustained eGFR ,60 mL/min/1.73 m (%) 0 0 0.1 0.4 3.2 5.3 Neuropathy Confirmed clinical neuropathy (%) 6.8 5.6 9.3 17.5‡ 23.6 32.7‡ Data are mean (SD) unless otherwise indicated. *Renal measurements (AER or eGFR) were completed for 1,415 subjects at DCCT closeout and 1,217 subjects at EDIC year 17 or 18 (1,194 with AER at year 17 or 18 and 1,187 with eGFR at year 18). For EDIC year 18, clinical characteristic values were carried from measurements from the most recent visit if not measured at year 18. AER and lipid data were collected at year 17 or 18. †P, 0.05 by the 2 2 Wilcoxon rank sum test or the x test comparing CON and INT. ‡P, 0.01 by the Wilcoxon rank sum test or the x test comparing CON and INT for all categories. ||Hypertension was defined by a systolic blood pressure $140 mmHg, diastolic blood pressure $90 mmHg, or use of antihypertensive medications. ** Hyperlipidemia was defined by an LDL cholesterol level$130 mg/dL (3.4 mmol/L) or the use of lipid-lowering agents. ††End of DCCT HbA values are time-averaged mean HbA throughout the DCCT; EDIC year 17/18 HbA values are time-averaged mean EDIC HbA .Mean(SD) 1c 1c 1c 1c HbA levels time-averaged through DCCT/EDIC were 7.8% (0.9%) and 8.3% (1.0%) among participants assigned to INT and CON, respectively. 1c §Medication data were not collected during the DCCT. ACE inhibitors were prohibited during the DCCT. At EDIC year 1, ACE inhibitor use was 5.6% in the INT and 6.9% in the CON groups. ARBs were not available until later during EDIC. Antihypertensive use at EDIC year 1 was 8.7% in the INT and 10.1% in the CON groups. Primary prevention cohort = 1–5 years duration, ,30 mg albuminuria per 24 h, and no retinopathy in either eye at baseline. ARB, angiotensin II receptor blocker; eGFR, estimated GFR; ESRD, end-stage renal disease; NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy. care.diabetesjournals.org Nathan 13 provider, some of whom were DCCT/ than 99% (1,422 of 1,441) completed to include episodes that were EDIC investigators. the study. After another 20 years of recognized and treated by the patients. follow-up in EDIC, 88% of the original To qualify as severe hypoglycemia, an Whereas the DCCT was a controlled cohort (95% of the survivors) is being episode had to require assistance from clinical trial, EDIC was observational. actively followed in DCCT/EDIC clinical another and included coma or seizures The frequency of interactions with the centers. or episodes requiring glucagon, IV subjects and of the outcome dextrose, or oral carbohydrate measurements decreased substantially Glycemia administered by another person. (Table 1); however, the methods of The DCCT INT did not uniformly achieve Although the intent was to limit bias of measuring glycemia, other metabolic the goal HbA of ,6.05%; however, 1c ascertainment by collecting the outcomes, and complications 44% reached that level at least once hypoglycemia events at quarterly visits remained identical to those used during the trial (10). The median of the for both INT and CON subjects, INT during DCCT. Several procedures were quarterly measured HbA levels in INT 1c subjects were seen and contacted added to measure atherosclerosis was 7% compared with 9% in CON more frequently than those in the (Table 1). (Fig. 1). There was almost no crossover CON group, and some of the between INT and CON during the DCCT, differences in hypoglycemia may be RESULTS other than the protocol-dictated change attributable to differences in the to INT for women assigned to CON who Subjects frequency of ascertainment. The were planning pregnancy and during The characteristics of the DCCT cohort frequency of severe hypoglycemia pregnancy (14). 97% of study time was at baseline and at study end, which (62/100 patient-years) and the subset spent on assigned therapy. During EDIC, represents the EDIC baseline, and at of episodes involving coma or seizure the adoption of INT by the original CON the most recent EDIC annual (16/100 patient-years) were both group and the transition for all subjects examinationin2012are shownin threefold higher than in the CON group. to their own health care providers Table 2. The baseline characteristics Despite the increased frequency of resulted in a narrowing and then were well matched between the INT hypoglycemia, there were no adverse disappearance of the differences in and CON for the primary prevention effects of INT or of repeated severe HbA maintained during DCCT (Fig. 1). and secondary intervention cohorts. 1c episodes, on rigorously and repeatedly The changes over time largely reflect measured cognitive function in adults the effects of INT versus CON. Although Adverse Effects or adolescents, either during the DCCT in most long-term studies loss to The two major adverse events or after even longer-term follow-up follow-up may compromise the experienced by INT subjects were (18–20). Weight gain with INT resulted integrity and interpretation of study hypoglycemia and weight gain (15–17). in significantly more subjects becoming results, the follow-up in DCCT and The definition established for severe overweight or obese compared with subsequently in EDIC has been virtually hypoglycemia, which has subsequently CON (17). The 4.6 kg difference in complete. At the end of DCCT, after an been adopted by many studies, was weight during the DCCT largely average of 6.5 years (range 3–9), more meant to be relatively inclusive but not dissipated during the EDIC. Outcomes More detailed descriptions of the individual outcomes are presented in the subsequent articles in this series (21–25). In brief, DCCT INT reduced the early stages of microvascular complications by 35–76% compared with CON (Fig. 2) (10). 