Background Intensive diabetes therapy aimed at achieving nearnormoglycemia reduces the risk of microvascular and neurologiccomplications of type 1 diabetes. We studied whether the useof intensive therapy as compared with conventional therapy duringthe Diabetes Control and Complications Trial (DCCT) affectedthe long-term incidence of cardiovascular disease.
Methods The DCCT randomly assigned 1441 patients with type 1diabetes to intensive or conventional therapy, treating themfor a mean of 6.5 years between 1983 and 1993. Ninety-threepercent were subsequently followed until February 1, 2005, duringthe observational Epidemiology of Diabetes Interventions andComplications study. Cardiovascular disease (defined as nonfatalmyocardial infarction, stroke, death from cardiovascular disease,confirmed angina, or the need for coronary-artery revascularization)was assessed with standardized measures and classified by anindependent committee.
Results During the mean 17 years of follow-up, 46 cardiovasculardisease events occurred in 31 patients who had received intensivetreatment in the DCCT, as compared with 98 events in 52 patientswho had received conventional treatment. Intensive treatmentreduced the risk of any cardiovascular disease event by 42 percent(95 percent confidence interval, 9 to 63 percent; P=0.02) andthe risk of nonfatal myocardial infarction, stroke, or deathfrom cardiovascular disease by 57 percent (95 percent confidenceinterval, 12 to 79 percent; P=0.02). The decrease in glycosylatedhemoglobin values during the DCCT was significantly associatedwith most of the positive effects of intensive treatment onthe risk of cardiovascular disease. Microalbuminuria and albuminuriawere associated with a significant increase in the risk of cardiovasculardisease, but differences between treatment groups remained significant(P0.05) after adjusting for these factors.
Conclusions Intensive diabetes therapy has long-term beneficialeffects on the risk of cardiovascular disease in patients withtype 1 diabetes.
Type 1 diabetes mellitus is associated with long-term complicationsthat affect the eyes, kidneys, and peripheral and autonomicnervous systems.1 Although the pathophysiological basis of thesecomplications remains uncertain, hyperglycemia appears to playa central role. Epidemiologic studies have demonstrated a strongassociation between the level of glycemia and the occurrenceof these diabetic complications.2 The Diabetes Control and ComplicationsTrial (DCCT) and the Epidemiology of Diabetes Interventionsand Complications (EDIC) study, DCCT's long-term follow-up study,have demonstrated a consistent salutary effect of intensivetherapy, aimed at achieving glucose control as close to thenondiabetic range as safely possible, on the development andprogression of retinopathy, nephropathy, and neuropathy.3,4The DCCT/EDIC study has established a causal role of hyperglycemiain the development and progression of the microvascular complicationsof type 1 diabetes.
Although cardiovascular disease is not specific to diabetes,it is more prevalent among patients with type 1 or type 2 diabetesthan among those without diabetes.5,6 Type 1 diabetes is associatedwith at least a 10-fold increase in cardiovascular disease ascompared with an age-matched nondiabetic population.6,7 An associationbetween hyperglycemia and cardiovascular disease has been suggestedby some,8 but not all,9 studies of patients with type 1 diabetes.However, controlled clinical trials of patients with type 1or type 2 diabetes have not demonstrated a reduction in theoccurrence of cardiovascular disease with long-term intensivediabetes therapy. During the DCCT, fewer cardiovascular eventsoccurred in the intensive-treatment group than in the conventional-treatmentgroup, but the small number of events in the relatively youngcohort precluded a determination of whether the use of intensivediabetes therapy affected the risk of cardiovascular disease.10Using long-term follow-up data on the DCCT/EDIC cohort, we evaluatedwhether intensive therapy reduces the risk of cardiovascularevents among patients with type 1 diabetes.
Methods
Detailed descriptions of the methods of the DCCT and EDIC follow-upstudy have been published previously.3,4,11,12 The DCCT, a randomized,controlled clinical trial conducted between 1983 and 1993, wasdesigned to compare the effects of an intensive diabetes treatmentregimen with those of conventional therapy.
Study Population
Of the 1441 patients with type 1 diabetes who were 13 to 40years old at the time of randomization, 1422 completed the DCCT;the mean follow-up was 6.5 years. At baseline, eligibility criteriaexcluded patients with a history of cardiovascular disease orwith hypertension (defined by a blood pressure of 140/90 mmHg or more) or hypercholesterolemia (defined by a serum cholesterollevel obtained after an overnight fast that was at least 3 SDabove age- and sex-specific means).11 Of the surviving cohort,1394 — representing 97 percent of the original cohort— agreed to join the long-term EDIC follow-up study in1994. The current report includes follow-up data obtained throughFebruary 1, 2005, at which point 93 percent of the originalcohort (96 percent of 1397 surviving participants) remainedin the study. The DCCT/EDIC study was approved by the institutionalreview boards of all participating centers, and all participantsprovided written informed consent.
Study Procedures
During the DCCT, participants were examined annually. Glycosylatedhemoglobin values were measured quarterly,13 and fasting lipidlevels, serum creatinine values, and other risk factors forcardiovascular disease were measured annually in a central laboratory.11Microalbuminuria and albuminuria were defined by urinary albuminexcretion of at least 40 mg in a 24-hour period and of at least300 mg in a 24-hour period, respectively.11 Renal disease wasdefined by the development of a serum creatinine level of atleast 2 mg per deciliter (177 µmol per liter) or the needfor dialysis or kidney transplantation. Electrocardiograms wereobtained and examined annually by readers who were unaware ofpatients' treatment assignments. During the EDIC follow-up study,the methods used in the DCCT were continued, but glycosylatedhemoglobin was measured annually and fasting lipid levels andrenal function were measured in alternate years.12
Treatment
Intensive therapy consisted of three or more daily injectionsof insulin or treatment with an external insulin pump, withdose adjustments based on at least four self-monitored glucosemeasurements per day. Daily glucose goals were 70 to 120 mgper deciliter (3.9 to 6.7 mmol per liter) before meals and peaklevels of less than 180 mg per deciliter (10.0 mmol per liter)after meals. The goal for glycosylated hemoglobin was less than6.05 percent — 2 SD above the mean value for persons withoutdiabetes. Conventional therapy had no glucose goals beyond thoseneeded to prevent symptoms of hyperglycemia and hypoglycemiaand consisted of one or two daily injections of insulin. Theabsolute difference between groups in the mean glycosylatedhemoglobin value at the end of the mean 6.5 years of the DCCTwas approximately 2 percentage points (7.4 percent in the intensive-treatmentgroup vs. 9.1 percent in the conventional-treatment group, P<0.01).At the end of the DCCT, the conventional-treatment group wasoffered intensive treatment and all participants returned totheir own health care providers for diabetes care. Subsequently,differences in treatment dissipated, with only a trivial, nonsignificantdifference between groups in the fraction of patients usingthree or more daily injections of insulin or an insulin pump(Table 1). Differences in the mean (±SD) glycosylatedhemoglobin value also narrowed in the intensive-treatment andconventional-treatment groups over the entire 11 years of theEDIC follow-up study (8.0±1.2 percent and 8.2±1.2percent, respectively; P=0.03).
