Background During the United Kingdom Prospective Diabetes Study(UKPDS), patients with type 2 diabetes mellitus who receivedintensive glucose therapy had a lower risk of microvascularcomplications than did those receiving conventional dietarytherapy. We conducted post-trial monitoring to determine whetherthis improved glucose control persisted and whether such therapyhad a long-term effect on macrovascular outcomes.
Methods Of 5102 patients with newly diagnosed type 2 diabetes,4209 were randomly assigned to receive either conventional therapy(dietary restriction) or intensive therapy (either sulfonylureaor insulin or, in overweight patients, metformin) for glucosecontrol. In post-trial monitoring, 3277 patients were askedto attend annual UKPDS clinics for 5 years, but no attemptswere made to maintain their previously assigned therapies. Annualquestionnaires were used to follow patients who were unableto attend the clinics, and all patients in years 6 to 10 wereassessed through questionnaires. We examined seven prespecifiedaggregate clinical outcomes from the UKPDS on an intention-to-treatbasis, according to previous randomization categories.
Results Between-group differences in glycated hemoglobin levelswere lost after the first year. In the sulfonylurea–insulingroup, relative reductions in risk persisted at 10 years forany diabetes-related end point (9%, P=0.04) and microvasculardisease (24%, P=0.001), and risk reductions for myocardial infarction(15%, P=0.01) and death from any cause (13%, P=0.007) emergedover time, as more events occurred. In the metformin group,significant risk reductions persisted for any diabetes-relatedend point (21%, P=0.01), myocardial infarction (33%, P=0.005),and death from any cause (27%, P=0.002).
Conclusions Despite an early loss of glycemic differences, acontinued reduction in microvascular risk and emergent riskreductions for myocardial infarction and death from any causewere observed during 10 years of post-trial follow-up. A continuedbenefit after metformin therapy was evident among overweightpatients. (UKPDS 80; Current Controlled Trials number, ISRCTN75451837
[controlled-trials.com]
.)
The United Kingdom Prospective Diabetes Study (UKPDS), a randomized,prospective, multicenter trial, showed that intensive glucosetherapy in patients with newly diagnosed type 2 diabetes mellituswas associated with a reduced risk of clinically evident microvascularcomplications and a nonsignificant reduction of 16% in the relativerisk of myocardial infarction (P=0.052).1 In patients whosebody weight was more than 120% of their ideal weight2 and whoprimarily received metformin, reductions in the risk of myocardialinfarction of 39% (P=0.01) and of death from any cause of 36%(P=0.01) were observed. The results of the UKPDS, which werepublished in 1998, have appeared to be influential in subsequentdiabetes management.3,4
In patients with type 1 diabetes, the Diabetes Control and ComplicationsTrial/Epidemiology of Diabetes Interventions and Complications(DCCT/EDIC) study reported a postinterventional microvascularbenefit and the emergence of macrovascular risk reduction fromearlier improved glycemic control during an 8-year period.5The Steno-2 Study reported a similar outcome during a 5.5-yearperiod after earlier multifactorial risk reduction among patientswith type 2 diabetes.6 In both trials, enhanced risk reductionsoccurred despite the loss of within-trial differences in glucoselevels and, in the Steno-2 Study, diminished differences inblood pressure and lipid levels, suggesting the persistenceof effects of earlier improved metabolic management.
We report here the results of a 10-year, postinterventionalfollow-up of the UKPDS survivor cohort that examined whethera continued microvascular benefit from earlier improved glucosecontrol was evident and whether such therapy had a long-termeffect on macrovascular outcomes.