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. Analyses of the relationship between metabolic control, measured by the “updated mean” HbA and 1c including approximately 18,000 HbA 1c measurements for each therapy Figure 1—Median HbA concentrations during DCCT, the “training” period between DCCT and 1c group, revealed a strong association EDIC, and EDIC. P, 0.001 for INT vs. CON during entire DCCT and for the first 3 years during EDIC. with each of the three complications Reprinted and modified with permission from Nathan et al. Diabetes Control and Complications (26,27). The difference in updated Trial/Epidemiology of Diabetes Interventions and Complications study at 30 years: advances and contributions. Diabetes 2013;62:3976–3986. mean HbA levels between the 1c 14 DCCT/EDIC at 30 Years: Overview Diabetes Care Volume 37, January 2014 could be ameliorated by intensive glycemic therapy. The DCCT/EDIC convincingly demonstrated that the glucose hypothesis was correct and that an intervention that aimed to achieve glycemia as close to the nondiabetic range as safely possible reduced all of the microvascular and cardiovascular complications of diabetes. Translating the findings of the DCCT/EDIC into clinical care has substantially improved the long-term health of people with type 1 diabetes. Funding. The DCCT/EDIC has been supported by U01 Cooperative Agreement Grants (1982–1993, 2011–2016) and contracts (1982–2011) with the Division of Diabetes Figure 2—Summary of reduction in major complications with INT compared with CON during Endocrinology and Metabolic Diseases of the DCCT, EDIC, and combined study periods. 3+step devel, Prim: three-step or more development National Institute of Diabetes and Digestive of retinopathy based on Early Treatment of Diabetic Retinopathy scale (ref. 13) in the primary and Kidney Diseases (current grant numbers prevention group. Scnd: secondary intervention group. Microalb: microalbuminuria defined as U01 DK094176 and U01 DK094157), and albumin excretion $40 mg/24 h. Macroalb: macroalbuminuria defined as albumin excretion through support by the National Eye .300 mg/24 h. Reduced GFR: estimated GFR ,60 mL/min/1.73 m . CVD events: CVD including Institute, the National Institute of myocardial infarctions, stroke, and CVD death. Reprinted with permission from Nathan et al. Neurological Disorders and Stroke, the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Genetic Clinical Research Centers Program Complications study at 30 years: advances and contributions. Diabetes 2013;62:3976–3986. (1993–2007), and the Clinical Translational Science Center Program (2006–present), Bethesda, MD. therapy groups explained the vast mechanism, metabolic memory has lasted The following industry contributors have had no majority (.98%) of the difference in for at least 10 years. role in the DCCT/EDIC study but have provided free or discounted supplies or equipment to complications between the groups The long-term EDIC follow-up has support participants’ adherence to the study: (26), leaving little room for other allowed the study of the impact of INT Abbott Diabetes Care (Alameda, CA); Animas established or putative risk factors to (Westchester, PA); Bayer Diabetes Care (North versus CON on more advanced play a role in the trial’s differential America Headquarters, Tarrytown, NY); Becton, complications than were studied during Dickinson and Company (Franklin Lakes, NJ); outcomes. the DCCT. Major beneficial effects of INT CanAm (Atlanta, GA); Eli Lilly (Indianapolis, IN); on advanced complications (34), LifeScan (Milpitas, CA); Medtronic Diabetes including retinopathy (35), nephropathy (Minneapolis, MI); Nova Diabetes Care EDIC/Metabolic Memory (Billerica, MA); Omron (Shelton, CT); OmniPod (reduced glomerular filtration rate Considering the powerful effect that Insulin Management System (Bedford, MA); [GFR]) (36), and autonomic mani- glycemic separation had on the outcomes Roche Diabetes Care (Indianapolis, IN); and festations of neuropathy (37), have Sanofi (Bridgewater, NJ). during DCCT, the subsequent narrowing been demonstrated (Fig. 2). Finally, and then disappearance of the difference Duality of Interest. No potential conflicts of measurements of atherosclerosis in interest relevant to this article were reported. in HbA levels between the two original 1c several macrovascular beds, including Author Contributions. D.M.N. researched the therapy groups during EDIC could carotid intima media thickness (38) and data and wrote the manuscript. D.M.N. is the logically have been expected to result in computed tomography–measured guarantor of this work and, as such, had full the subsequent parallel development of access to all the data in the study and takes coronary artery calcification (39), have complications. However, the first 4 years responsibility for the integrity of the data and revealed less atherosclerosis in the INT the accuracy of the data analysis. of the EDIC follow-up demonstrated a group. The clinical expression of these further widening of the differences in changes, fatal and nonfatal myocardial outcomes, after adjusting for EDIC infarctions and stroke, were also reduced References baseline outcomes (28). This pheno- 1. Banting FG, Best CH. The internal secretion by INT, with a 58% reduction in CVD menon of a durable effect on complica- of the pancreas: 1922. 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Diabetes CarePubmed Central

Published: Dec 11, 2013

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