Table 1. Clinical Characteristics of the DCCT/EDIC Cohort.
Outcomes
The primary outcome was the time to the first of any of thefollowing cardiovascular events: nonfatal myocardial infarctionor stroke; death judged to be due to cardiovascular disease;subclinical myocardial infarction; angina, confirmed by ischemicchanges on exercise tolerance testing or by clinically significantobstruction on coronary angiography; or the need for revascularizationwith angioplasty or coronary-artery bypass.14 Subclinical ("silent")myocardial infarctions were identified on the annual electrocardiograms.15
Medical records describing cardiovascular events, includingelectrocardiographic findings and cardiac enzyme levels, weresubmitted for adjudication to a committee whose three memberswere unaware of patients' treatment assignments. Only cardiovascularevents that were considered definite were counted.16
Statistical Analysis
The DCCT/EDIC Study Research Group specified in 1996 that noanalyses comparing the cardiovascular events between groupswould be performed until 50 patients in the original conventional-treatmentgroup had had a cardiovascular event, providing the study witha statistical power of 85 percent to detect a 50 percent reductionin the risk of cardiovascular events between groups. No interimanalyses were performed until that milestone was reached atthe beginning of 2005. This article is based on all events thathad occurred as of February 1, 2005. Analyses were conductedaccording to the intention-to-treat principle on the basis ofthe original DCCT treatment assignment. Results that were nominallysignificant (two-sided P<0.05) are cited.
Clinical characteristics were compared with the use of the Wilcoxonrank-sum test for quantitative variables and the chi-squaretest for categorical variables.17 The cumulative incidence ofa cardiovascular event (the first of any) within groups wasestimated according to the Kaplan–Meier method, the differencebetween groups was evaluated by means of the log-rank test,and the hazard ratio comparing intensive with conventional treatmentand 95 percent confidence intervals were estimated by meansof a Cox proportional-hazards model. The corresponding riskreduction was calculated as 100x(1–the hazard ratio).Event rates, including multiple events in the same patient,are presented as the number per 100 patient-years, and the differencewas evaluated, with allowance for repeated events and overdispersion.18Proportional-hazards models were used to assess the effectsof time-dependent covariates (mean glycosylated hemoglobin valueupdated to the time of the cardiovascular event during the DCCTor, if no event occurred during the DCCT, to the end of theDCCT; or the development of renal disease, microalbuminuria,or albuminuria) and the effect of the treatment group, afteradjustment for such covariates.19 The effect of the glycosylatedhemoglobin value during the EDIC trial was not assessed in theseanalyses.
The DCCT and EDIC studies were designed entirely by the DCCT/EDICStudy Research Group, which collected the data. The writingcommittee prepared the article and vouches for its completenessand accuracy.
Results
The major characteristics relevant to cardiovascular diseaseare described at baseline, at the end of the DCCT, and at year11 of the EDIC study (Table 1). At baseline, no patients inthe DCCT had hypertension or hypercholesterolemia, on the basisof the standards at the time, and only 5 percent had microalbuminuria(urinary albumin excretion of at least 40 mg per 24 hours).There were no significant differences between the intensive-treatmentand conventional-treatment groups in any risk factors for cardiovasculardisease at baseline, except for a minimally higher systolicblood pressure in the conventional-treatment group. At the endof the DCCT, the two groups had diverged with regard to theprevalence of several established and putative risk factorsfor cardiovascular disease. Microalbuminuria and albuminuriawere more prevalent (13 percent vs. 7 percent, P<0.01, and3 percent vs. 1 percent, P<0.05, respectively) in the conventional-treatmentgroup than in the intensive-treatment group, and the glycosylatedhemoglobin value was higher (9.1±1.5 percent vs. 7.4±1.1percent, P<0.01) in the conventional-treatment group. Byyear 11 of the EDIC study, the prevalences of microalbuminuriaand albuminuria remained greater in the former conventional-treatmentgroup and the prevalence of a serum creatinine value of at least2 mg per deciliter was also significantly greater in this group(2 percent vs. 0 percent, P<0.05). There were only trivialor nonsignificant differences between the groups in the prevalenceof other conventional risk factors for cardiovascular diseaseat the end of the DCCT and at year 11 of the EDIC study; theabsolute difference in the glycosylated hemoglobin value betweengroups was only 0.1 percent at year 11 of the EDIC study (P=0.38)(Table 1).
A total of 144 cardiovascular events occurred in 83 patientsduring the mean 17 years of follow-up, 46 among 31 patientsoriginally assigned to intensive treatment and 98 among 52 patientsoriginally assigned to conventional treatment (Table 2). Therespective event rates were 0.38 and 0.80 per 100 patient-years(P=0.007). Although the rates of individual clinical eventsthat made up the main outcome were not significantly differentbetween groups, they were consistently lower, usually by atleast 50 percent, in the intensive-treatment group than in theconventional-treatment group.
Table 2. Cardiovascular Events in Each Original Treatment Group of the DCCT.