Methods
Patients
The recruitment of patients, study protocol, and methods forthe UKPDS have been reported previously.7,8 Approval was obtainedfrom the ethics committees at all 23 clinical centers, and thestudy conformed to the Declarations of Helsinki guidelines.Briefly, 5102 of 7616 patients who underwent screening wereenrolled from 1977 to 1991. All patients provided written informedconsent. Patients were between the ages of 25 and 65 years andhad a fasting plasma glucose level of more than 108 mg per deciliter(6.0 mmol per liter) on two occasions after their general practitionershad diagnosed type 2 diabetes. By self-report, 81% of the patientswere white, 10% Asian Indian, and 9% Afro-Caribbean. A totalof 2514 patients were excluded because of the following conditions:ketonuria, a serum creatinine level of more than 175 µmolper liter (2.0 mg per deciliter), myocardial infarction in theprevious year, current angina or heart failure, more than onemajor vascular event, retinopathy requiring laser treatment,malignant hypertension, uncorrected endocrine disorder, occupationsprecluding insulin therapy, severe concurrent illness limitinglife expectancy, inadequate understanding of the study protocol,or unwillingness to enter the study.
After a 3-month dietary run-in period, patients with a fastingplasma glucose level of more than 108 mg per deciliter but lessthan 270 mg per deciliter (15.0 mmol per liter) were randomlyassigned to receive conventional glucose control (diet) or intensiveglucose control (sulfonylurea or insulin or, if more than 120%of ideal body weight, metformin2). All patients were seen quarterlyin UKPDS clinics.7 The median follow-up for the sulfonylurea–insulinand metformin groups was 10.0 years1 and 10.7 years,9 respectively.
Post-Trial Monitoring
All surviving patients entered the post-trial monitoring programafter the intervention trial closed on September 30, 1997. A10-year follow-up was planned to coincide with a projected deathrate of 50%. In September 1998, when the UKPDS results werepublished,10,11 patients and clinicians were advised that itwas necessary to lower levels of blood glucose and blood pressureas much as possible. Patients returned to community or hospital-baseddiabetes care according to their clinical needs, with no attemptto maintain previously randomized therapies. They were seenannually for 5 years in UKPDS clinics, with continued standardizedcollection of outcome data; measurements of blood pressure,fasting plasma glucose, glycated hemoglobin, plasma creatinine,and the ratio of albumin to creatinine; and results on two questionnaires,the European Quality of Life–5 Dimensions (EQ-5D)12 anda questionnaire on the use of health resources.
Clinical examinations every 3 years were continued. Patientswho were unable to attend clinics were sent EQ-5D and health-resourcequestionnaires, and additional questionnaires were sent to theirgeneral practitioners to capture possible clinical outcomes.In years 6 to 10, these questionnaires were used to follow patientsremotely, since funding for clinic visits was not available.Final questionnaires were sent to all remaining patients afterthe cutoff for the censoring of post-trial data on September30, 2007.
Clinical Outcomes
The study administrator obtained full documentation for allputative outcomes from hospitals and general practitioners,whether reported at clinic visits or by means of questionnaires.The vital status for all patients who were still living in theUnited Kingdom was obtained from the Office of National Statistics.Members of the UKPDS end-point committee, who were unaware ofassignments to study groups, adjudicated outcomes exactly asthey had during the original trial. The seven prespecified UKPDSaggregate clinical outcomes7 were any diabetes-related end point(sudden death, death from hyperglycemia or hypoglycemia, fatalor nonfatal myocardial infarction, angina, heart failure, fatalor nonfatal stroke, renal failure, amputation, vitreous hemorrhage,retinal photocoagulation, blindness in one eye, or cataractextraction), diabetes-related death (sudden death or death frommyocardial infarction, stroke, peripheral vascular disease,renal disease, hyperglycemia, or hypoglycemia), death from anycause, myocardial infarction (sudden death or fatal or nonfatalmyocardial infarction), stroke (fatal or nonfatal stroke), peripheralvascular disease (amputation of at least one digit or deathfrom peripheral vascular disease), and microvascular disease(vitreous hemorrhage, retinal photocoagulation, or renal failure).
