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Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus

  1. Birgit Fullerton1,*,
  2. Klaus Jeitler2,
  3. Mirjam Seitz3,
  4. Karl Horvath4,
  5. Andrea Berghold5,
  6. Andrea Siebenhofer1

Editorial Group: Cochrane Metabolic and Endocrine Disorders Group

Published Online: 14 FEB 2014

Assessed as up-to-date: 21 DEC 2012

DOI: 10.1002/14651858.CD009122.pub2


How to Cite

Fullerton B, Jeitler K, Seitz M, Horvath K, Berghold A, Siebenhofer A. Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD009122. DOI: 10.1002/14651858.CD009122.pub2.

Author Information

  1. 1

    Goethe University, Institute for General Practice, Frankfurt am Main, Hesse, Germany

  2. 2

    Medical University of Graz, EBM Review Center, Department of Internal Medicine and Institute for Medical Informatics, Statistics and Documentation, Graz, Austria

  3. 3

    München, Germany

  4. 4

    Medical University of Graz, Department of Internal Medicine, Division of Endocrinology and Metabolism, Graz, Austria

  5. 5

    Medical University of Graz, Institute for Medical Informatics, Statistics and Documentation, Graz, Austria

*Birgit Fullerton, Institute for General Practice, Goethe University, Theodor-Stern-Kai 7, Frankfurt am Main, Hesse, 60590, Germany. fullerton@allgemeinmedizin.uni-frankfurt.de.

Publication History

  1. Publication Status: New
  2. Published Online: 14 FEB 2014

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Characteristics of included studies [ordered by study ID]
Bucharest-Düsseldorf 1984

MethodsRandomised controlled clinical trial (RCT)

Randomisation ratio: 1:1:1

Superiority design


ParticipantsInclusion criteria: patients hospitalised due to metabolic decompensation or initiation of insulin treatment, age: 15-40 years

Exclusion criteria: admission primarily because of severe acute or chronic disorders unrelated to diabetes, mental retardation or psychiatric diseases, clinically overt diabetic nephropathy (urinary protein excretion exceeding 0.5 g/day and/or raised serum creatinine levels), proliferative retinopathy or blindness, severe foot complications

Diagnostic criteria: patients with type 1 diabetes mellitus (ketosis-prone)


InterventionsNumber of study centres: 1

Treatment before studya


OutcomesOutcomes reported in abstract of publication: HbA1c, incidence rates of ketoacidosis, hospitalisation rates, frequency of severe hypoglycaemia


Study detailsRun-in period: -

Study terminated before regular end: no


Publication detailsLanguage of publication: English

Funding: non-commercial (insulin and syringes were provided by various pharmaceutical companies)

Publication status: peer-reviewed journal/full article


Stated aim of studyQuote from publication: "It has been questioned whether aiming at near-normoglycaemia by intensified insulin treatment regimens is feasible and safe for the majority of patients with insulin-dependent diabetes"


NotesaThree different treatment groups were studied, two groups were followed-up for two years, but for this review only the first year is relevant


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskQuote from publication: "Patients were group randomised to 3 different treatment regimens. The first consecutive 100 patients meeting the eligibility criteria (group A) continues the standard treatment….The second 100 patients (group B)….The last 100 patients (group C)".
Comment: inappropriate sequence generation

Allocation concealment (selection bias)High riskComment: not described and inappropriate sequence generation

Blinding of participants and personnel (performance bias)
Objective Outcomes
Low riskComment: no blinding of participants and personnel, but risk of bias considered low for objective outcomes

Blinding of participants and personnel (performance bias)
Subjective Outcomes
High riskComment: no blinding of participants and personnel

Blinding of outcome assessment (detection bias)
Objective Outcomes
Unclear riskComment: not described

Blinding of outcome assessment (detection bias)
Subjective Outcomes
High riskQuote from publication: "Severe hypoglycaemia and ketoacidosis were assessed by a standardised interview and by a review of patients records"
Comment: likely not blinded

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: analysis excluded patients who dropped out, however dropout rate was low

Selective reporting (reporting bias)Unclear riskComment: data presentation seems complete, but no study protocol available

Other biasLow riskComment: no other risks of bias found

DCCT1 1993

MethodsParallel randomised controlled clinical trial

Randomisation ratio: 1:1

Superiority design


ParticipantsInclusion criteria: age: 13-39 years, IDDM for 1-5 years, urinary albumin excretion < 40 mg/24h

Exclusion criteria: hypertension, hypercholesterolaemia, severe diabetic complications or medical conditions, retinopathy (as detected by seven-field stereoscopic fundus photography)

Diagnostic criteria: insulin dependence, as evidenced by deficient C-peptide secretion


InterventionsNumber of study centres: 29

Treatment before study: -


OutcomesOutcomes reported in abstract of publication: retinopathy, microalbuminuria, nephropathy, neuropathy, severe hypoglycaemia


Study detailsRun-in period: -

Study terminated before regular end: yes ("In June 1993, after an average follow-up of 6.5 years (range, 3 to 9), the independent data monitoring committee determined that the study results warranted terminating the trial")


Publication detailsLanguage of publication: English

Funding: non-commercial and commercial (various corporate sponsors, see DCCT 1987)

Publication status: peer-reviewed journal/full article


Stated aim of studyQuote from publication: "Will intensive therapy prevent the development of diabetic retinopathy in patients with no retinopathy (primary prevention), and will intensive therapy affect the progression of early retinopathy (secondary intervention)? Although retinopathy was the principal study outcome, we also studied renal, neurologic, cardiovascular, and neuropsychological outcomes and the adverse effects of the two treatment regimens"


NotesIDDM: insulin-dependent diabetes mellitus


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from protocol: "For large samples, the Urn procedure minimizes the potential for selection bias, i.e., minimizes the potential that the clinics may influence the assignment of treatments to subjects by guessing which treatment will be assigned next. The Urn procedure, however, does not guarantee equal numbers of subjects in each treatment group. Rather, the probability of a substantial imbalance in the numbers assigned to each treatment is virtually eliminated by this procedure. Within either the primary prevention or secondary intervention trial, the probability that more than 370 of the 700 subjects would be assigned to either group is only 0.0073. The exact number of subjects to be randomised to either group is unknown because the exact number of subjects to be recruited within each clinic-retinopathy stratum is unknown."

Quote from publication: "Randomization was stratified according to the primary-prevention and secondary-intervention cohorts at each centre".