A life-table analysis of the cumulative incidence of a firstcardiovascular event showed that intensive treatment was associatedwith a 42 percent reduction in risk, as compared with conventionaltreatment (95 percent confidence interval, 9 to 63 percent;P=0.02) (Figure 1A). The risk of the first occurrence of nonfatalmyocardial infarction, stroke, or death from cardiovasculardisease was reduced 57 percent with intensive treatment, ascompared with conventional treatment (95 percent confidenceinterval, 12 to 79 percent; P=0.02) (Figure 1B).
Figure 1. Cumulative Incidence of the First of Any of the Predefined Cardiovascular Disease Outcomes (Panel A) and of the First Occurrence of Nonfatal Myocardial Infarction, Stroke, or Death from Cardiovascular Disease (Panel B).
As compared with conventional treatment, intensive treatment reduced the risk of any predefined cardiovascular disease outcome by 42 percent (95 percent confidence interval, 9 to 63 percent; P=0.02) (Panel A) and reduced the risk of the first occurrence of nonfatal myocardial infarction, stroke, or death from cardiovascular disease by 57 percent (95 percent confidence interval, 12 to 79 percent; P=0.02) (Panel B).
Proportional-hazards models, adjusted for selected baselinefactors, were used to assess the association of time-dependentcovariates with the risk of cardiovascular disease in the combinedcohort and the effect of the DCCT treatment group before andafter adjustment for each factor (Table 3). The hazard ratiofor intensive as compared with conventional treatment, adjustedonly for baseline factors, was 0.53 (P=0.005). A history ofrenal disease did not have a significant effect on the riskof cardiovascular disease or on the treatment-group effect,perhaps because of the small number of such patients (35). Ahistory of microalbuminuria or of albuminuria was significantlyassociated with an increase in the risk of cardiovascular diseaseby a factor of more than 2.5 and explained part of the treatment-groupeffect, as reflected by the increase in the hazard ratio andP value. The difference in cardiovascular disease outcomes betweengroups remained significant after adjustment for these factors.
Table 3. Proportional-Hazards Models of the Effect of Time-Dependent Covariates on the Risk of Cardiovascular Disease and of the Effect of the Treatment Group after Adjustment for the Time-Dependent Covariate.
An updated glycosylated hemoglobin value during the DCCT (meanglycosylated hemoglobin value updated to the time of the cardiovascularevent during the DCCT or, if no event occurred during the DCCT,to the end of the DCCT) that was 10 percent lower in one patientthan in another (e.g., 7.2 percent vs. 8.0 percent) was associatedwith a hazard ratio of 0.80, representing a 20 percent reductionin the risk of a cardiovascular event (95 percent confidenceinterval, 9 to 30 percent; P<0.001). The use of the updatedlog mean glycosylated hemoglobin value during the DCCT explaineda large part of the treatment-group effect on the risk of cardiovasculardisease, the treatment-group hazard ratio being closer to 1and no longer significant (P=0.61) after adjustment. There wereno significant differences between groups in the use of medicationsknown to affect the risk of cardiovascular disease, except forthe use of beta-blockers, which was more common in the conventional-treatmentgroup than in the intensive-treatment group (7 percent vs. 3percent, P<0.05) at year 11 of the EDIC study (Table 1).
We determined which baseline characteristics of the entire cohortin the DCCT were associated with the occurrence of the cardiovasculardisease outcome independent of treatment assignment (Table 4).At baseline, older age (31 vs. 27 years), a longer durationof diabetes (7 vs. 6 years), the presence of retinopathy, currentsmoking, a higher body-mass index (24.0 vs. 23.3), higher totaland low-density lipoprotein cholesterol levels (194 vs. 175mg per deciliter [5.0 vs. 4.5 mmol per liter] and 127 vs. 109mg per deciliter [3.3 vs. 2.8 mmol per liter], respectively),higher glycosylated hemoglobin levels (9.5 percent vs. 9.0 percent),and a higher albumin excretion rate (19.3 vs. 15.7 mg per 24hours), and assignment to conventional treatment were all associatedwith the development of cardiovascular disease.
Table 4. Clinical Characteristics of EDIC Participants at Baseline in the DCCT According to the Presence or Absence of Cardiovascular Disease over the Course of the DCCT/EDIC Study.
Discussion
Controlled clinical trials involving patients with type 1 diabetesand those with type 2 diabetes have conclusively demonstratedthat intensive diabetes therapy aimed at lowering glycemic levelsreduces the risk of diabetic retinopathy, nephropathy, and neuropathy.3,20In addition, the DCCT/EDIC study demonstrated that a periodof approximately 6.5 years of intensive diabetes therapy hada long-term, sustained effect on the subsequent risk of microvascularcomplications.4 The pathophysiological mechanisms responsiblefor the improvement in outcomes and for the prolonged effectsof early intervention remain unclear; we have referred to thelatter phenomenon as "metabolic memory." It is in this contextthat we evaluated the effect of intensive diabetes therapy onthe long-term risk of cardiovascular disease.
The primary outcome was defined as a cardiovascular event thatincluded clinical findings or the need for revascularization.As compared with conventional therapy, intensive diabetes therapyreduced the risk of a cardiovascular event by 42 percent andreduced the risk of severe clinical events, including nonfatalmyocardial infarction, stroke, or death from cardiovasculardisease, by 57 percent. The risk of each of the individual cardiovascularevents was reduced to a similar degree. These findings extendour previous observations that intensive as compared with conventionaltherapy reduces the progression of atherosclerosis, measuredby carotid intima–media thickness, and the prevalenceof coronary-artery calcification.21,22
There are several potential explanations for the effectivenessof a period of intensive diabetes management on the long-termrisk of cardiovascular disease outcomes. First, the same glycemicmechanisms that reduce the incidence of microvascular diseasemay also apply to the development of atherosclerosis and resultingcardiovascular disease. Patients who had a cardiovascular eventwere more likely to have had retinopathy and had higher albuminexcretion rates at baseline. Epidemiologic evidence has shownthat any elevation in glycemia, even within the subdiabeticrange, increases the risk of cardiovascular disease.23 Thus,a reduction in the glycosylated hemoglobin value might be expectedto have beneficial effects on cardiovascular disease. The long-termeffect of hyperglycemia on the risk of microvascular complicationsmay be mediated by the generation of advanced glycation endproducts, which have been implicated in cardiovascular disease.24,25,26
Alternatively, the beneficial effect of intensive therapy onthe risk of cardiovascular disease may be a result of the reductionin the incidence of microvascular disease. Both renal diseaseand autonomic neuropathy have been proposed as risk factorsfor cardiovascular disease.27,28,29 To the extent that intensivetherapy reduces these risk factors,3,30 cardiovascular diseasemay also be reduced.