Statistical Analysis
We performed the analyses according to the intention-to-treatprinciple, with descriptive statistics presented as numbersand percentages or appropriate measures of central tendencyand dispersion. Continuous and categorical study variables werecompared between the conventional-therapy group and the intensive-therapygroups with the use of nonparametric tests. Kaplan–Meiertime-to-event analyses were used for aggregate clinical outcomes,with log-rank tests used for differences between previous study-groupassignments. Since recruitment was performed during a 14-yearperiod, patients could have been in the interventional trialfor 6 to 20 years. Since there was no common time from randomizationto the start of post-trial monitoring, we used serial hazard-ratioplots with confidence intervals (after checking that proportional-hazardsassumptions were not violated) to illustrate possible changesin post-trial relative risks, with P values calculated onlyat the end of follow-up. Absolute risk rates are expressed asthe number of events per 1000 person-years.
Post-trial monitoring was initiated by the investigators andwas sponsored for 5 years by the Medical Research Council andthen by the University of Oxford. The investigators designedand conducted the study, analyzed the data, and prepared themanuscript, independently of any funding bodies. The investigatorsvouch for the completeness and accuracy of the data.
Results
Patients
A total of 4209 patients were randomly assigned to receive eitherconventional therapy or intensive therapy (Figure 1). Of thesepatients, baseline characteristics for the 3277 patients whoentered post-trial monitoring are shown in Table 1. In the sulfonylurea–insulingroup, patients who had been assigned to receive intensive therapyhad lower levels of mean glycated hemoglobin and fasting plasmaglucose than those who received conventional therapy (P<0.001for both comparisons) but had a higher median weight (P=0.01)and mean body-mass index (P=0.005). More patients who had initiallybeen assigned to receive intensive therapy were receiving acombination of oral and insulin therapy (64%) than were thosewho had originally been assigned to receive conventional therapy(46%). No significant differences were observed for any variablesbetween patients for whom final-year data were available andthose for whom final-year data were not available, except thatpatients for whom such data were available were 2 years older(P=0.002) and were less likely to be white (P<0.001) (Table 1).
Of the 4209 patients who underwent randomization in the original United Kingdom Prospective Diabetes Study, 78% entered post-trial monitoring. Of the 1138 patients who were assigned to receive conventional therapy, 411 were overweight. These were compared with the 342 overweight patients who were assigned to receive intensive therapy with metformin. Vital status was not available for any of the patients who left the United Kingdom during follow-up. For patients for whom no final-year data were available, the analysis may not have captured all nonfatal events. Overall, 3.5% of patients were lost to follow-up.
Table 1. Baseline Characteristics of the Patients.
The majority of patients (92 to 97%) attended UKPDS clinicsin years 1 to 5. The median follow-up periods in the sulfonylurea–insulinand metformin groups were 16.8 years and 17.7 years, respectively— equivalent to 61,106 and 12,431 person-years, respectively,with 8.5 and 8.8 years of post-trial follow-up. Mortality overallwas 44.0%, and leading causes of death were cardiovascular disease(51.5%) and cancer (24.2%). Baseline differences in combinationsof glucose therapy disappeared by 5 years, at which time 5%of the patients were on diet alone, 46% were receiving oraltherapy, and 49% were receiving insulin (with or without oraltherapy). Baseline differences in mean glycated hemoglobin levelsbetween the intensive-therapy group and the conventional-therapygroup were lost by 1 year, with similar glycated hemoglobinimprovements thereafter in all groups (Figure 2A and 2B). Themean body weight did not differ at baseline or thereafter betweenthe two groups (Figure 2C and 2D). No significant differencesin lipid levels were seen at baseline (Table 1). Levels of bloodpressure and plasma creatinine and the ratio of albumin to creatininedid not differ significantly between the two groups at any time,except that plasma creatinine levels in the metformin groupwere 15% higher on average than those in the conventional-therapygroup (P<0.04) (Fig. 1 and 2 in the Supplementary Appendix,available with the full text of this article at www.nejm.org).
Figure 2. Mean Glycated Hemoglobin Levels and Body Weight.
Glycated hemoglobin levels for patients who were originally assigned to receive either sulfonylurea–insulin or conventional therapy (Panel A) or metformin or conventional therapy (Panel B) are shown. Panels C and D show the corresponding mean body weights in the two groups. Clinical data were not available in years 6 through 10, when questionnaires were used. The vertical bars represent 95% confidence intervals.