Comment: urn randomizations procedures (Wei 1988)

Allocation concealment (selection bias)Low riskQuote from protocol: "The list of random assignments will be kept confidential and accessible only to the Coordinating Center staff at the time of randomizations. Randomization into one of the two treatment groups will be accomplished by a telephone call to the Coordinating Center after all criteria for entry into the study have been satisfied and documented at the Coordinating Center. At the time of randomizations, the next treatment assignment for that subjects clinic-retinopathy stratum is communicated by telephone to the treatment centre staff, with written verification to follow."
Comment: allocation concealment considered appropriate

Blinding of participants and personnel (performance bias)
Objective Outcomes
Low riskQuote from publication: "The two treatment regimens will, of necessity, be conducted in an unmasked manner.” ; “With the exception of HbA1c, all centrally determined outcome measurements will ordinarily be masked from the investigator responsible for the treatment regimens and from the subjects.“
Comment: treatment assignment not blinded, risk of bias considered low for objective outcomes

Blinding of participants and personnel (performance bias)
Subjective Outcomes
High riskQuote from publication: "The two treatment regimens will, of necessity, be conducted in an unmasked manner.” ; “With the exception of HbA1c, all centrally determined outcome measurements will ordinarily be masked from the investigator responsible for the treatment regimens and from the subjects.“
Comment: treatment assignment not blinded

Blinding of outcome assessment (detection bias)
Objective Outcomes
Low riskQuote from publication: “The Morbidity and Mortality Classification Committee classified deaths and cardiovascular events. Coding was performed without knowledge of treatment assignment, according to pre-established criteria"
Comment: objective outcomes were assessed in a blinded manner

Blinding of outcome assessment (detection bias)
Subjective Outcomes
Unclear riskComment: due to the open design of the trial it is likely that it was not possible to have a blinded assessment of all subjective outcomes

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote from publication: "Each subject will then be included in the assigned treatment group in all statistical analyses regardless of the eventual therapeutic course. Thus subjects who fail to comply with or who are unable to complete the assigned treatment regimen will nevertheless be included in the originally assigned group for statistical analyses"
Comment: ITT analysis

Selective reporting (reporting bias)Low riskComment: no reason to assume selective reporting found

Other biasLow riskComment: no other risks of bias found

DCCT2 1993

MethodsParallel randomised controlled clinical trial

Randomisation ratio: 1:1

Superiority design


ParticipantsInclusion criteria: age: 13-39 years, IDDM for 1-15 years, urinary albumin excretion < 200 mg/24h, very mild-to-moderate nonproliferative retinopathy

Exclusion criteria: hypertension, hypercholesterolaemia, severe diabetic complications or medical conditions

Diagnostic criteria: insulin dependence, as evidenced by deficient C-peptide secretion


InterventionsNumber of study centres: 29

Treatment before study:


OutcomesOutcomes reported in abstract of publication: retinopathy, microalbuminuria, nephropathy, neuropathy, severe hypoglycaemia


Study detailsRun-in period:

Study terminated before regular end: yes ("In June 1993, after an average follow-up of 6.5 years (range, 3 to 9), the independent data monitoring committee determined that the study results warranted terminating the trial")


Publication detailsLanguage of publication: English

Funding: non-commercial and commercial (various corporate sponsors, see DCCT 1987)

Publication status: peer-reviewed journal/full article


Stated aim of studyQuote from publication: "Will intensive therapy prevent the development of diabetic retinopathy in patients with no retinopathy (primary prevention), and will intensive therapy affect the progression of early retinopathy (secondary intervention)? Although retinopathy was the principal study outcome, we also studied renal, neurologic, cardiovascular, and neuropsychological outcomes and the adverse effects of the two treatment regimens"


NotesIDDM: insulin-dependent diabetes mellitus


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from protocol: "For large samples, the Urn procedure minimizes the potential for selection bias, i.e., minimizes the potential that the clinics may influence the assignment of treatments to subjects by guessing which treatment will be assigned next. The Urn procedure, however, does not guarantee equal numbers of subjects in each treatment group. Rather, the probability of a substantial imbalance in the numbers assigned to each treatment is virtually eliminated by this procedure. Within either the primary prevention or secondary intervention trial, the probability that more than 370 of the 700 subjects would be assigned to either group is only 0.0073. The exact number of subjects to be randomised to either group is unknown because the exact number of subjects to be recruited within each clinic-retinopathy stratum is unknown."

Quote from publication: "Randomization was stratified according to the primary-prevention and secondary-intervention cohorts at each centre".

Comment: urn randomizations procedures (Wei 1988)

Allocation concealment (selection bias)Low riskQuote from protocol: "The Coordinating Center disclosed the random assignment of each patient to the clinic via telephone at the time of randomizations".The list of random assignments will be kept confidential and accessible only to the Coordinating Center staff at the time of randomizations. Randomization into one of the two treatment groups will be accomplished by a telephone call to the Coordinating Center after all criteria for entry into the study have been satisfied and documented at the Coordinating Center. At the time of randomizations, the next treatment assignment for that subjects clinic-retinopathy stratum is communicated by telephone to the treatment centre staff, with written verification to follow."
Comment: allocation concealment considered appropriate

Blinding of participants and personnel (performance bias)
Objective Outcomes
Low riskQuote from publication: "The two treatment regimens will, of necessity, be conducted in an unmasked manner.” ; “With the exception of HbA1c, all centrally determined outcome measurements will ordinarily be masked from the investigator responsible for the treatment regimens and from the subjects.“
Comment: treatment assignment not blinded, risk of bias considered low for objective outcomes

Blinding of participants and personnel (performance bias)
Subjective Outcomes
High riskQuote from publication: "The two treatment regimens will, of necessity, be conducted in an unmasked manner.” ; “With the exception of HbA1c, all centrally determined outcome measurements will ordinarily be masked from the investigator responsible for the treatment regimens and from the subjects.“
Comment: treatment assignment not blinded

Blinding of outcome assessment (detection bias)
Objective Outcomes
Low riskQuote from publication: “The Morbidity and Mortality Classification Committee classified deaths and cardiovascular events. Coding was performed without knowledge of treatment assignment, according to pre-established criteria".
Comment: objective outcomes were assessed in a blinded manner

Blinding of outcome assessment (detection bias)
Subjective Outcomes
Unclear riskComment: due to the open design of the trial it is likely that it was not possible to have a blinded assessment of all subjective outcomes

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote from publication: "Each subject will then be included in the assigned treatment group in all statistical analyses regardless of the eventual therapeutic course. Thus subjects who fail to comply with or who are unable to complete the assigned treatment regimen will nevertheless be included in the originally assigned group for statistical analyses"
Comment: ITT analysis

Selective reporting (reporting bias)Low riskComment: no reason to assume selective reporting found

Other biasLow riskComment: no other risks of bias found

Holman 1983

MethodsRandomised controlled clinical trial (RCT)

Randomisation ratio: 1:1

Superiority design


ParticipantsInclusion criteria: type 1 diabetes with background retinopathy

Exclusion criteria: age > 60, proliferative retinopathy, renal impairment (creatinine > 175 µmol/L), more than one significant cardiovascular event (or one in the previous year), other major disease

Diagnostic criteria: -


InterventionsNumber of study centres: diabetic clinics in Oxford and Aylesbury

Treatment before study: conventional care


OutcomesOutcomes reported in abstract of publication: HbA1c, renal and sensory-nerve function, low-density-lipoprotein-cholesterol and whole-blood low-shear viscosity, rate of progression of retinopathy


