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Intervention Review

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Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus

  1. Bianca Hemmingsen1,*,
  2. Søren S Lund2,
  3. Christian Gluud3,
  4. Allan Vaag4,
  5. Thomas P Almdal5,
  6. Jørn Wetterslev6

Editorial Group: Cochrane Metabolic and Endocrine Disorders Group

Published Online: 11 NOV 2013

DOI: 10.1002/14651858.CD008143.pub3


How to Cite

Hemmingsen B, Lund SS, Gluud C, Vaag A, Almdal TP, Wetterslev J. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD008143. DOI: 10.1002/14651858.CD008143.pub3.

Author Information

  1. 1

    Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen, Denmark

  2. 2

    Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

  3. 3

    Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, The Cochrane Hepato-Biliary Group, Copenhagen, Denmark

  4. 4

    Rigshospitalet and Copenhagen University, Department of Endocrinology, Diabetes and Metabolism, København N, Denmark

  5. 5

    Copenhagen University Hospital Gentofte, Department of Medicine F, Hellerup, Denmark

  6. 6

    Rigshospitalet, Copenhagen University Hospital, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Copenhagen, Denmark

*Bianca Hemmingsen, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, DK-2100, Denmark. biancahemmingsen@hotmail.com. bh@ctu.rh.dk.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 11 NOV 2013

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This is not the most recent version of the article. View current version (29 JUL 2015)

 
Characteristics of included studies [ordered by study ID]
ACCORD 2008

Methods2 x 2 factorial randomised clinical trial


ParticipantsInclusion criteria:
1. Type 2 diabetes mellitus defined according to the 1997 ADA criteria for ≥ 3 months
2. HbA1c level (obtained < 3 months before anticipated date of randomisation) of
a. 7.5%-11%: (i) If on insulin < 1 U/kg and on 0 or 1 oral anti-diabetic agent or (ii) If not on insulin, and on 0, 1, or 2 oral anti-diabetic agents
b. 7.5%-9%: (i) If on insulin < 1 U/kg and on 2 oral anti-diabetic agents, (ii) If on insulin > 1 U/kg and 0 oral anti-diabetic agents, or (iii) If not on insulin and on 3 oral anti-diabetic agents
3. stable diabetes therapy for > 3 months
4. age at randomisation
a. 40-79 years (inclusive) for anyone with a history of clinical cardiovascular disease, or
b. 55-79 years (inclusive) for anyone without a history of clinical cardiovascular disease (the age eligibility was modified on the basis of the results of the vanguard phase, so some participants were aged ≥ 80 years at randomisation)
5. at high risk for cardiovascular disease events, defined as
a. presence of clinical cardiovascular disease (prior myocardial infarction, stroke, arterial revascularization, angina with ischaemic changes on electrocardiogram at rest, changes on a graded exercise test, or positive cardiac imaging test results)
b. if no clinical cardiovascular disease, evidence in the past 2 years suggesting high likelihood of cardiovascular disease (1 risk factor: microalbuminuria, ankle-brachial index < 0.9, left ventricular hypertrophy by electrocardiogram or echocardiography, or > 50% stenosis of a coronary, carotid, or lower extremity artery), or
c. presence of ≥ 2 of the following factors that increase cardiovascular disease risk: LDL-cholesterol > 130 mg/dL (1 mg/dL = 0.02586 mmol/L) treated with lipid-lowering medication or untreated, low HDL-cholesterol (< 40 mg/dL for men and < 50 mg/dL for women), systolic blood-pressure > 140 mmHg or diastolic blood pressure > 95 mmHg treated with blood pressure-lowering medication or untreated, current cigarette smoking, or BMI > 32 kg/m2
6. In addition, all participants must be eligible for either the blood pressure trial or the lipid trial

Exclusion criteria:
1. history of hypoglycaemic coma/seizure within last 12 months
2. hypoglycaemia requiring third party assistance in last 3 months with concomitant glucose < 60 mg/dL (3.3 mmol/L)
3. history consistent with type 1 diabetes mellitus
4. unwilling to do frequent capillary blood glucose self-monitoring or unwilling to inject insulin several times a day
5. BMI > 45 kg/m2
6. serum creatinine > 1.5 mg/dL (132.6 ųmol/L) obtained within the previous 2 months
7. transaminase > 2 times upper limit of normal or active liver disease
8. any ongoing medical therapy with known adverse interactions with the glycaemic interventions (e.g., corticosteroids, protease inhibitors)
9. cardiovascular event or procedure (as defined for study entry) or hospitalisation for unstable angina within last 3 months
10. current symptomatic heart failure, history of NYHA class III or IV congestive heart failure at any time, or ejection fraction (by any method) < 25%
11. a medical condition likely to limit survival to less than 3 years or a malignancy other than non-melanoma skin cancer within the last 2 years
12. any factors likely to limit adherence to interventions
13. failure to obtain informed consent from participant
14. currently participating in another clinical trial
15. living in the same household as an already randomised ACCORD participant
16. any organ transplant
17. weight loss > 10% in last 6 months
18. pregnancy, currently trying to become pregnant, or of child-bearing potential and not practicing birth control
19. participants with recurrent requirements for phlebotomy or transfusion of red blood cells

Diagnostic criteria:
Type 2 diabetes mellitus defined according to the 1997 ADA criteria:

  • fasting plasma glucose > 126 mg/dL (> 7.0 mmol/L), or
  • symptoms of hyperglycaemia with casual plasma glucose > 200 mg/dL (>11.1 mmol/L), or
  • 2 hour plasma glucose > 200 mg/dL (> 11.1 mmol/L) after a 75 gram oral glucose load


InterventionsNumber of study centres: 77

Anti-diabetic interventions (intervention group): HbA1c < 6 % (fasting self monitored blood glucose < 5.6 mmol/L (100 mg/dL) or 2 hours blood glucose < 7.8 mmol/L (140 mg/dL) were also "action required threshold"). The treatment algorithm depends on how many anti-diabetic drugs the patient enters the trial with. Therapeutic regimens were individualised on the basis of group assignment and the response to therapy. When the glycaemic target was not achieved with 3 oral anti-diabetic drugs, insulin therapy was initiated. The following anti-diabetic drugs were available: biguanides, insulin secretagogues, thiazolidinediones, alpha-glucosidase inhibitors and insulins (for detailed description, please see study protocol p 62-63). Diet and lifestyle advice

Anti-diabetic interventions (control group):

HbA1c 7%-7.9% (fasting self monitored blood glucose > 5.0 mmol/L (90 mg/dL) was also "action required threshold")
The therapeutic regimes were individualised; see above. Diet and lifestyle advice

Concomitant treatment of cardiovascular risk factors:
Both groups: about 5800 participants were randomised in the lipid component of the ACCORD trial. Eligible participants were randomised to fenofibrate or placebo; all participants were treated with simvastatin. The participants, who were not enrolled in the lipid portion of the ACCORD were treated by their usual physician
About 4200 participants were randomised to the blood pressure part of the ACCORD, where many classes of antihypertensives and combinations may be used (protocol p 70). The participants who were not in the blood pressure trial were treated by their usual physician. ACE inhibitors were prescribed to all participants with previously cardiovascular disease or one cardiovascular risk factor (besides type 2 diabetes mellitus)

Concomitant target values of cardiovascular risk factors: all participants were advised to take aspirin daily
Lipid-lowering: for the participants not randomised to the lipid-lowering part of the ACCORD the recommended LDL-cholesterol goals were based on the National Cholesterol Education Program (NCEP) 2001 guidelines (initiation of pharmacologic treatment: LDL-cholesterol > 130 mg/dL, treatment goal: < 100 mg/dL (2.59 mmol/L)); the same LDL goal was stated for both arms in the lipid-lowering part of the trial
Blood pressure: in the blood pressure part of the trial the treatment goal in the intense group was: systolic blood pressure < 120 mmHg. In the less intense treatment arm of the blood pressure trial, the treatment target was a systolic blood pressure < 140 mmHg. For participants not in the blood pressure part of ACCORD, were treated by their usual physician. For participants not in the blood pressure trial the recommended blood pressure goal was 140/85 mmHg


OutcomesOutcomes reported in abstract of publication: composite outcome of non-fatal myocardial infarction, non-fatal stroke or death from cardiovascular causes, Death from any cause, non-fatal myocardial infarctions, microvascular outcomes, onset of albuminuria, eye complications, neuropathy, hypoglycaemia, HbA1c, and quality of life


Study detailsTitration period: when metformin was initiated, it was titrated to maximum dose over 4 weeks

Run-in period: potential participants will be asked to monitor capillary blood sugars 2 to 4 weeks pre-randomisation

Study terminated before regular end (for benefit / because of adverse events): yes


Publication detailsLanguage of publication: English

Publication status: peer review journal

Commercial funding: companies provided study medications, equipment, or supplies: Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca, Bayer HealthCare, Closer Healthcare, GlaxoSmithKline, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis, and Schering-Plough

Non-commercial funding:
National Heart, Lung, and Blood Institute; by other components of the National Institutes of Health, including the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute; by the Centers for Disease Control and Prevention; and by General Clinical Research Centers


Stated aim for studyQuote from publication: "The overall goal of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is to address this challenge by testing three complementary medical treatment strategies for type 2 diabetes to enhance the options for reducing the still very high rate of major CVD morbidity and mortality in this disease."


NotesAbbreviations: ACCORD: Action to Control Cardiovascular Risk in Diabetes; ADA: American Diabetes Association; BMI: body mass index; CVD: cardiovascular disease; HbA1c: glycosylated haemoglobin A1c; LDL: low density lipoprotein

Values for fasting blood glucose are calculated from mg/dL to mmol/L by dividing with 18


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from publication: "An internet-based, web browser randomization procedure will be employed in ACCORD. Clinical Sites access the study web site and initiate the interactive randomization page. Entry into this area is password protected and encrypted."

Allocation concealment (selection bias)Low riskQuote from publication: "An internet-based, web browser randomization procedure will be employed in ACCORD. Clinical Sites access the study web site and initiate the interactive randomization page. Entry into this area is password protected and encrypted."

Blinding of outcome assessment (detection bias)
Objective outcomes
Low riskQuote from publication: "During the data collection phases of the trial, this subcommittee will oversee the work of the Event Classification Working Group (made up of ACCORD investigators, who may or may not be on the Morbidity and Mortality Subcommittee), who will meet on a regular basis, and who will use the procedures and criteria adopted by the trial to classify the occurrence of clinical events in a masked fashion and to monitor event ascertainment/classification quality control."

Blinding of outcome assessment (detection bias)
Subjective outcomes
High riskComments: quality of life was assessed by the patient filling out a scoring scheme. The patients were the outcome assessors and not blinded to the intervention; no numbers of the participants with mild hypoglycaemia available

Incomplete outcome data (attrition bias)
Objective outcomes
Unclear riskComments: in the Appendix to the main publication it is described; a total of 37 patients refused the approach they were randomised to, 50 were lost to follow-up and 688 discontinued intervention (a total of 775 participants). In the main publication it is described that 162 participants withdrew consent. It is unclear whether the 162 participants are calculated together with the other number reported in the Appendix. However, in the publication of the long-term follow-up (5 years) the number of participants with unknown vital status and lost to follow-up for the primary outcome is reported. However, the reasons for lost to follow-up is not reported

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskOf the 2053 participants participating in the health related quality of life, data were available for 416 participants after 48 months. Reasons for lost to follow-up not adequately described; no numbers of the participants with mild hypoglycaemia available

Selective reporting (reporting bias)Low riskComments: some of the predefined outcomes are still not published, as the analysis might not be finish yet

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?High riskComments: Companies provided study medications, equipment or supplies: Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca, Bayer HealthCare, Closer Healthcare, GlaxoSmithKline, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis, and Schering-Plough

Trials according to risk of biasLow riskComments: adequate sequence generation and allocation concealment 

ADDITION-Europe 2011

MethodsCluster-randomised clinical trial


ParticipantsInclusion criteria:

  • practices were eligible if they were able to provide data for the calculation of the diabetes risk score for at least 70% of their patients 
  • individuals eligible for an invitation for screening were people registered with one of the participating general practices, aged 40 to 69 years in UK and Denmark (the Netherlands 50 – 59 years)
  • not known to have diabetes and with a diabetes risk score of > 0.17 (corresponding to the top 25% of the population distribution)


Exclusion criteria:

  • In screening practices, eligible participants deemed unfit for screening by their general practitioner were not invited for biochemical testing
  • illness with a life expectancy of less than 12 months
  • psychological or psychiatric disorders that might invalidate informed consent
  • being housebound
  • pregnant or lactation


Diagnostic criteria: WHO 1999


InterventionsNumber of study centres: 343
Anti-diabetic interventions (intervention group): < 7%, but change in anti-diabetic medicine with HbA1c > 6.5%

Anti-diabetic interventions (control group): standard care

Concomitant treatment of cardiovascular risk factors:
Intensive intervention group: ACE-inh to patients with blood pressure ≥ 120/80 mmHg and previous cardiovascular event or cardiovascular risk factor other than diabetes

Conventional intervention group: standard care

Concomitant target values of cardiovascular risk factors:

  • intensive intervention group
  • blood pressure target: ≤135/85 mmHg; treatment threshold ≥120/80mmHg
  • statin to with all patients with cholesterol ≥3.5mmol/L; target cholesterol < 5mmol/L; for patients with ischaemic heart disease cholesterol < 4.5 mmol/L
  • consider 75 mg aspirin daily if no contradictions


OutcomesOutcomes reported in abstract of publication: all-cause mortality, cardiovascular events and cardiovascular risk factors


Study detailsTitration period: none
Run-in period: none

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: Novo Nordisk, Astra, Pfizer, GlaxoSmithKline, Servier, HemoCue and Merck

Non-commercial funding: Research Foundation for General Practice, Danish Centre for Evaluation and Health Technology Assessment, Danish National Board of Health, Danish Medical Research Council, Aarhus University Research Foundation, Wellcome Trust, UK Medical Research Council, UK NIHR Health Technology Assessment Programme, UK National Health Service R&D, UK National Institute for Health Research, Julius Center for Health Sciences and Primary Care, University Medical Center


Stated aim for studyQuote from publication: "No evidence from trials is available to show whether early intensive multifactorial treatment improves outcomes when started between detection by screening and clinical diagnosis. We did the multicentre Anglo-Danish-Dutch Study of Intensive Treatment In People with Screen Detected Diabetes in Primary Care (ADDITION-Europe) to investigate this issue."


NotesAbbreviations: ADDITION: Anglo-Danish-Dutch Study of Intensive Treatment In People with Screen Detected Diabetes in Primary Care; HbA1c: glycosylated haemoglobin A1c; WHO: World Health Organization


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The practices were randomly assigned to provide routine diabetes care or intensive multifactorial treatment in a 1:1 ratio, by statisticians in each centre, according to a computer-generated list, independent of measurement teams."

Allocation concealment (selection bias)Low riskQuote: "The practices were randomly assigned to provide routine diabetes care or intensive multifactorial treatment in a 1:1 ratio, by statisticians in each centre, according to a computer-generated list, independent of measurement teams."

Blinding of outcome assessment (detection bias)
Objective outcomes
Low riskQuote: "Patients were unaware of their general practice’s group assignment throughout the study.”
“All staff collecting data from records and undertaking health assessments were unaware of patients’ treatment group allocations. For each endpoint possibly met, the relevant clinical information (e.g., death certificates, post-mortem reports, medical records, hospital discharge summaries, electrocardiographs, laboratory results, etc) were sent to two members of the expert committee within the country for independent adjudication according to an agreed protocol. Committee members were unaware of treatment allocations."

Blinding of outcome assessment (detection bias)
Subjective outcomes
Low riskQuote: "Patients were unaware of their general practice’s group assignment throughout the study."

Quality of life was assessed by the patient filling out a scoring scheme. The patients were blinded to the intervention; mild hypoglycaemia not reported

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskNumber and reasons for lost to follow-up adequately described in publication

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskNumber lost to follow-up described for the health related quality of life assessment, but no reasons provided; mild hypoglycaemia not reported

Selective reporting (reporting bias)Low riskComments: primary and secondary outcomes reported as described in protocol

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?High riskReceived funding from the pharmaceutical industry

Trials according to risk of biasLow riskComments: Adequate sequence generation and allocation concealment

ADDITION-Leicester

MethodsSubgroup of ADDITION-Europe, please see above


ParticipantsSubgroup of ADDITION-Europe, please see above


InterventionsSubgroup of ADDITION-Europe, please see above


OutcomesSubgroup of ADDITION-Europe, please see above


Study detailsSubgroup of ADDITION-Europe, please see above


Publication detailsSubgroup of ADDITION-Europe, please see above


Stated aim for studySubgroup of ADDITION-Europe, please see above


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskSubgroup of ADDITION-Europe, please see above

Allocation concealment (selection bias)Unclear riskSubgroup of ADDITION-Europe, please see above

Blinding of outcome assessment (detection bias)
Objective outcomes
Unclear riskSubgroup of ADDITION-Europe, please see above

Blinding of outcome assessment (detection bias)
Subjective outcomes
Unclear riskSubgroup of ADDITION-Europe, please see above

Incomplete outcome data (attrition bias)
Objective outcomes
Unclear riskSubgroup of ADDITION-Europe, please see above

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskSubgroup of ADDITION-Europe, please see above

Selective reporting (reporting bias)Unclear riskSubgroup of ADDITION-Europe, please see above

Free from academic bias (assessed from primary author)?Unclear riskSubgroup of ADDITION-Europe, please see above

Free from sponsor bias?Unclear riskSubgroup of ADDITION-Europe, please see above

Trials according to risk of biasUnclear riskSubgroup of ADDITION-Europe, please see above

ADDITION-Netherlands

MethodsSubgroup of ADDITION-Europe, please see above


ParticipantsSubgroup of ADDITION-Europe, please see above


InterventionsSubgroup of ADDITION-Europe, please see above


OutcomesSubgroup of ADDITION-Europe, please see above


Study detailsSubgroup of ADDITION-Europe, please see above


Publication detailsSubgroup of ADDITION-Europe, please see above


Stated aim for studySubgroup of ADDITION-Europe, please see above


NotesSubgroup of ADDITION-Europe, Please see below


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskSubgroup of ADDITION-Europe, please see above

Allocation concealment (selection bias)Unclear riskSubgroup of ADDITION-Europe, please see above

Blinding of outcome assessment (detection bias)
Objective outcomes
Unclear riskSubgroup of ADDITION-Europe, please see above

Blinding of outcome assessment (detection bias)
Subjective outcomes
Unclear riskSubgroup of ADDITION-Europe, please see above

Incomplete outcome data (attrition bias)
Objective outcomes
Unclear riskSubgroup of ADDITION-Europe, please see above

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskSubgroup of ADDITION-Europe, please see above

Selective reporting (reporting bias)Unclear riskSubgroup of ADDITION-Europe, please see above

Free from academic bias (assessed from primary author)?Unclear riskSubgroup of ADDITION-Europe, please see above

Free from sponsor bias?Unclear riskSubgroup of ADDITION-Europe, please see above

Trials according to risk of biasUnclear riskSubgroup of ADDITION-Europe, please see above

ADVANCE 2008

MethodsFactorial randomised clinical trial


ParticipantsInclusion criteria:

  • 55 years or older at entry
  • elevated risk of vascular disease (high risk for vascular disease was defined by a diagnosis of type 2 diabetes mellitus made 10 or more years earlier; or age 65 years or older at entry; or a history of any of the following: major macrovascular disease (including myocardial infarction, stroke, hospitalisation for transient ischaemic attack or unstable angina, or revascularization procedure)), major microvascular disease (including macroalbuminuria, proliferative retinopathy or retinal photocoagulation, or macular oedema), or another major risk factor for vascular disease (current cigarette smoking, total cholesterol > 6.0 mmol/L, HDL-cholesterol < 1.0 mmol/L or microalbuminuria)
  • diagnosis of type 2 diabetes mellitus first made at age 30 years or older


Exclusion criteria:

  • definite indication for, or contraindication to any of the study treatments
  • a definite indication for long-term insulin therapy at the time of study entry


Diagnostic criteria: NR


InterventionsNumber of study centres: 215
Anti-diabetic interventions (intervention group):

HbA1c ≤ 6.5%; all participants were given gliclazide (modified release, 30 to 120 mg daily) and were required to discontinue any other sulphonylurea. On the basis of the HbA1c at each visit, this protocol initially advised increasing the dose of gliclazide (modified release), with the sequential addition or increase in dose of metformin, glitazones, acarbose, or insulin (advising the initial use of basal insulin, with the addition of short-acting insulin at meals)

Anti-diabetic interventions (control group): strategy of standard glucose control with HbA1c target levels defined on the basis of local guidelines. Participants using gliclazide (modified release) when they entered the study were required to substitute this drug with another sulphonylurea, if continued therapy was required

Concomitant treatment of cardiovascular risk factors:
Both groups: participants were also assigned to placebo or preterax (a combination of perindopril and indapamide)

Concomitant target values of cardiovascular risk factors: NR


OutcomesOutcomes reported in abstract of publication: HbA1c, major macrovascular events, microvascular
events, nephropathy, retinopathy, death from cardiovascular causes or death from any cause, severe hypoglycaemia and costs of complications


Study detailsTitration period: none described, but titration is assumed to have been done when initiating some of the oral anti-diabetic drugs (e.g., metformin)
Run-in period: potentially eligible participants entered a 6-week run-in period, during which they continued their usual methods of glucose control and received a fixed combination of perindopril and indapamide

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: supported by grants from Servier (the major financial sponsor). Servier manufactures gliclazide (modified release) and the fixed combination of perindopril and indapamide

Non-commercial funding: The National Health and Medical Research Council of Australia


Stated aim for studyQuote from publication: "The aim of ADVANCE is to see if treatment to lower blood pressure and control glucose levels more tightly than usual reduces the risk of all complications in adults with type 2 diabetes"


NotesThe participants will be followed after the intervention period in an ongoing follow-up study (timeframe 2014).

Abbreviations: ADVANCE: Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation; HbA1c: glycosylated haemoglobin A1c; NR: Not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from publication: "A central, computer-based randomisation service will assign patients to treatments stratified by the study centre, history of CVD or microvascular disease and background use of perindopril at baseline."

Allocation concealment (selection bias)Low riskQuote from publication: "A central, computer-based randomisation service will assign patients to treatments stratified by the study centre, history of CVD or microvascular disease and background use of perindopril at baseline."

Blinding of outcome assessment (detection bias)
Objective outcomes
Low riskQuote from publication: "An independent End Point Adjudication Committee, unaware of the group assignments, reviewed source documentation for all suspected primary end points and deaths."

"An independent End Point Adjudication Committee, unaware of the group assignments, reviewed source documentation for all suspected primary end points and deaths."

"Primary and secondary outcomes were validated by an independent adjudication committee whose members were unaware of the treatment assignments."