Microalbuminuria and albuminuria were each strongly associatedwith an increased risk of cardiovascular disease, and each explainedsome, but not all, of the DCCT treatment-group effect. The treatment-groupeffect remained significant after adjustment for these factors,suggesting that other effects of intensive therapy are at work.Adjusting for the updated mean glycosylated hemoglobin valueduring the DCCT explained the majority of the effect of intensiveas compared with conventional therapy on the risk of cardiovasculardisease. The results demonstrate that differences in glycosylatedhemoglobin values during the DCCT accounted for much of thecardiovascular benefit accompanying intensive therapy, mediatedin part by the reduction in the incidence of microalbuminuriaor albuminuria.
We believe that the DCCT/EDIC study is unique in its long-termobjective documentation of glycemic control, established andputative risk factors for cardiovascular disease, and the statusof microvascular and cardiovascular complications. The virtuallycomplete follow-up for more than two decades of the DCCT/EDICcohort, whose members at baseline had no or minimal microvasculardisease, no hypertension or hypercholesterolemia (by the standardsat the time), and no clinical evidence of cardiovascular diseaseat baseline, facilitated the study of incident cardiovasculardisease. However, several caveats apply to our data. First,the total number of events remains relatively low, precludingdefinitive assessment of treatment effects on the risks of thedifferent types of cardiovascular events. Second, some of thecardiovascular events, such as the need for revascularization,are dependent on clinicians' judgment and are subject to applicationbias. Third, the fraction of silent myocardial infarctions wasrelatively high as compared with that in other studies.9 Finally,the interventions were unmasked during the DCCT and EDIC study,thus possibly introducing bias in the ascertainment of cardiovascularevents or in the application of therapies that may have affectedthe risk of cardiovascular disease.
Although we cannot entirely discount these sources of potentialbias, the uniform collection of historic data, the clinicalseverity of the cardiovascular outcomes, the masked adjudicationof events, and the treatment of the DCCT/EDIC participants predominantlyby non-DCCT clinicians for most of their follow-up substantiallydiminish the risk of bias. Although the relatively large fractionof silent myocardial infarctions is noteworthy, other studieshave demonstrated that their outcome may be as severe as thatof symptomatic infarctions.31 In addition, the difference betweenthe treatment groups in the frequency of silent infarctions,detected on electrocardiograms obtained annually by graderswho were unaware of patients' study assignments, paralleledthe other outcomes. The only difference in medications betweengroups that may have confounded the outcome was the more commonuse of beta-blockers in the conventional-treatment group. Thiswould have decreased the relative benefits of intensive therapyon the risk of cardiovascular disease.
The salutary effect of a mean of 6.5 years of intensive therapyon the risk of cardiovascular events is evidence that intensivediabetes management reduces the incidence of cardiovasculardisease. This benefit reinforces the original DCCT message thatintensive therapy should be implemented as early as possiblein people with type 1 diabetes. The relative reduction in therisk of nonfatal myocardial infarctions, stroke, and death fromcardiovascular disease, of 57 percent — the most clinicallycompelling outcome — exceeds the reductions in risk achievedwith other proven interventions, such as medications that lowercholesterol and blood pressure. The large reduction in the riskof cardiovascular events will further improve the projectedlong-term health and economic benefits of intensive therapyfor diabetes.32
Supported by contracts with the Division of Diabetes, Endocrinologyand Metabolic Disease of the National Institute of Diabetesand Digestive and Kidney Diseases and by the General ClinicalResearch Center Program, National Center for Research Resources.No other potential conflict of interest relevant to this articlewas reported.
* Persons and institutions participating in the DCCT/EDIC StudyResearch Group are listed in the Appendix.
Source Information
The Writing Committee — David M. Nathan, M.D. (chair), Patricia A. Cleary, M.S., Jye-Yu C. Backlund, M.S., Saul M. Genuth, M.D., John M. Lachin, D.Sc., Trevor J. Orchard, M.D., Philip Raskin, M.D., and Bernard Zinman, M.D. — vouches for the accuracy and integrity of the data.
Address reprint requests to the DCCT/EDIC Research Group at Box NDIC/DCCT, Bethesda, MD 20892, or at dnathan{at}partners.org.