Study detailsRun-in period: -

Study terminated before regular end: no


Publication detailsLanguage of publication: English

Funding: non-commercial funding

Publication status: peer-reviewed journal/full article


Stated aim of studyQuote from publication: "The randomised prospective study of insulin-dependent diabetic patients with background retinopathy aimed to determine the degree to which near-normal glycaemia can be achieved in an unselected clinic population with two injections per day and whether the progress of diabetic complications could be retarded"


NotesHbA1c: glycosylated haemoglobin level


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote from publication: "Patients were randomised to two treatment groups by means of sealed envelopes with stratification for body-weight and blood pressure"
Comment: sequence generation not described

Allocation concealment (selection bias)Unclear riskQuote from publication: "Patients were randomised to two treatment groups by means of sealed envelopes with stratification for body-weight and blood pressure"
Comment: allocation concealment not adequately described

Blinding of participants and personnel (performance bias)
Objective Outcomes
Low riskQuote from publication: "All A patients were intensively educated in the care of their diabetes; the U group continued their usual therapy and attended the routine diabetic clinic"
Comment: neither participants nor personnel blinded, but risk of bias considered low for objective outcomes

Blinding of participants and personnel (performance bias)
Subjective Outcomes
High riskQuote from publication: "All A patients were intensively educated in the care of their diabetes; the U group continued their usual therapy and attended the routine diabetic clinic"
Comment: neither participants nor personnel blinded

Blinding of outcome assessment (detection bias)
Objective Outcomes
Low riskQuote from publication: "All readings were made by the same research nurse who was aware of the patient´s group but had no record of previous measurements. Ophthalmoscopy…was undertaken by an ophthalmologist without knowledge of the patients group.”
Comment: blinded assessment of primary outcome

Blinding of outcome assessment (detection bias)
Subjective Outcomes
Unclear riskQuote from publication: "All readings were made by the same research nurse who was aware of the patient´s group but had no record of previous measurements"
Comment: assessment not blinded, but some measures were taken to avoid bias

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskQuote from publication: "Data are shown for all patients where available. The initial comparison of groups would be unchanged if the 5 patients who did not complete two years in the study were excluded, with the exception of the vibration sensory threshold, in which case the changes over 2 years were assessed in relation to possible confounding variables by analysis of covariance"
Comment: complete case analysis, missingness likely not random, but number of missing values not very large

Selective reporting (reporting bias)Unclear riskComment: there is insufficient information to assess whether a risk of selective outcome reporting is present

Other biasLow riskComment: no other sources of bias became apparent

Linn 1996

MethodsParallel randomised controlled clinical trial

Randomisation ratio: 1:1

Superiority design


ParticipantsInclusion criteria: newly diagnosed type 1 diabetes, adults

Exclusion criteria: -

Diagnostic criteria: IDDM defined on the basis of insulin dependency according to WHO 1985


InterventionsNumber of study centres: 1

Treatment before study: -


OutcomesOutcomes reported in abstract of publication: glucagon-stimulated C-peptide, microalbuminuria, retinopathy, neuropathy, HbA1c, hypoglycaemia frequency, insulin sensitivity


Study detailsRun-in period: -

Study terminated before regular end: no


Publication detailsLanguage of publication: English

Funding: -

Publication status: peer-reviewed journal/full article


Stated aim of studyQuote from publication: "In this study, intensive insulin treatment was initiated in newly diagnosed adult patients to determine if it preserved endogenous insulin secretion longer than conventional therapy"


Notes-


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from publication: "…randomizations was performed with the use of computer-selected random numbers"
Comment: considered adequate

Allocation concealment (selection bias)Unclear riskComment: not described

Blinding of participants and personnel (performance bias)
Objective Outcomes
Low riskQuote from publication: "The I group contacted the diabetes educator by visit or telephone once per month to review and adjust the regimens".
Comment: neither participants nor personnel blinded, but risk of bias considered low for objective outcomes

Blinding of participants and personnel (performance bias)
Subjective Outcomes
High riskQuote from publication: "The I group contacted the diabetes educator by visit or telephone once per month to review and adjust the regimens".

Comment: neither participants nor personnel blinded

Blinding of outcome assessment (detection bias)
Objective Outcomes
Unclear riskComment: not described

Blinding of outcome assessment (detection bias)
Subjective Outcomes
Unclear riskComment: not described

Incomplete outcome data (attrition bias)
All outcomes
High riskQuote from publication: "Forty-two of 49 randomised patients completed the 5 years, and only their data were included"
Comment: no reasons given for the withdrawals, analysis not ITT

Selective reporting (reporting bias)Unclear riskComment: information insufficient to make judgement

Other biasUnclear riskComment: no other risks of bias found, but amount of information considered insufficient to make judgement

MCSG 1995

MethodsRandomised controlled clinical trial (RCT)

Randomisation ratio: 1:1

Superiority design


ParticipantsInclusion criteria: patients with insulin-dependent diabetes mellitus (IDDM); age: 16 - 60 years; microalbuminuria (albumin excretion >30 and <200μg/min); onset of diabetes before the age of 39; sitting blood pressure below 160/95 mm Hg

Exclusion criteria: arterial hypertension; albuminuria by dipstick test, antihypertensive treatment, clinical evidence of cardiovascular, peripheral vascular, or renal disease

Diagnostic criteria: -


InterventionsNumber of study centres: nine hospital based specialist diabetes centres

Treatment before study: conventional care


OutcomesOutcomes reported in abstract of publication: development of clinical albuminuria (defined as albumin excretion greater than 200 μg/min on at least two consecutive occasions, and rate of change of albumin excretion), HbA1c, blood pressure


Study detailsRun-in period: -

Study terminated before regular end: no


Publication detailsLanguage of publication: English

Funding: non-commercial funding

Publication status: peer-reviewed journal/full article


Stated aim of studyQuote from publication: "To study the effect of intensive therapy of diabetes on the progression to clinical albuminuria in insulin dependent diabetic patients with microalbuminuria"


NotesIDDM: insulin-dependent diabetes mellitus


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote from publication: "Patients were stratified by age and sex and randomised to either intensive therapy or conventional therapy by a centralised procedure"
Comment: method used for the allocation sequence generation was not exactly described

Allocation concealment (selection bias)Low riskQuote from publication: "Patients were stratified by age and sex and randomised to either intensive therapy or conventional therapy by a centralised procedure"
Comment: “Centralised procedure” is likely adequate

Blinding of participants and personnel (performance bias)
Objective Outcomes
Low riskQuote from publication: "Clear glycaemic targets were set in the intensive therapy group and they adjusted their treatment regimen in consultation with the investigation team"
Comment: patients and investigators were not blinded, but risk of bias considered low for objective outcomes

Blinding of participants and personnel (performance bias)
Subjective Outcomes
High riskQuote from publication: "Clear glycaemic targets were set in the intensive therapy group and they adjusted their treatment regimen in consultation with the investigation team"
Comment: patients and investigators were not blinded