Blinding of outcome assessment (detection bias)
Subjective outcomes
Unclear riskComments: health-related quality of life is not published yet

Incomplete outcome data (attrition bias)
Objective outcomes
Unclear riskComments: only 7 (intensive) and 10 (conventional) had unknown vital status. Number of participants not completing final visit are reported for each intervention group; however, the reasons are not reported

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskHealth-related quality of life is not published yet. Mild hypoglycaemia is reported by the participants, who were not blinded to the intervention

Selective reporting (reporting bias)Low riskComments: some of the predefined outcomes are still not published, as the analysis might not be finish yet

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?High riskServier

Trials according to risk of biasLow riskComments: adequate sequence generation and allocation concealment

Araki 2012

MethodsFactorial randomised clinical trial


ParticipantsInclusion criteria:

  • age 65–85 years
  • HbA1c ≧ 7.9% or HbA1c ≧7.4% with at least one of following criteria: BMI ≧25 kg/m2, blood pressure ≧ 130/85 mmHg, serum total cholesterol ≧ 200 mg/dL (or low-density lipoprotein cholesterol ≧ 120 mg/dL in participants without coronary heart disease) or ≧ 180 mg/dL (or ow-density lipoprotein cholesterol ≧100 mg/dL in participants with coronary heart disease), triglycerides ≧ 150 mg/dL and HDL-C < 40 mg/dL


Exclusion criteria:

  • recent (<6 months) myocardial infarction or stroke
  • acute or serious illness, aphasia and severe dementia


Diagnostic criteria: the diagnosis of diabetes was made according to the criteria of Japan Diabetes Society at that time

Fasting plasma glucose > 126 mg/dL and 2 hr post load glucose > 200 mg/dL, or casual plasma glucose > 200 mg/dL


InterventionsNumber of study centres: 39
Anti-diabetic interventions (intervention group):

Publication: HbA1c < 6.9% (NGSP; equivalent to DCCT); Protocol: HbA1c < 6.5% (JDS). If HbA1c levels did not reduce to < 6.9%, oral hypoglycaemic drugs (sulphonylurea, biguanides, a-glucosidase inhibitors and pioglitazone) or insulin therapy was introduced by the physician.

Anti-diabetic interventions (control group): discrepancy between publication and protocol. Publication: Goals as attending doctors consider to be proper, but local guidelines recommend HbA1c < 7.4%. Protocol: Conventional treatment group: goals as attending doctors consider to be proper:at least fasting plasma glucose < 200 mg/dl or HbA1c < 9.0%. Thorugh correspondence it was clarified that there was no specific gaol. To prevent diabetic come, the physicians were asked to avoid remarkable hyperglycaemia (fasting plasma glucose < 200mg/dL or HbA1c < 9%). Oral hypoglycaemic agents as in standard care.

Concomitant treatment of cardiovascular risk factors:
Intensive group: blood pressure < 130/85 mmHg, total cholesterol < 180 mg/dL (if coronary heart disease is present), or < 200mg/dL (if coronary heart disease is absent), triglycerides < 150 mg/dL, HDL cholesterol > 40mg/dL, and BMI < 25.

Conventional: Standard treatment, not further specified


OutcomesOutcomes reported in abstract of publication: HbA1c, coronary revascularization, fatal and non-fatal events, and composite events


Study detailsTitration period: none
Run-in period: none

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: none

Non-commercial funding: this study was financially supported by Research Grants for Longevity Sciences from the Ministry of Health and Labour, and Welfare (H12- Choju-016, H15-Chojyu-016, H17-Choju-Ordinal- 013) and the Japan Foundation for Aging and Health 


Stated aim for studyQuote from publication: "To evaluate long-term, multiple risk factor intervention on physical, psychological and mental prognosis, and development of complications and cardiovascular disease in elderly type 2 diabetes patients."


NotesAbbreviations: BMI: Body mass index; HbA1c: glycosylated haemoglobin A1c; HDL: high density lipoprotein; JDS: Japanese Diabetes Society; NGSP: National Glycohemoglobin Standardization Program


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from publication: "A total of 1173 diabetic outpatients were enrolled and randomly allocated to..."

Comments: through correspondence it was clarified that randomisation and allocation was made though central data centre

Allocation concealment (selection bias)Low riskQuote from publication: "A total of 1173 diabetic outpatients were enrolled and randomly allocated to..."

Comments: through correspondence it was clarified that randomisation and allocation was made though central data centre

Blinding of outcome assessment (detection bias)
Objective outcomes
Low riskQuote from publication: "Fatal and non-fatal events during follow up were certified by at least two members of the expert committee, masked to the participants’ diagnosis and risk factor status."

Blinding of outcome assessment (detection bias)
Subjective outcomes
Unclear riskDo not assess health-related quality of life or report mild hypoglycaemia

Incomplete outcome data (attrition bias)
Objective outcomes
Unclear riskComments: reports that 104 participants are lost to follow-up. Not reported the reasons or which group they belonged to. Through correspondence it was clarified that 57 in the intensive group and 47 in the conventional group had unknown mortality status. For non-fatal myocardial infarction it was not available to assess in 196 participants in the intensive group and 200 participants in the conventional group at the end of follow-up. Reasons for dropouts was according to the authors transfer to different clinic or long-term care probably due to disabilities or dementia

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskDo not assess health-related quality of life or report mild hypoglycaemia

Selective reporting (reporting bias)Low riskComments: the trial has been completed recently and all the data are not yet published. The reporting of all outcomes was insufficient in the publications, but additional data were provided by the author. Some outcomes are still not reported fully, but the authors are still working on the data from the trial in order to get them published

Free from academic bias (assessed from primary author)?Low riskComments: first authors first publication on the topic

Free from sponsor bias?Low riskComments: no commercial funding

Trials according to risk of biasLow riskAdequate sequence generation and allocation concealment

Bagg 2001

MethodsRandomised clinical trial


ParticipantsInclusion criteria:

  • Type 2 diabetes mellitus of < 15 years duration
  • HbA1c > 8.9%


Exclusion criteria:

  • age > 75 or < 40 years
  • BMI > 40 kg/m2
  • current diastolic blood pressure > 100 mmHg
  • creatinine > 0.16 mmol/L
  • any severe concurrent illness
  • left ventricular failure, myocardial infarction, or unstable angina in the 6 months prior to enrolment
  • recent (< 6 weeks) commencement of vasoactive cardiac medications


Diagnostic criteria:

  • age at diagnosis > 35 years
  • no episodes of ketoacidosis in the past
  • insulin independence for more than 12 months or fasting plasma C-peptide > 0.21 pmol/L if duration of disease less than 12 months


InterventionsNumber of study centres: 1

Anti-diabetic interventions (intervention group):

HbA1c < 7%
Medication adjusted to following targets: before meal capillary glucose: 4–7 mmol/L, 2 hour after meal < 10 mmol/L
Initially oral hypoglycaemic agents before commencing insulin In patients treated with diet only at baseline the initial primary therapy with oral hypoglycaemic drug was determined by the BMI:
(1) BMI < 32 kg/m2: A sulphonylurea was chosen as the initial therapy. BMI > 32 kg/m2: metformin was chosen as initial therapy
(2) Once the initial oral hypoglycaemic drug had reached the maximum tolerated dose (glipizide 10 mg twice a day or metformin 1 g three times a day), the secondary drug was added and increased to the maximum tolerated dose
(3) Bedtime intermediate-acting insulin was started at 2 U/kg and increased to twice a day if glycaemic targets were not met. Premixed or short-acting insulin could be instituted if necessary to meet glycaemic targets. Patients taking insulin were continued on one oral hypoglycaemic agent, defined by the BMI as in (1)
Dietary and nursing advice at least one time during the intervention period.

Anti-diabetic interventions (control group): avoid symptomatic hyperglycaemia and fortnightly fasting capillary glucose tests of > 17 mmol/L. Similar stepped care as intensive group if they were persistent hyperglycaemic. Patients received dietary and nursing advice in at least one occasion if this had not been provided in the 12 month before enrolment in the study

Concomitant treatment of cardiovascular risk factors:
Both groups: NR

Concomitant target values of cardiovascular risk factors:

Both groups: NR


OutcomesOutcomes reported in abstract of publication: HbA1c, flow-mediated dilatation and glyceryl trinitrate-mediated dilatation, weight, blood pressure, serum lipids, total body fat mass and trunk fat mass, peripheral fat mass


Study detailsTitration period: we assume metformin was titrated, when initiated

Run-in period: none

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: none

Non-commercial funding: The AMP Society of New Zealand, Health Research Council of New Zealand, Auckland Medical Research Foundation and University of Auckland Staff Research Fund


Stated aim for studyQuote from publication: "The aims of this study were to elucidate the factors that contribute to endothelial activation and fibrinolytic abnormalities in patients with poorly controlled type 2 diabetes and to determine whether improved glycaemic control reduces endothelial activation." 

"To examine the effects of improved glycaemic control over 20 weeks on the type and distribution of weight change in patients with type 2 diabetes who at baseline have poor glycaemic control."


NotesAbbreviations: HbA1c: Glycosylated haemoglobin A1c; BMI: Body mass index; NR: Not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote from publication: "Patients were randomised on the basis of gender, age and smoking status to either a usual control (n = 22) or improved control (n = 21)."

The author recalls the trial as randomised by computer generated sequence, but is not able to confirm this

Allocation concealment (selection bias)Unclear riskComments: no description

Blinding of outcome assessment (detection bias)
Objective outcomes
Unclear riskComments: blinding of the predefined objective outcomes were not reported

Quote from publication: "Two observers were blinded to the intervention and the sequence in which the images were acquired performed all measurements in duplicate."

Blinding of outcome assessment (detection bias)
Subjective outcomes
High riskComments: health-related quality of life is not assessed. Participants reporting mild hypoglycaemia are not blinded to the intervention

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskQuote: "Four patients in IC were withdrawn after randomization: one suffered a brainstem cerebrovascular accident after 2 weeks, one developed unstable angina after 6 weeks and two other patients developed nonvascular illness requiring hospitalization."

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskComments: health-related quality of life is not assessed. Lost to follow-up for mild hypoglycaemia adequately described

Selective reporting (reporting bias)Low riskComments: all predefined primary and secondary outcomes were assessed

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?Low riskComments: no industry funding

Trials according to risk of biasUnclear riskUnclear sequence generation and allocation concealment

Becker 2003

MethodsRandomised clinical trial


ParticipantsInclusion criteria:

  • type 2 diabetes mellitus
  • age between 40 and 75 years
  • Caucasian ethnicity


Exclusion criteria:

  • no established diagnosis of diabetes according to WHO criteria in the absence of glucose-lowering medication
  • carcinoma
  • other comorbidity preventing three monthly visits to the study centre or seriously impairing well-being
  • language problems
  • psychological problems


Diagnostic criteria: WHO criteria


InterventionsNumber of study centres: 1

Anti-diabetic interventions (intervention group):

Fasting capillary blood glucose < 6.5 mmol/L
Regimen: oral anti-diabetic agents in increasing doses up to their usual maximum before other anti-diabetic agents were added

In patients with a BMI ≥ 27 kg/m2, metformin was the first step. If the assigned target values for glycaemic control were not reached either glibenclamide, gliclazide, or glipizide was added.

In patients with a BMI < 27 kg/m2, sulphonylurea was the first step. If the assigned target values were not reached on tablets alone, bedtime intermediate-acting insulin was added (and metformin, if any, discontinued). If target values were not reached with this combination therapy, sulphonylurea was discontinued and twice-daily injections of a mixture of short- and intermediate-acting insulin was initiated. If glycaemic control remained poor, multiple insulin injection therapy was considered.

Anti-diabetic interventions (control group): fasting capillary blood glucose < 8.5 mmol/L. Same treatment algorithm as for intensive glycaemic control

Concomitant treatment of cardiovascular risk factors:
Both groups: NR

Concomitant target values of cardiovascular risk factors: NR


OutcomesOutcomes reported in abstract of publication: positive affect, perceived treatment burden, general well-being scores, according to achieved HbA1c the following is reported: triglycerides, total cholesterol, blood pressure, and in the albumin creatinine ratio, HDL cholesterol, proinsulin, insulin, fibrinogen and von Willebrand factor and fibrinogen


Study detailsTitration period: we assume metformin was titrated, when initiated

Run-in period: none

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: Univé Health Insurance

Non-commercial funding: none


Stated aim for studyQuote from publication: "...the association between on the one hand changes in glycaemic control and on the other hand within-subject changes of both classic cardiovascular risk factors and less conventional cardiovascular risk indicators that are typically associated with type 2 diabetes (proinsulin, insulin, fibrinogen, von Willebrand factor and the urinary albumin creatinine ratio)."


NotesThere is discrepancy in the number of participants between the two publications. In the article published in the Netherlands Journal of Medicine 372 participants were invited of which 232 gave informed consent. The data presented in the article from Netherlands Journal of Medicine included 214 patients with type 2 diabetes mellitus. The recruitment period was from June 1992 until December 1993. In the article published in Diabetes Care, 296 patients with type 2 diabetes mellitus were potentially eligible, of which 229 gave informed consent and 199 patients were randomised. The recruitment period was June 1992 to February 1994. We corresponded with two of the authors, who unfortunately were not able to clarify the discrepancy between the publications. We used baseline data from the publication from the Netherlands Journal of Medicine because the baseline characteristics of the participants were reported according to the groups the participants were randomised to. The publication from the Diabetes Care reported baseline characteristics according to the (percentage) achieved decrease in HbA1c

Abbreviations: HbA1c: glycosylated haemoglobin A1c; BMI: body mass index; HDL: high density lipoprotein


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote from publication: "After the baseline assessment, patients were randomly assigned to..."

Allocation concealment (selection bias)Unclear riskComments: not described

Blinding of outcome assessment (detection bias)
Objective outcomes
Unclear riskComments: not described

Blinding of outcome assessment (detection bias)
Subjective outcomes
High riskComments: health-related quality of life assessed by the patient, who was not blinded to the intervention. Mild hypoglycaemic not reported

Incomplete outcome data (attrition bias)
Objective outcomes
Unclear riskComments: the number of participants in the two articles of the trial, does not harmonise

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskComments: the number of participants in the two articles of the trial, does not harmonise

Selective reporting (reporting bias)High riskComments: no trial protocol or design article available. However, partial reporting of outcome exist (Appendix 11)

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?Low riskUnivé Health Insurance

Trials according to risk of biasUnclear riskComments: unclear sequence generation and allocation concealment

Blonde 2009

MethodsRandomised clinical trial


ParticipantsInclusion criteria:

  • adults (≧ 18 years) diagnosed with type 2 diabetes at least 3 months
  • currently taking metformin ± sulphonylurea ± glinides ± thiazolidinedione at a stable dose for the past 3 months (at either the maximal tolerated dose or at least half of the maximum recommended dose according to package insert)
  • insulin naive
  • body mass index ≦ 45 kg/m2
  • HbA1c between 7.0 and 9.0% (inclusive)


Exclusion criteria:

  • women who were pregnant, breast feeding or unwilling to use adequate contraception
  • known or suspected allergies to trial products
  • previous participation in any trial within the past 3 months
  • current substance abuse


Diagnostic criteria: NR


InterventionsNumber of study centres: 52 or 69 sites. number differs on the clinicaltrial.gov website

Anti-diabetic interventions (intervention group): fasting plasma glucose 3.9–5.0 mmol/L

Participants continued their oral anti-diabetic drug at stable doses during the trial; however, dose reduction or discontinuation of sulphonylureas or glinides was allowed (at investigator’s discretion) if a subject was experiencing hypoglycaemia. Subjects self titrated their insulin dose every 3 days according to the mean of self-measured fasting blood glucose values the three previous days using the forced titration algorithm:

mean fasting plasma glucose <3.9 mmol/L; reduce dose by 3 U
mean fasting plasma glucose between 3.9–5.0 mmol/L; no change
mean fasting plasma glucose > 5.0 mmol/L; increase dose by 3 U

Treat-to-target dose titration scheme, subcutaneus injection, once daily

Anti-diabetic interventions (control group): fasting plasma glucose 4.4–6.1 mmol/L

Participants continued their oral antidiabetic drug at stable doses during the trial; however, dose reduction or discontinuation of sulphonylureas or glinides was allowed (at investigator’s discretion) if a subject was experiencing hypoglycaemia. Subjects self titrated their insulin dose every 3 days according to the mean of self-measured fasting plasma glucose values the three previous days using the forced titration algorithm:

mean fasting plasma glucose <4.4 mmol/L; reduce dose by 3 U

fasting plasma glucose between 4.4–6.1 mmol/L; no change

fasting plasma glucose > 6.1 mmol/L; increase dose by 3 U

Treat-to-target dose titration scheme, subcutaneus injection, injection, once daily

Concomitant treatment of cardiovascular risk factors:
Both groups: NR

Concomitant target values of cardiovascular risk factors: NR


OutcomesOutcomes reported in abstract of publication: HbA1c, insulin dosing, hypoglycaemia, major hypoglycaemia and weight


Study detailsTitration period: not reported

Run-in period: none

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: Novo Nordisk

Non-commercial funding: no


Stated aim for studyQuote from publication: "To compare efficacy and safety of two fasting plasma glucose (FPG) titration targets [4.4–6.1 mmol/l (80–110 mg/dl) and 3.9–5.0 mmol/l (70–90 mg/dl)] using a patient-directed, treat-to-target algorithm for once-daily basal insulin in insulin-naïve subjects with type 2 diabetes suboptimally treated with oral antidiabetes drugs (OADs)."


NotesAbbreviations: HbA1c: Glycosylated haemoglobin A1c; NR: Not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote from publication: "…,eligible subjects were randomized to one…"

Allocation concealment (selection bias)Unclear riskQuote from publication: "…,eligible subjects were randomized to one…"

Blinding of outcome assessment (detection bias)
Objective outcomes
Unclear riskComments: number lost to follow up described, but no reasons provided

Blinding of outcome assessment (detection bias)
Subjective outcomes
High riskComments: health related quality of life not assessed. Mild hypoglycaemia reported by the participants, who were not blinded to the intervention

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskComments: numbers lost to follow-up with detailed description provided on clinicaltrial.gov website

Incomplete outcome data (attrition bias)
Subjective outcomes
Low riskComments: numbers lost to follow-up with detailed description provided on clinicaltrial.gov website

Selective reporting (reporting bias)Low riskComments: outcomes reported as stated in trial protocol

Free from academic bias (assessed from primary author)?Low riskComments: primary authors first article on the topic

Free from sponsor bias?High riskComments: sponsored by pharmaceutical company

Trials according to risk of biasUnclear riskComments: Unclear sequence generation and allocation concealment

Cao 2011

MethodsRandomised clinical trial


ParticipantsInclusion criteria:

  • Type 2 diabetes mellitus
  • open elective gastrectomy for gastric cancer


Exclusion criteria:

  • age was less than 16 years
  • severe obesity (BMI > 30 kg/m2) or severe malnutrition (BMI <15 kg/m2)
  • expected surgical intensive care unit stay after surgery was less than 24 hours
  • tumour was unresectable or the patient with late-stage cancer underwent palliative surgery
  • pregnancy
  • took corticosteroids, steroids, growth hormone, or immunosuppressive drugs within 2 weeks prior to the trial
  • patient received neoadjuvant chemotherapy
  • patient was diagnosed with gastric stump cancer or recurrent gastric cancer


Diagnostic criteria: WHO criteria 1999


InterventionsNumber of study centres: 1

Anti-diabetic interventions (intervention group): blood glucose target between 4.4 and 6.1 mmol/L. In intensive group treatment, the insulin infusion was started if the blood glucose levels exceeded 6.1 mmol/l and was adjusted to maintain the blood glucose target between 4.4 and 6.1 mmol/L

Anti-diabetic interventions (control group): blood glucose target between 10.0 and 11.0 mmol/L. In conventional group treatment, the insulin infusion was started if the blood glucose level exceeded 12.0 mmol/L and was adjusted to maintain the blood glucose target between 10.0 and 11.0 mmol/L

Concomitant treatment of cardiovascular risk factors:
Both groups: NR

Concomitant target values of cardiovascular risk factors:
Both groups: NR


OutcomesOutcomes reported in abstract of publication: hypoglycaemia, mortality, morbidity, days to suture removal, postoperative hospital stay, postoperative duration of antibiotic use, HOMA-IR and HLA-DR expression on monocytes, fasting blood glucose and fasting insulin


Study detailsTitration period: none

Run-in period: none

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English and Chinese

Publication status: peer-reviewed journal

Commercial funding: none

Non-commercial funding: yes (Health Science and Technology Development Project of Shandong)


Stated aim for studyQuote from publication: "This study was to compare the effect of intensive insulin therapy (IIT) to conventional insulin therapy (CIT) on postoperative outcomes among type 2 diabetes mellitus (DM) patients who underwent D2 gastrectomy for gastric cancer."


NotesAbbreviations: HbA1c: Glycosylated haemoglobin A1c; BMI: Body mass index; WHO: World Health Organization


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from publication: "A simple randomization method (300 random numbers were generated through a random number table) with concealment was used for allocating the patients to different groups in this prospective study."

Allocation concealment (selection bias)Low riskQuote from publication: "A simple randomization method (300 random numbers were generated through a random number table) with concealment was used for allocating the patients to different groups in this prospective study."

Blinding of outcome assessment (detection bias)
Objective outcomes
Low riskQuote: "However, to minimize the bias, the staff responsible for adjustment of insulin dose and monitoring of blood glucose levels was unaware of clinical decision-making and important outcome measurements."

Blinding of outcome assessment (detection bias)
Subjective outcomes
Unclear riskComments: health-related quality of life and mild hypoglycaemia is not assessed

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskComments: no patients lost to follow-up

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskComments: health-related quality of life and mild hypoglycaemia is not assessed

Selective reporting (reporting bias)Unclear riskComments: no design article or protocol available

Free from academic bias (assessed from primary author)?Low riskComments: primary authors first article on the topic

Free from sponsor bias?Low riskComments: only non-commercial funding

Trials according to risk of biasLow riskAdequate sequence generation and allocation concealment

Cooray 2011

MethodsRandomised clinical trial


ParticipantsInclusion criteria:

  • 50 and 70 years
  • without diabetes complications (i.e. cardiovascular disease, angiopathy, microangiopathy, retinopathy or nephropathy)


Exclusion criteria: none reported

Diagnostic criteria: NR


InterventionsNumber of study centres: NR

Anti-diabetic interventions (intervention group):

Clarified through correspondence: In the intensified glycaemic control group we aimed to reduce the HbA1c with 1% unit.

Anti-diabetic interventions (control group): conventional treatment

Concomitant treatment of cardiovascular risk factors:
Both groups: NR

Concomitant target values of cardiovascular risk factors:

Both groups: NR


OutcomesOutcomes reported in abstract of publication: cognitive domains


Study detailsTitration period: none

Run-in period: none

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: none

Non-commercial funding: Yes


Stated aim for studyQuote from publication: "The purpose of the present study was to characterise abnormalities in brain function in T2DM, and to investigate if such abnormalities could be reversed by a 2-month period of intensified glucose control."