Clinical Outcomes
In the sulfonylurea–insulin group as compared with theconventional-therapy group, significant reductions in relativerisk that had been observed during the interventional trialfor any diabetes-related end point and microvascular diseasewere maintained. At 10 years, the risk reductions in the sulfonylurea–insulingroup were 9% for any diabetes-related end point (0.04) and24% for microvascular disease (P=0.001) (Table 2 and Figure 3and Figure 4). In addition, post-trial risk reductions emergedin the sulfonylurea–insulin group for diabetes-relateddeath (17%, P=0.01), myocardial infarction (15%, P=0.01), anddeath from any cause (13%, P=0.007). No significant risk reductionswere observed during or after the trial for stroke or peripheralvascular disease.
Figure 3. Hazard Ratios for Four Prespecified Aggregate Clinical Outcomes.
Hazard ratios for patients in the United Kingdom Prospective Diabetes Study who had any diabetes-related end point (Panels A and B), myocardial infarction (Panels C and D), or microvascular disease (Panels E and F) or who died from any cause (Panels G and H) are shown for the sulfonylurea–insulin group versus the conventional-therapy group and for the metformin group versus the conventional-therapy group. The overall values at the end of the study,1 in 1997, are shown (red squares), along with the annual values during the 10-year post-trial monitoring period (blue diamonds). Numbers of first events in an aggregate outcome that accumulated in each group are shown at 2-year intervals. The vertical bars represent 95% confidence intervals.
Figure 4. Kaplan–Meier Curves for Four Prespecified Aggregate Clinical Outcomes.
The proportions of patients in the United Kingdom Prospective Diabetes Study who had any diabetes-related end point (Panels A and B), myocardial infarction (Panels C and D), or microvascular disease (Panels E and F) or who died from any cause (Panels G and H) are shown for the sulfonylurea–insulin group versus the conventional-therapy group and for the metformin group versus the conventional-therapy group. Kaplan–Meier plots for cumulative incidence and log-rank P values are shown at 5-year intervals during a 25-year period from the start of the interventional trial.
Among patients in the metformin group, as compared with overweightpatients in the conventional-therapy group, significant reductionsin relative risk that were observed during the interventionaltrial for any diabetes-related outcome, diabetes-related death,myocardial infarction, and death from any cause were maintained.At 10 years, the risk reduction for any diabetes-related endpoint was 21% (P=0.01), for diabetes-related death 30% (P=0.01),for myocardial infarction 33% (P=0.005), and for death fromany cause 27% (P=0.002) (Table 2 and Figure 3 and Figure 4).No significant risk reductions were observed during or afterthe trial for microvascular disease, stroke, or peripheral vasculardisease.
Discussion
With more than 66,000 person-years of follow-up, this largepost-trial study showed that benefits of an intensive strategyto control blood glucose levels in patients with type 2 diabeteswere sustained for up to 10 years after the cessation of randomizedinterventions. Benefits persisted despite the early loss ofwithin-trial differences in glycated hemoglobin levels betweenthe intensive-therapy group and the conventional-therapy group— a so-called legacy effect. The trial showed the extendedeffects of improved glycemic control in patients with newlydiagnosed type 2 diabetes, some of whom were followed for upto 30 years. The trial also showed that there were differencesin outcomes between an intensive glucose-control strategy usingsulfonylurea or insulin and that using metformin in overweightpatients.