Blinding of outcome assessment (detection bias)
Objective Outcomes
Unclear riskQuote from publication: "A blood sample was drawn for measurement of glycated haemoglobin concentration; these measurements were done in four participating centres that regularly exchanged quality control samples and cross validated results"
Comment: not described if the outcome assessors were blinded

Blinding of outcome assessment (detection bias)
Subjective Outcomes
Unclear riskQuote from publication: "At each visit a medical history was taken, including a record of severe episodes of hypoglycaemia or ketoacidosis…"
Comment: not described if the outcome assessors were blinded

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: not described; withdrawals in both groups are reported, but the reasons are not reported separately for each group

Selective reporting (reporting bias)Unclear riskComment: there is insufficient information to assess whether a risk of selective outcome reporting is present

Other biasUnclear riskComment: some information presented in the paper was inconsistent

MDCCT 1994

MethodsParallel randomised controlled clinical trial

Randomisation ratioa : 1:1(1978), 2:1 (in favour of intensive therapy, 1978-1984), 2:1 (in favour of control treatment, after 1984)

Superiority design


ParticipantsInclusion criteria: received a renal allograft as treatment for end-stage diabetic nephropathy

Exclusion criteria: -

Diagnostic criteria: insulin-dependent type 1 diabetes


InterventionsNumber of study centres: 1

Treatment before study: -


OutcomesOutcomes reported in abstract of publication: haemoglobin A1 level, renal glomerular mesangial expansion, volume fraction of mesangial matrix per glomerulus, increase in arteriolar hyalinosis, widening of the glomerular basement membrane, increase of volume fraction of the total mesangium, incidence of severe hypoglycaemic episodes, cognitive function


Study detailsRun-in period: -

Study terminated before regular end: no


Publication detailsLanguage of publication English

Funding: partially commercial

Publication status: peer-reviewed journal/full article


Stated aim of studyQuote from publication: "To determine whether optimised glycaemic control in type I diabetic recipients of renal allografts will prevent or delay diabetic renal lesions in the allograft"


NotesaInitially patients were randomised before transplantation, after 2 years, patients were randomised three months after transplantation to exclude patients whose grafts were rejected


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote from publication: "The subjects were recruited from the large population of type I diabetics with uremia who sought kidney transplantation at the University of Minnesota…About 300 patients were invited to join the study…The remaining 99 were originally randomised equally between the two treatment groups (before transplantation). Two years later, we began randomizations 3 months after transplantation…and to exclude patients whose grafts were rejected during this high-risk period. Between 1978 and 1984, randomizations was 2:1 in favour of the maximized group, since we hypothesized that this group would have more withdrawals from the trial…To balance the size of the two groups, in 1985 we began 2:1 randomizations in favour of the standard group"
Comment: sequence generation not described

Allocation concealment (selection bias)Unclear riskComment: not described

Blinding of participants and personnel (performance bias)
Objective Outcomes
Low riskQuote from publication: "The patients in the maximized group were contacted frequently by the study dietitian"
Comment: neither participants nor personnel blinded, but risk of bias considered low for objective outcomes

Blinding of participants and personnel (performance bias)
Subjective Outcomes
High riskQuote from publication: "The patients in the maximized group were contacted frequently by the study dietitian"
Comment: neither participants nor personnel blinded

Blinding of outcome assessment (detection bias)
Objective Outcomes
Unclear riskComment: not described

Blinding of outcome assessment (detection bias)
Subjective Outcomes
Unclear riskComment: not described

Incomplete outcome data (attrition bias)
All outcomes
High riskQuote from publication: "Conclusions of our study may be tempered somewhat by the relatively high proportion of patients for whom data could not be evaluated". “The rate of voluntary withdrawal tended to be higher in the maximized than the standard group.”
Comment: high number of dropouts; analysis of drop-outs suggests non-randomness of missing data; complete case analysis

Selective reporting (reporting bias)Unclear riskComment: results on hypoglycaemia insufficiently reported

Other biasUnclear riskComment: several analyses and publications before the end of the trial; some inconsistencies in the reporting of results

Oslo 1987

MethodsParallel randomised controlled clinical trial

Randomisation ratio:1:1:1

Superiority design


ParticipantsInclusion criteria: age: 18-45 years, diabetes duration > 7 years, but < 30 years, diabetes diagnosis before age = 30, negative for C-peptide

Exclusion criteria: clinical signs of nephropathy (serum creatinine ≤ 150 µmol/L), systemic hypertension (diastolic blood pressure ≤ 100 mm Hg), history of neuropathy, proliferative retinopathy, pregnant, medication other than insulin (apart from contraceptives)

Diagnostic criteria: C-peptide negative insulin dependent diabetes


InterventionsNumber of study centres: 1

Treatment before study: two daily insulin injections of mixed insulin


OutcomesOutcomes reported in abstract of publication: HbA1c, hypoglycaemic coma, ketoacidosis, cutaneous infections at injection site, insulin antibodies, retinopathy, urinary albumin excretion, glomerular hyperfiltration, sensory and motor nerve conduction velocity


Study detailsRun-in period: 2 months

Study terminated before regular end: no


Publication detailsLanguage of publication: English

Funding: partially commercial

Publication status: peer-reviewed journal/full article


Stated aim of studyQuote from publication: "To study the influence of long-term near-normoglycaemia on early stages of microangiopathy and neuropathy in young insulin dependent diabetic patients"


NotesFor several outcomes results have only be reported after 2 years


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from publication: "To ensure comparable treatment groups a block randomizations procedure was chosen. The patients were randomised into three groups by a computer programme making the best possible distribution of basic characteristics in the following priority: Age, duration of disease, sex, initial HbA1c value and retinopathy grading"
Comment: considered adequate

Allocation concealment (selection bias)Unclear riskComment: not described

Blinding of participants and personnel (performance bias)
Objective Outcomes
Low riskComment: not blinded, but risk of bias considered low for objective outcomes

Blinding of participants and personnel (performance bias)
Subjective Outcomes
High riskComment: not blinded

Blinding of outcome assessment (detection bias)
Objective Outcomes
Low riskQuote from publication: "To avoid observer bias, all pictures were coded and evaluated in a masked manner by the ophthalmologist"
Comment: blinded outcome assessment of retinopathy, unclear for other outcomes

Blinding of outcome assessment (detection bias)
Subjective Outcomes
Unclear riskComment: not described

Incomplete outcome data (attrition bias)
All outcomes
High riskQuote from publication: "Data collected until change of treatment was used for statistical analysis"
Comment: About 35% of the patients in the control group and 15% of patients in the treatment groups changed the treatment arm at some point during the study; it is not clear across the different publications of the Oslo study how these data were handled. Since the proportion of patients changing treatment was substantial, risk of bias was considered high

Selective reporting (reporting bias)Unclear riskComment: data were analysed for many different times of follow-up

Other biasUnclear riskComment: reporting insufficient to assess the risk of other biases

Steno 1 1983

MethodsRandomised controlled clinical trial (RCT)