NotesGroup of healthy controls are not included


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComments: not described in publication; the authors of the trial clarified that the trial was randomised

Allocation concealment (selection bias)Unclear riskComments: not described

Blinding of outcome assessment (detection bias)
Objective outcomes
Unclear riskComments: not described

Blinding of outcome assessment (detection bias)
Subjective outcomes
Unclear riskComments: not described

Incomplete outcome data (attrition bias)
Objective outcomes
Unclear riskComments: not described

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskComments: not described

Selective reporting (reporting bias)High riskComments: report in the publication that they collect data on hypoglycaemia, but no data are reported. No design article available

Free from academic bias (assessed from primary author)?Low riskComments: first authors first article on the topic

Free from sponsor bias?Low riskComments: no pharmaceutical funding

Trials according to risk of biasUnclear riskUnclear sequence generation and allocation concealment

DIGAMI 2 2005

MethodsRandomised clinical trial


ParticipantsInclusion criteria:

  • patients with established type 2 diabetes mellitus or an admission blood glucose > 11.0 mmol/L, admitted to participating coronary care units
  • suspect acute myocardial infarction due to symptoms (chest pain > 15 min during the preceding 24 hour) and/or recent electrocardiogram signs (new Q-waves and/or ST-segment deviations in two or more leads)


Exclusion criteria:

  • inability to cope with insulin treatment or to receive information on the study
  • residence outside the hospital catchment area
  • participation in other studies, or previous participation in DIGAMI 2


Diagnostic criteria:

Known type 2 diabetes mellitus was based on case history, record based information on diabetes and that the patient had been prescribed diabetes related therapy (lifestyle oriented and/or glucose-lowering drugs). Those with glucose > 11 mmol/L were accepted as having diabetes based on this elevated glucose level and subsequently higher than normal glucose values


InterventionsNumber of study centres: 44

Anti-diabetic interventions (intervention group): fasting blood glucose level of 5 to 7 mmol/L and a non-fasting level of < 10 mmol/L. A 24 hour insulin-glucose infusion (for further details see Malmberg 1995) followed by a subcutaneous insulin-based long-term glucose control. Insulin was given as short-acting insulin before meals and intermediate long-acting insulin in the evening

Anti-diabetic interventions (control group): no predefined target values, standard care. Routine metabolic management according to local practice

Concomitant treatment of cardiovascular risk factors:
Both groups: patients without contraindications were prescribed aspirin, thrombolytic agents, beta-blockers, lipid-lowering drugs, ACE- inhibitors, and revascularization procedures when appropriate

Concomitant target values of cardiovascular risk factors: NR


OutcomesOutcomes reported in abstract of publication: all-cause mortality, non-fatal reinfarction, stroke, and hypoglycaemia


Study detailsRun-in period: none

Titration period: none

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: Aventis Sweden, Novo Nordic Denmark, and AFA Insurance Denmark

Non-commercial funding: The Swedish Heart-Lung Foundation


Stated aim for studyQuote from publication: "In DIGAMI 2, three treatment strategies were compared: group 1, acute insulin–glucose infusion followed by insulin-based long-term glucose control; group 2, insulin–glucose infusion followed by standard glucose control; and group 3, routine metabolic management according to local practice."


NotesThere are three intervention groups in the DIGAMI 2 trial. We have chosen to report two of the groups in our analyses: the one with the most intensive treatment strategy (group 1) and the group with standard care (group 3)

Abbreviations: DIGAMI: Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction; NR: Not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from publication: "The computer-based randomization was centralized to the study coordinating office open 24 h/day (Karolinska Hospital, Stockholm, Sweden). An attempt for balanced randomization was performed directly after a patient had been evaluated for inclusion, given informed consent, and after baseline variables had been collected. Telecommunicated information about baseline variables were transferred into the computer and the subsequent randomization was based on an algorithm including important prognostic markers in the first DIGAMI trial...."

Allocation concealment (selection bias)Low riskQuote from publication: "The computer-based randomization was centralized to the study coordinating office open 24 h/day (Karolinska Hospital, Stockholm, Sweden). An attempt for balanced randomization was performed directly after a patient had been evaluated for inclusion, given informed consent, and after baseline variables had been collected. Telecommunicated information about baseline variables were transferred into the computer and the subsequent randomization was based on an algorithm including important prognostic markers in the first DIGAMI trial...."

Blinding of outcome assessment (detection bias)
Objective outcomes
Low riskQuote from publication: "An independent committee comprising three experienced cardiologists adjudicated all events blindly and could, as indicated, ask for any type of information felt needed to ensure a correct classification of the events and the reasons for mortality."

Quote from publication of the extended follow-up period: "Events during the extended follow-up were adjudicated by two of the present investigators (L. Rydén, L. G. Mellbin) by scrutinising copies of relevant parts of the hospital records and/or death certificates. Both investigators were blinded to treatment group status of patients."

Blinding of outcome assessment (detection bias)
Subjective outcomes
High riskComments: health-related quality of life not assessed. Mild hypoglycaemia assumedly measured by the unblinded participants

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskComments: no patients were lost to follow-up during the randomised clinical trial. In the extension period patients lost to is balanced and adequately described

Incomplete outcome data (attrition bias)
Subjective outcomes
Low riskComments: no patients were lost to follow-up during the randomised clinical trial. In the extension period patients lost to is balanced and adequately described

Selective reporting (reporting bias)Low riskComments: outcomes reported as stated in trial protocol

Free from academic bias (assessed from primary author)?High riskComments: primary author has published DIGAMI 1996

Free from sponsor bias?High riskComment: Aventis and Novo Nordic

Trials according to risk of biasLow riskAdequate sequence generation and allocation concealment

Fantin 2011

MethodsRandomised clinical trial


ParticipantsInclusion criteria:

  • type 2 diabetes mellitus
  • ages of 30 and 80 years old
  • referred for PCI with bare stent metal


Exclusion criteria:

  • malignant neoplasia
  • haemodialysis
  • renal failure
  • acute and chronic inflammatory or infectious diseases
  • use of drugs that could interfere with the evaluation of inflammatory markers (corticosteroids, nonsteroidal anti-inflammatory drugs, immunosuppressants)
  • clear indication for drug-eluting stent implantation, restenosis of the target vessel, revascularization procedures in the last 30 days, or acute coronary syndromes in the last 30 days


Diagnostic criteria:

Diabetes was defined as the presence of a fasting plasma glucose concentration 126 mg/dl or greater on the day of the angioplasty. Patients with diabetes were also considered to be those with previous diagnosis or use of specific medication, oral drugs, or insulin

Type 2 diabetes mellitus was defined as the onset of diabetes after the age of 40 years, initially treated by diet and/or oral anti-diabetic medication


InterventionsNumber of study centres: 1

Anti-diabetic interventions (intervention group):

Targeting glucose levels between 80 and 100 mg/dl in pre-meal periods and lower than 140 mg/dl in random glucose measurements

Iv infusion of insulin in dextrose 5%, 1 U per 10 ml for 24 hours after PCI, using a modified protocol

If glucose levels dropped under the desirable range, insulin infusion was maintained at least at 1 IU/h, dextrose 5% was changed for dextrose 10%, and dextrose 50% was injected or glucose sachets were offered, depending on the patient condition and glucose levels. If glucose levels risen above the desirable range, then the insulin infusion rate was raised. This protocol was maintained for 24 hours

Anti-diabetic interventions (control group): 250 mg/dl or less. Standard treatment, patients received iv saline at low drip rates, and hyperglycaemia was managed with the usual clinical practice of the institution that comprises sc regular insulin administration (4–8 U) as needed, according to each patient’s clinical situation, with a target of 250 mg or less per decilitre

Concomitant treatment of cardiovascular risk factors:
Both groups: all patients received the same dose of aspirin before the procedure

Patients treated with coronary stents were maintained on ticlopidine 250 mg twice daily or clopidogrel 75 mg/day for 1 month in addition to aspirin

Concomitant target values of cardiovascular risk factors: NR


OutcomesOutcomes reported in abstract of publication: Glycaemia, insulinaemia, CRP, soluble ligand CD40, ET-1, IL-6 and protein oxidation


Study detailsRun-in period: none

Titration period: none

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: none

Non-commercial funding: Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (Grant 05/19366), Conselho Nacional de Desenvolvimento Científico e Tecnológico, and Fundo de Incentivo á pesquisa e Eventos (Hospital de Clínicas de Porto Alegre)


Stated aim for studyQuote from publication: "The objective of the study was to evaluate the effects of normalizing glycemia through iv insulin per 24 h on markers of oxidative stress and inflammation in patients with diabetes submitted to percutaneous coronary intervention (PCI) with stent."


NotesAbbreviations:

CD-40: Cluster of Differentiation 40; CRP: C-reactive protein; ET-1: Endothelin-1; IL-6: Interleukin 6; PCI: Percutaneous coronary intervention


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from correspondence: "A numerical performance was done in a numerical sequence (1 to 70), in an Excel worksheet and the treatment that each patient was assigned was selected in blocks."

Allocation concealment (selection bias)Low riskQuote from correspondence: "Each number was cut and inserted into sealed envelopes.

The person who withdrew the numbers of the envelopes was not a member of the study team."

Blinding of outcome assessment (detection bias)
Objective outcomes
Low riskQuote from correspondence: "The randomization was done just after PCI, the operators did not know which treatment the subjects would receive.

Furthermore, the individual who analysed biochemistry samples did not know which treatment each subject received also. During the study period (24h) all members of the trial knew which treatment was being administrated. During the follow up, despite the person that made the call was a member of the trial, at the moment of the follow up, the person did not have available the information about which group the subject was previously randomized."

Blinding of outcome assessment (detection bias)
Subjective outcomes
High riskComments: health-related quality of life not assessed. Mild hypoglycaemia assume assessed by non-blinded participants

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskComments: through correspondence, stated that mortality status known for all participants at the end of follow-up. Lost to follow-up for other outcomes adequately described in publication

Incomplete outcome data (attrition bias)
Subjective outcomes
Low riskComments: lost to follow-up for outcomes adequately described in publication

Selective reporting (reporting bias)Low riskComments: primary and secondary outcomes from the trial protocol reported

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?Low riskComments: no commercial funding

Trials according to risk of biasLow riskComments: adequate sequence generation and allocation concealment

Guo 2008

MethodsRandomised clinical trial


ParticipantsInclusion criteria:

  • duration of type 2 diabetes mellitus less than 1 year
  • age 30-70 years
  • informed consent for the participation and regular monthly visit at diabetic clinic


Exclusion criteria:

  • other types of diabetes
  • liver disease
  • coronary heart disease
  • cerebral or peripheral vascular disease
  • renal disease except diabetic renal disease
  • carotis intima-media thickness < 1.3 mm at baseline


Diagnostic criteria: WHO 1999


InterventionsNumber of study centres: 1.

Anti-diabetic interventions (intervention group):

Fasting plasma glucose 4.0 to 7.0 mmol/L, HbA1c < 7%

The hypoglycaemic agents included:

  • glipizide (max 15 mg daily)
  • metformin (max 2250 mg daily)
  • α-glucosidase inhibitors (max of 150 mg daily)
  • bedtime intermediate-acting insulin was added if HbA1c concentrations ≥ 7% after maximum oral hypoglycaemic treatment was reached


Advice on diet and physical exercise

Anti-diabetic interventions (control group): no treatment goal; routine outpatient service, dosage of their medications were adjusted if needed General health and diabetes-related advice

Concomitant treatment of cardiovascular risk factors:

Intensive:

  • hypertension; captopril and/or extended release nifedipine were used
  • simvastatin was used for hypercholesterolaemia
  • delayed-release aspirin was given as a secondary prevention


Conventional: Standard care, not specified

Concomitant target values of cardiovascular risk factors:

Intensive intervention group:

Systolic blood pressure (mmHg): < 130

Diastolic blood pressure (mmHg): < 80

Total cholesterol (mmol/L): < 4.5

LDL-cholesterol (mmol/L): < 3.0

HDL-cholesterol (mmol/L): > 1.1

Triglycerides (mmol/L): < 1.5

Conventional intervention group: Standard care, not specified


OutcomesOutcomes reported in abstract of publication: fasting plasma glucose, HbA1c, total cholesterol, low-density lipoprotein cholesterol and carotid intima-media thickness


Study detailsTitration period: when metformin was initiated we assume it was titrated

Run-in period: none

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: NR

Non-commercial funding: NR


Stated aim for studyQuote from publication: "We sought to determine whether a 6-month intensive multitherapy program resulted in better goal attainment than usual care and its effect on the development of cIMT among patients with newly diagnosed type 2 diabetes mellitus."


NotesAbbreviations: HbA1c: Glycosylated haemoglobin A1c; HDL: High density lipoprotein; LDL: Low density lipoprotein


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from publication: "All patients in this study were randomly assigned by computer program to receive intensive multitherapy or to serve as controls in a proportion of 3:1."

Allocation concealment (selection bias)Low riskQuote from publication: "All patients in this study were randomly assigned by computer program to receive intensive multitherapy or to serve as controls in a proportion of 3:1."

Blinding of outcome assessment (detection bias)
Objective outcomes
Unclear riskComments: not reported

Blinding of outcome assessment (detection bias)
Subjective outcomes
Unclear riskComments: none of our subjective outcomes reported

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskComments: no patients were lost to follow-up

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskComments: Comment: none of our subjective outcomes reported

Selective reporting (reporting bias)Unclear riskComments: no trial protocol or design article available

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?Unclear riskComments: no funding described

Trials according to risk of biasLow riskComments: adequate sequence generation and allocation concealment

IDA 2009

MethodsRandomised clinical trial


ParticipantsInclusion criteria: type 2 diabetes mellitus, and accepted for percutaneous coronary intervention as treatment for coronary artery disease

Exclusion criteria:

  • acute myocardial infarction within 48 hours before the intervention
  • inability to participate for physical or psychological reasons
  • residency outside the hospital catchment areas


Diagnostic criteria: all patients had previously known diabetes accepted as type 2 if the patient was > 35 years of age at onset of disease and without any demand of insulin during at least two years thereafter


InterventionsNumber of study centres: 2.

Anti-diabetic interventions (intervention group):

HbA1c < 6.5%, fasting blood glucose 5-7 mmol/L and blood glucose before meals < 10 mmol/L
Elective patients: Attempts were made to optimise glycaemic control during three weeks preceding the percutaneous coronary intervention
Acute patients: patients, in whom revascularization was deemed necessary within few days, were immediately brought to the best possible glucose control by means of a glucose-insulin infusion aiming at a blood glucose level of 4-9 mmol/L; the infusion continued for at least 12 hours after the percutaneous coronary intervention. Thereafter the treatment was identical for elective and acute patients
Both elective and acute patients: Treatment with fast-acting meal insulin three times daily and long-acting insulin at bedtime
This treatment was initiated by bed-time insulin with the dose adjusted to obtain fasting blood glucose of 5–7 mmol/L. If blood glucose still exceeded 10 mmol/L insulin human or insulin lispro was added before meals

Anti-diabetic interventions (control group): Standard treatment. continuation of ongoing antidiabetic treatment, or changes assessed by physician

Concomitant treatment of cardiovascular risk factors:
Both groups: All participants received optimal medical care and use of aspirin, statins, beta-blocker, and anti-hypertensive treatment were recommended

Concomitant target values of cardiovascular risk factors: NR


OutcomesOutcomes reported in abstract of publication: HbA1c, fasting blood glucose and restenosis


Study detailsTitration period: none

Run-in period: none

Study terminated before regular end (for benefit / because of adverse events): yes


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: AFA insurance

Non-commercial funding: The Swedish Heart Lung foundation


Stated aim for studyQuote from publication: "The primary objective was to test the hypothesis that improved glucose control, achieved by adding or optimising insulin treatment, will reduce the rate of restenosis after PCI in patients with type 2 diabetes."


NotesThe baseline characteristics (except for previous cardiovascular disease) are only reported for 82 patients (intensive: 39, standard: 43), who completed follow-up. The SD for age, average duration of diabetes, glycaemic control and fasting blood glucose is calculated from IQR

Abbreviations: HbA1c: glycosylated haemoglobin A1c; IDA: Insulin Diabetes Angioplasty


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentral computer-generated. Quote from publication: “…subsequently randomised to an intensified insulin-based glucose control (I-group) or to continue ongoing glucose-lowering treatment (C-group).“

Allocation concealment (selection bias)Low riskCentral computer-generated. Quote from publication:“…subsequently randomised to an intensified insulin-based glucose control (I-group) or to continue ongoing glucose-lowering treatment (C-group).“

Blinding of outcome assessment (detection bias)
Objective outcomes
Unclear riskQuote from publication: "All procedural and follow-up angiograms were analysed offline with the cardiovascular measurement system (Medis, Leiden, The Netherlands) by two blinded interventionists."

Comments: Only blinding of the trial's primary outcome reported, and not for our objective outcomes

Blinding of outcome assessment (detection bias)
Subjective outcomes
Unclear riskComments: none of our subjective outcomes assessed

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskFrom correspondence: no patients were lost to follow-up and vital status were known on all participants

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskComments: none of our subjective outcomes assessed

Selective reporting (reporting bias)Unclear riskComments: no trial protocol or design article available

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?High riskComments: AFA Insurance

Trials according to risk of biasLow riskComments: adequate sequence generation and allocation concealment

Jaber 1996

MethodsRandomised clinical trial


ParticipantsInclusion criteria: not specified; only description in text: "Urban African-American patients with NIDDM currently attending a university affiliated general internal medicine outpatient clinic were considered for inclusion."

Exclusion criteria:

  • insulin-dependent diabetes mellitus
  • renal dysfunction (serum creatinine > 133 μmol/L)
  • hepatic disorder (concentration of serum aminotransferases 3 times above normal)
  • significant cardiac complications within the last 6 month
  • mental incompetence
  • history of non-compliance with regular clinical visits within the last 2 years


Diagnostic criteria: NR


InterventionsNumber of study centres: 1.

Anti-diabetic interventions (intervention group): regimens were adjusted or titrated to achieve fasting blood glucose ≤ 6.6 mmol/L and 2 hour post-prandial glucose concentrations of < 10 mmol/L or to reach maximum daily doses of the sulphonylurea
Advice about diabetes and lifestyle
Anti-diabetic interventions (control group): not defined; standard care

Concomitant treatment of cardiovascular risk factors:
both groups: NR

Concomitant target values of cardiovascular risk factors: NR


OutcomesOutcomes reported in abstract of publication: HbA1c, fasting blood glucose, blood pressure, lipid profile, renal function parameters, weight, and quality of life


Study detailsTitration period: none

Run-in period: none

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: Upjohn

Non-commercial funding: Diabetes Research and Education Foundation


Stated aim for studyQuote from publication: "To assess the effectiveness of a pharmaceutical care model on the management of non-insulin-dependent diabetes mellitus (NIDDM) in urban African-American patients."


NotesThe baseline characteristics are from the participants, who completed the trial

Abbreviations: HbA1c: haemoglobin A1c; NR: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote from publication:v "A randomized, parallel fashion..."

Allocation concealment (selection bias)Unclear riskQuote from publication: "A randomized, parallel fashion..."

Blinding of outcome assessment (detection bias)
Objective outcomes
Unclear riskComments: not described

Blinding of outcome assessment (detection bias)
Subjective outcomes
High riskComments: health related quality of life assessed by the unblinded participants

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskQuote from publication: "Six patients in the intervention group dropped out or were discharged from the study. Of those, 4 found it difficult to comply with the frequency of the visits, 1 discharged by the study investigators because of unstable angina within the first 2 weeks of the study, and 1 was lost to follow up."

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskComments: response rate not reported on the health-related quality of life not reported in the publication

Selective reporting (reporting bias)High riskComments: no trial protocol or design article available. However, partial reporting of outcome exist (Appendix 11)

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?High riskComments: Grant from Upjohn

Trials according to risk of biasUnclear riskUnclear sequence generation and allocation concealment

Kumamoto 2000

MethodsRandomised clinical trial


ParticipantsInclusion criteria:

  • no retinopathy or simple retinopathy determined by clinical funduscopic evaluation
  • urinary albumin excretion < 300 mg/24 hour and serum creatinine level < 1.5 mg/dL
  • absence of diabetic somatic or autonomic neuropathy severe enough to require treatment
  • < 70 years of age
  • otherwise healthy (no other findings such as hypertension, hypercholesterolaemia, severe diabetic complications, or other severe medical conditions)


Exclusion criteria: none described

Diagnostic criteria: all of the patients were diagnosed as being affected with type 2 diabetes mellitus by their characteristics of no history of ketoacidosis, negative islet cell antibody, and daily urinary C-peptide excretion more than 20 pg


InterventionsNumber of study centres: 1.

Anti-diabetic interventions (intervention group):

  • fasting blood glucose concentration (< 140 mg/dL)
  • 2 hour postprandial blood glucose concentration < 200 mg/dL
  • HbA1c < 7.0%
  • mean amplitude of glycaemic excursions < 100 mg/dL


The group was administered insulin 3 or more times daily (rapid-acting insulin at each meal and intermediate-acting insulin at bedtime); the dosage was adjusted according to the self-monitored results of blood glucose. Adjustment doses of insulin were usually 2-4 U at each point
Diet and exercise advice

Anti-diabetic interventions (control group): glycaemic control as close to the fasting blood glucose concentration of < 140 mg/dL without symptoms of hyperglycaemia or hypoglycaemia; the group was administered 1 or 2 daily injections of intermediate-acting insulin
Diet and exercise advice

Concomitant treatment of cardiovascular risk factors:
Both groups: NR

Concomitant target values of cardiovascular risk factors: all attending physicians were asked to achieve good treatment of cardiovascular risk factors. No prespecified target values


OutcomesOutcomes reported in abstract of publication: retinopathy, nephropathy, neuropathy, and cost evaluation


Study detailsTitration period: none

Run-in period: none

Study terminated before regular end (for benefit / because of adverse events): No


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: the publication of one of the articles was made possible by an unrestricted educational grant from Aventis Pharma

Non-commercial funding: Diabetes Mellitus Research Grants, the Ministry of Health and Welfare, Japan


Stated aim for studyQuote from publication: "The Kumamoto study was a randomized clinical trial, designed to compare intensive insulin therapy, using the multiple insulin injection therapy with the conventional insulin injection therapy, to evaluate their effects on the development and the progression of the microvascular complications in NIDDM patients in both the primary-prevention cohort and the secondary-intervention cohort."


NotesFasting blood glucose is read from figure and converted from mg/dL to mmol/L by dividing with 18.

All patients were stratified to a primary-prevention cohort (patients with no retinopathy and urinary albumin excretion < 30 mg/24 hour) and a secondary-intervention cohort (patients were required to have simple retinopathy and urinary albumin excretion < 300 mg/24 hour).

After 6 years, the selection of insulin treatment regimens were left to the patients. Only two patients in the conventional insulin injection treatment group selected multiple insulin injection therapy, all other patients in both the conventional insulin injection treatment group and multiple insulin injection treatment group wanted to adhere to the same treatment regimens. Therefore, the follow-up study was initiated by the patients

Abbreviations: HbA1c: Glycosylated haemoglobin A1c; NR: Not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: not described

Allocation concealment (selection bias)Unclear riskQuote from publication: "One hundred and ten patients were divided into 2 cohorts - the primary-prevention cohort (n = 55) and the secondary-intervention cohort (n = 55)."

Comment: not described

Blinding of outcome assessment (detection bias)
Objective outcomes
Unclear riskQuote from publication: "The evaluation on the fundus photography was masked to the randomization status in both primary prevention and secondary intervention cohorts"
Comment: unknown whether other objective outcomes were blinded when evaluated

Blinding of outcome assessment (detection bias)
Subjective outcomes
High riskComments: health-related quality of life not assessed; mild hypoglycaemia reported by unblinded participants

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskQuote: "After 10 years, 97 patients remained in the study, nine patients died (three in the MIT group and six in the CIT group) and four patients moved to other cities (two in each of the MIT and CIT groups)."