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Appendix
The following persons and institutions participated in the DCCT/EDICStudy Research Group: Study Chairs — S. Genuth, D.M. Nathan;Albert Einstein College of Medicine — S. Engel, J.B. Friday,H. Martinez (past), H. Shamoon, H. Engel; Case Western ReserveUniversity — W. Dahms, L. Mayer, S. Pendegras, H. Zegarra,D. Miller, L. Singerman, S. Smith-Brewer, S. Genuth (past);Cornell University Medical Center — D. Brillion, M. Lackaye,M. Heinemann, V. Reppuci, T. Lee; Henry Ford Health System —F. Whitehouse, D. Kruger, A. Galpern, J.D. Carey; InternationalDiabetes Center — R. Bergenstal, M. Johnson, D. Kendall,M. Spencer, D. Noller, K. Morgan, D. Etzwiler (deceased); JoslinDiabetes Center — A. Jacobson, E. Golden, G. Sharuk, PaulArrigg, R. Baeser, O. Ganda, J. Rosenzweig, H. Wolpert, P. Economides,O. Handy, L. Rand (past); Massachusetts General Hospital —D.M. Nathan, M. Larkin, S. Fritz (past), J. Godine, C. McKitrick,P. Lou; Mayo Foundation — F.J. Service, G. Ziegler, J.Pach, J. Lindsey; Medical University of South Carolina —J. Colwell, D. Wood, R. Mayfield, K. Hermayer, M. Szpiech, T.Lyons, J. Parker, A. Farr, S. Elsing, T. Thompson, J. Selby,M. Bracey; Northwestern University — M. Molitch, B. Schaefer,L. Jampol, D. Weinberg, A. Lyon, Z. Strugula, J. Shankle, P.Astlesford; University of California, San Diego — O. Kolterman,G. Lorenzi, M. Goldbaum; University of Iowa — W. Sivitz,M. Bayless, R. Zeither (past), T. Weingeist, E. Stone, H. CulverBoidt, K. Gehres, S. Russell; University of Maryland Schoolof Medicine — M. Hebdon, D. Counts, S. Johnsonbaugh, A.Kowarski (past), D. Ostrowski (past), T. Donner, S. Steidl,B. Jones; University of Michigan — W. Herman, D. Greene(past), C. Martin, M.J. Stevens, A.K. Vine, S. Elner; Universityof Minnesota — J. Bantle, B. Rogness, T. Olsen, E. Steuer;University of Missouri — D. Hainsworth, D. Goldstein (past),S. Hitt, J. Giangiacomo; University of New Mexico — D.Schade, M. Burge, J. Canady, M. Schluter, A. Das, D. Hornbeck(past); University of Pennsylvania — S. Schwartz, P.A.Bourne, B.J. Maschak-Carey (past), L. Baker (deceased), S. Braunstein,A. Brucker; University of Pittsburgh — T. Orchard, N.Silvers, T. Songer, B. Doft, S. Olson, R.L. Bergren, L. Lobes,M. Fineman, A. Drash (past); University of South Florida —J. Malone, E.A. Tanaka, J. Vaccaro-Kish (past), C. Berger, R.Gstalder, P.R. Pavan, A. Morrison; University of Tennessee —S. Dagogo-Jack, C. Wigley, S. Schussler (past), A. Kitabchi,H. Lambeth (past), M.B. Murphy, S. Moser, D. Meyer, A. Iannacone,M. Bryer-Ash (past), E. Chaum; University of Texas SouthwesternUniversity Medical Center — P. Raskin, S. Strowig, A.Edwards, J. Alappatt (past), C. Wilson (past), S. Park (past),Y. He; University of Toronto — B. Zinman, A. Barnie, S.MacLean, R. Devenyi, M. Mandelcorn, M. Brent; University ofWashington — J. Palmer, S. Catton, J. Kinyoun, L. VanOttingham (past), J. Ginsberg (past); University of WesternOntario — J. Dupre, J. Harth, C. Canny (past), D. Nicolle;Vanderbilt University — M. May, J. Lipps, R. Lorenz (past),L. Survant, S. Feman (past), K. Tawansy, A. Agarwal, T. Adkins;Washington University, St. Louis — N. White, L. Levandoski,J. Santiago (deceased), I. Boniuk, G. Grand, M. Thomas, D. Burgess,D. Joseph, K. Blinder, G. Shah; Yale University School of Medicine— W. Tamborlane, P. Gatcomb, K. Stoessel, K. Taylor; ClinicalCoordinating Center (Case Western Reserve University) —B. Dahms, R. Trail, J. Quin; Data-Coordinating Center (GeorgeWashington University, Biostatistics Center) — J. Lachin,P. Cleary, D. Kenny (past), J. Backlund, W. Sun, B. Rutledge,B. Waberski, K. Klump, K. Chan, L. Diminick, B. Petty (past),A. Determan (past), M. Hawkins; National Institute of Diabetesand Digestive and Kidney Disease Program Office — C. Cowie,J. Fradkin, C. Siebert (past), R. Eastman (past); Central FundusPhotograph Reading Center (University of Wisconsin) —M. Davis, R. Danis, L. Hubbard, P. Geithman, L. Kastorff, M.Neider, D. Badal, B. Esser, K. Miner, H. Wabers, K. Glander,J. Joyce, N. Robinson, C. Hurtenbach, C. Hannon; Central BiochemistryLaboratory (University of Minnesota) — M. Steffes, J.Bucksa, B. Chavers; Central Carotid Ultrasound Unit (New EnglandMedical Center) — D. O'Leary, L. Funk, J. Polak; CentralElectrocardiographic Reading Unit (University of Minnesota)— R. Crow, C. O'Donnell (past), B. Gloeb, S. Thomas; ComputedTomography Reading Center (Harbor UCLA Research and EducationInstitute) — R. Detrano, N. Wong, M. Fox, L. Kim, R. Oudiz;External Advisory Committee — G. Weir (chair), C. Clark,R. D'Agostino, M. Espeland, B. Klein, T. Manolio, L. Rand, D.Singer, M. Stern; Molecular Risk Factors Program Project (MedicalUniversity of South Carolina) — M. Lopes-Virella, W.T.Garvey, T.J. Lyons, A. Jenkins, R. Klein, G. Virella, A.A. Jaffa,D. Zheng, D. Lackland, D. McGee, R.K. Mayfield, M. Brabham;Genetic Studies Group (Hospital for Sick Children) — A.Boright, A. Paterson, S. Scherer, B. Zinman; Lipoprotein Distribution/ObesityGroup (University of Washington) — J. Brunzell, J. Hokanson,S. Marcovina, J. Purnell, S. Sibley, S. Deeb, K. Edwards; Editor,EDIC Publications — D.M. Nathan.
Chisalita, S I, Johansson, G S, Liefvendahl, E, Back, K, Arnqvist, H J
(2009). Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF2. J Mol Endocrinol
43: 231-239
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McGeechan, K., Liew, G., Macaskill, P., Irwig, L., Klein, R., Klein, B. E. K., Wang, J. J., Mitchell, P., Vingerling, J. R., de Jong, P. T. V. M., Witteman, J. C. M., Breteler, M. M. B., Shaw, J., Zimmet, P., Wong, T. Y.
(2009). Prediction of Incident Stroke Events Based on Retinal Vessel Caliber: A Systematic Review and Individual-Participant Meta-Analysis. Am J Epidemiol
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Ito, H., Takeuchi, Y., Ishida, H., Antoku, S., Abe, M., Mifune, M., Togane, M.
(2009). High frequencies of diabetic micro- and macroangiopathies in patients with type 2 diabetes mellitus with decreased estimated glomerular filtration rate and normoalbuminuria. Nephrol Dial Transplant
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Bertoni, A. G., Kitzman, D. W.