Randomisation ratio: 1:1

Superiority design


ParticipantsInclusion criteria: type 1 diabetes with background retinopathy, postprandial C-peptide ≤ 0.2 nmol/L, serum creatine ≤ 150 μmol/L, age 18-51 years, diabetes onset before age 30, diabetes duration < 35 years

Exclusion criteria: -

Diagnostic criteria: type 1 diabetes


InterventionsNumber of study centres: 1

Treatment before study: 1-3 insulin injections


OutcomesOutcomes reported in abstract of publication: mean blood glucose, HbA1c, retinal morphology, retinal function, proliferative retinopathy


Study detailsRun-in period: -

Study terminated before regular end: no


Publication detailsLanguage of publication: English

Funding: non-commercial

Publication status: peer-reviewed journal/full article


Stated aim of studyQuote from publication: "The aim of the study was to evaluate the effect of near-normal glycaemic control on retinopathy"


NotesHbA1c: glycosylated haemoglobin level; IDDM: insulin-dependent diabetes mellitus


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote from publication: "Patients were randomised to unchanged conventional treatment or to continuous subcutaneous insulin infusion".
Comment: sequence generation not described

Allocation concealment (selection bias)Unclear riskQuote from publication: "Patients were randomised to unchanged conventional treatment or to continuous subcutaneous insulin infusion ".
Comment: allocation concealment not described

Blinding of participants and personnel (performance bias)
Objective Outcomes
Low riskComment: patients and investigators were not blinded, but risk of bias considered low for objective outcomes

Blinding of participants and personnel (performance bias)
Subjective Outcomes
High riskComment: patients and investigators were not blinded

Blinding of outcome assessment (detection bias)
Objective Outcomes
Low riskQuote from publication: "At the end of the study all fundus photographs were mixed and read in a ‘blind’ fashion by two ophthalmologists who had to agree whether the photographs showed deterioration, no change, or improvement"
Comment: blinded outcome assessment of retinopathy, unclear for other outcomes

Blinding of outcome assessment (detection bias)
Subjective Outcomes
Unclear riskComment: not described

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: all 30 patients were included in the analysis, but it is not clear whether there were missing data and how they were treated

Selective reporting (reporting bias)Unclear riskComment: there is insufficient information to assess whether a risk of selective outcome reporting is present

Other biasUnclear riskComment: HbA1c baseline difference between treatment groups, inconsistencies regarding number of enrolled patients across publications

Steno 2 1986

MethodsParallel randomised controlled clinical trial

Randomisation ratio: 1:1

Superiority design


ParticipantsInclusion criteria: 18-50 years, postprandial C-peptide level < 0.2 nmol/L, diabetes duration: 5 - 26 years, supine systolic blood pressure < 160 mm Hg, diastolic blood pressure < 95 mm Hg, consistently negative albustix reaction on 24h urine, raised urinary albumin excretion (30 to 300 mg/24h) in two of three tests in 3-month period (incipient diabetic nephropathy)

Exclusion criteria: history of renal disease, active proliferative retinopathy, laser treatment, psychiatric disorders, medication other than oral contraceptives, unable to sense hypoglycaemia

Diagnostic criteria: insulin-dependent diabetes


InterventionsNumber of study centres: 1

Treatment before study: subcutaneous depot injections of intermediate-acting insulin preparations, often mixed with short-acting insulin, two to three times daily


OutcomesOutcomes reported in abstract of publication: glycosylated haemoglobin, manifestation of clinical diabetic nephropathy


Study detailsRun-in period: -

Study terminated before regular end: no


Publication detailsLanguage of publication: English

Funding: non-commercial

Publication status: peer-reviewed journal/full article


Stated aim of studyQuote from publication: "to evaluate the effect…of strict metabolic control on kidney function in patients with microalbuminuria, using serial analysis of albumin excretion before and during the study period.”


Notes-


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote from publication: "The 36 patients were matched in pairs according to urinary albumin level, degree of metabolic control, and sex and were assigned randomly to either continuous insulin infusion or unchanged conventional treatment"
Comment: sequence generation not described

Allocation concealment (selection bias)Unclear riskComment: not described

Blinding of participants and personnel (performance bias)
Objective Outcomes
Low riskComment: neither participants or personnel blinded, but risk of bias considered low for objective outcomes

Blinding of participants and personnel (performance bias)
Subjective Outcomes
High riskComment: not blinded

Blinding of outcome assessment (detection bias)
Objective Outcomes
Unclear riskComment: not described

Blinding of outcome assessment (detection bias)
Subjective Outcomes
Unclear riskComment: not described

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: all 36 patients were included in the analysis, likely no dropouts, although this was not explicitly stated

Selective reporting (reporting bias)Unclear riskComment: no protocol was available, but no evidence for selective reporting found in the manuscript. Adverse events were likely collected but not reported on

Other biasUnclear riskComment: inconsistencies regarding number of enrolled patients across publications

Verrillo 1988

MethodsParallel randomised controlled clinical trial

Randomisation ratio: 1.1

Superiority design


ParticipantsInclusion criteria: age: 18-50 years; diabetes for 15-30 years, supine systolic blood pressure under 150 mm Hg and a supine diastolic blood pressure under 95 mm Hg, no evidence of ischaemic heart disease according to Minnesota code, urinary protein excretion below 0.5 g/day; background retinopathy

Exclusion criteria: -

Diagnostic criteria: no residual endogenous insulin secretory capacity defined as a plasma C-peptide concentration below 0.1 pmol per mL in the postabsorptive state, and 6 min after the intravenous injection of 1 mg glucagon


InterventionsNumber of study centres: -

Treatment before study: subcutaneous injections of intermediate-acting insulin preparations, often mixed with short acting insulin, not more than twice daily


OutcomesOutcomes reported in abstract of publication: plasma glucose profile, glycosylated haemoglobin, retinal morphology, retinopathy


Study detailsRun-in period: -

Study terminated before regular end: no


Publication detailsLanguage of publication: English

Funding: -

Publication status: peer-reviewed journal/full article


Stated aim of studyQuote from publication: "…to evaluate (a) the degree of glycaemic control which can be achieved and maintained in patients with IDDM by using a more intensive insulin regimen employing long-acting insulin as basal cover and soluble insulin at mealtimes, and (b) what is the effect of this treatment on the rate of deterioration of already established retinopathy”


NotesIDDM: insulin dependent diabetes mellitus


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote from publication: "Originally, the patients were identified in a screening for retinopathy by ophthalmoscopy through dilated pupils in our outpatient clinic. Of the 54 consecutive insulin-treated diabetic patients with background retinopathy, 44 agreed to take part in the study. They were randomly allocated to one of the treatment regimens – UCT or ICT. Block randomizations was performed to ensure comparable groups".
Comment: sequence generation not described

Allocation concealment (selection bias)Unclear riskComment: not described

Blinding of participants and personnel (performance bias)
Objective Outcomes
Low riskQuote from publication: "The UCT patients attended to the routine diabetic clinic; ICT patients were seen in the outpatient clinic every four weeks for the first year and then every eight weeks"
Comment: not blinded, , but risk of bias considered low for objective outcomes