Incomplete outcome data (attrition bias)
Subjective outcomes
Low riskQuote: "After 10 years, 97 patients remained in the study, nine patients died (three in the MIT group and six in the CIT group) and four patients moved to other cities (two in each of the MIT and CIT groups)." Health-related quality of life not assessed

Selective reporting (reporting bias)Unclear riskComments: the prolongation of the intervention period (8 and 10 years of follow-up) was initiated by the patients and the outcomes not predefined in previous publication

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?High riskComments: the publication of one of the articles was made possible by an unrestricted educational grant from Aventis Pharma

Trials according to risk of biasUnclear riskUnclear sequence generation and allocation concealment

Lu 2010

MethodsRandomised controlled clinical trial


ParticipantsInclusion criteria:

  • type 2 diabetes mellitus for at least two years
  • treated with hypoglycaemic agents and/or diet
  • microalbuminuria


Exclusion criteria:

  • glomerular nephritis
  • nephritic syndrome
  • urinary tract infections
  • chronic diarrhoea
  • heart failure
  • tuberculosis
  • recent medication of nephrotoxic drugs
  • severe diabetic complications
  • severe diseases of other systems


Diagnostic criteria: NR


InterventionsNumber of study centres: 1

Anti-diabetic interventions (intervention group): fasting blood glucose < 6.1 mmol/L, postprandial 2 hour glucose < 7.8 mmol/L
Diet and hypoglycaemic agents

Anti-diabetic interventions (control group): fasting blood glucose < 7.0 mmol/L, postprandial 2 hour glucose < 10.0 mmol/L. Diet and hypoglycaemic agents

Concomitant treatment of cardiovascular risk factors:
Both groups: Prohibited drugs: ACE-inhibitors, angiotensin receptor blockers, antiplatelet drugs, anticoagulants, vasodilators and antihyperlipidaemic drugs

Concomitant target values of cardiovascular risk factors:
Both groups:
Systolic blood pressure (mmHg): < 130
diastolic blood pressure (mmHg): < 80


OutcomesOutcomes reported in abstract of publication: urine albumin excretion rate, triglyceride, cholesterol, and fibrinogen.


Study detailsTitration period: none described

Run-in period: none described

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: none

Non-commercial funding: Shaanxi Provincial Science and Technology Plan projects


Stated aim for studyQuote from publication: "This clinical trial was designed to investigate the therapeutic effect of intensive glycemic control on type 2 diabetes patients with early DN"


NotesAbbreviations: ACE inhibitors: Angiotensin-converting enzyme inhibitor


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "A total of 41 patients were divided into two groups randomly..."

Allocation concealment (selection bias)Unclear riskQuote: "... 21 of them were allocated in intensive glycemic control group (Group A) and the other 20 patients were enrolled into regular glycemic control group (Group B)."

Blinding of outcome assessment (detection bias)
Objective outcomes
Unclear riskComments: blinding of objective outcomes not described

Blinding of outcome assessment (detection bias)
Subjective outcomes
Unclear riskComments: subjective outcomes not assessed

Incomplete outcome data (attrition bias)
Objective outcomes
Unclear riskComments: not described if there was any dropouts

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskComments: subjective outcomes not assessed

Selective reporting (reporting bias)Unclear riskComments: no trial protocol or design article available

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?Low riskComments: no industry funding

Trials according to risk of biasUnclear riskComments: unclear sequence generation and allocation concealment

Melidonis 2000

MethodsRandomised clinical trial


ParticipantsInclusion criteria:

  • acute coronary event (unstable angina or acute myocardial infarction) within the preceding 24 hours
  • type 2 diabetes mellitus


Exclusion criteria:

  • inability or refusal to give informed consent for the methods of the study
  • patients with type 1 and insulin-treated patients with type 2 diabetes mellitus


Diagnostic criteria: WHO 1985


InterventionsNumber of study centres: 1.

Anti-diabetic interventions (intervention group): blood glucose between 8.3 to 11.0 mmol/L in the first 48 hours after an acute coronary event, thereafter normoglycaemia
Patients received insulin by infusion for at least 48 hours according to a predefined protocol (please see publication for further details). Subcutaneous insulin treatment four times daily was started immediately after insulin infusion cessation until the end of hospitalisation to maintain normoglycaemia (three doses of soluble insulin administered subcutaneously before meals, plus a dose of intermediate-acting insulin in the evening)

Anti-diabetic interventions (control group): no specified target

Concomitant treatment of cardiovascular risk factors:
BOTH GROUPS: All patients were treated with the optimal anti-anginal therapy for their ischaemic event. Thrombolytic treatment was administered when there were no contraindications in patients with onset of symptoms within 10 hours (streptokinase (1.5 X 10-6 U over 60 min))

Concomitant target values of cardiovascular risk factors: NR


OutcomesOutcomes reported in abstract of publication: plasma tissue plasminogen activator and fibrinogen


Study detailsTitration period: none

Run-in period: none

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: none

Non-commercial funding: funded by the department in which the trial was conducted


Stated aim for studyQuote from publication: "In our study, we tested the hypothesis that intensive insulin treatment during an evolving acute coronary event (UA or AMI) improves the fibrinolytic function in diabetic patients."


NotesThe number reported for fasting blood glucose is the mean daily plasma glucose (determined by at least four pre meal glucose values)

Abbreviations: WHO: World Health Organization


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from publication: the randomisation was made by using a table of random number

Allocation concealment (selection bias)Unclear riskComments: not described

Blinding of outcome assessment (detection bias)
Objective outcomes
Unclear riskQuote from publication: "All samples were analyzed blinded to the clinical data"
Comments: Only blinding of blood samples reported, but not blinding of clinical data

Blinding of outcome assessment (detection bias)
Subjective outcomes
High riskComments: mild hypoglycaemia reported by unblinded participants

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskComments: lost to follow-up adequately described for the objective outcomes

Incomplete outcome data (attrition bias)
Subjective outcomes
Low riskComments: lost to follow-up adequately described for the subjective outcome assessed

Selective reporting (reporting bias)Unclear riskComments: no trial protocol or design article available

Free from academic bias (assessed from primary author)?Low riskComment: no academic bias

Free from sponsor bias?Low riskComment: no industry funding

Trials according to risk of biasUnclear riskAdequate sequence generation and unclear allocation concealment

Natarajan 2012

MethodsRandomised clinical trial


ParticipantsInclusion criteria:

  • patients booked for catheter-based revascularization with balloon angioplasty and coronary stent placement
  • type 2 diabetes mellitus
  • on 0-2 oral glucose-lowering agents and able to double the dose of (or add) at least one glucose lowering agent. If HbA1c is 10.0 to 10.4% then must be on only 0-1 oral antidiabetic agents (the dose of one agent must be ≤ ½ max dose) and able to take metformin (i.e. no previous intolerance; and serum creatinine < 130 mmol/L


Exclusion criteria:

  • planned staged procedure for multivessel percutaneous coronary intervention taking place over > 30 days
  • estimated left ventricular ejection fraction < 35%, if known
  • NYHA class 3 or 4 symptoms of congestive heart failure
  • HbA1c < 6,1% or > 10,4% Current or anticipated need for insulin or thiazolidinediones within the next 6 months
  • on > 50% of the maximum doses of an insulin secretagogue and unable to take metformin because of previous intolerance, or because of a serum creatinine ≥ 130 μmol/L
  • refusal to take insulin
  • refusal to do home glucose monitoring
  • history of hypoglycaemia requiring 3rd party assistance in the last 2 years
  • noncardiac illness expected to limit survival
  • renal insufficiency (participants not on metformin: creatinine > 180 μmol/L; participants on metformin: creatinine > 130 μmol/L)
  • known hepatic disease (ALT > 2 X upper normal level, if known)
  • suspected or known pregnancy
  • refusal/unable to return for follow-up
  • enrolled in a competing randomised trial


Diagnostic criteria: NR


InterventionsNumber of study centres: 6

Anti-diabetic interventions (intervention group):

Fasting capillary glucose levels of 4.0-5.4 mmol/L

Subjects assigned insulin were initially treated with NPH insulin (Novolin NPH, Novo Nordisk A/S, Bagsvaerd, Denmark, 100 IU/ml) 10 units at bedtime and then followed a titration algorithm to achieve fasting capillary glucose levels of 4.0–5.4 mmol/l. Insulin was continued for 6 months following the PCI procedure by protocol, although patients were given the option to continue insulin indefinitely. All subjects received counselling regarding diet and activity

Anti-diabetic interventions (control group): HbA1c < 8.4%. Subjects assigned usual care were advised to continue their oral diabetes medications, measure glucose levels at least daily, and discuss any changes in glucose-lowering therapy with their physician. If the 12-week A1c was greater than 8.4%, the dose of one oral agent was increased or (if maximal doses were already prescribed) another agent was added (metformin was not used if the serum creatinine was ≥130 μmol/l); all subjects received counselling regarding diet and activity

Concomitant treatment of cardiovascular risk factors:
Both groups: Standard antiplatelet and antithrombotic regimens; abciximab was recommended

Concomitant target values of cardiovascular risk factors: NR


OutcomesOutcomes reported in abstract of publication: reduction in HbA1c, fasting blood glucose, hypoglycaemic events, neo intimal volume and lumen loss


Study detailsTitration period: NR

Run-in period: for those undergoing scheduled qualifying percutaneous coronary intervention, a 2-day run-in phase allowed coordinators to determine candidates' ability to self-inject insulin and to self-monitor blood and record blood glucose. Those undergoing diagnostic angiography and possible percutaneous coronary intervention were required to complete an abbreviated run-in phase requiring patients to demonstrate one successful glucose test and one successful injection of saline

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: Funding from Heart and Stroke Foundation of Ontario

Non-commercial funding: funded by pharmaceutical company


Stated aim for studyQuote from publication: "The objective of this study was to determine whether insulin-mediated glucose lowering reduces in-stent restenosis in patients with diabetes undergoing PCIs."


NotesAbbreviations: ALT: Alanine aminotransferase; HbA1c: Glycosylated haemoglobin A1c; NR: Not reported; PCI: Percutanous coronary interventions


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from publication: "Central randomization by telephone assigned subjects in a 1:1 ratio using permuted blocks stratified by vessel size, planned versus ad hoc PCI, and participating site"

Allocation concealment (selection bias)Low riskQuote from publication: "Central randomization by telephone assigned subjects in a 1:1 ratio using permuted blocks stratified by vessel size, planned versus ad hoc PCI, and participating site"

Blinding of outcome assessment (detection bias)
Objective outcomes
Unclear riskQuote from publication: "We employed blinded quantitative analyses of angiographic and IVUS images at a core laboratory (G.B.J.M., M.R.) using standard methods"

Comments: Blinding of outcome assessors not reported for our objective outcomes

Blinding of outcome assessment (detection bias)
Subjective outcomes
Unclear riskComments: health-related quality of life not assessed. No hypoglycaemic episodes reported, and not described how they would have been assessed

Incomplete outcome data (attrition bias)
Objective outcomes
Unclear riskComments: number lost to follow-up is adequately for the trials primary outcome, but not for the objective outcomes of our review

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskComments: number lost to follow-up is adequately for the trials primary outcome, but not for the subjective outcome of our review

Selective reporting (reporting bias)Unclear riskComments: outcomes described in trial protocol reported in publication. However, partial reporting exist for some outcomes. It might be that the authors are working on the data in order to get them fully reported (Appendix 11)

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?Unclear riskComments: received funding from pharmaceutical company

Trials according to risk of biasLow riskAdequate sequence generation and allocation concealment

REMBO 2008

MethodsRandomised clinical trial


ParticipantsInclusion criteria:

  • age 18 to 80 years
  • NYHA classification II-III
  • stable chronic heart insufficiency with unchanged medications at least two weeks before entry to trial
  • left ventricular ejection fraction ≤ 45%
  • type 2 diabetes mellitus


Exclusion criteria:

  • myocardial infarction (< 3 months before the randomisation)
  • unstable angina pectoris
  • congenital coronary artery disease
  • acquired myocardial infarction with substantial haemodynamic stenosis
  • hypertrophic or restrictive cardiomyopathy
  • chronic pulmonary heart disease
  • arterial hypertension with systolic pressure > 180 mmHg and diastolic pressure >110 mmHg despite antihypertensive treatment
  • acute inflammatory disease
  • kidney insufficiency (plasma creatinine > 160 micromol/L)
  • active liver disease (alanine aminotransferase and aspartate aminotransferase levels > 3 times normal level)
  • electrolyte disruptions
  • decompensated chronic heart insufficiency


Diagnostic criteria: NR


InterventionsNumber of study centres: 1

Anti-diabetic interventions (intervention group):

HbA1c < 7% in participants receiving sulphonylurea
HbA1c < 6.5% in participants receiving insulin
All participants received gliclazide, extended release; as a second step, metformin was added. If these two agents did not fulfil the glycaemic target, insulin was initiated

Anti-diabetic interventions (control group): not specified, standard care
Concomitant treatment of cardiovascular risk factors:
Both groups: all participants were receiving optimal treatment for chronic heart failure (e.g., ACE inhibitors, diuretics)

Concomitant target values of cardiovascular risk factors: NR


OutcomesOutcomes reported in abstract of publication: clinico-functional status, quality of life and parameters of remodeling; reporting according to achieved HbA1c level: renin–angiotensin–aldosterone system activity and renal function


Study detailsTitration period: we assume metformin was titrated, when initiated

Run-in period: 2 weeks

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: Russian

Publication status: peer-reviewed journal

Commercial funding: NR

Non-commercial funding: NR


Stated aim for studyQuote from publication: "..to evaluate the influence of strict glycaemic control on chronic heart disease in patients with type 2 diabetes mellitus." [Translated from Russia]


NotesAll SD, except for the BMI, is calculated from IQR

Abbreviations: ACE: angiotensinogen converting enzyme; HbA1c: glycosylated haemoglobin A1c; NYHA: New York Heart Association; REMBO: Rational Effective Multicomponent Therapy in the Struggle Against DiaBetes Mellitus in Patients With COngestve Heart Failure


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote from publication: (from English abstract): "As a result of randomization 2 groups were performed - active with achievement of target levels of glycemia (n=41) and usual treatment (n=40)."

Allocation concealment (selection bias)Unclear riskComments: not described

Blinding of outcome assessment (detection bias)
Objective outcomes
Unclear riskComments: not described

Blinding of outcome assessment (detection bias)
Subjective outcomes
High riskComment: health-related quality of life assessed by the unblinded participants

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskComments: no patients lost to follow-up

Incomplete outcome data (attrition bias)
Subjective outcomes
Low riskComments: no patients lost to follow-up

Selective reporting (reporting bias)Unclear riskComments: no trial protocol or design article available

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?Unclear riskComments: no funding sources described

Trials according to risk of biasUnclear riskComments: unclear sequence generation and allocation concealment

Service 1983

MethodsRandomised clinical trial


ParticipantsInclusion criteria: recent onset (2 years or less) of insulin-requiring diabetes

Exclusion criteria: none described

Diagnostic criteria: participants were stratified as having type 1 or type 2 diabetes mellitus by basal and postprandial C-peptide values of less than 1 (type 1 diabetes mellitus) and more than 1 (type 2 diabetes mellitus) ng/ml


InterventionsNumber of study centres: 1

Anti-diabetic interventions (intervention group): HbA1c to normal range and to maintain 80 minute postprandial plasma glucose well below 150 mg/dL (8.3 mmol/L). Complex insulin treatment tailored to each individual and all methods available at the time the trial started

Anti-diabetic interventions (control group): eliminate symptoms, but not to a degree to reduce 80 minute postprandial plasma glucose below 150 mg/dL. A single daily injection of intermediate acting insulin

Concomitant treatment of cardiovascular risk factors:
Both groups: NR

Concomitant target values of cardiovascular risk factors:
Both groups: NR


OutcomesOutcomes reported in abstract of publication: peripheral nerve function


Study detailsTitration period: none

Run-in period: none

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: none

Non-commercial funding: NINCDS, Heerick Funds and Borchard, Upton 


Stated aim for studyQuote from publication: "A prospective, stratified, randomized 3-year clinical trial was conducted on the effect of rigorous versus conventional glucose control on peripheral nerve function......"


NotesThe trial included both patients with type 1 diabetes mellitus and type 2 diabetes mellitus, but the participants were stratified prior to randomisation
Two patients with type 2 diabetes mellitus randomised to intensive glucose control dropped out early in the trial. The baseline characteristics for these participants are not reported. The baseline characteristics above are from the 18 participants with type 2 diabetes mellitus, who completed the trial

Abbreviations: NR: Not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from publication: "After stratification, each patient was randomly assigned by a table of random numbers to conventional glucose control by continuation of the currently used insulin treatment or to rigorous glucose control."

Allocation concealment (selection bias)Unclear riskComments: not described, but the trial was randomised (see above)

Blinding of outcome assessment (detection bias)
Objective outcomes
Unclear riskQuote from publication: "..every 6 months, each patient was examined by the same neurologist (who was unaware of the patients treatment group)….."
Comments: not described for the objective outcomes

Blinding of outcome assessment (detection bias)
Subjective outcomes
Unclear riskSubjective outcomes not assessed

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskComments: 7 patients were excluded from analysis; 2: Treatment was no longer required; 1: Treatment was not followed; 4: Early dropouts (< 6 months)

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskSubjective outcomes not assessed

Selective reporting (reporting bias)Unclear riskComments: no trial protocol or design article available

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?Low riskComments: no industry funding

Trials according to risk of biasUnclear riskAdequate sequence generation and unclear allocation concealment

Stefanidis 2003

MethodsRandomised clinical trial


ParticipantsInclusion criteria: patients with type 2 diabetes mellitus admitted to coronary care unit with non-ST segment elevation acute coronary syndromes within the preceding 24 hours

Exclusion criteria:

  • insulin-treated diabetes mellitus
  • pathologic Q waves on the baseline electrocardiogram
  • evolution in persistent ST-segment elevation myocardial infarction
  • arrhythmias, and atrioventricular and intraventricular conduction disturbances that might have influenced either the global cardiac contractility or Doppler time intervals measurements
  • septal or free left ventricular end-diastolic wall thickness > 12 mm
  • Doppler evidence of more than a mild degree of left or right valvular regurgitation or stenosis
  • use of inotropes
  • revascularization intervention during the study period


Diagnostic criteria: type 2 diabetes mellitus was defined based on patient history or when plasma glucose levels were > 200 mg/dL at admission


InterventionsNumber of study centres: 1

Anti-diabetic interventions (intervention group): near normal glycaemia defined as 6.6 to 8.2 mmol/L. Soluble insulin by infusion, immediately after the first echocardiographic examination and subsequent randomisation, for 72 hours, according to a predefined protocol

Anti-diabetic interventions (control group): no specific glucose target. Usual protocols, with oral hypoglycaemic drugs or 2 daily doses of intermediate acting insulin. Supplementary small doses of short-acting insulin were administered subcutaneously only if glucose levels were > 250 mg/dL

Concomitant treatment of cardiovascular risk factors:
Both groups: all participants were treated with an optimal anti-anginal regimen

Concomitant target values of cardiovascular risk factors: no predefined targets


OutcomesOutcomes reported in abstract of publication: Transient ischaemia


Study detailsTitration period: none

Run-in period: none

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: none

Non-commercial funding: the trial was conducted as a part of a PhD thesis


Stated aim for studyQuote from publication: "In this context, this open-label, randomised study assessed the impact of insulin administration on global myocardial performance during acute coronary syndromes, using a new Doppler-derived index (DI) that combines elements of systolic and diastolic phase periods of the cardiac cycle"


NotesFasting blood glucose is converted from mg/dL to mmol/L by dividing with 18

Abbreviations:


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from publication: "The patients were randomised to receive..."

The randomisation procedure was done by using a table of random number

Allocation concealment (selection bias)Unclear riskComments: not described, but the trial was randomised (see above)

Blinding of outcome assessment (detection bias)
Objective outcomes
Unclear riskQuote from publication: "Images were obtained within 3 hours from admission and 72 hours later and stored on high-quality videotapes for later blinded analysis."
Comment: Only blinding for the primary and secondary outcomes in the publication is reported. Blinding of our objective outcome is not described

Blinding of outcome assessment (detection bias)
Subjective outcomes
Unclear riskComments: mild hypoglycaemia reported by unblinded participants

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskQuote from publication: "Three patients from both groups were excluded from the analysis because there was objective evidence of development of persistent ST-elevation myocardial infarction. Two patients from group A and 1 from group B underwent percutaneous coronary intervention during the study period for intractable ischemia and were also excluded from the study."

Incomplete outcome data (attrition bias)
Subjective outcomes
Low riskQuote from publication: "Three patients from both groups were excluded from the analysis because there was objective evidence of development of persistent ST-elevation myocardial infarction. Two patients from group A and 1 from group B underwent percutaneous coronary intervention during the study period for intractable ischemia and were also excluded from the study."

Selective reporting (reporting bias)Low riskComments: the predefined primary outcome is reported

Free from academic bias (assessed from primary author)?High riskComments: the primary author has written another publication about the same intervention (Melidonis 2000)

Free from sponsor bias?Low riskComments: no industry funding

Trials according to risk of biasUnclear riskComments: adequate sequence generation and unclear allocation concealment

Steno-2 2008

MethodsRandomised clinical trial


ParticipantsInclusion criteria:

  • type 2 diabetes mellitus
  • urine albumin excretion rates of 30–300 mg in a 24 hour urine sample


Exclusion criteria:

  • age older than 65 or younger than 40
  • a stimulated serum C-peptide concentration less than 600 pmol/L 6 min after intravenous injection of 1 mg glucagon
  • pancreatic insufficiency or diabetes secondary to pancreatitis
  • alcohol abuse
  • non-diabetic kidney disease
  • malignancy
  • life-threatening disease with death probable within 4 years


Diagnostic criteria: WHO criteria (1985)


InterventionsNumber of study centres: 1.

Anti-diabetic interventions (intervention group):

HbA1c < 6.5%

  • if patients were unable to maintain glycosylated haemoglobin values below 6.5% by means of diet and increased physical activity alone after three months, an oral hypoglycaemic agent was started
  • overweight patients (BMI > 25) received metformin (maximum, 1 gm twice daily)
  • lean patients, or overweight patients who had contraindications to metformin therapy, received gliclazide (maximum, 160 mg twice daily)
  • as the second step, metformin was added to the regimen of lean patients and gliclazide to that of overweight patients if hyperglycaemia was not controlled
  • if the HbA1c exceeded 7.0% despite maximal doses of oral agents, the addition of neutral protamine Hagedorn (NPH) insulin at bedtime was recommended. When insulin was started, lean patients stopped metformin treatment and overweight patients stopped gliclazide therapy unless it was the only oral hypoglycaemic agent given. The insulin dose was adjusted on the basis of the morning fasting blood glucose concentration. If the daily dose of insulin exceeded 80 U at bedtime or there was no decrease in the HbA1c, patients were switched to regimens in which regular and NPH insulin was given two to four times a day


Anti-diabetic interventions (control group): HbA1c < 7.5% (1993-1999), HbA1c < 6.5% (2000-2001). Treatment according to the 1988 recommendations of the Danish Medical Association

Concomitant treatment of cardiovascular risk factors:
Intensive:

Treatment with ACE-inhibitor irrespective of blood pressure: yes (1993-2001)

Aspirin therapy:

  • for patients with known ischaemia: yes (1993-2001)
  • for patients with peripheral vascular disease: yes (1993-2001)
  • for patients without coronary heart disease or peripheral vascular disease: no (1993-1999); yes (2000-2001)


Vitamin E and vitamin C

Non-medical interventions: exercise at least 30 min/day and invitation to smoking cessation

Conventional: treatment with ACE-inhibitor irrespective of blood pressure: no (1993-1999); yes (2000-2001)

Aspirin therapy:

  • for patients with known ischaemia: yes (1993-2001)
  • for patients with peripheral vascular disease: no (1993-2001)
  • for patients without coronary heart disease or peripheral vascular disease: No (1993-1999); no (2000-2001)


Concomitant target values of cardiovascular risk factors:

Intensive:

Systolic blood pressure (mmHg): < 140 (1993-1999); < 130 (2000-2001)

Diastolic blood pressure (mmHg): < 85 (1993-1999); < 80 (2000-2001)

Total cholesterol (mmol/L): < 4.9 (1993-1999); < 4.5 (2000-2001)

Triglycerides (mmol/L): < 1.7 (1993-1999); < 1.7 (2000-2001)

Conventional:

Systolic blood pressure (mmHg): < 160 (1993-1999); < 135 (2000-2001)

Diastolic blood pressure (mmHg): < 95 (1993-1999); < 85 (2000-2001)

Total cholesterol (mmol/L): < 6.5 (1993-1999); < 4.9 (2000-2001)

Triglycerides (mmol/L): < 2.2 (1993-1999); < 2.0 (2000-2001)


OutcomesOutcomes reported in abstract of publication: glycosylated haemoglobin, systolic and diastolic blood pressure,
serum cholesterol and triglyceride levels, urinary albumin excretion rate, cardiovascular disease, nephropathy, retinopathy, autonomic neuropathy, all-cause mortality, death from cardiovascular causes, end-stage renal disease, retinal photocoagulation, major side effects, and quality-adjusted life expectancy


Study detailsTitration period: none

Run-in period: none

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: Novo Nordisk A/S

Non-commercial funding: The Danish Health Research Council


Stated aim for studyQuote from publication: "Our randomised trial was designed to find out whether intensive multifactorial intervention that includes changes in behaviour and pharmacological therapy, slows the initiation and progression of microvascular complications in microalbuminuric patients with type 2 diabetes compared with a standard multifactorial treatment."