(2009). Coronary Artery Calcium: A Clue to the Enigma of Tight Glycemic Control and Cardiovascular Disease?. Diabetes
58: 2448-2449
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Waden, J., Forsblom, C., Thorn, L. M., Gordin, D., Saraheimo, M., Groop, P.-H., on behalf of the Finnish Diabetic Nephropathy Stud,
(2009). A1C Variability Predicts Incident Cardiovascular Events, Microalbuminuria, and Overt Diabetic Nephropathy in Patients With Type 1 Diabetes. Diabetes
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Raz, I.
(2009). Introduction to the Second World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy): Dilemmas in clinical practice. Diabetes Care
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(2009). Changing the Treatment Paradigm for Type 2 Diabetes. Diabetes Care
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Gallwitz, B.
(2009). Implications of Postprandial Glucose and Weight Control in People With Type 2 Diabetes: Understanding and implementing the International Diabetes Federation guidelines. Diabetes Care
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(2009). Is Hyperglycemia a Causal Factor in Cardiovascular Disease?: Does proving this relationship really matter? Yes. Diabetes Care
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(2009). Glucose Control and Cardiovascular Disease: Is it important? No. Diabetes Care
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(2009). Shifting the Disease Management Paradigm From Glucose: What are the pros?. Diabetes Care
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Conway, B., Costacou, T., Orchard, T.
(2009). Is glycaemia or insulin dose the stronger risk factor for coronary artery disease in type 1 diabetes?. Diabetes and Vascular Disease Research
6: 223-230
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Tanaka, J., Qiang, L., Banks, A. S., Welch, C. L., Matsumoto, M., Kitamura, T., Ido-Kitamura, Y., DePinho, R. A., Accili, D.
(2009). Foxo1 Links Hyperglycemia to LDL Oxidation and Endothelial Nitric Oxide Synthase Dysfunction in Vascular Endothelial Cells. Diabetes
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Redberg, R. F., Benjamin, E. J., Bittner, V., Braun, L. T., Goff, D. C. Jr, Havas, S., Labarthe, D. R., Limacher, M. C., Lloyd-Jones, D. M., Mora, S., Pearson, T. A., Radford, M. J., Smetana, G. W., Spertus, J. A., Swegler, E. W.
(2009). ACCF/AHA 2009 performance measures for primary prevention of cardiovascular disease in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Performance Measures (Writing Committee to Develop Performance Measures for Primary Prevention of Cardiovascular Disease) developed in collaboration with the American Academy of Family Physicians; American Association of Cardiovascular and Pulmonary Rehabilitation; and Preventive Cardiovascular Nurses Association Endorsed by the American College of Preventive Medicine, American College of Sports Medicine, and Society for Women's Health Research.. J Am Coll Cardiol
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WRITING COMMITTEE MEMBERS, , Redberg, R. F., Benjamin, E. J., Bittner, V., Braun, L. T., Goff, D. C. Jr, Havas, S., Labarthe, D. R., Limacher, M. C., Lloyd-Jones, D. M., Mora, S., Pearson, T. A., Radford, M. J., Smetana, G. W., Spertus, J. A., Swegler, E. W.
(2009). ACCF/AHA 2009 Performance Measures for Primary Prevention of Cardiovascular Disease in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Performance Measures (Writing Committee to Develop Performance Measures for Primary Prevention of Cardiovascular Disease): Developed in Collaboration With the American Academy of Family Physicians; American Association of Cardiovascular and Pulmonary Rehabilitation; and Preventive Cardiovascular Nurses Association: Endorsed by the American College of Preventive Medicine, American College of Sports Medicine, and Society for Women's Health Research. Circulation
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(2009). Controlling the complications of diabetes: It's about the sugar. CMAJ
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(2009). La maitrise des complications du diabete: une question de sucre. CMAJ
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McGeechan, K., Liew, G., Macaskill, P., Irwig, L., Klein, R., Klein, B. E.K., Wang, J. J., Mitchell, P., Vingerling, J. R., deJong, P. T.V.M., Witteman, J. C.M., Breteler, M. M.B., Shaw, J., Zimmet, P., Wong, T. Y.
(2009). Meta-analysis: Retinal Vessel Caliber and Risk for Coronary Heart Disease. ANN INTERN MED
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Chillaron, J. J., Goday, A., Flores-Le-Roux, J. A., Benaiges, D., Carrera, M. J., Puig, J., Cano-Perez, J. F., Pedro-Botet, J.
(2009). Estimated Glucose Disposal Rate in Assessment of the Metabolic Syndrome and Microvascular Complications in Patients with Type 1 Diabetes. J. Clin. Endocrinol. Metab.
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Ceriello, A., Esposito, K., Ihnat, M., Thorpe, J., Giugliano, D.
(2009). Long-Term Glycemic Control Influences the Long-Lasting Effect of Hyperglycemia on Endothelial Function in Type 1 Diabetes. J. Clin. Endocrinol. Metab.
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Weinrauch, L. A., Lewis, E. F.
(2009). Aiming for the best control of glycemia in patients with heart failure and type 2 diabetes the "sweet spot".. J Am Coll Cardiol
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Diabetes Control and Complications Trial/Epidemiol,
(2009). Modern-Day Clinical Course of Type 1 Diabetes Mellitus After 30 Years' Duration: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications and Pittsburgh Epidemiology of Diabetes Complications Experience (1983-2005). Arch Intern Med
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Narendran, P.
(2009). Cardiovascular benefit of intensive glucose control: approaching closure. British Journal of Diabetes & Vascular Disease
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Hemmingsen, B., Lund, S. S, Wetterslev, J., Vaag, A.
(2009). Oral hypoglycaemic agents, insulin resistance and cardiovascular disease in patients with type 2 diabetes. Eur J Endocrinol
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Kazempour-Ardebili, S., Lecamwasam, V. L., Dassanyake, T., Frankel, A. H., Tam, F. W.K., Dornhorst, A., Frost, G., Turner, J. J.O.