In the sulfonylurea–insulin group, the significant reductionof 25% in the risk of microvascular disease that was observedduring the interventional trial in the intensive-therapy group1was sustained throughout the post-trial period, despite therapid convergence of glycated hemoglobin levels in the two groupsand a similar use of glucose-lowering therapies, and the reductionin the risk of any diabetes-related end point was also sustained.Clinically relevant post-trial risk reductions emerged overtime for myocardial infarction (15%, P=0.01) and death fromany cause (13%, P=0.007), although differences during the interventionalphase of the trial were not significant.1
In the metformin group, which consisted of patients who wereoverweight, substantial risk reductions for myocardial infarction(39%, P=0.01) and death from any cause (36%, P=0.01) were observedin the intensive-therapy group during the original trial, eventhough the difference in glycated hemoglobin levels betweenthe metformin group and the conventional-therapy group9 wassmaller than the difference between the sulfonylurea–insulingroup and the conventional-therapy group.1 These risk reductionswere sustained throughout the post-trial period, despite similaritiesin glycated hemoglobin levels and in the use of glucose-loweringtherapy. During the interventional phase of the trial and thepost-trial period, microvascular risk reductions of 29% and26%, respectively, were similar to those achieved in the sulfonylurea–insulingroup, but neither difference was significant, probably becausethere were relatively few patients in this randomized comparison.
Although the UKPDS conclusively showed the benefit of improvedglycemic control in reducing the risk of microvascular disease,risk reductions for myocardial infarction and death from anycause were observed only with extended post-trial follow-up.Similarly, in the Action in Diabetes and Vascular Disease: Preteraxand Diamicron Modified Release Controlled Evaluation (ADVANCE)trial (ClinicalTrials.gov number, NCT00145925
[ClinicalTrials.gov]
),13 in which 11,140patients with type 2 diabetes were randomly assigned to receiveeither intensive glucose control or standard glucose control,patients in the intensive-control group had a mean glycatedhemoglobin level that was 0.8% lower than that in the standard-controlgroup. However, at the same time, they had a reduction in majormicrovascular events of 14% (95% confidence interval [CI], 3to 33) but a nonsignificant reduction in major macrovascularevents of only 6% (95% CI, –6 to 16) after a median of5 years of follow-up.
In the randomized Action to Control Cardiovascular Risk in Diabetes(ACCORD) trial (NCT00000620
[ClinicalTrials.gov]
),14 there was a nonsignificant reductionof 10% in the composite primary outcome of nonfatal myocardialinfarction, nonfatal stroke, and death from cardiovascular causesamong 10,251 patients with type 2 diabetes who were assignedeither to a group with a target glycated hemoglobin level ofless than 6.0% or to a group with a target level of 7.0 to 7.9%at the time the trial was stopped, after 3.5 years, becauseof an unexplained excess rate of death from any cause (22%,P=0.04). Both the ADVANCE and ACCORD trials involved high-riskpatients who were 8 and 12 years older, respectively, than thepatients in the UKPDS. In addition, at randomization in theADVANCE and ACCORD trials, patients had been treated for diabetesfor 8 and 10 years, respectively, whereas patients in the UKPDShad newly diagnosed disease. About a third of the patients inthe ADVANCE and ACCORD trials had a history of macrovasculardisease, as compared with 7.5% in the UKPDS.7 Both the ADVANCEand ACCORD trials suggested that near-normal glycemia did notreduce cardiovascular events in the short term.