NotesThe SD for duration of diabetes is calculated from IQR
The number used for previously cardiovascular disease is the number of ischaemia on resting or stress electrocardiogram

Abbreviations: BMI; Body mass index; HbA1c: Glycosylated haemoglobin; WHO: World Health Organization


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComments: sequence was computer generated

Allocation concealment (selection bias)Low riskComments: allocation was performed with the use of sealed opaque envelopes

Blinding of outcome assessment (detection bias)
Objective outcomes
Low riskQuote from publication: "All events were defined a priori and evaluated by an Endpoint Committee unaware of patient treatment allocation."

Blinding of outcome assessment (detection bias)
Subjective outcomes
High riskComments: mild hypoglycaemia reported by unblinded participants

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskMortality status known for all participants at the end of follow-up; lost to follow-up for other objective outcomes adequately described

Incomplete outcome data (attrition bias)
Subjective outcomes
Low riskLost to follow-up for subjective outcomes adequately described

Selective reporting (reporting bias)Low riskComments: all predefined outcomes were assessed

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?High riskComments: supported by grants from Novo Nordisk A/S

Trials according to risk of biasLow riskComments: adequate sequence generation and allocation concealment

UGDP 1975

MethodsRandomised clinical trial


ParticipantsInclusion criteria:

  • maturity onset diabetes diagnosed within 12 months prior to enrolment in the study (the time of diagnosis was determined by the date of the first glucose tolerance test or by the time which hypoglycaemic treatment had been first initiated)
  • free of life-endangering diseases and a minimal life expectancy of five years at entry into the study in the clinician´s judgement
  • a diagnostic glucose tolerance test in which the sum of the four individual blood glucose values was ≥ 500 mg/100 mL
  • free of ketoacidosis and other major diabetic symptoms on diet alone during a four-week observation period immediately preceding entry into the study
  • patient willing and able to participate in the study


Exclusion criteria: a prior history of ketoacidosis

Diagnostic criteria: the results of the glucose tolerance test provided the primary basis for the diagnosis of diabetes for patients admitted to the study; a sum of four glucose values from glucose tolerance test had to be equal or greater than 500 mg/100 mL


InterventionsNumber of study centres: 12
Anti-diabetic interventions (intervention group):

Maintain blood glucose in normal range
Normal defined as: fasting blood glucose level below 110 mg/100 mL and a level of less than 210 mg/100 mL one hour after ingestion of 50 gm of glucose and one and one-half hours after the morning insulin injection
The insulin variable treatment group: In the event that both above limits were exceeded at a scheduled test, the insulin dose was to be raised by at least two units. The investigators were to decrease the insulin dosage when it appeared necessary in order to prevent hypoglycaemic episodes, A minimum of five units per day was stipulated in the low end of the dosage scale
Diet
Anti-diabetic interventions (control group):

Minimise the likelihood of hypoglycaemic reactions without reducing the insulin dose to pharmacologically inactive amounts
The insulin standard treatment group: The only scheduled modifications in the number of units of insulin prescribed for patients in the insulin standard group that were permitted after initiation of treatment were those which resulted from a change of the patient´s weight which in turn led to changes in the patient´s body surface and corresponding dosage category:
Units of insulin/body surface in square meters:
(10 U/ under 1.5)
(12 U/ 1.5-1.69)
(14 U/ 1.7-1.89)
(16U/ 1.9 and over)
Diet

Concomitant treatment of cardiovascular risk factors:
Both groups: NR

Concomitant target values of cardiovascular risk factors: NR


OutcomesOutcomes reported in abstract of publication: fatal and non-fatal events (not specified further)


Study detailsTitration period: none

Run-in period: four weeks on diet

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: none

Non-commercial funding: The National Institute of Arthritis, Metabolism, and Digestive Diseases of the Public Health Service


Stated aim for studyQuote from publication: "The University Group Diabetes Program is a long-term prospective clinical trial designed to evaluate the effects of various hypoglycemic agents on vascular complications in patients with asymptomatic adult-onset diabetes."


NotesPatients were randomised to five different therapeutic regimes: Insulin variable, insulin standard, tolbutamide, phenformin, and placebo. We have chosen the IVAR (Insulin Variable) group as an intensive group and ISTD (Insulin Standard) as the conventional group

At the time the study was conducted HbA1c was not used to measure glycaemic control

Fasting blood glucose calculated from mg/dL to mmol/L by dividing with 18

Sixty-nine of the patients enrolled did not meet the diagnostic criterion of the glucose tolerance test (17 in insulin standard, 13 in insulin variable)

The age is only reported for all treatments group, i.e., 1027 participants, whereof only 414 participants are of relevance for this review

Previous cardiovascular disease is reported as a history of angina pectoris

Abbreviations: UGDP: University Group Diabetes Program


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from publication: "Patients enrolled in the UGDP were randomly assigned to one of the five treatment groups."

Quote: "Separate allocation schedules were used for each of the participating Clinical Centers. These schedules were prepared using a table of random numbers and were designed to insure a specified number of patients in each of the treatment groups in a given clinic at periodic intervals throughout the course of the recruitment."

Allocation concealment (selection bias)Low riskQuote from publication: "All assignments were made by the UGDP coordinating centre."

Blinding of outcome assessment (detection bias)
Objective outcomes
Low riskQuote from publication: "…blind evaluation long-term observation of patients, and central collection, editing, and monitoring of the observed data."

Blinding of outcome assessment (detection bias)
Subjective outcomes
High riskComments: health related quality of life not reported. Mild hypoglycaemia reported from participants not blinded to the investigation

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskQuote from publication: "Patients who indicated that they were no longer willing or able to participate in the UGDP or who had missed four consecutive quarterly examinations were classified as dropouts. A patient classified as dropout remained classified in this way until he/she returned to the clinic for follow-up examination or until the date of death."

Quote from publication: ".....the percentage of patients classified as dropouts was 15.0 for PLBO, 18.0 for ISTD and 18.0 for IVAR."

Incomplete outcome data (attrition bias)
Subjective outcomes
Low riskQuote from publication: "Patients who indicated that they were no longer willing or able to participate in the UGDP or who had missed four consecutive quarterly examinations were classified as dropouts. A patient classified as dropout remained classified in this way until he/she returned to the clinic for follow-up examination or until the date of death."

Quote from publication: ".....the percentage of patients classified as dropouts was 15.0 for PLBO, 18.0 for ISTD and 18.0 for IVAR."

Selective reporting (reporting bias)Low riskComments: all predefined primary and secondary outcomes were reported

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?Low riskComments: no industry funding

Trials according to risk of biasLow riskComments: adequate sequence generation and allocation concealment

UKPDS 1998

MethodsRandomised clinical trial


ParticipantsInclusion criteria:
Newly-diagnosed patients with type 2 diabetes mellitus aged 25-65 years inclusive and had fasting plasma glucose greater than 6 mmol/L on two mornings, 1-3 weeks apart, were eligible for the study; every participant randomised in the UKPDS 33 or UKPDS 34 had a fasting plasma glucose of 6.1 to 15.0 mmol/L after three months diet (body weight > 120% of ideal body weight for the entry in the UKPDS-34 1998)

Exclusion criteria:

  • ketonuria more than 3 mmol/L
  • serum creatinine greater than 175 ųmol/L
  • myocardial infarction in the previous year
  • current angina or heart failure
  • more than one major vascular event
  • retinopathy requiring laser treatment
  • malignant hypertension
  • uncorrected endocrine disorder
  • occupation that precluded insulin therapy (e.g., driver of heavy goods vehicle)
  • severe concurrent illness that would limit life or require extensive systemic treatment
  • inadequate understanding
  • unwillingness to enter the study


Diagnostic criteria: main criterion for type 2 diabetes mellitus was fasting plasma glucose > 6 mmol/L on two mornings 1-3 weeks apart


InterventionsNumber of study centres: 23

Anti-diabetic interventions (intervention group):

Fasting plasma glucose less than 6 mmol/L and, in insulin-treated patients; pre-meal glucose concentrations of 4 to 7 mmol/L
One of the following sulphonylureas: chlorpropamide 100-500 mg, glibenclamide 2.5-20 mg or glipizide 2.5-40 mg
Metformin up to 2550 mg, distributed on two doses a day
Patients assigned insulin started on once daily ultralente insulin or isophane insulin. If the daily dose was more than 14 U or pre-meal or bedtime home blood glucose measurements were more than 7 mmol/L, a short-acting insulin, usually soluble (regular) insulin was added (basal/bolus regimen)

All participants had to continue their assigned treatment as long as possible. Additional therapies for participants assigned to sulphonylurea/metformin were metformin/glibenclamide, and if hyperglycaemia recurred then initiating of insulin

The protocol was amended to allow the early addition of metformin when fasting plasma glucose was greater than 6 mmol/L on maximum doses of sulphonylurea in symptomless patients in the intensive group. Patients were changed to insulin therapy if marked hyperglycaemia recurred
In the last eight centres recruited in 1988, patients allocated to sulphonylurea had insulin added early, rather than metformin, when fasting plasma glucose was greater than 6 mmol/L on maximum doses of sulphonylurea

Dietary advice
Anti-diabetic interventions (control group):

To maintain fasting plasma glucose below 15 mmol/L without symptoms of hyperglycaemia
If marked hyperglycaemia or symptoms occurred, patients were secondarily randomised to treatment with sulphonylurea or insulin therapy (UKPDS-34 1998, also metformin). If marked hyperglycaemia recurred in participants secondarily allocated sulphonylurea, metformin was added. In those secondarily allocated metformin, glibenclamide was added. Patients with marked hyperglycaemia or symptoms on both agents were changed to insulin. Throughout, the aim of fasting plasma glucose below 15 mmol/L without symptoms was maintained

Dietary advice

Concomitant treatment of cardiovascular risk factors:
Both groups: regular aspirin therapy was only advised, if there was a specific indication such as a recent myocardial infarction; blood pressure lowering and lipid-lowering - see below

Concomitant target values of cardiovascular risk factors:
Both groups: lipid-lowering treatment was initiated if total cholesterol were greater than 8.5 mmol/L or triglyceride were greater than 4.0 mmol/L, if dietary advice not could reduce these values satisfactorily

The Hypertension in Diabetes Study randomly allocated patients with blood pressure ≥ 160/90 mmHg to tight control aiming for < 150/85 mmHg with either an ACE-inhibitor or a beta-blocker or to less tight control aiming for < 200/105 mmHg. In all 1148 patients were also included in the Hypertension Diabetes Study


OutcomesOutcomes reported in abstract of publication: HbA1c, any diabetes-related endpoint, any diabetes-related death, all-cause mortality, any diabetes-related aggregate endpoint, hypoglycaemic episodes, weight gain, stroke, costs of intervention, and quality of life


Study detailsTitration period: metformin was titrated

Run-in period: patients with newly-diagnosed diabetes were initially treated with diet for 3 months. Those who remained symptom-free but who had continuing fasting hyperglycaemia, plasma glucose > 6.0 and < 15.0 mmol/L were randomly allocated to active policy or to diet policy in the main randomisation (UKPDS 33 and UKPDS 34)

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: Hoechst, Lilly, Novo-Nordisk and Lipha

Non-commercial funding: The Oxford Medical School Research Fund, the Charles Wolfson Charitable Trust, Clothworker's Foundation and the Alan and Babette Sainsbury Charitable Fund (grants for the pilot study). British Diabetic Association, Medical Research Council, National Eye Institute and National Institute of Digestive, Diabetes and Kidney Disease of the National Institutes of Health, USA, The Health Promotion Research Trust


Stated aim for studyQuote from publication: "We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial." (UKPDS 33 1998)

"This study investigated whether intensive glucose control with metformin has any specific advantage or disadvantage." (UKPDS 34 1998)


NotesRury Holman confirmed a total overlap between the conventional group in the UKPDS 33 and the UKPDS 34. As UKPDS 33 had a larger number of participants; age, duration of disease, glycaemic control, fasting blood glucose, BMI, previously cardiovascular disease, duration of intervention, duration of follow-up are only taken from the participants of the UKPDS 33. The two baseline characteristics in which the UKPDS 34 1998 are particular different from the data noted above are HbA1c and BMI

The number of patients with previous cardiovascular disease is taken from the meta-analyses by Turnbull et al (Turnbull 2009)

The number of males and females is calculated as the number of patients randomised to the UKPDS 33 1998, plus the number randomised to intensive control in UKPDS 34 1998. Fasting glycaemic control: SD is calculated from IQR

Abbreviations: ACE: angiotensin-converting enzyme; UKPDS: United Kingdom Prospective Diabetes Study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from publication: "Randomisation of patients was computer generated..."

Allocation concealment (selection bias)Low riskQuote from publication: "...allocations in sealed opaque envelopes, with a check maintained on numerical sequence, dates of opening and results."

Blinding of outcome assessment (detection bias)
Objective outcomes
Low riskQuote from publication: "Members of the UKPDS end-point committee, who were unaware of assignments to study groups, adjudicated outcomes exactly..."

Blinding of outcome assessment (detection bias)
Subjective outcomes
High riskComments: health-related quality of life and mild hypoglycaemia assessed by the participants unblinded to the intervention

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskQuote: "At the end of the trial, the vital status of 76 (2.0%) patients who had emigrated was not known; 57 and 19 in intensive and conventional groups, respectively, which reflects the 70/30 randomisation. A further 91 (2.4%) patients (65 in the intensive group) could not be contacted in the last year of the study for assessment of clinical endpoints."

Comments: number and reason for lost to follow-up for our objective outcomes are adequately reported

Incomplete outcome data (attrition bias)
Subjective outcomes
Low riskComments: number and reasons for lost to follow-up for our subjective outcomes are adequately reported

Selective reporting (reporting bias)Low riskComments: all predefined outcomes reported

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?High riskComments: Hoechst, Lilly, Novo-Nordisk and Lipha

Trials according to risk of biasLow riskAdequate sequence generation and allocation concealment

VA CSDM 1995

MethodsRandomised clinical trial


ParticipantsInclusion criteria:

  • men
  • age from 40 to 69 years
  • elevated HbA1c values (> 3 SD above the normal mean (5.05% + 3 x 0.50 ≥ 6.55%)
  • insulin treatment or maximum dose of sulphonylurea


Exclusion criteria:

  • documented type 2 diabetes mellitus of > 15 years duration
  • history of more than one myocardial infarction or a myocardial infarction within 6 months before entry
  • angina pectoris class III or IV (Canadian Heart Association), refractory to medical therapy
  • congestive heart failure class III or IV (NYHA), refractory to medical treatment, or any patient currently in need of digitalis;
  • transient cerebral ischaemic attacks first appearing within 1 year before entry
  • documented cerebrovascular attack in the last 6 months or cerebrovascular attacks with more than minor functional impairment, preventing protocol adherence
  • malignancies or other life-threatening diseases, if likely to cause death within 7 years
  • autonomic neuropathy defined as orthostatic hypotension, gastroparesis, or diabetic diarrhoea
  • symptomatic, documented pancreatic insufficiency, pancreatic diabetes, or other documented malabsorptive disease
  • history of hypoglycaemic reactions with loss of consciousness or any clinical condition with seizure disorders
  • history of ketoacidosis or other evidence of insulin dependency
  • current endocrine disease, except corrected hypothyroidism, or mild primary hypogonadism not requiring medication;
  • currently taking beta-blockers that cannot be discontinued or replaced by cardioselective agents (i.e., metoprolol in doses ≤ 100 mg/day)
  • current participation in any other clinical trial
  • allergies or intolerance to sulphonylureas
  • albuminuria > 65 mg/ 3 hour (0.52 gm/24 hour) and/or albumin/creatinine > 0.33
  • serum creatinine > 1.6 mg/dL
  • ongoing diabetic gangrene or previous amputation from documented diabetic gangrene
  • fasting C-peptide level < 0.21 pmol/mL
  • uncooperative or unreliable, including alcoholism, or unable to follow instructions as decided by investigator
  • severe obesity (> 60% above ideal body weight)
  • haemoglobinopathy, i.e., sickle-cell trait or haematological conditions interfering with HbA1c monitoring
  • liver disease (transaminase > 3 times normal or serum bilirubin > 1.9 mg/dL)
  • living alone, without regular access to a person who can assist or be called in emergency
  • any underlying condition(s) that the physician feels may prevent adherence to protocol therapy


Diagnostic criteria: fasting plasma C-peptide > 0.21 pmol/L


InterventionsNumber of study centres: 5

Anti-diabetic interventions (intervention group): maintain mean HbA1c < 7.5%
Treament is adjusted with home blood glucose monitoring aiming, at fasting blood glucose of 4.48 to 6.44 mmol/L and other preprandial levels ≤ 7.28 mmol/L
Participants moved to the next step if the HbA1c goal was not met:

  • one injection of evening intermediate or long-acting insulin
  • continued evening insulin combined with daytime glipizide in step increments of 2.5-5.0 mg/week until HbA1c goal or maximum dose is reached
  • two injections of insulin alone, no glipizide
  • multiple daily insulin injections, no glipizide


Anti-diabetic interventions (control group): avoiding excessive hyperglycaemia, or symptoms of excessive glycosuria, ketonuria, or hypoglycaemia, consistent with conventional therapy provided patients with type 2 diabetes mellitus in the medical community. (Alert HbA1c < 12.9%). One injection of insulin. If treatment aims cannot be met by diet, exercise, or insulin adjustments, including mixtures, a maximum of two daily injections can be prescribed for patients in this group

Concomitant treatment of cardiovascular risk factors:
Both groups: hypertension, dyslipidaemia, smoking, and obesity were treated similarly in all patients following the guidelines of the ADA

Concomitant target values of cardiovascular risk factors: values from the guidelines of the ADA


OutcomesOutcomes reported in abstract of publication: HbA1c separation, hypoglycaemic reactions, microalbuminuria, albumin:creatinine, urinary albumin excretion, macrovascular events, retinal morphology, retinopathy, visual acuity, insulin doses, all-cause mortality, cardiovascular mortality, and quality of life


Study detailsTitration period: oral anti-diabetic drugs were titrated

Run-in period: none

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: Roerig/Pfizer Pharmaceuticals

Non-commercial funding: cooperative Studies Program of the Department of Veterans Affairs Medical Research Service


Stated aim for studyQuote from publication: "The relative risks and benefits of intensive therapy in NIDDM are not well defined. Accordingly, we designed a feasibility study that compared standard therapy and intensive therapy in a group of NIDDM men who required insulin due to sustained hyperglycaemia."


NotesThe Veteran Affairs Diabetes Feasibility Trial was conducted as a pilot study and was a precursor for the subsequent VADT. Fasting blood glucose is calculated from mg/dL to mmol/L by dividing with 18

Abbreviations: ADA: American Diabetes Association; HbA1c: glycosylated haemoglobin A1c; NYHA: New York Heart Association; VACSDM: Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComments: no description

Allocation concealment (selection bias)Unclear riskQuote from publication: "Patients were randomised into..."

Blinding of outcome assessment (detection bias)
Objective outcomes
Low riskQuote from publication: "An End-Points Committee of consultants external to the study and masked to treatment assignment used predetermined criteria to decide whether an event occurred and to categorize it."

Blinding of outcome assessment (detection bias)
Subjective outcomes
High riskComments: health-related quality of life and mild hypoglycaemia assessed by non-blinded participants

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskQuote from publication: "The participation of three patients on intensive therapy was terminated at 14, 17, and 24 months for causes apparently unrelated to diabetic treatment: one moved to unknown address, one had septicaemia leading to irreversible coma, and one developed psychotic depression. A fourth patient in the intensive group voluntarily withdrew at the 7th month."

Incomplete outcome data (attrition bias)
Subjective outcomes
Low riskQuote from publication: "The number of patients at entry was 78 in the standard (STD) group and 75 in the intensive (INT) group; the number of patients evaluated at 24 months was 74 (4 patients died) and 67 (4 patients died and there were 4 dropouts due to severe illness not related to the study endpoints), respectively. Comments: lost to follow-up adequately reported for subjective outcomes."