Blinding of participants and personnel (performance bias)
Subjective Outcomes
High riskComment: not blinded

Blinding of outcome assessment (detection bias)
Objective Outcomes
Low riskQuote from publication: "Colour photographs and angiograms were evaluated blindly by a senior ophthalmologist, the identity of the patient and number of examination being masked"
Comment: outcomes assessment blinded

Blinding of outcome assessment (detection bias)
Subjective Outcomes
Unclear riskComment: not described

Incomplete outcome data (attrition bias)
All outcomes
High riskQuote from publication: "Subsequent to randomizations…., six patients were lost to follow-up"
Comment: drop-outs not considered in analysis

Selective reporting (reporting bias)Unclear riskComment: incomplete reporting on some outcomes (e.g. mild hypoglycaemia)

Other biasUnclear riskComment: no other risks of bias found, but reporting insufficient to make judgement

Wysocki 2003

MethodsParallel randomised controlled clinical trial

Randomisation ratio: 1:1

Superiority design


ParticipantsInclusion criteria: school-aged children (6-15 years), type 1 diabetes for at least 2 years or for 1 year with a negligible stimulated C-peptide level, reside in a family situation, telephone service at home, plan to continue treatment at the enrolling centre throughout the study

Exclusion criteria: other chronic medical conditions (except well-controlled Hashimoto thyroiditis or well-controlled asthma), inpatient psychiatric treatment within the previous six months, caregivers not literate in English, caregivers treated for psychosis, major depression, bipolar disorder or substance abuse in the prior 6 months

Diagnostic criteria: type 1 diabetes mellitus


InterventionsNumber of study centres: 2

Treatment before study: -

Titration period: 18 months


OutcomesOutcomes reported in abstract of publication: severe hypoglycaemia, HbA1c, decline in IQ


Study detailsRun-in period: -

Study terminated before regular end: no


Publication detailsLanguage of publication: English

Funding: non-commercial

Publication status: peer-reviewed journal/full article


Stated aim of studyQuote from publication: "The objective of this study was to determine whether severe hypoglycaemia in children with type 1 diabetes is associated with cognitive decline over 18 months”; “The primary purpose of the trial was to identify variables that predict benefit from the two regimens"


NotesIQ: intelligence quotient


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote from publication: "Randomization was stratified according to the patient´s age and HbA1c and was performed by the trial coordinator at the other centre"
Comment: not adequately described

Allocation concealment (selection bias)Unclear riskQuote from publication: "Randomization was stratified according to the patient´s age and HbA1c and was performed by the trial coordinator at the other centre"
Comment: not adequately described

Blinding of participants and personnel (performance bias)
Objective Outcomes
Low riskQuote from publication: "Intensive therapy (IT) patients received approximately four times more contacts with nurses, dietitians, and psychologists than those in the usual care (UC) group"
Comment: neither participants nor personnel blinded, but risk of bias considered low for objective outcomes

Blinding of participants and personnel (performance bias)
Subjective Outcomes
High riskQuote from publication: "Intensive therapy (IT) patients received approximately four times more contacts with nurses, dietitians, and psychologists than those in the usual care (UC) group"Comment: neither participants nor personnel blinded

Blinding of outcome assessment (detection bias)
Objective Outcomes
Unclear riskComment: not described

Blinding of outcome assessment (detection bias)
Subjective Outcomes
High riskQuote from publication: "…Parents documented this information immediately after any apparent severe hypoglycaemia episode. Parents telephoned the study nurse during the next business day to review each such episode to verify that it met the DCCT criteria"
Comment: likely not blinded

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: it is not clearly described whether there were any dropouts or missing data

Selective reporting (reporting bias)Unclear riskComment: the study likely investigated other outcomes, which were not mentioned in this study. Also, no reference is given to other articles on this study or a study protocol. It is not quite clear what the primary aim of the overall study was

Other biasHigh riskComment: gender shows a large baseline difference, all articles seem partial reports of a larger study, which is not well referenced; inconsistent baseline data reporting across different publications

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Azar 1999No relevant outcomes

Bangstad 1992No specified glucose targets in treatment groups

Barr 2001Not randomised controlled trial

Beck-Nielsen 1990No specified glucose targets in treatment groups

Biesenbach 1988No specified glucose targets in treatment groups

Bougneres 1993No specified glucose targets in treatment groups

Christensen 1987No specified glucose targets in treatment groups

Christiansen 1987No specified glucose targets in treatment groups

Ciavarella 1985No specified glucose targets in treatment groups

Crepaldi 1989No specified glucose targets in treatment groups

de Beaufort 1989No specified glucose targets in treatment groups

Ditzel 1987Study duration < 1 year

Dzien 1988Not randomised controlled trial

Edelmann 1987No specified glucose targets in treatment groups

Eschwege 1979No specified glucose targets in treatment groups

Franklin 2006No specified glucose targets in treatment groups

Goicolea 1987No specified glucose targets in treatment groups

Itoh 1990No separate analysis of patients with type 1 diabetes

Kaufman 2005Not randomised controlled trial

Kordella 2005Not randomised controlled trial

Kritz 1983Not randomised controlled trial

KROC 1988Study duration < 1 year

Levy 1984Study duration < 1 year

Malmberg 1997No specified glucose targets in treatment groups

Montanya 1997No specified glucose targets in treatment groups

Nosadini 1988No specified glucose targets in treatment groups

Perlman 1984No specified glucose targets in treatment groups

Podgorski 1987Study duration < 1 year

Rodger 1988Study duration < 1 year

Rosenstock 1988Not randomised controlled trial

Saito 1996Not randomised controlled trial

SDIS 1993No specified glucose targets in treatment groups

Shah 1989No specified glucose targets in treatment groups

Skare 1986No specified glucose targets in treatment groups

Tubner 1996No specified glucose targets in treatment groups

Weinrauch 2009No specified glucose targets in treatment groups

Wiseman 1985No specified glucose targets in treatment groups

 
Comparison 1. Intensive glucose control versus conventional glucose control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Retinopathy71660Risk Ratio (IV, Random, 95% CI)0.71 [0.44, 1.16]

 2 Manifestation of retinopathy2768Risk Ratio (IV, Random, 95% CI)0.27 [0.18, 0.42]

 3 Progression of retinopathy, random effects model4860Risk Ratio (IV, Random, 95% CI)1.10 [0.54, 2.24]

 4 Progression of retinopathy, random effects model, all studies, Steno 1 after 2 years4859Risk Ratio (IV, Random, 95% CI)0.68 [0.47, 0.99]

 5 Progression of retinopathy, random effects model, stratified by follow-up duration4860Risk Ratio (IV, Random, 95% CI)1.10 [0.54, 2.24]

    5.1 Follow-up duration >= 2 years
2764Risk Ratio (IV, Random, 95% CI)0.61 [0.49, 0.76]

    5.2 Follow-up duration < 2 years
296Risk Ratio (IV, Random, 95% CI)2.32 [1.16, 4.63]

 6 Progression of retinopathy, fixed-effect model, stratified by follow-up duration4860Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.55, 0.84]