Our findings are consistent with those of the EDIC study,5 whichwas a follow-up study involving a cohort of 1441 patients withtype 1 diabetes in the DCCT.15 In the DCCT, patients betweenthe ages of 13 and 39 years who did not have a history of cardiovasculardisease were randomly assigned to receive either intensive insulintherapy or conventional insulin therapy for a mean of 6.5 years;subsequently, 93% of the patients were followed for 11 years.At the end of that trial, the mean glycated hemoglobin levelwas 7.4% in the intensive-therapy group and 9.1% in the conventional-therapygroup. After all major cardiovascular and peripheral vascularevents were combined, patients in the intensive-therapy grouphad a nonsignificant reduction in the risk of macrovasculardisease of 41% (95% CI, –10 to 68).15 Nevertheless, bythe end of the follow-up period, intensive therapy had significantlyreduced the risk of any cardiovascular disease event by 42%(95% CI, 9 to 63; P=0.02),5 and after 6 years, it had resultedin decreased progression of carotid intima–media thickness.16The EDIC study also showed a sustained reduction in the riskof progressive retinopathy 4 years after the end of the trial,despite increasing hyperglycemia,17 and showed persistent benefitswith respect to albumin excretion after 7 to 8 years.18 A comparisonof the findings of the EDIC study and those of the UKPDS suggestthat improved glucose control may result in a larger cardiovascularrisk reduction in patients with type 1 diabetes than among thosewith type 2 diabetes, which is consistent with the results ofone meta-analysis.19
In the randomized Steno-2 Study, postinterventional benefitsin patients with type 2 diabetes were reported after a 7.8-yearmultifactorial, intensive risk-reduction program with multipledrug combinations and behavior modification, with a follow-upof 13.3 years.6 An overall absolute reduction in the risk ofdeath of 20% (P=0.02) was observed, with a hazard ratio of 0.54(95% CI, 0.32 to 0.89) for death in the intensive-therapy group,as compared with the conventional-therapy group. There was noevidence of a change in the hazard ratio once the formal interventionwas stopped, but differences in glycated hemoglobin levels weremaintained throughout the follow-up period. The Steno-2 Studyalso showed that the long-term effects of tight glycemic controland therapy with aspirin, antihypertensive agents, and lipid-loweringdrugs appeared to be additive. Although persistent differencesin risk-factor levels might have explained most of the benefitobserved, a legacy effect could not be ruled out.
The pathophysiological mechanisms responsible for such a legacyeffect of intensive glycemic control are unclear. A number ofmechanisms have been proposed,5 including increased intracellularformation of advanced glycation end products.20 Long-term hyperglycemiais associated with a slow onset of microvascular disease, whichmay be mediated by the gradual accumulation of advanced glycationend products that are subsequently slowly degraded with intensiveglycemic control. This mechanism may also be implicated in thedevelopment of cardiovascular disease. Thus, the sustained postinterventionalbenefit in the UKPDS might be explained in part by a lag phasebefore a reduction in events could occur because of improvedglycemic control in the conventional-therapy group after theimplementation of guidelines for stricter control on the basisof the results of the UKPDS. At the same time, the benefit ofprevious improved glycemic control in the intensive-therapygroup would be expected to diminish only slowly.
Our study has certain limitations. Questionnaires may not havecaptured all nonfatal outcomes. Biochemical and clinical measurementswere not collected after the fifth year, although after thefirst year it was already evident that differences in glycatedhemoglobin levels had been lost. The absence of risk-factorinformation in the period between the sixth year and the 10thyear precludes proportional-hazards analyses assessing possibleeffects of time-dependent covariates, such as microalbuminuria.
Our results show a sustained legacy effect of an intensive glucose-controlstrategy that appears to be longer than previously reported.These observations indicate that intensive glucose control startingat the time of diagnosis is associated with a significantlydecreased risk of myocardial infarction and death from any cause,in addition to the well-established reduction in the risk ofmicrovascular disease. On the basis of extensive trial evidence,strategies for cardiovascular risk reduction in patients withtype 2 diabetes emphasize the importance of lipid-lowering therapywith statins21 and of targeted antihypertensive treatment.22,23,24(A companion article in this issue of the Journal reports the10-year, postinterventional data on blood-pressure control fromthe UKPDS.25)
Our results highlight the added importance of glucose loweringin reducing the risk of coronary events and death from any cause.The findings strengthen the rationale for attaining optimalglycemic control and indicate emergent long-term benefits oncardiovascular risk.
Supported for the first 5 years of post-trial monitoring bythe U.K. Medical Research Council, U.K. Department of Health,Diabetes UK, the British Heart Foundation, and the U.K. NationalInstitute for Health and for the final 5 years by Bristol-MyersSquibb, GlaxoSmithKline, Merck Serono, Novartis, Novo Nordiskand Pfizer. The original UKDPS interventional trial was supportedby the U.K. Medical Research Council, British Diabetic Association,U.K. Department of Health, U.S. National Eye Institute, U.S.National Institute of Diabetes and Digestive and Kidney Diseases,British Heart Foundation, Wellcome Trust, Charles Wolfson CharitableTrust, Clothworkers' Foundation, Health Promotion Research Trust,Alan and Babette Sainsbury Trust, Oxford University MedicalResearch Fund Committee, Novo Nordisk, Bayer, Bristol-MyersSquibb, Hoechst, Lilly, Lipha, and Farmitalia Carlo Erba, withconsumables or logistical support from Boehringer Mannheim,Becton Dickinson, Owen Mumford, Securicor, Kodak, Cortecs Diagnostics,Glaxo Wellcome, SmithKline Beecham, Pfizer, Zeneca, Pharmacia,Upjohn, and Roche.