Selective reporting (reporting bias)Low riskComments: All predefined primary and secondary outcomes were reported

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?High riskComments: Roerig/Pfizer Pharmaceuticals

Trials according to risk of biasUnclear riskUnclear sequence generation and allocation concealment

VADT 2009

MethodsRandomised clinical trial


ParticipantsInclusion criteria:

  • Male and female veterans
  • > 41 years old
  • nonresponsive to a maximum dose of at least one oral agent and/or daily insulin injections (Nonresponsiveness is defined as having centrally measured HbA1c level > 4 SD above the normal mean, that is, > 7.5%, or else local HbA1c > 8.3%)


Exclusion criteria:

  • angina pectoris class III or IV (Canadian Heart Association)
  • congestive heart failure class III or IV (NYHA)
  • stroke, myocardial infarction, invasive revascularization within the past 6 months
  • ongoing diabetic gangrene
  • severe obesity (BMI ≥ 40 kg/m2)
  • haemoglobinopathy interfering with HbA1c monitoring
  • serum creatinine > 1.6 mg/dL
  • transaminase > 3 times the upper limit of normal or serum bilirubin > 1.9 mg/dL
  • conditions likely to cause death within 7 years
  • autonomic neuropathy (orthostatism, gastroparesis, or diabetic diarrhoea)
  • type 1 diabetes or pancreatic insufficiency, pancreatic diabetes, or other malabsorptive disease
  • recurrent seizures (within the past year) while on anti seizure medication
  • hypopituitarism
  • pregnancy, lactation, or planning a pregnancy
  • active psychosis, alcoholism, or other substance abuse
  • living alone, without access to a person who can assist in an emergency
  • conditions that may prevent adherence to protocol (unable to self-care or a severe illness or treatment)
  • current participation in another trial


Diagnostic criteria: Fasting plasma C-peptide > 0.21 pg per cc


InterventionsNumber of study centres: 20

Anti-diabetic interventions (intervention group):

HbA1c ≤ 6%. A priority is to avoid hypoglycaemia, even if asymptomatic. The goal for HbA1c level was an absolute reduction of 1.5 percentage points in the intensive intervention group, as compared with conventional intervention group.
For obese patients (BMI ≥ 27 kg/m2) entering on oral agents alone, the following algorithm was used:

  1. metformin starts at 500 mg and increases up to 2000 mg and rosiglitazone 4 mg twice a day
  2. initiate insulin, or if on insulin, adjust to one evening injection of intermediate or long-acting preparation targeted to normal fasting glucose (i.e., 80–115 mg/dL)
  3. add morning insulin and may add alpha-glucosidase inhibitors
  4. multiple daily insulin injections with retention of oral agents (at least one oral sensitizer)
  5. any necessary combination


For lean patients entering on oral agents alone, Step 1 is different in that glimepiride (8 mg) is used in combination with rosiglitazone. Steps 2–5 are the same as for obese patients. All patients entering on insulin proceed directly to Step 2; the treatment protocol may be changed if new modalities become available during the intervention period

Anti-diabetic interventions (control group):

Well-being, avoidance of deterioration of HbA1c, keeping levels at 8–9% and preventing symptoms of glycosuria, hypoglycaemia, and ketonuria; the treatment outline is not rigid

For obese patients (BMI ≥ 27 kg/m2) entering on oral agents alone, the pharmacological steps are as follows:

  • metformin 500 mg and up to 1000 mg and rosiglitazone 4 mg
  • add intermediate or long-acting insulin, 1 U/9 lb, for subjects not previously on insulin
  • increase metformin to 1000 mg twice a day
  • increase rosiglitazone to 8 mg/day
  • increase insulin dose (may add alpha-glucosidase inhibitors)
  • any necessary combination, including nateglinide or glimepiride


For lean patients entering on oral agents alone, the steps are as follows:

  • glimepiride 2 mg and rosiglitazone 4 mg
  • add intermediate or long-acting insulin, 1 U/9 lb
  • increase glimepiride to 8 mg daily before noon
  • increase rosiglitazone to 8 mg daily before noon
  • the two last intervention opportunities are the same as in obese patients


Patients on insulin at entry proceed to Step 2. The treatment protocol may be changed if new modalities become available

Concomitant treatment of cardiovascular risk factors:
Both groups: Basic tenets in type 2 diabetes mellitus are instructed and enforced in both treatment arms for education, diet, blood pressure, and lipid control

Concomitant target values of cardiovascular risk factors:
Blood pressure < 130/80 mmHg
LDL-cholesterol < 2.6 mmol/L
HDL-cholesterol > 1.2 mmol/L for men and > 1.4 mmol/L for women
Aspirin: 81-325 mg


OutcomesOutcomes reported in abstract of publication: primary outcome (major cardiovascular event, a composite of myocardial infarction, stroke, death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischaemic gangrene), microvascular complications, adverse events, and hypoglycaemia


Study detailsTitration period: when metformin is initiated, the dose is titrated

Run-in period: none

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: GlaxoSmithKline, Novo Nordisk, Roche Diagnostics, Sanofi-Aventis, Amylin, and Kos Pharmaceuticals

Non-commercial funding: the Veterans Affairs Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development, the American Diabetes Association, and the National Eye Institute


Stated aim for studyQuote from publication: "The primary goal of the Veterans Affairs Diabetes Trial (VADT) was to compare the effects of intensive and standard glucose control on cardiovascular events."


NotesCholesterol is converted from mg/dL to mmol/L by dividing by 39

SD deviation of fasting blood glucose is calculated from IQR. Value of fasting blood glucose is converted from mg/dL to mmol/L by dividing with 18

Abbreviations: BMI: Body mass index; HbA1c: Glycosylated haemoglobin A1c; HDL: High density lipoprotein; LDL: Low density lipoprotein; VADT: Veterans Affairs Diabetes Trial


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from publication: "Patients were randomly assigned with the use of a permuted-block design with a block size of six and stratified according to study site, the previous occurrence of a macrovascular event, and current insulin use. The randomization codes were generated by the study’s biostatistician at the Hines Cooperative Studies Program Coordinating Center. Study sites did not have access to the codes."

Allocation concealment (selection bias)Low riskComments: see above

Blinding of outcome assessment (detection bias)
Objective outcomes
Low riskQuote from publication: "Primary and secondary CV endpoints are determined by the independent Endpoints Committee, masked to treatment assignment, by evaluation of supporting documentation."

Blinding of outcome assessment (detection bias)
Subjective outcomes
High riskComments: mild hypoglycaemia assessed by non-blinded participants

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskQuote from publication: "Deaths occurring after withdrawal from the study were included in the analysis." Reason for lost to follow-up for the other objective outcomes reported

Incomplete outcome data (attrition bias)
Subjective outcomes
Low riskReason for lost to follow-up for mild hypoglycaemia reported; health-related quality of life not published yet

Selective reporting (reporting bias)Low riskCerebrovascular disease and inoperable coronary artery disease are not listed as a part of the primary composite outcome in the design article of the trial, but is reported in the main publication of the results. These outcomes were, however, a part of the operations manual for the trial, which preceded the actual inception of the trial according to the investigators

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?High riskComments: GlaxoSmithKline, Novo Nordisk, Roche Diagnostics, Sanofi-Aventis, Amylin, and Kos Pharmaceuticals

Trials according to risk of biasLow riskAdequate sequence generation and allocation concealment

Yang 2007

MethodsRandomised clinical trial


ParticipantsInclusion criteria:

  • 35-75 years old
  • diagnoses of type 2 diabetes mellitus within one year before entry to trial


Exclusion criteria:

  • Severe liver and renal dysfunction
  • acute or chronic infectious diseases
  • cancer
  • people with endocrine disease and long-term hormone use
  • macrovascular lesions


Diagnostic criteria: WHO 1999


InterventionsNumber of study centres: 1

Anti-diabetic interventions (intervention group): Fasting blood glucose < 7.0 mmol/L, 2 hour postprandial glucose < 10 mmol/L, HbA1c < 7.0%. Mainly by multiple subcutaneous insulin injections

Anti-diabetic interventions (control group): not specified, routine outpatient treatment

Concomitant treatment of cardiovascular risk factors:
Both groups: not specified

Concomitant target values of cardiovascular risk factors:

Intensive:

Total cholesterol (mmol/L): < 4.7
LDL-cholesterol (mmol/L): < 2.7
HDL-cholesterol (mmol/L): > 1.1

Triglycerides (mmol/L): < 1.7

Conventional: not specified, routine outpatient


OutcomesOutcomes reported in abstract of publication: Carotis intima thickness


Study detailsTitration period: NR

Run-in period: NR

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: Chinese

Publication status: peer-reviewed journal

Commercial funding: none reported

Non-commercial funding: supported by the national program for Key Science and Technology Projects


Stated aim for studyQuote from publication: "To investigate whether long-term intensive glycemic and lipid control would ameliorate the carotid intima medial thickness (IMT) in patients with type 2 diabetes mellitus (T2DM)."


NotesAbbreviations: HbA1c: Glycosylated haemoglobin A1c; NR: Not reported; WHO: World Health Organization


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote from publication: "89 patients who were willing to sign informed consent were randomly allocated into intense group and conventional group."

Allocation concealment (selection bias)Unclear riskComments: not described

Blinding of outcome assessment (detection bias)
Objective outcomes
Unclear riskComments: blinding not reported

Blinding of outcome assessment (detection bias)
Subjective outcomes
Unclear riskComments: no subjective outcomes reported

Incomplete outcome data (attrition bias)
Objective outcomes
Unclear riskComments: no withdrawals or drop-outs reported

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskComments: no subjective outcomes reported

Selective reporting (reporting bias)Unclear riskComments: no trial protocol or design article available

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?Low riskComments: supported by the National Program for Key Science and Technology Projects (2001BA702B01)

Trials according to risk of biasUnclear riskComments: unclear sequence generation and allocation concealment

Zhang 2011

MethodsRandomised clinical trial


ParticipantsInclusion criteria:

  • aged ≥30 years when initially diagnosed type 2 diabetes
  • aged ≥55 years when grouping
  • one or more high risk factors of cardiovascular diseases as follows: aged ≥65 years; diabetes duration ≥10 years; with macrovascular diseases (cerebral apoplexy, transient ischaemic attack, myocardial infarct, coronary artery bypass surgery or coronary artery imaging); with microvascular diseases (heavy proteinuria, retina laser therapy, proliferative retinopathy, macular edema); other risk factors of vascular diseases (smoking, total cholesterol >6 mmol/l, high density lipoprotein cholesterol-C <1.0 mmol/L, microalbuminuria)


Exclusion criteria:

  • contraindication of perindopril, indapamide and gliclazide sustained-release tablets
  • contraindication of HbA1c ≤6.5%
  • insulin treatment


Diagnostic criteria: WHO 1999


InterventionsNumber of study centres: 1

Anti-diabetic interventions (intervention group):

HbA1c of 6.5% or less, with the purpose of making sure the difference value of HbA1c between the two groups ≥1%; the intensive control group took gliclazide sustained-release tablets 30–120 mg/d and stopped taking other sulphonylureas. The dose of gliclazide sustained-release tablets was adjusted according to the HbA1c level, and non-sulphonylurea drugs or insulin were added in order to ensure that the level of HbA1c was no higher than 6.5%

Anti-diabetic interventions (control group): standard control with HbA1c target based on local guidelines. Antihyperglycaemic agents except gliclazide sustained-release tablets

Concomitant treatment of cardiovascular risk factors:
Both groups: The article seems a bit contrary: "Patients in both groups with hypertension or hyperlipidemia used antihypertensive or lipid-lowering therapy routinely." and another section: "In the initial period, all patients received a daily fixed-dose perindopril/indapamide (2.0 mg/0.625 mg) combination. The patients who could tolerate well and would like to comply with the treatment were selected and randomized. During this initial period, the previous hypoglycemic treatments remained unchanged. After randomization, patients received a double-blind form of therapy, taking the medical dosage increasing to 4.0 mg/1.25 mg after three months or taking only placebos. If patients needed angiotensin-converting enzyme inhibitor therapy, they could start, continue or switch to use an open-label perindopril (2–4 mg/d) at any time. In order to ensure that the level of blood pressure (BP) ≤160/90 mmHg."

Concomitant target values of cardiovascular risk factors: NR


OutcomesOutcomes reported in abstract of publication: quality of life


Study detailsTitration period: none

Run-in period: 6 weeks

Study terminated before regular end (for benefit / because of adverse events): no


Publication detailsLanguage of publication: English

Publication status: peer-reviewed journal

Commercial funding: none

Non-commercial funding: grant from Anhui Science and Technology Agency R&D Projects (No. 08020303075)


Stated aim for studyQuote from publication: "This study was performed to determine the effects of intensive glucose control therapy on QOL of elderly patients with type 2 diabetes in Anhui Province."


NotesAbbreviations: HbA1c: Glycosylated haemoglobin A1c; NR: Not reported; WHO: World Health Organization


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "..and the remaining 97 cases (62 male and 35 female) of patients were randomly assigned to the standard control group (49 cases) and the intensive control group (48 cases)."

Allocation concealment (selection bias)Unclear riskComments: not described

Blinding of outcome assessment (detection bias)
Objective outcomes
Unclear riskComments: blinding of the outcome assessors not described

Blinding of outcome assessment (detection bias)
Subjective outcomes
Unclear riskComments: mild hypoglycaemia and health related quality of life reported by unblinded participants

Incomplete outcome data (attrition bias)
Objective outcomes
Unclear riskQuote from publication: "Three patients died, and 7 patients were withdrawn (only telephone follow-up)." No reasons for the seven of the participants lost to follow-up provided

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskQuote from publication: response rate for health-related quality of life not reported

Selective reporting (reporting bias)High riskComments: no trial protocol or design article available. However, the trials primary outcome is only partial reported (Appendix 11)

Free from academic bias (assessed from primary author)?Low riskComments: no academic bias

Free from sponsor bias?Low riskComments: no commercial funding

Trials according to risk of biasUnclear riskComments: unclear sequence generation and allocation concealment

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Abdelmalak 2010Patients with type 2 diabetes mellitus are reported together with patients without diabetes

ADOPT 2010No predefined differences in glycaemic target

Asma 2011No predefined differences in glycaemic target

Barbosa 1983Not including participants with type 2 diabetes mellitus

BARI 2D 2009No predefined differences in glycaemic target

Barnett 2008Not a randomised controlled clinical trial

Blaha 2009Patients with type 2 diabetes mellitus are reported together with patients without diabetes

Brocco 2001Not a randomised controlled clinical trial

Brown 2011Not a randomised controlled clinical trial

Chan 2009No predefined differences in glycaemic target

Chen 2011Not a randomised controlled clinical trial

Chen 2012No predefined differences in glycaemic target

Cheung 2006Reporting patients with and without type 2 diabetes mellitus together

Clark 1985Not a randomised controlled clinical trial

Clauson 1996No predefined differences in glycaemic target

Cleveringa 2010No predefined differences in glycaemic target

Corpus 2004Not a randomised controlled clinical trial

Crasto 2011No predefined differences in glycaemic target

Desimone 2012No predefined differences in glycaemic target

DIGAMI 1996Patients with type 1 and type 2 diabetes mellitus reported together

Du 2009No predefined differences in glycaemic target

Eastman 1997Not a randomised controlled clinical trial

Eibl 2004Not a randomised controlled clinical trial

Evans 1982Not a randomised controlled clinical trial

Farcasiu 2011No predefined differences in glycaemic target

Fenske 2012Not a randomised controlled clinical trial

Furnary 1999Not a randomised controlled clinical trial

HEART 2D 2009Randomised into two groups targeting the same HbA1c with different strategies (basal versus prandial)

Hu 2011No predefined differences in glycaemic target

Johansen 2007No predefined differences in glycaemic target

Joss 2002No predefined differences in glycaemic target

Kanaoka 2011Not a randomised controlled clinical trial

Kawamori 1991No predefined differences in glycaemic target

Lazar 2004Patients with type 1 and type 2 diabetes mellitus reported together

Leibowitz 2010Not a randomised controlled clinical trial

MacMahon 2009No predefined differences in glycaemic target

Mehuys 2011No predefined differences in glycaemic target

Menard 2005No predefined differences in glycaemic target

Naqvi 2011Reporting patients with and without type 2 diabetes mellitus together

Nerenberg 2012Reporting patients with and without type 2 diabetes mellitus together

Olivarius 2001No predefined differences in glycaemic target

ORIGIN 2012Reporting patients with type 2 diabetes mellitus and impaired glucose tolerance together

Piatt 2010No predefined differences in glycaemic target

Pimazoni-Netto 2011Reporting patients with and without type 2 diabetes mellitus together

Plotnikoff 2011No predefined differences in glycaemic target

Polonsky 2011No predefined differences in glycaemic target

PROactive 2005No predefined differences in glycaemic target

Rauch et alNot a randomised controlled clinical trial

Retnakaran 2010Not a randomised controlled clinical trial

Ryan 2004Not a randomised controlled clinical trial

Schaan 2011No predefined differences in glycaemic target

Schauer 2012No predefined differences in glycaemic target

Shi 2010No predefined differences in glycaemic target

Tian 2012No predefined differences in glycaemic target

UKPDS-44 1999No predefined differences in glycaemic target

van Bruggen 2009No predefined differences in glycaemic target

Vivas 2011Reporting patients with and without type 2 diabetes mellitus together

Weng 2008No predefined differences in glycaemic target

Wexler 2012No predefined differences in glycaemic target

Zhao 2010No predefined differences in glycaemic target

 
Characteristics of ongoing studies [ordered by study ID]
ADVANCE-ON

Trial name or titleAction in Diabetes and Vascular Disease Preterax and Diamicron MR Controlled Evaluation Post Trial Observational Study (ADVANCE-ON)

MethodsObservational (post-randomisation)

ParticipantsPatients with type 2 diabetes mellitus

InterventionsNo intervention given. Only follow-up

OutcomesPrimaty outcomes: major macrovascular events, death from any cause
Secondary outcomes: death from cardiovascular cause, major clinical microvascular events, major microvascular and macrovascular events assessed composite, stroke, requirement for renal replacement therapy, death from renal disease, development of severe diabetes eye disease, major hypoglycaemia, and myocardial infarction

Starting dateJanuary 2010

Contact informationhmonaghan@george.org.au

Estimated study completion dataDecember 2013

Notes

Chen 2009

Trial name or titleThe Benefits of Intensive Glycemic Control in Elderly Patients With Type 2 Diabetes

MethodsRandomised clinical trial

ParticipantsElderly patients with type 2 diabetes mellitus

InterventionsIntensive glycaemic control versus conventional glycaemic control

OutcomesPrimary outcomes: the primary study outcomes are a composite of macrovascular events and a composite of microvascular events, considered both jointly and separately
Secondary outcomes: death from any cause, disability from any cause, total coronary events, total cerebrovascular events, heart failure, peripheral vascular events, all cardiovascular events, and hospitalisation for 24 hours or more

Starting dateFebruary 2009

Contact informationchenhs@vghtpe.gov.tw

Estimated study completion dataDecember 2010

Notes

DARE

Trial name or titleDARE: Diabetes in cArdiac REhabilitation

MethodsRandomised clinical trial

ParticipantsPatients with type 2 diabetes mellitus and recent myocardial infarction

InterventionsIntensive treatment group: the patients will treated by insulin under a basal-bolus regimen with strict glycaemic control;
conventional treatment group, in which the previous anti-diabetic treatment will be continued

OutcomesPrimary outcomes: improvement of peak VO2, peak workload, ventilatory threshold
Secondary outcomes: number of patients, in each group of treatment, having improved from at least 20% their peak VO2, after cardiac rehabilitation. Influence of improvement of glycaemic control on cardiac rehabilitation on exercise capacities

Starting dateJuly 2005

Contact informationbruno.verges@chu-dijon.fr

Estimated study completion dataTrial is now completed and data are analysed

NotesCorrespodence with the contact author has confirmed that the trial is completed

GLUCOSURG1

Trial name or titleGLUCOSURG1 (Resolution of Type 2 Diabetes Mellitus: Intensive vs. Conventional Glycaemic Control After Obesity Surgery)

MethodsRandomised clinical trial

ParticipantsPatients with Type 2 Diabetes Mellitus who have been approved for obesity surgery

InterventionsIntensive glycaemic control (fasting capillary glucose levels between 5-7 mmol/L) versus conventional glycaemic control (7-9 mmol/L)

OutcomesPrimary outcomes: percentage of patients with type 2 diabetes mellitus who achieve fasting blood glucose of less than 5.6 mmol/L and/or HbA1c of less than 6%
Secondary outcomes: percentage of type 2 diabetes mellitus patients with a reduction in the doses/number of diabetes medications used preoperatively, microvascular events

Starting dateDecember 2010

Contact informationa.miras@nhs.net

Estimated study completion dataDecember 2013

Notes

HFDM

Trial name or titleHFDM (Optimized Glycemic Control in Heart Failure Patients With DM2: "Effect on Left Ventricular Function and Skeletal Muscle")

MethodsRandomised clinical trial

ParticipantsPatients with type 2 diabetes mellitus and heart failure

InterventionsIntensive glycaemic control versus conventional glycaemic control

OutcomesPrimary outcomes: left ventricular function, muscle strength and mass
Secondary outcomes: hormonal and metabolic profile, 6-minutes hall walk test, exercise capacity and peak oxygen consumption

Starting dateMarch 2010

Contact informationroni.r.nielsen@gmail.com

Estimated study completion dataMarch 2012

Notes

LIMBISCH

Trial name or titleLIMBISCH (Normalization of Fasting Glucose and the Incidence of Restenosis After Peripheral Angioplasty)

MethodsRandomised clinical trial

ParticipantsPatients with type 2 diabetes mellitus and limb ischaemia

InterventionsInsulin therapy incorporating the target of normal fasting glucose (< 5.5 mmol/L) and glycated haemoglobin < 6.5% compared with standard care to achieve a glycated haemoglobin < 7.0% in patients with type 2 diabetes mellitus and limb ischaemia

OutcomesPrimary outcome: reduction of restenosis after peripheral angioplasty
Secondary outcome: identification of new peripheral markers predictive of restenosis

Starting dateDecember 2008

Contact informationpiatti.piermarco@hsr.it

Estimated study completion dataJune 2010

Notes

REMIT Pilot Trial

Trial name or titleREMIT Pilot Trial (Remission Evaluation of Metabolic Interventions in Type 2 Diabetes)

MethodsRandomised clinical trial

ParticipantsPatients with type 2 diabetes mellitus diagnosed by a physician within 3 years prior to enrolment

InterventionsIntensive glycaemic control versus conventional glycaemic control

OutcomesPrimary outcomes: proportion of participants achieving normoglycaemia in the experimental group 1 compared to the control group, proportion of participants achieving normoglycaemia in the experimental group 2 compared to the control group
Secondary outcomes: proportion of participants with normal glucose tolerance, proportion of participants with normal fasting plasma glucose, change in fasting plasma glucose from baseline, HbA1C, change in weight from baseline, rate of symptomatic hypoglycaemic episodes, rate of severe hypoglycaemic episodes

Starting dateSeptember 2010

Contact informationgerstein@mcmaster.ca

Estimated study completion dataAugust 2013

Notes

RESET-IT

Trial name or titleEarly Intermittent Intensive Insulin Therapy as an Effective Treatment of Type 2 Diabetes (RESET-IT)

MethodsRandomised clinical trial

ParticipantsPatients with type 2 diabetes mellitus

InterventionsIntensive insulin versus continuous metformin

Outcomesbeta-cell function,insulin sensitivity

Starting date2012

Contact informationrretnakaran@mtsinai.on.ca

Estimated study completion data2014

NotesInvestigator contacted for specification of glycaemic targets

VADT-FS 2008

Trial name or titleThe VA Diabetes Trial Follow-up Study (VADT-FS)

MethodsObservational follow-up study

ParticipantsPatients with type 2 diabetes mellitus

InterventionsNo intervention given. Only follow-up of the participants from the VADT

OutcomesPrimary outcome: long-term effect of intensive glycaemic control in type 2 diabetes mellitus on major cardiovascular complications
Secondary outcomes: long-term effects of intensive glycaemic control in type 2 diabetes mellitus on: a) cardiovascular mortality, b) major microvascular complications, c) health-related quality of life, and d) total mortality

Starting dateFebruary 2008

Contact informationTamara.Paine@va.gov

Estimated study completion dataMay 2017

NotesThis is an observational follow-up study of VADT (VADT 2009).