    6.1 Follow-up duration > 1 year
2764Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.48, 0.75]

    6.2 Follow-up duration <= 1 year
296Risk Ratio (M-H, Fixed, 95% CI)2.38 [1.16, 4.88]

 7 Progression of retinopathy, random effects model, stratified by follow-up duration, OR4860Odds Ratio (IV, Random, 95% CI)1.28 [0.39, 4.26]

    7.1 Follow-up duration > 1 year
2764Odds Ratio (IV, Random, 95% CI)0.48 [0.35, 0.65]

    7.2 Follow-up duration <= 1 year
296Odds Ratio (IV, Random, 95% CI)4.28 [1.36, 13.49]

 8 Manifestation of nephropathy, random-effects model, RR31475Risk Ratio (IV, Random, 95% CI)0.56 [0.46, 0.68]

 9 Manifestation of nephropathy, random-effects model, alternative measure in Oslo 198731475Risk Ratio (IV, Random, 95% CI)0.56 [0.46, 0.68]

 10 Manifestation of nephropathy, fixed-effect model, RR31475Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.47, 0.69]

 11 Manifestation of nephropathy, random-effects model, OR31475Odds Ratio (IV, Random, 95% CI)0.48 [0.34, 0.67]

 12 Progression of nephropathy, random-effects model, RR3179Risk Ratio (IV, Random, 95% CI)0.79 [0.37, 1.70]

 13 Progression of nephropathy, fixed-effect model, RR3179Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.38, 1.30]

 14 Progression of nephropathy, random-effects model, OR3179Odds Ratio (IV, Random, 95% CI)0.70 [0.26, 1.91]

 15 Manifestation of neuropathy, random-effects model, RR31203Risk Ratio (IV, Random, 95% CI)0.35 [0.23, 0.53]

 16 Manifestation of neuropathy, fixed-effect model, RR31203Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.23, 0.51]

 17 Manifestation of neuropathy, random-effects model, OR31203Odds Ratio (IV, Random, 95% CI)0.31 [0.20, 0.48]

 18 Severe hypoglycaemia, random-effects model, RR112108Risk Ratio (IV, Random, 95% CI)1.50 [1.17, 1.91]

 19 Severe hypoglycaemia, assistance of other person41653Risk Ratio (IV, Random, 95% CI)1.64 [1.27, 2.12]

 20 Severe hypoglycaemia, coma or hospital admission71818Risk Ratio (IV, Random, 95% CI)1.67 [1.09, 2.55]

 21 Severe hypoglycaemia, random-effects model, RR, without DCCT9667Risk Ratio (IV, Random, 95% CI)1.13 [0.83, 1.52]

 22 Severe hypoglycaemia, stratified by baseline HbA1c112108Risk Ratio (IV, Random, 95% CI)1.50 [1.17, 1.91]

    22.1 Baseline HbA1c < 9.0
31583Risk Ratio (IV, Random, 95% CI)1.68 [1.29, 2.19]

    22.2 Baseline HbA1c >= 9.0
8525Risk Ratio (IV, Random, 95% CI)1.04 [0.66, 1.64]

 23 Severe hypoglycaemia, random-effects model, RR, without Bucharest-Düsseldorf101918Risk Ratio (IV, Random, 95% CI)1.45 [1.12, 1.88]

 24 Severe hypoglycaemia, random-effects model, RR, without DCCT and Bucharest-Düsseldorf8477Risk Ratio (IV, Random, 95% CI)1.05 [0.77, 1.44]

 25 Severe hypoglycaemia, stratified by baseline HbA1c, without Bucharest-Düsseldorf101918Risk Ratio (IV, Random, 95% CI)1.45 [1.12, 1.88]

    25.1 Baseline HbA1c < 9.0
31583Risk Ratio (IV, Random, 95% CI)1.68 [1.29, 2.19]

    25.2 Baseline HbA1c >= 9.0
7335Risk Ratio (IV, Random, 95% CI)0.86 [0.52, 1.42]

 26 Severe hypoglycaemia, coma or hospital admission, without Bucharest-Düsseldorf61628Risk Ratio (IV, Random, 95% CI)1.58 [0.98, 2.56]

 27 Severe hypoglycaemia, stratified by baseline HbA1c, fixed-effect model112108Risk Ratio (IV, Fixed, 95% CI)1.70 [1.53, 1.89]

    27.1 Baseline HbA1c < 9.0
31583Risk Ratio (IV, Fixed, 95% CI)1.75 [1.57, 1.94]

    27.2 Baseline HbA1c >= 9.0
8525Risk Ratio (IV, Fixed, 95% CI)1.04 [0.66, 1.64]

 28 Severe hypoglycaemia, stratified by baseline HbA1c, OR112108Odds Ratio (IV, Random, 95% CI)1.91 [1.24, 2.95]

    28.1 Baseline HbA1c < 9.0
31583Odds Ratio (IV, Random, 95% CI)2.77 [1.78, 4.31]

    28.2 Baseline HbA1c >= 9.0
8525Odds Ratio (IV, Random, 95% CI)1.17 [0.66, 2.08]

 29 Ketoacidosis91924Peto Odds Ratio (Peto, Fixed, 95% CI)1.33 [0.95, 1.86]

 30 Ketoacidosis, CSII396Peto Odds Ratio (Peto, Fixed, 95% CI)4.93 [1.18, 20.60]

 31 Ketoacidosis, MI4332Peto Odds Ratio (Peto, Fixed, 95% CI)0.62 [0.11, 3.67]

 32 Ketoacidosis, MI or CSII31511Peto Odds Ratio (Peto, Fixed, 95% CI)1.28 [0.90, 1.82]

 33 All-cause mortality102039Peto Odds Ratio (Peto, Fixed, 95% CI)1.02 [0.48, 2.19]

 
Summary of findings for the main comparison. Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus

Patient or population: persons with type 1 diabetes mellitus

Settings: outpatient clinics in North America and Europe
Intervention: intensive glucose control

Comparison: conventional glucose control

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlIntensive treatment

Macrovascular complications

Follow-up: 1 - 6.5 years
See comment⊕⊕⊝⊝
lowa
Macrovascular outcomes were not considered as primary outcomes in any of the included studies and most studies did not report this outcome; myocardial infarctions and strokes were very rare




Microvascular complications


Manifestation of retinopathy
Follow-up: 5 - 6.5 years
232 per 100063 per 1000
(42 to 97)
RR 0.27
(0.18 to 0.42)
768 (2)⊕⊕⊕⊕
highb

Progression of retinopathy
Follow-up duration ≥ 2 years; follow-up: 5 - 6.5 years
387 per 1000236 per 1000
(190 to 294)
RR 0.61
(0.49 to 0.76)
764 (2)⊕⊕⊕⊝
moderatec