Dr. Holman reports receiving grant support from Asahi KaseiPharma, Bayer Healthcare, Bayer Schering Pharma, Bristol-MyersSquibb, GlaxoSmithKline, Merck, Merck Serono, Novartis, NovoNordisk, Pfizer, and Sanofi-Aventis, consulting fees from Amylin,Eli Lilly, GlaxoSmithKline, Merck, and Novartis, and lecturefees from Astella, Bayer, GlaxoSmithKline, King Pharmaceuticals,Eli Lilly, Merck, Merck Serono, Novo Nordisk, Takeda, and Sanofi-Aventis,and owning shares in Glyme Valley Technology, Glyox, and Oxtech;Dr. Paul, receiving consulting fees from Amylin; Dr. Bethel,receiving grant support from Novartis and Sanofi-Aventis andlecture fees from Merck and Sanofi-Aventis; Dr. Matthews, receivinglecture and advisory fees from Novo Nordisk, GlaxoSmithKline,Servier, Merck, Novartis, Novo Nordisk, Eli Lilly, Takeda, andRoche and owning shares in OSI Pharmaceuticals and ParticleTherapeutics; and Dr. Neil, receiving consulting fees from Merck,Pfizer, Schering-Plough, and Solvay Healthcare. The Oxford Centrefor Diabetes, Endocrinology and Metabolism (OCDEM) has a Partnershipfor the Foundation of OCDEM, with Novo Nordisk, Takeda and Servier.No other potential conflict of interest relevant to this articlewas reported.
We thank the patients and staff at the participating centers:Radcliffe Infirmary, Oxford; Royal Infirmary, Aberdeen; SellyOak Hospital, Birmingham; St. George's Hospital and HammersmithHospital, London; City Hospital, Belfast; North StaffordshireCity General Hospital, Stoke-on-Trent; Royal Victoria Hospital,Belfast; St. Helier Hospital, Carshalton; Whittington Hospital,London; Norfolk and Norwich Hospital, Norwich; Lister Hospital,Stevenage; Ipswich Hospital, Ipswich; Ninewells Hospital, Dundee;Northampton Hospital, Northampton; Torbay Hospital, Torquay;Peterborough District Hospital, Peterborough; Scarborough Hospital,Scarborough; Derbyshire Royal Infirmary, Derby; Manchester RoyalInfirmary, Manchester; Hope Hospital, Salford; Leicester GeneralHospital, Leicester; and Royal Devon and Exeter Hospital, Exeter(all in the United Kingdom); and the Northern Ireland GeneralRegister Office for provision of vital-status data. We acknowledgethe major contribution of the late Carole Cull.
Source Information
From the Diabetes Trials Unit (R.R.H., S.K.P., M.A.B.), the Division of Public Health and Primary Health Care (H.A.W.N.), and the National Institute of Health Research (NIHR) School for Primary Care Research (H.A.W.N.), Oxford Centre for Diabetes, Endocrinology, and Metabolism (R.R.H., S.K.P., M.A.B., D.R.M., H.A.W.N.); and the NIHR Oxford Biomedical Research Centre (R.R.H., D.R.M., H.A.W.N.) — both in Oxford, United Kingdom. This article (10.1056/NEJMoa0806470) was published at www.nejm.org on September 10, 2008. It will appear in the October 9 issue of the Journal.
Address reprint requests to Dr. Holman at the Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom, or at rury.holman{at}dtu.ox.ac.uk.
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