Xiang 2010

Trial name or titleThe Effect of Intensive Multifactorial Therapy on Endothelial Function in Newly Diagnosed Type 2 Diabetes

MethodsRandomised clinical trial

ParticipantsNewly diagnosed patients with type 2 diabetes mellitus

InterventionsIntensive multifactorial intervention versus conventional multifactorial intervention

OutcomesEndothelial function, endothelium related cytokines such as ET-1, vWF, as well as blood glucose, HbA1c at different time points

Starting dateApril 2010

Contact informationGuangda64@hotmail.com

Estimated study completion data2020

Notes

 
Comparison 1. Intensive glycaemic control versus conventional glycaemic control

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

 1 All-cause mortality2434325Risk Ratio (M-H, Random, 95% CI)1.00 [0.92, 1.08]

 2 All-cause mortality; stratified according to risk of bias2434325Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.94, 1.07]

    2.1 Lower risk of bias
1333344Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.94, 1.07]

    2.2 High risk of bias
11981Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.37, 1.37]

 3 All-cause mortality; stratified according to sequence generation2434325Risk Ratio (M-H, Random, 95% CI)1.00 [0.92, 1.08]

    3.1 Adequate sequence generation
1733707Risk Ratio (M-H, Random, 95% CI)1.00 [0.92, 1.09]

    3.2 Unclear/inadequate sequence generation
7618Risk Ratio (M-H, Random, 95% CI)0.74 [0.36, 1.50]

 4 All-cause mortality; stratified according to allocation concealment2434325Risk Ratio (M-H, Random, 95% CI)1.00 [0.92, 1.08]

    4.1 Adequate allocation concealment
1733707Risk Ratio (M-H, Random, 95% CI)1.00 [0.92, 1.09]

    4.2 Unclear/inadequate allocation concealment
7618Risk Ratio (M-H, Random, 95% CI)0.74 [0.36, 1.50]

 5 All-cause mortality; stratified according to blinding (study level)2434325Risk Ratio (M-H, Random, 95% CI)1.00 [0.92, 1.08]

    5.1 Adequate blinding
1733635Risk Ratio (M-H, Random, 95% CI)1.00 [0.92, 1.09]

    5.2 Unclear/inadequate blinding
7690Risk Ratio (M-H, Random, 95% CI)0.64 [0.27, 1.49]

 6 All-cause mortality; stratified according to outcome data (outcome level)2434325Risk Ratio (M-H, Random, 95% CI)1.00 [0.92, 1.08]

    6.1 Complete outcome data
1811497Risk Ratio (M-H, Random, 95% CI)0.96 [0.88, 1.06]

    6.2 Incomplete outcome data
622828Risk Ratio (M-H, Random, 95% CI)1.06 [0.87, 1.29]

 7 All-cause mortality; stratified according to outcome reporting bias (study level)2434325Risk Ratio (M-H, Random, 95% CI)1.00 [0.92, 1.08]

    7.1 Adequate outcome reporting
1333256Risk Ratio (M-H, Random, 95% CI)1.00 [0.91, 1.10]

    7.2 Unclear/inadequate outcome reporting
111069Risk Ratio (M-H, Random, 95% CI)0.65 [0.33, 1.30]

 8 All-cause mortality; stratified according to academic bias2434325Risk Ratio (M-H, Random, 95% CI)1.00 [0.92, 1.08]

    8.1 Low risk of academic bias
2233470Risk Ratio (M-H, Random, 95% CI)0.98 [0.90, 1.08]

    8.2 High risk of academic bias
2855Risk Ratio (M-H, Random, 95% CI)1.11 [0.89, 1.38]

 9 All-cause mortality; stratified according to source of funding2434325Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.94, 1.07]

    9.1 Industry funded
1532206Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.94, 1.07]

    9.2 No industry funding
92119Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.81, 1.32]

 10 All-cause mortality; stratified according to study duration2434325Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.94, 1.07]

    10.1 Long duration (> 2.0 years)
1233275Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.94, 1.07]

    10.2 Short duration (≤ 2 years)
121050Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.36, 1.68]

 11 All-cause mortality; stratified according to diagnostic criteria2434325Risk Ratio (M-H, Random, 95% CI)1.00 [0.92, 1.08]

    11.1 Diagnostic criteria for T2D described
1922892Risk Ratio (M-H, Random, 95% CI)1.01 [0.92, 1.12]

    11.2 Diagnostic criteria for T2D not described
511433Risk Ratio (M-H, Random, 95% CI)0.93 [0.83, 1.05]

 12 All-cause mortality; stratified according to intervention2434325Risk Ratio (M-H, Random, 95% CI)1.00 [0.92, 1.08]

    12.1 Exclusively dealing with glycaemic control in usual care setting
1228354Risk Ratio (M-H, Random, 95% CI)1.01 [0.92, 1.12]

    12.2 Glycaemic control as a part of acute intervention
3903Risk Ratio (M-H, Random, 95% CI)1.11 [0.89, 1.38]

    12.3 Glycaemic control initiated with surgical intervention
4429Risk Ratio (M-H, Random, 95% CI)0.63 [0.21, 1.92]

    12.4 Multimodal intervention in usual care setting
54639Risk Ratio (M-H, Random, 95% CI)0.87 [0.62, 1.23]

 13 All-cause mortality; hazard ratio7Hazard Ratio (Random, 95% CI)1.00 [0.87, 1.15]

 14 All-cause mortality; available case2333521Risk Ratio (M-H, Random, 95% CI)1.00 [0.92, 1.09]

 15 All-cause mortality; best-case scenario2334247Risk Ratio (M-H, Random, 95% CI)0.82 [0.74, 0.91]

 16 All-cause mortality; worst-case scenario2334247Risk Ratio (M-H, Random, 95% CI)1.20 [0.97, 1.49]

 17 Cardiovascular mortality2234177Risk Ratio (M-H, Random, 95% CI)1.06 [0.94, 1.21]

 18 Cardiovascular mortality; stratified according to risk of bias2234177Risk Ratio (M-H, Random, 95% CI)1.07 [0.94, 1.22]

    18.1 Lower risk of bias
1133196Risk Ratio (M-H, Random, 95% CI)1.08 [0.92, 1.26]

    18.2 High risk of bias
11981Risk Ratio (M-H, Random, 95% CI)0.74 [0.29, 1.93]

 19 Cardiovascular mortality; stratified according to sequence generation2234177Risk Ratio (M-H, Random, 95% CI)1.06 [0.94, 1.21]

    19.1 Adequate sequence generation
1533559Risk Ratio (M-H, Random, 95% CI)1.07 [0.93, 1.23]

    19.2 Unclear/inadequate sequence generation
7618Risk Ratio (M-H, Random, 95% CI)0.67 [0.22, 2.00]

 20 Cardiovascular mortality; stratified according to allocation concealment2234177Risk Ratio (M-H, Random, 95% CI)1.06 [0.94, 1.21]

    20.1 Adequate allocation concealment
1533559Risk Ratio (M-H, Random, 95% CI)1.07 [0.93, 1.23]

    20.2 Unclear/inadequate allocation concealment
7618Risk Ratio (M-H, Random, 95% CI)0.67 [0.22, 2.00]

 21 Cardiovascular mortality; stratified according to blinding (study level)2234177Risk Ratio (M-H, Random, 95% CI)1.06 [0.94, 1.21]

    21.1 Adequate blinding
1533487Risk Ratio (M-H, Random, 95% CI)1.07 [0.93, 1.23]

    21.2 Unclear/inadequate blinding
7690Risk Ratio (M-H, Random, 95% CI)0.54 [0.14, 2.03]

 22 Cardiovascular mortality; stratified according to outcome data (outcome level)2234177Risk Ratio (M-H, Random, 95% CI)1.06 [0.94, 1.21]

    22.1 Adequate outcome data
1711427Risk Ratio (M-H, Random, 95% CI)1.10 [0.96, 1.27]

    22.2 Incomplete outcome data
522750Risk Ratio (M-H, Random, 95% CI)1.08 [0.75, 1.54]

 23 Cardiovascular mortality; stratified according to outcome reporting bias (study level)2234177Risk Ratio (M-H, Random, 95% CI)1.06 [0.94, 1.21]

    23.1 Adequate outcome reporting
1233186Risk Ratio (M-H, Random, 95% CI)1.07 [0.92, 1.24]

    23.2 Unclear/inadequate outcome reporting
10991Risk Ratio (M-H, Random, 95% CI)0.64 [0.21, 1.93]

 24 Cardiovascular mortality; stratified according to academic bias2234177Risk Ratio (M-H, Random, 95% CI)1.06 [0.94, 1.21]

    24.1 Low risk of academic bias
2033322Risk Ratio (M-H, Random, 95% CI)1.05 [0.90, 1.23]

    24.2 High risk of academic bias
2855Risk Ratio (M-H, Random, 95% CI)1.14 [0.86, 1.51]

 25 Cardiovascular mortality; stratified according to source of funding2234177Risk Ratio (M-H, Random, 95% CI)1.06 [0.94, 1.21]

    25.1 Industry funding
1332047Risk Ratio (M-H, Random, 95% CI)1.06 [0.90, 1.26]

    25.2 No industry funding
92130Risk Ratio (M-H, Random, 95% CI)1.02 [0.70, 1.50]

 26 Cardiovascular mortality; stratified according to study duration2234177Risk Ratio (M-H, Random, 95% CI)1.06 [0.94, 1.21]

    26.1 Long duration (> 2 years)
1233275Risk Ratio (M-H, Random, 95% CI)1.06 [0.91, 1.24]

    26.2 Short duration (≤ 2 years)
10902Risk Ratio (M-H, Random, 95% CI)0.83 [0.25, 2.71]

 27 Cardiovascular mortality; stratified according to diagnostic criteria2234177Risk Ratio (M-H, Random, 95% CI)1.06 [0.94, 1.21]

    27.1 Diagnostic criteria for T2D described
1822822Risk Ratio (M-H, Random, 95% CI)1.17 [1.04, 1.31]

    27.2 Diagnostic criteria for T2D not described
411355Risk Ratio (M-H, Random, 95% CI)0.87 [0.74, 1.03]

 28 Cardiovascular mortality; stratified according to intervention2234177Risk Ratio (M-H, Random, 95% CI)1.06 [0.94, 1.21]

    28.1 Exclusively dealing with glycaemic control in usual care setting
1228354Risk Ratio (M-H, Random, 95% CI)1.09 [0.92, 1.29]

    28.2 Glycaemic control as a part of acute intervention
3903Risk Ratio (M-H, Random, 95% CI)1.14 [0.86, 1.51]

    28.3 Glycaemic control initiated with surgical intervention
2281Risk Ratio (M-H, Random, 95% CI)0.95 [0.14, 6.57]

    28.4 Multimodal intervention in usual care setting
54639Risk Ratio (M-H, Random, 95% CI)0.86 [0.47, 1.56]

 29 Cardiovascular mortality; hazard ratio6Hazard Ratio (Random, 95% CI)1.05 [0.84, 1.31]

 30 Cardiovascular mortality; available case2233451Risk Ratio (M-H, Random, 95% CI)1.06 [0.94, 1.20]

 31 Cardiovascular mortality; best-case scenario2234177Risk Ratio (M-H, Random, 95% CI)0.71 [0.56, 0.88]

 32 Cardiovascular mortality; worst-case scenario2234177Risk Ratio (M-H, Random, 95% CI)1.54 [1.09, 2.18]

 33 Macrovascular complications1432846Risk Ratio (M-H, Random, 95% CI)0.91 [0.82, 1.02]

 34 Macrovascular complications; stratified according to intervention1432846Risk Ratio (M-H, Random, 95% CI)0.91 [0.82, 1.02]

    34.1 Exclusively dealing with glycaemic control in usual care setting
927666Risk Ratio (M-H, Random, 95% CI)0.92 [0.83, 1.01]

    34.2 Glycaemic control as a part of acute intervention
1780Risk Ratio (M-H, Random, 95% CI)1.09 [0.91, 1.32]

    34.3 Glycaemic control initiated with surgical intervention
170Risk Ratio (M-H, Random, 95% CI)1.67 [0.43, 6.45]

    34.4 Multimodal intervention in usual care setting
34330Risk Ratio (M-H, Random, 95% CI)0.79 [0.54, 1.16]

 35 Non-fatal myocardial infarction1430417Risk Ratio (M-H, Random, 95% CI)0.87 [0.77, 0.98]

 36 Non-fatal myocardial infarction; stratified according to study duration1430417Risk Ratio (M-H, Random, 95% CI)0.87 [0.77, 0.98]

    36.1 Long duration (> 2 years)
1030181Risk Ratio (M-H, Random, 95% CI)0.87 [0.76, 1.00]

    36.2 Short duration ( ≤ 2 years)
4236Risk Ratio (M-H, Random, 95% CI)0.81 [0.23, 2.78]

 37 Non-fatal myocardial infarction; stratified according to risk of bias1430417Risk Ratio (M-H, Random, 95% CI)0.87 [0.77, 0.98]

    37.1 Lower risk of bias
929988Risk Ratio (M-H, Random, 95% CI)0.87 [0.75, 1.01]

    37.2 High risk of bias
5429Risk Ratio (M-H, Random, 95% CI)0.82 [0.34, 1.99]

 38 Non-fatal myocardial infarction; stratified according to source of funding1430417Risk Ratio (M-H, Random, 95% CI)0.87 [0.77, 0.98]

    38.1 Industry funded
828594Risk Ratio (M-H, Random, 95% CI)0.86 [0.73, 1.00]

    38.2 No industry funding
61823Risk Ratio (M-H, Random, 95% CI)1.00 [0.67, 1.49]

 39 Non-fatal myocardial infarction; stratified according to diagnostic criteria1319277Risk Ratio (M-H, Random, 95% CI)0.84 [0.74, 0.96]

    39.1 Diagnostic criteria for T2D described
1319277Risk Ratio (M-H, Random, 95% CI)0.84 [0.74, 0.96]

 40 Non-fatal myocardial infarction; stratified according to intervention1430417Risk Ratio (M-H, Random, 95% CI)0.87 [0.77, 0.98]

    40.1 Exclusively dealing with glycaemic control in usual care setting
828111Risk Ratio (M-H, Random, 95% CI)0.85 [0.76, 0.95]

    40.2 Glycaemic control as a part of acute intervention
3903Risk Ratio (M-H, Random, 95% CI)1.15 [0.84, 1.58]

    40.3 Glycaemic control initiated with surgical intervention
170Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    40.4 Multimodal intervention in usual care setting
21333Risk Ratio (M-H, Random, 95% CI)0.63 [0.22, 1.83]

 41 Non-fatal myocardial infarction; available case1428103Risk Ratio (M-H, Random, 95% CI)0.87 [0.77, 0.97]

 42 Non-fatal myocardial infarction; best-case scenario1430417Risk Ratio (M-H, Random, 95% CI)0.34 [0.24, 0.47]

 43 Non-fatal myocardial infarction; worst-case scenario1430417Risk Ratio (M-H, Random, 95% CI)2.28 [1.62, 3.19]

 44 Non-fatal stroke1330003Risk Ratio (M-H, Random, 95% CI)1.00 [0.84, 1.19]

 45 Non-fatal stroke; stratified according to intervention1330000Risk Ratio (M-H, Random, 95% CI)0.99 [0.84, 1.18]

    45.1 Exclusively dealing with glycaemic control in usual care setting
727697Risk Ratio (M-H, Random, 95% CI)1.01 [0.87, 1.16]

    45.2 Glycaemic control as a part of acute intervention
3900Risk Ratio (M-H, Random, 95% CI)1.19 [0.62, 2.30]

    45.3 Glycaemic control initiated with surgical intervention
170Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    45.4 Multimodal intervention in usual care setting
21333Risk Ratio (M-H, Random, 95% CI)0.68 [0.19, 2.49]

 46 Amputation of lower extremity1111200Risk Ratio (M-H, Random, 95% CI)0.65 [0.45, 0.94]

 47 Amputation of lower extremity; stratified according to intervention1111200Risk Ratio (M-H, Random, 95% CI)0.65 [0.45, 0.94]

    47.1 Exclusively dealing with glycaemic control in usual care setting
56677Risk Ratio (M-H, Random, 95% CI)0.70 [0.45, 1.09]

    47.2 Glycaemic control as a part of acute intervention
2123Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    47.3 Glycaemic control initiated with surgical intervention
170Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    47.4 Multimodal intervention in usual care setting
34330Risk Ratio (M-H, Random, 95% CI)0.54 [0.27, 1.07]

 48 Cardiac revascularization73532Risk Ratio (M-H, Random, 95% CI)0.81 [0.65, 1.01]

 49 Cardiac revascularization; stratified according to intervention73532Risk Ratio (M-H, Random, 95% CI)0.81 [0.65, 1.01]

    49.1 Exclusively dealing with glycaemic control in usual care setting
32054Risk Ratio (M-H, Random, 95% CI)0.85 [0.67, 1.07]

    49.2 Glycaemic control as a part of acute intervention
175Risk Ratio (M-H, Random, 95% CI)2.17 [0.21, 22.89]

    49.3 Glycaemic control initiated with surgical intervention
170Risk Ratio (M-H, Random, 95% CI)2.0 [0.19, 21.06]

    49.4 Multimodal intervention in usual care setting
21333Risk Ratio (M-H, Random, 95% CI)0.50 [0.26, 0.94]

 50 Peripheral revascularization813547Risk Ratio (M-H, Random, 95% CI)0.93 [0.81, 1.06]

 51 Peripheral revascularization; stratified according to intervention813547Risk Ratio (M-H, Random, 95% CI)0.93 [0.81, 1.06]

    51.1 Exclusively dealing with glycaemic control in usual care setting
413194Risk Ratio (M-H, Random, 95% CI)0.93 [0.81, 1.07]

    51.2 Glycaemic control as a part of acute intervention
2123Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    51.3 Glycaemic control initiated with surgical intervention
170Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    51.4 Multimodal intervention in usual care setting
1160Risk Ratio (M-H, Random, 95% CI)0.6 [0.23, 1.57]

 52 Microvascular complications625927Risk Ratio (M-H, Random, 95% CI)0.88 [0.82, 0.95]

 53 Microvascular complications; stratified according to intervention625927Risk Ratio (M-H, Random, 95% CI)0.88 [0.82, 0.95]

    53.1 Exclusively dealing with glycaemic control in usual care setting
425697Risk Ratio (M-H, Random, 95% CI)0.87 [0.78, 0.97]

   53.2 Glycaemic control as a part of acute intervention
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    53.3 Glycaemic control initiated with surgical intervention
170Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    53.4 Multimodal intervention in usual care setting
1160Risk Ratio (M-H, Random, 95% CI)0.89 [0.80, 1.00]

 54 Nephropathy1128096Risk Ratio (M-H, Random, 95% CI)0.75 [0.59, 0.95]

 55 Nephropathy; stratified according to intervention1128096Risk Ratio (M-H, Random, 95% CI)0.75 [0.59, 0.95]

    55.1 Exclusively dealing with glycaemic control in usual care setting
927866Risk Ratio (M-H, Random, 95% CI)0.79 [0.61, 1.01]

   55.2 Glycaemic control as a part of acute intervention
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    55.3 Glycaemic control initiated with surgical intervention
170Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    55.4 Multimodal intervention in usual care setting
1160Risk Ratio (M-H, Random, 95% CI)0.54 [0.35, 0.85]

 56 End-stage renal disease828145Risk Ratio (M-H, Random, 95% CI)0.87 [0.71, 1.06]

 57 End-stage renal disease; stratified according to intervention828145Risk Ratio (M-H, Random, 95% CI)0.87 [0.71, 1.06]

    57.1 Exclusively dealing with glycaemic control in usual care setting
627915Risk Ratio (M-H, Random, 95% CI)0.88 [0.72, 1.07]

   57.2 Glycaemic control as a part of acute intervention
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    57.3 Glycaemic control initiated with surgical intervention
170Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    57.4 Multimodal intervention in usual care setting
1160Risk Ratio (M-H, Random, 95% CI)0.17 [0.02, 1.35]

 58 Retinopathy910300Risk Ratio (M-H, Random, 95% CI)0.79 [0.68, 0.92]

 59 Retinopathy; stratified according to intervention910300Risk Ratio (M-H, Random, 95% CI)0.79 [0.69, 0.92]

    59.1 Exclusively dealing with glycaemic control in usual care setting
710070Risk Ratio (M-H, Random, 95% CI)0.80 [0.67, 0.94]

   59.2 Glycaemic control as a part of acute intervention
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    59.3 Glycaemic control initiated with surgical intervention
170Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    59.4 Multimodal intervention in usual care setting
1160Risk Ratio (M-H, Random, 95% CI)0.76 [0.58, 0.99]

 60 Retinal photocoagulation811212Risk Ratio (M-H, Random, 95% CI)0.77 [0.61, 0.97]

 61 Retinal photocoagulation; stratified according to intervention811212Risk Ratio (M-H, Random, 95% CI)0.77 [0.61, 0.97]

    61.1 Exclusively dealing with glycaemic control in usual care setting
610982Risk Ratio (M-H, Random, 95% CI)0.82 [0.65, 1.03]

   61.2 Glycaemic control as a part of acute intervention
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    61.3 Glycaemic control initiated with surgical intervention
170Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    61.4 Multimodal intervention in usual care setting
1160Risk Ratio (M-H, Random, 95% CI)0.52 [0.29, 0.91]

 62 Adverse events1337672Risk Ratio (M-H, Random, 95% CI)1.06 [1.02, 1.11]

    62.1 Adverse events
2403Risk Ratio (M-H, Random, 95% CI)1.18 [0.87, 1.60]

    62.2 Serious adverse events
1124280Risk Ratio (M-H, Random, 95% CI)1.06 [1.02, 1.10]

    62.3 Drop-outs due to adverse events
1112989Risk Ratio (M-H, Random, 95% CI)1.47 [0.84, 2.56]

 63 Serious adverse events; stratified according to intervention1124280Risk Ratio (M-H, Random, 95% CI)1.06 [1.02, 1.10]

    63.1 Exclusively dealing with glycaemic control in usual care setting
723927Risk Ratio (M-H, Random, 95% CI)1.06 [1.02, 1.10]

    63.2 Glycaemic control as a part of acute intervention
2123Risk Ratio (M-H, Random, 95% CI)0.95 [0.41, 2.18]

    63.3 Glycaemic control initiated with surgical intervention
170Risk Ratio (M-H, Random, 95% CI)1.0 [0.07, 15.36]

    63.4 Multifactorial intervention in usual care setting
1160Risk Ratio (M-H, Random, 95% CI)3.0 [0.12, 72.56]

 64 Drop-outs due to adverse events; stratified according to intervention1112989Risk Ratio (M-H, Random, 95% CI)1.47 [0.84, 2.56]

    64.1 Exclusively dealing with glycaemic control in usual care setting
712636Risk Ratio (M-H, Random, 95% CI)1.50 [0.80, 2.79]

    64.2 Glycaemic control as a part of acute intervention
2123Risk Ratio (M-H, Random, 95% CI)1.35 [0.39, 4.65]

    64.3 Glycaemic control initiated with surgical intervention
170Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    64.4 Multimodal intervention in usual care setting
1160Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 65 Congestive heart failure1229815Risk Ratio (M-H, Random, 95% CI)0.98 [0.87, 1.10]

 66 Congestive heart failure; stratified after intervention1129733Risk Ratio (M-H, Random, 95% CI)0.99 [0.88, 1.12]

    66.1 Exclusively dealing with glycaemic control in usual care setting
627587Risk Ratio (M-H, Random, 95% CI)1.01 [0.87, 1.17]

    66.2 Glycaemic control as a part of acute intervention
3903Risk Ratio (M-H, Random, 95% CI)0.68 [0.34, 1.37]

    66.3 Glycaemic control initiated with surgical intervention
170Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    66.4 Multimodal intervention in usual care setting
11173Risk Ratio (M-H, Random, 95% CI)0.70 [0.30, 1.62]

 67 Hypoglycaemia1948205Risk Ratio (M-H, Random, 95% CI)1.80 [1.51, 2.14]

    67.1 Mild hypoglycaemia
1519411Risk Ratio (M-H, Random, 95% CI)1.54 [1.35, 1.75]

    67.2 Severe hypoglycaemia
1728794Risk Ratio (M-H, Random, 95% CI)2.18 [1.53, 3.11]

 68 Mild hypoglycaemia; stratified according to intervention1519411Risk Ratio (M-H, Random, 95% CI)1.54 [1.35, 1.75]

    68.1 Exclusively dealing with glycaemic control in usual care setting
918200Risk Ratio (M-H, Random, 95% CI)1.58 [1.37, 1.81]