Progression of retinopathy
Follow-up duration < 2 years; follow-up: 1 year
149 per 1000346 per 1000
(173 to 690)
RR 2.32
(1.16 to 4.63)
96 (2)⊕⊕⊝⊝
lowd

Manifestation of nephropathy
Follow-up: 3.5 - 6.5 years
284 per 1000159 per 1000
(131 to 193)
RR 0.56
(0.46 to 0.68)
1475 (3)⊕⊕⊕⊝
moderatee

Progression of nephropathy
Follow-up: 5 - 6.5 years
14 per 100011 per 1000 (5 to 24)RR 0.79

(0.37 t0 1.70)
179 (3)⊕⊝⊝⊝
very lowf

Manifestation of neuropathy
Follow-up: 5 - 6.5 years
139 per 100049 per 1000
(32 to 74)
RR 0.35
(0.23 to 0.53)
1203 (3)⊕⊕⊕⊕
highg

Progression of neuropathySee commentNot adequately investigated



Adverse events


Severe hypoglycaemia, baseline HbA1c < 9.0

Follow-up: 1.5 - 6.5 years
351 per 1000590 per 1000
(453 to 769)
RR 1.68
(1.29 to 2.19)
1583 (3)1a. ⊕⊕⊝⊝
lowh

Severe hypoglycaemia, baseline HbA1c9.0

Follow-up: 1 - 5 years
104 per 1000108 per 1000
(68 to 170)
RR 1.04
(0.66 to 1.64)
525 (8)1b. ⊕⊕⊝⊝
lowh

Ketoacidosis

Follow-up: 1 - 2 years
21 per 100095 per 1000

(50 to 866)
OR 4.93

(1.18 to 20.60)
96 (3)2. ⊕⊝⊝⊝
very lowi
In studies using insulin pumps

Health-related quality of life

Follow-up: 6.5 years
See comment1441 (2)⊕⊕⊕⊝
moderatej
Only the DCCT reported on this outcome using several instruments (Diabetes-Quality of Life Measure (DQHL), Symptom-Checklist-90R, Medical Outcome Study 36-Item Short Form (SF-36)); none of these measures showed a statistically significant difference between the intervention and comparator groups





All-cause mortality

Follow up: 1 - 6.5 years
14 per 100013 per 1000

(13 to 60)
OR 1.02 (0.48 to 2.19)2039 (10)⊕⊕⊕⊝
moderatek
Overall, the mortality rate was very low in all studies except MDCCT 1994, investigating renal allograft as treatment for end-stage diabetic nephropathy

Costs

Follow up: 1 - 6.5 years
See comment1441 (2)⊕⊕⊕⊝
moderatej
Only the DCCT reported on this outcome; intensive treatment using multiple injections was calculated to cost 4014 US$/year, intensive treatment using CSII 5784 US$/year and conventional treatment 1666 US$/year taking into account resources used for therapy and handling side-effects; considering the reduction of future diabetes complications, intensive therapy was found to be highly cost-effective





**The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; CSII: continuous subcutaneous insulin infusion; DCCT: 'Diabetes Complications Clinical Trial'; HbA1c: glycosylated haemoglobin A1c; OR: odds ratio; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 The basis for the assumed risk is the number of events in the control groups
aDowngraded by two levels owing to outcome measures either not being addressed as primary endpoints or reported in included studies and few events
bNot downgraded because of few participants due to large effect size (RR < 0.5)
cDowngraded by one level owing to substantial diversity in outcome measures definition
dDowngraded by two levels owing to few participants and substantial diversity in outcome measures definition
eDowngraded by one level owing to indirectness (surrogate outcome measures)
fDowngraded by three levels owing to few participants, indirectness (surrogate outcome measures) and imprecise results (confidence intervals include null effect and appreciable benefit or harm)
gLarge effect size
hDowngraded by two levels owing to risk of bias in outcome definition and observational nature of subgroup analyses
iDowngraded by three levels owing to imprecision (wide confidence intervals), low number of participants and observational nature of subgroup analyses
jDowngraded by one level because only one study group (DCCT) investigated this outcome in two studies
kDowngraded by one level owing to imprecise results (confidence intervals include null effect and appreciable benefit or harm)
 
Table 1. Glycaemic targets for type 1 diabetes mellitus in different treatment guidelines

CountryGuidelineYearHbA1c

CanadaCanadian Diabetes Association (Canadian 2008)2008≤ 7.0%

GermanyDeutsche Diabetes Gesellschaft (Martin 2007)2007< 7.0%

UKNational Institute for Health and Clinical Excellence (NICE) (NICE 2010)2010< 7.5% (in case of increased arterial disease risk: < 6.5%)

USAAmerican Association of Clinical Endocrinologists (AACE) (Rodbard 2007)2007≤ 6.5%

USAAmerican Diabetes Association (ADA) (ADA 2010)2010< 7.0%

 HbA1c: glycosylated haemoglobin A1c
 
Table 2. Overview of study populations

Characteristic

Study ID
Intervention(s) and comparatorScreened / eligible
[N]
Randomised
[N]
Safety
[N]
ITT
[N]
Finishing study
[N]
Randomised finishing study
[%]

(1) Bucharest-Düsseldorf 1984I: intensive therapy (group B)2001001001009898.0

C: basic (group C)1001001009292.0

total:20020020019095.0







(2) DCCT1 (primary prevention) 1993I: intensive therapy-348348348--

C: conventional Therapy378378378--

total:726726726-a-







(3) DCCT2 (secondary intervention) 1993I: intensive therapy-363363363--

C: conventional therapy352352352--

total:715715715-a-a







(4) Linn 1996I: intensive therapy4923--23-

C: conventional therapy19--19--

total:49b--4285.7







(5) MSCG 1995I: intensive therapy-3636363186.1

C: conventional therapy3434343191.2

total:7070706288.6







(6) MDCCT 1994I: intensive therapy9852--2548.1

C: conventional therapy47--2348.9

total:99--4848.5







(7) Holman 1983I: intensive therapy (Group A)823636363597.2

C: conventional therapy (Group U)3838383489.5

total:7474746993.2







(8) Oslo 1987I1: intensive 1: multiple injections451515151386.7

I2: intensive 2: continuous insulin infusion1515151386.7

C: conventional1515151066.7

total:4545453680







(9) Steno 1 1983I: intensive therapy3815151515100

C: conventional therapy15151515100

total:30303030100







(10) Steno 2 1986I: intensive therapy4918181818100

C: conventional therapy18181818100

total:36363636100







(11) Verrillo 1988I: intensive therapy542222221881.8

C: conventional therapy2222222090.9

total:4444443886.4







(12) Wysocki 2003I: intensive therapy142727272--

C: conventional therapy707070--

total:142142142--







Grand totalAll interventions 1115c

All c omparators 1108c

All interventions and c omparators 2230c

 aIn the DCCT1 and DCCT2 combined, 1433 (99.4%) of 1441 patients finished the study
bForty-nine participants were randomised, authors only included data of 42 participants completing five years
cNumbers do not match exactly because of 'b'
C: comparator; I: intervention