(2009). Assessing Glycemic Control in Maintenance Hemodialysis Patients With Type 2 Diabetes. Diabetes Care
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Groop, P.-H., Thomas, M. C., Moran, J. L., Waden, J., Thorn, L. M., Makinen, V.-P., Rosengard-Barlund, M., Saraheimo, M., Hietala, K., Heikkila, O., Forsblom, C., on behalf of the FinnDiane Study Group,
(2009). The Presence and Severity of Chronic Kidney Disease Predicts All-Cause Mortality in Type 1 Diabetes. Diabetes
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Hage, F. G., Venkataraman, R., Zoghbi, G. J., Perry, G. J., DeMattos, A. M., Iskandrian, A. E.
(2009). The scope of coronary heart disease in patients with chronic kidney disease.. J Am Coll Cardiol
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Chaturvedi, N.
(2009). Metabolic Memory in the Autonomic Neuropathy of Diabetes: Implications for Pathogenesis and Patient Care. Circulation
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Pop-Busui, R., Low, P. A., Waberski, B. H., Martin, C. L., Albers, J. W., Feldman, E. L., Sommer, C., Cleary, P. A., Lachin, J. M., Herman, W. H., for the DCCT/EDIC Research Group,
(2009). Effects of Prior Intensive Insulin Therapy on Cardiac Autonomic Nervous System Function in Type 1 Diabetes Mellitus: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC). Circulation
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Clement, M., Bhattacharyya, O., Conway, J. R.
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Clement, M., Bhattacharyya, O., Conway, J. R.
(2009). Vaut-il vraiment la peine d'exercer un strict controle glycemique pour le diabete de type 2?: OUI. cfp
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Dale, A. C., Midthjell, K., Nilsen, T. I., Wiseth, R., Vatten, L. J.
(2009). Glycaemic control in newly diagnosed diabetes patients and mortality from ischaemic heart disease: 20-year follow-up of the HUNT Study in Norway. Eur Heart J
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Bartnik, M., Cosentino, F.
(2009). Dysglycaemia, cardiovascular outcome and treatment. Is the jury still out?. Eur Heart J
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Davis, S. M., Donnan, G. A.
(2009). Antiplatelet Activity. Stroke
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Roy, M. S., Hallman, D. M., Fu, Y.-P., Machado, M., Hanis, C. L.
(2009). Assessment of 193 Candidate Genes for Retinopathy in African Americans With Type 1 Diabetes. Arch Ophthalmol
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Nansel, T. R., Iannotti, R. J., Simons-Morton, B. G., Plotnick, L. P., Clark, L. M., Zeitzoff, L.
(2009). Long-Term Maintenance of Treatment Outcomes: Diabetes Personal Trainer Intervention for Youth With Type 1 Diabetes. Diabetes Care
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Weiss, A. S., Smits, G., Wiseman, A. C.
(2009). Twelve-Month Pancreas Graft Function Significantly Influences Survival Following Simultaneous Pancreas-Kidney Transplantation. CJASN
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Brasacchio, D., Okabe, J., Tikellis, C., Balcerczyk, A., George, P., Baker, E. K., Calkin, A. C., Brownlee, M., Cooper, M. E., El-Osta, A.
(2009). Hyperglycemia Induces a Dynamic Cooperativity of Histone Methylase and Demethylase Enzymes Associated With Gene-Activating Epigenetic Marks That Coexist on the Lysine Tail. Diabetes
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Cheng, A. Y.Y., Leiter, L. A.
(2009). Cardiovascular risk and glycemic control. CMAJ
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Ko, G. T.C., So, W.-Y., Tong, P. C., Chan, W.-B., Yang, X., Ma, R. C., Kong, A. P., Ozaki, R., Yeung, C.-Y., Chow, C.-C., Chan, J. C.
(2009). Effect of interactions between C peptide levels and insulin treatment on clinical outcomes among patients with type 2 diabetes mellitus. CMAJ
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Kahn, S. E.
(2009). Glucose Control in Type 2 Diabetes: Still Worthwhile and Worth Pursuing. JAMA
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Nathan, D. M.
(2009). Progress in Diabetes Research--What's Next. JAMA
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(2009). U-500 Insulin: When More With Less Yields Success. Diabetes Spectr.
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Cheng, J. W. M., Bhatt, S. H., Goldman-Levine, J. D.
(2009). The Benefit and Risk of Antidiabetic Agents Used in Patients With Heart Disease. Journal of Pharmacy Practice
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(2009). Diabetes in the young: what are their long term health prospects?. Arch. Dis. Child.
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Chait, A., Bornfeldt, K. E.
(2009). Diabetes and atherosclerosis: is there a role for hyperglycemia?. J. Lipid Res.
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Campbell, I. W
(2009). Review: Durable glycaemia -- the promised land. British Journal of Diabetes & Vascular Disease
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(2009). Early and Aggressive Initiation of Insulin Therapy for Type 2 Diabetes: What Is the Evidence?. Clin. Diabetes
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Cryer, P. E., Axelrod, L., Grossman, A. B., Heller, S. R., Montori, V. M., Seaquist, E. R., Service, F. J.
(2009). Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab.
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Amiel, S. A., Cryer, P. E.
(2009). Attenuated Sympathoadrenal Responses, but Not Severe Hypoglycemia, During Aggressive Glycemic Therapy of Early Type 2 Diabetes. Diabetes
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Garg, S. K., Voelmle, M. K., Gottlieb, P.
(2009). Feasibility of 10-Day Use of a Continuous Glucose-Monitoring System in Adults With Type 1 Diabetes. Diabetes Care
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Engberding, N., San Martin, A., Martin-Garrido, A., Koga, M., Pounkova, L., Lyons, E., Lassegue, B., Griendling, K. K.
(2009). Insulin-Like Growth Factor-1 Receptor Expression Masks the Antiinflammatory and Glucose Uptake Capacity of Insulin in Vascular Smooth Muscle Cells. Arterioscler. Thromb. Vasc. Bio.
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Cameron, C. G. MSc, Bennett, H. A. BPharm PhD
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Ceriello, A., Ihnat, M. A., Thorpe, J. E.
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Panero, F., Novelli, G., Zucco, C., Fornengo, P., Perotto, M., Segre, O., Grassi, G., Cavallo-Perin, P., Bruno, G.