    68.2 Glycaemic control as a part of acute intervention
3903Risk Ratio (M-H, Random, 95% CI)2.13 [0.83, 5.50]

    68.3 Glycaemic control initiated with operation
2148Risk Ratio (M-H, Random, 95% CI)35.00 [2.19, 560.18]

    68.4 Multimodal intervention in usual care setting
1160Risk Ratio (M-H, Random, 95% CI)1.14 [0.95, 1.37]

 69 Severe hypoglycaemia; stratified according to intervention1728794Risk Ratio (M-H, Random, 95% CI)2.18 [1.53, 3.11]

    69.1 Exclusively dealing with glycaemic control in usual care setting
1028082Risk Ratio (M-H, Random, 95% CI)2.44 [1.78, 3.35]

    69.2 Glycaemic control as a part of acute intervention
2123Risk Ratio (M-H, Random, 95% CI)7.00 [0.38, 128.61]

    69.3 Glycaemic control initiated with surgical intervention
4429Risk Ratio (M-H, Random, 95% CI)4.67 [0.81, 26.84]

    69.4 Multimodal intervention in usual care setting
1160Risk Ratio (M-H, Random, 95% CI)0.71 [0.34, 1.51]

 70 Health-related quality of life; EQ5D22776Mean Difference (IV, Random, 95% CI)0.0 [-0.02, 0.02]

 71 Quality of life: mental component52648Std. Mean Difference (IV, Random, 95% CI)-0.04 [-0.13, 0.04]

    71.1 Change in score from baseline
3906Std. Mean Difference (IV, Random, 95% CI)0.04 [-0.09, 0.18]

    71.2 End of follow-up value
41742Std. Mean Difference (IV, Random, 95% CI)-0.09 [-0.19, 0.01]

 72 Quality of life: physical component41556Std. Mean Difference (IV, Random, 95% CI)-0.04 [-0.14, 0.06]

    72.1 Change in score from baseline
2743Std. Mean Difference (IV, Random, 95% CI)-0.06 [-0.21, 0.08]

    72.2 End of follow-up value
3813Std. Mean Difference (IV, Random, 95% CI)-0.02 [-0.16, 0.11]

 73 Cost of intervention24319Std. Mean Difference (IV, Random, 95% CI)0.05 [-0.02, 0.12]

 
Summary of findings for the main comparison. Intensive glycaemic control versus conventional glycaemic control for type 2 diabetes mellitus

Intensive glycaemic control versus conventional glycaemic control for type 2 diabetes mellitus

Patient or population: participants with type 2 diabetes mellitus
Settings: mostly outpatients
Intervention: intensive glycaemic control versus conventional glycaemic control

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

Assumed riskCorresponding risk

ControlIntensive glycaemic control versus conventional glycaemic control

All-cause mortality
Follow-up: median 24 months
95 per 100095 per 1000
(87 to 103)
RR 1
(0.92 to 1.08)
34325
(24)
⊕⊕⊕⊝
moderatea
-

Cardiovascular mortality
Follow-up: median 27 months
45 per 100048 per 1000
(42 to 55)
RR 1.06
(0.94 to 1.21)
34177
(22)
⊕⊕⊕⊝
moderatea
-

Non-fatal myocardial infarction
Follow-up: median 60 months
48 per 100041 per 1000
(37 to 47)
RR 0.87
(0.77 to 0.98)
30417
(14)
⊕⊕⊕⊝
moderatea
-

Non-fatal stroke
Follow-up: median 54.6 months
29 per 100029 per 1000
(25 to 35)
RR 1
(0.84 to 1.19)
30003
(13)
⊕⊕⊕⊝
moderateb
-

Amputation of lower extremity
Follow-up: median 65.1 months
13 per 10009 per 1000
(6 to 12)
RR 0.65
(0.45 to 0.94)
11200
(11)
⊕⊕⊝⊝
lowc
-

End-stage renal disease
Follow-up: median 93.6 months
16 per 100014 per 1000
(11 to 17)
RR 0.87
(0.71 to 1.06)
28145
(8)
⊕⊕⊕⊝
moderateb
-

Hypoglycaemia - Severe hypoglycaemia
Follow-up: median 12 months
29 per 100064 per 1000
(45 to 91)
RR 2.18
(1.53 to 3.11)
28794
(17)
⊕⊕⊕⊕
high
Trial sequential analysis showed firm evidence for a 30% relative risk increase with intensive glycaemic control.

*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; 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.

 aDowngraded by one due to trial sequential analysis showing that more data are needed; funnel plot indicates small trial bias
bDowngraded by one due to a relatively few number of participants reporting non-fatal stroke or end-stage renal disease
cDowngraded by two due to trial sequential analysis showing that more data are needed, a relatively few number of participants reporting amputation of lower extremity and most of the events stemming from one trial only
 
Table 1. Glycaemic control in trials

Characteristic

Study ID
Glycaemic target, intensive treatmentGlycaemic target, conventional treatmentGlycaemic control at the end of follow-up, HbA1c (%) or other used glycaemic measurement (mmol/L) (mean(SD))Number of participants achieving treatment goalComment

ACCORD 2008HbA1c < 6%

Fasting SMBGa < 5.6 mmol/L (100 mg/dL) or

2 hour blood glucose < 7.8 mmol/L (140 mg/dL)
HbA1c 7%-7.9%

Fasting SMBGa > 5.0 mmol/L (90 mg/dL)
I: 6.4 (0.7)

C: 7.5 (0.8)
I: NR

C: NR
Data are from the end of the intervention period.

SD is calculated from IQR

ADDITION-EuropeHbA1c < 7%, but change in antidiabetic medicine with HbA1c > 6.5%Not specifiedI: 6.6 (1.0)

C: 6.7 (1.0)
I: 1143 out of 1513

C: 878 out of 1226
Number of participants achieving glycaemic target are the number of participants with HbA1c less than 7% at the end of follow-up. Number read from figure

ADVANCE 2008HbA1c ≤ 6.5%Glycaemic target of HbA1c defined from
local guidelines
I: HbA1c: 6.5 (1.0)

C: HbA1c: 7.2 (1.4)
I: 3133 (at the end of follow-up)

C: No specified target

Araki 2012 

HbA1c < 6.9%
Prevent diabetic come and avoid remarkable hyperglycaemia (fasting blood glucose < 200 mg/dl or HbA1c < 9%)I: 7.7 (1.10)

C: 7.8 (1.12)
I: 343

C: 304
The number of participants measured for the achieved glycaemic control was 325 in the intensive group and 338 in the conventional group

Bagg 2001HbA1c < 7%

Before meal capillary glucose: 4-7 mmol/L, 2 hour blood glucose < 10 mmol/L
Avoid symptomatic hyperglycaemia and fortnightly fasting capillary glucose test > 17 mmol/LI: HbA1c: 7.0 (0.4)

C: HbA1c: 10.2 (0.2)
I: 3

C: No specific target

Becker 2003Fasting capillary blood glucose < 6.5 mmol/LFasting capillary blood glucose < 8.5 mmol/LI: 7.2 (1.2)

C: 7.4 (1.4)
I: NR

C: NR

Blonde 2009Fasting plasma glucose 3.9–5.0 mmol/LFasting plasma glucose 4.4–6.1 mmol/LI: HbA1c: 6.9

C: HbA1c: 6.9
I: NR

C: NR
The glycaemic treatment goal in the trial was measured as fasting blood glucose levels. The proportion of participants achieving the target

Cao 2011Blood glucose target between 4.4 and 6.1 mmol/Lblood glucose target between 10.0 and 11.0 mmol/LI: (Postoperative) 5.5 (0.8) mmol/L

C: (Postoperative) 9.9 (1.0) mmol/L
I: NR

C: NR

Cooray 2011Reduce the HbA1c with 1% unitContinue unchanged conventional glycaemic controlI: NR

C: NR
I: NR

C: NR

DIGAMI 2 2005Insulin infusion until stable normoglycaemia and at least for 24 hours. Subcutaneous insulin was initiated at the cessation of the infusion. The treatment goal for patients in group 1 was a fasting blood glucose level of 5-7 mmol/L and a non-fasting level of < 10 mmol/LStandard glucose controlI: HbA1c: 7.0 (1.0)
FBG (target): 8.0 (2.0)

C: HbA1c: 7.0 (1.3)
FBG: 8.6 (3.0)
I: NR

C: NR
HbA1c and fasting blood glucose is read from figure

Fantin 2011Targeting glucose levels between 80 and 100 mg/dL in pre meal periods and lower than 140 mg/dL in random glucose measurements250 mg/dl or lessI: FBG: 8.9 (3.5)

C: FBG: 11.1 (5.4)
I: NR

C: NR
Value for fasting blood glucose is calculated from text. mg/dl is calculated to mmol/L by dividing with 18

Guo 2008HbA1c < 7.0%

Fasting plasma glucose 4-7 mmol/L
No treatment goalI: HbA1c: 6.3 (0.9)
FPG (target): 7.1 (1.7)

C: HbA1c: 7.1 (0.9)
FPG: 8.3 (2.6)
I: 142

C: No specific target

IDA 2009HbA1c < 6.5%

Fasting blood glucose 5-7 mmol/L, before meal < 10 mmol/L
Standard treatmentI: HbA1c (median): 6.3 (1.5)

C: HbA1c (median): 6.6 (0.9)
I: 37 (HbA1c)

C: No specific target
SD is calculated from IQR

Jaber 1996Fasting blood glucose ≤ 6.6 mmol/L, 2 hour postprandial glucose < 10 mmol/L, or to reach maximum daily doses of sulphonylureaNot definedI: 9.2 (2.1)
FBG (target): 8.5 (2.3)

C: 12.1 (3.7)
FBG: 11.0 (3.9)
I: NR

C: NR
Measurement of glycated haemoglobin is not further specified

Kumamoto 2000HbA1c < 7.0%

Fasting blood glucose (< 140 mg/dL), 2 hour postprandial glucose < 200 mg/dL, mean amplitude of glycaemic excursions < 100 mg/dL
Fasting blood glucose close to < 140 mg/dL without symptoms of hyperglycaemia or hypoglycaemia.I: 7.2 (1.0)
FBG (target): 6.3 (1.6)

C: 9.4 (1.3)
FBG (target): 7.4 (1.6)
I: 14

C: 3

Lu 2010Fasting blood glucose < 6.1 mmol/L, postprandial 2 hour glucose < 7.8 mmol/LFasting blood glucose < 7.0 mmol/L, postprandial 2 hour glucose < 10.0 mmol/L.I: 6.1 (0.5)

C: 7.8 (0.7)
I: NR

C: NR

Melidonis 2000Blood glucose 8.3-11.0 mmol/L in the first 48 hours after an acute coronary event, thereafter normoglycaemiaNo specific targetI: HbA1c not measured.
Plasma glucose (target): 6.6 mmol/L (0.5)

C: HbA1c not measured.
Plasma glucose: 10.5 mmol/L (2.1)
I: NR

C: NR
The reported plasma glucose value is for the last day of hospitalisation

Natarajan 2012Fasting capillary glucose levels of 4.0-5.4 mmol/LHbA1c < 8.4%I: 6.9 (0.8)

C: 7.6 (1.5)
I: NR

C: NR

REMBO 2008HbA1c < 7% in participants receiving sulphonylurea;

HbA1c < 6.5% in participants receiving insulin
Not specified, standard careI (median): 6.7 (1.2)

C (median): 6.7 (1.2)
I: NR

C: NR
SD is calculated from IQR

Service 1983HbA1c to normal range, and to maintain 80 minute postprandial plasma glucose below 150 mg/dL (8.3 mmol/L)Eliminate symptoms, but not to a degree to reduce 80 minute postprandial plasma glucose below 150 mg/dLI (median): 8.7

C (median): 9.4
I: 3

C: 4

Stefanidis 2003Near normal glycaemia (defined as 6.6-8.2 mmol/L)No specific targetI: 8 (1.1)
Plasma glucose (target): 6.9 mmol/L (1.8)

C: 8 (1.0)
Plasma glucose: 9.9 mmol/L (1.7)
I: 31

C: NR
We assume HbA1c is unchanged at the end of follow-up due to the short intervention period.

The reported plasma glucose value is for the last day of hospitalisation

Steno-2 2008HbA1c < 6.5%HbA1c < 7.5% (1993-1999), HbA1c < 6.5% (2000-2001)I: 7.9 (1.2)

C: 9.0 (1.8)
I: 13

C: 3
Data are from the end of the intervention period (7.8 years of follow-up).

Number of patients achieved glycaemic target is read from figure.

UGDP 1975Maintain blood glucose in normal range (defined as fasting blood glucose < 110mg/100 mL, blood glucose < 210 mg/100 mL one hour after ingestion of 50 gm glucose and one and one-half hours after the morning insulin injection)Minimize the likelihood of hypoglycaemic reactions without reducing the insulin dose to pharmacologically inactive amountsI: FBG (target): 6.7

C: FBG: 9.7
I: NR

C: NR
Value for fasting blood glucose is calculated from text. mg/dl is calculated to mmol/l by dividing with 18.

SD calculated from SE.

UKPDS 1998Fasting blood glucose < 6 mmol/L

In insulin treated patients; pre-meal glucose 4-7 mmol/L
Fasting blood glucose < 15 mmol/L without symptoms of hyperglycaemiaI (median): 8.1 (1.8)
FPG (target, median): 8.6 mmol/l

C (median): 8.7 (1.6)
FPG (target, median): 9.8 mmol/L
I: NR

C: NR
HbA1c used is the median for the last 5 years follow-up period. SD calculated from IQR.

Fasting plasma glucose read from figure, 10 years after randomisation.

Data are from the UKPDS 33

VA CSDM 1995Maintain mean HbA1c < 7.5%.
Treament is adjusted with home blood glucose monitoring aiming, at fasting blood glucose of 4.48 to 6.44 mmol/L and other pre prandial levels ≤ 7.28 mmol/L
Avoiding excessive hyperglycaemia, or symptoms of excessive glucosuria, ketonuria, or hypoglycaemia (alert HbA1c < 12.9%)I: HbA1c: 7.1 (0.7)

C: HbA1c: 9.2 (0.8)
I: 7 (maintained target)

C: No specified target
The value of HbA1c is estimated from figure after 24 months of follow-up.

The SD for HbA1c is calculated from SE

VADT 2009HbA1c ≤ 6%. The goal for HbA1c level was an absolute reduction of 1.5 percentage points in the intensive-therapy group, as compared with conventional intervention groupWell-being, avoidance of deterioration of HbA1c, keeping levels at 8–9% and preventing symptoms of glycosuria, hypoglycaemia, and ketonuriaI (median): 6.9 (0.9)

C (median): 8.4 (1.2)
I: NR

C: NR
HbA1c estimated from figure.

Data from glycaemic control are medians. SD calculated from IQR

Yang 2007Fasting blood glucose < 7.0 mmol/L, 2 hour postprandial glucose < 10 mmol/L, HbA1c < 7.0%Not specifiedI: 6.5 (1.1)

C: 6.8 (1.4)
I: NR

C: NR

Zhang 2011 HbA1c of 6.5% or less, with the purpose of making sure the difference value of HbA1c between the two groups ≥1%Standard control with HbA1c target based on local guidelinesI: 6.3 (0.7)

C: 7.0 (0.7)
I: NR

C: NR

 aIn the ACCORD trial, SMBG targets were defined as “action required” thresholds (see protocol at http://www.accordtrial.org/public/protocol_2005-05-11.pdf)
ACCORD: Action to Control Cardiovascular Risk in Diabetes, ADVANCE: Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation, DIGAMI: Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction, HbA1c: glycosylated haemoglobin A1c, IDA: Insulin Diabetes Angioplasty; IQR: Interquartile range, REMBO: Rational Effective Multicomponent Therapy in the Struggle Against DiaBetes Mellitus in Patients With COngestve Heart Failure, SE: Standard error, SMBG: self monitoring of blood glucose; UGDP: University Group Diabetes Program, UKPDS: United Kingdom Prospective Diabetes Study, VA CSDM: Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus, VADT: Veterans Affairs Diabetes Trial
C: control; I: intervention
 
Table 2. Overview of study populations

Characteristic Study IDIntervention(s) and controls[N] Screened/eligible[N] Randomised[N] finishing study (mortality)[N] finishing study (other outcomes)[N] Lost to follow-up mortality[N] Lost to follow-up other outcomes[%] Randomised finishing study (mortality)Follow-upa

1. ACCORD 2008I: targeting intensive glycaemic control19,716

 
512849194707110

Long-term follow-up: 209
403

Long-term follow-up: 421
95.9 

Intervention: 3.5 years

Follow-up: 5 years

C: targeting conventional glycaemic control512349194727102

Long-term follow-up: 204
372

Long-term follow-up: 396
96.0

total:10,25110,039947621277597.9 









2. ADDITION-Europe 2011I: targeting intensive glycaemic control1312 practices invited167 practices (1678 patients)161 practices (1678 participants)161 practices (1678 participants)0 practices (0 participants)0 practices (0 participants)96.4% of practices

100% of participants

C: targeting conventional glycaemic control176 practices (1379 patients)157 practices (1377 participants)157 practices (1377 participants)0 practices (2 participants)0 practices (2 participants)89.2 of practices

99.9% of participants

total:3057305530552299.9









3. ADVANCE 2008

 
I: targeting intensive glycaemic control12,877

 
557155645326724599.9 

 

C: targeting conventional glycaemic control5569555952741029599.8

total:11,14011,12310,6001754099.8 









4. Araki 2012I: targeting intensive glycaemic controlNR5855283895719690.3

C: targeting conventional glycaemic control5885413884720092.0

total:1173106991.1









5. Bagg 2001I: targeting intensive glycaemic controlMore than 1000 patients

 
2117174481.0 

 

C: targeting conventional glycaemic control22222200100.0

total:4339394490.7 









6. Becker 2003b

 
I: targeting intensive glycaemic control296

 
106N/AN/AN/A N/AN/A 

 

C: targeting conventional glycaemic control108N/AN/AN/A N/AN/A

total:231191188404382.7 









7. Blonde 2009I: targeting intensive glycaemic control472 patients were required for screening according to sample size estimation in publication, but number actually screened is not provided.122 121 107 1 15 99.1

C: targeting conventional glycaemic control122 122 104 0 18 100.0

total:24424321113399.6









8. Cao 2011I: targeting intensive glycaemic controlDicrepancy in the number reported in publication: 210 or 2209292920010028 days

C: targeting conventional glycaemic control87878700100

total:17917917900100









9. Cooray 2011I: targeting intensive glycaemic controlNR15N/AN/AN/AN/AN/A

C: targeting conventional glycaemic control13N/AN/AN/AN/AN/A

total:28









10. DIGAMI 2 2005

 
I: targeting intensive glycaemic control 

 
47447447400100.0Lost to follow-up in extension period of the study (total follow-up: median: 4.1 years). Intensive group: 43, conventional group: 33

C: targeting conventional glycaemic control30630630600100.0

total: 78078078000100.0 









11. Fantin 2011I: targeting intensive glycaemic control10073535320391.4

C: targeting conventional glycaemic control3535320391.4

total:7070640691.4









12. Guo 2008

 
I: targeting intensive glycaemic control 

 
16616616600100.0 

 

C: targeting conventional glycaemic control54545400100.0

total:22022022000100.0 









13. IDA 2009I: targeting intensive glycaemic control 

 
515151012100.0 

 

C: targeting conventional glycaemic control51515108100.0

total:102102102020100.0 









14. Jaber 1996

 

 
I: targeting intensive glycaemic control892

 
2317176673.9 

 

C: targeting conventional glycaemic control22222200100.0

total:4539396686.7 









15. Kumamoto 2000

 
I: targeting intensive glycaemic control 

 
5553532296.4 

 

C: targeting conventional glycaemic control5551514492.7

total:1101041046694.5 









16. Lu 2010

 

 
I: targeting intensive glycaemic control 

 
21 N/A N/A N/A N/AN/A 

 

C: targeting conventional glycaemic control20 N/A N/A N/A N/AN/A

total:41 N/A N/A N/A N/AN/A 









17. Melidonis 2000I: targeting intensive glycaemic control179

 
24242400100.0 

 

C: targeting conventional glycaemic control24242400100.0

total:48484800100.0 









18. Natarajan 2012I: targeting intensive glycaemic control19153636340294.4

C: targeting conventional glycaemic control4242340881

total:78786801087.2









19. REMBO 2008

 

 
I: targeting intensive glycaemic control 

 
41414100100.0 

 

C: targeting conventional glycaemic control40404000100.0

total:81818100100.0 









20. Service 1983I: targeting intensive glycaemic control 

 
10882280.0 

 

C: targeting conventional glycaemic control10101000100.0

total:2018182290.0 









21. Stefanidis 2003

 

 
I: targeting intensive glycaemic control239

 
3631315586.1 

 

C: targeting conventional glycaemic control3935354489.7

total:7566669988.0 









22. Steno-2 2008cI: targeting intensive glycaemic control315

 
80807901100.0 

 

C: targeting conventional glycaemic control80807802100.0

total:16016015703100.0 









23. UGDP 1975

 
I: targeting intensive glycaemic control 

 
204191167133793.6 

 

C: targeting conventional glycaemic control21020618242898.1

total:414397349176595.9 









24. UKPDS 1998dI: targeting intensive glycaemic control5102

 
3071301429495712298.1 

 

C: targeting conventional glycaemic control113811191093194598.3

total:4209413340427616798.2 









25. VA CSDM 1995e

 

 
I: Targeting intensive glycaemic control289

 
75757104100.0 

 

C: Targeting conventional glycaemic control78787800100.0

total:15315314904100.0 









26. VADT 2009fI: targeting intensive glycaemic control2239

 
8928927720120100.0 

 

C: targeting conventional glycaemic control8998997600139100.0

total:1791179115320259100.0 









27. Yang 2007

 
I: targeting intensive glycaemic control116

 
57575700100.0 

 

C: targeting conventional glycaemic control32323200100.0

total:89898900100.0 









28. Zhang 2011I: targeting intensive glycaemic control 106

 
 48 N/A 48 N/A 0100 

C: targeting conventional glycaemic control 49 N/A 39 N/A 1079.6 

total:97N/A87N/A1089.7 









Grand totalg

 

 
All interventions 

 

 
18,71717,451 

 

 

 

 

 
96393.2 

 

 

All controls16,19514,98689992.5

All interventions and controls34,91232,437186092.9

 "-" denotes not reported
aDuration of intervention and/or follow-up under randomised conditions until end of study
b"During the first year, ten patients found participation too much of a burden, six moved and one died (7%). One outlier (a woman with a BMI of 59) was excluded from the analyses. Thus, 106 patients in group 6 and 108 patients in group 8 were included in the analyses." It means 231 patients were randomised. It is not possible from the articles to find out which group they were randomised to. Of all randomised patients 43 did not make the visit after 2 years
cThe number is taken after 13.3 years of follow-up
d"At the end of the trial, the vital status of 76 (2.0%) patients who had emigrated was not known; 57 and 19 in intensive and conventional groups, respectively, which reflects the 70/30 randomisation. A further 91 (2.4%) patients (65 in the intensive group) could not be contacted in the last year of the study for assessment of clinical endpoints." The n [finishing study] is calculated from the lost to follow-up (mortality) from the UKPDS 33. It is not clear from the UKPDS 34 1998 to clarify how the participants lost to follow-up are distributed. It is reported that 13 participants had unknown vital status, and that the number lost to follow-up for other outcomes is 56. Therefore only data for the UKPDS 33 1998 are used
eMortality data were assessed on the participants lost to follow-up
fDeaths occurring after withdrawal from the study were included in the analysis
gTotals are not the sum of I and C for all columns, because not all trials provided data on the two intervention groups, but only the total
N/A: not applicable