(2009). Fasting Plasma C-Peptide and Micro- and Macrovascular Complications in a Large Clinic-Based Cohort of Type 1 Diabetic Patients. Diabetes Care
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Skyler, J. S., Bergenstal, R., Bonow, R. O., Buse, J., Deedwania, P., Gale, E. A.M., Howard, B. V., Kirkman, M. S., Kosiborod, M., Reaven, P., Sherwin, R. S.
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Skyler, J. S., Bergenstal, R., Bonow, R. O., Buse, J., Deedwania, P., Gale, E. A.M., Howard, B. V., Kirkman, M. S., Kosiborod, M., Reaven, P., Sherwin, R. S.
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Duckworth, W., Abraira, C., Moritz, T., Reda, D., Emanuele, N., Reaven, P. D., Zieve, F. J., Marks, J., Davis, S. N., Hayward, R., Warren, S. R., Goldman, S., McCarren, M., Vitek, M. E., Henderson, W. G., Huang, G. D., the VADT Investigators,
(2009). Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. NEJM
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Nathan, D. M., Buse, J. B., Davidson, M. B., Ferrannini, E., Holman, R. R., Sherwin, R., Zinman, B.
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Nathan, D. M., Buse, J. B., Davidson, M. B., Ferrannini, E., Holman, R. R., Sherwin, R., Zinman, B.
(2009). Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care
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Skyler, J. S., Bergenstal, R., Bonow, R. O., Buse, J., Deedwania, P., Gale, E. A.M., Howard, B. V., Kirkman, M. S., Kosiborod, M., Reaven, P., Sherwin, R. S.
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(2009). Reversal of Type 2 Diabetes Mellitus and Improvements in Cardiovascular Risk Factors After Surgical Weight Loss in Adolescents. Pediatrics
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Laczy, B., Hill, B. G., Wang, K., Paterson, A. J., White, C. R., Xing, D., Chen, Y.-F., Darley-Usmar, V., Oparil, S., Chatham, J. C.
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(2008). Prolonged Effect of Intensive Therapy on the Risk of Retinopathy Complications in Patients With Type 1 Diabetes Mellitus: 10 Years After the Diabetes Control and Complications Trial. Arch Ophthalmol
126: 1707-1715
[Abstract][Full Text]
Yang, X., Ko, G. T.C., So, W. Y., Ma, R. C.W., Kong, A. P.S., Lam, C. W.K., Ho, C. S., Chow, C.-C., Tong, P. C.Y., Chan, J. C.N.
(2008). Additive Interaction of Hyperglycemia and Albuminuria on Risk of Ischemic Stroke in Type 2 Diabetes: Hong Kong Diabetes Registry. Diabetes Care
31: 2294-2300
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Levin, A. MD, Hemmelgarn, B. MD PhD, Culleton, B. MD MSc, Tobe, S. MD, McFarlane, P. MD PhD, Ruzicka, M. MD PhD, Burns, K. MD, Manns, B. MD MSc, White, C. MD, Madore, F. MD MSc, Moist, L. MD MSc, Klarenbach, S. MD MSc, Barrett, B. MD MSc, Foley, R. MD MSc, Jindal, K. MD, Senior, P. MBBS PhD, Pannu, N. MD MSc, Shurraw, S. MD, Akbari, A. MD, Cohn, A. MD, Reslerova, M. MD PhD, Deved, V. MD, Mendelssohn, D. MD, Nesrallah, G. MD, Kappel, J. MD, Tonelli, M. MD SM, for the Canadian Society of Nephrology,
(2008). Guidelines for the management of chronic kidney disease. CMAJ
179: 1154-1162
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Goodarzi, M. O., Psaty, B. M.
(2008). Glucose Lowering to Control Macrovascular Disease in Type 2 Diabetes: Treating the Wrong Surrogate End Point?. JAMA
300: 2051-2053
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Shani, M., Taylor, T. R., Vinker, S., Lustman, A., Erez, R., Elhayany, A., Lahad, A.
(2008). Characteristics of Diabetics with Poor Glycemic Control Who Achieve Good Control. J Am Board Fam Med
21: 490-496
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Kilpatrick, E. S., Rigby, A. S., Atkin, S. L.
(2008). A1C Variability and the Risk of Microvascular Complications in Type 1 Diabetes: Data from the Diabetes Control and Complications Trial. Diabetes Care
31: 2198-2202
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Giorda, C. B., Avogaro, A., Maggini, M., Lombardo, F., Mannucci, E., Turco, S., Alegiani, S. S., Raschetti, R., Velussi, M., Ferrannini, E., for the Diabetes and Informatics Study Group,
(2008). Recurrence of Cardiovascular Events in Patients With Type 2 Diabetes: Epidemiology and risk factors. Diabetes Care
31: 2154-2159
[Abstract][Full Text]
Dasu, M. R., Devaraj, S., Zhao, L., Hwang, D. H., Jialal, I.
(2008). High Glucose Induces Toll-Like Receptor Expression in Human Monocytes: Mechanism of Activation. Diabetes
57: 3090-3098
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Nathan, D. M.
(2008). Glycemic Management of Type 2 Diabetes: How Tight Is Right and How to Get There. Arch Intern Med
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Selvin, E., Bolen, S., Yeh, H.-C., Wiley, C., Wilson, L. M., Marinopoulos, S. S., Feldman, L., Vassy, J., Wilson, R., Bass, E. B., Brancati, F. L.
(2008). Cardiovascular Outcomes in Trials of Oral Diabetes Medications: A Systematic Review. Arch Intern Med
168: 2070-2080
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Majumdar, S., Barrett, E.
(2008). Newer Insulins in Search of a Niche. ANN INTERN MED
149: 586-588
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(2008). Tight control of blood glucose and cardiovascular disease. BMJ
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Chalmers, J., Cooper, M. E.
(2008). UKPDS and the Legacy Effect. NEJM
359: 1618-1620
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The Juvenile Diabetes Research Foundation Continuo,
(2008). Continuous Glucose Monitoring and Intensive Treatment of Type 1 Diabetes. NEJM
359: 1464-1476
[Abstract][Full Text]
0.05) after adjusting for these factors. 
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