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Meta-Analysis
. 2014 Feb 14;2014(2):CD009122.
doi: 10.1002/14651858.CD009122.pub2.

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

Birgit Fullerton  1 , Klaus Jeitler, Mirjam Seitz, Karl Horvath, Andrea Berghold, Andrea Siebenhofer
Affiliations
Meta-Analysis

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

Birgit Fullerton et al. Cochrane Database Syst Rev. .

Abstract

Background: Clinical guidelines differ regarding their recommended blood glucose targets for patients with type 1 diabetes and recent studies on patients with type 2 diabetes suggest that aiming at very low targets can increase the risk of mortality.

Objectives: To assess the effects of intensive versus conventional glycaemic targets in patients with type 1 diabetes in terms of long-term complications and determine whether very low, near normoglycaemic values are of additional benefit.

Search methods: A systematic literature search was performed in the databases The Cochrane Library, MEDLINE and EMBASE. The date of the last search was December 2012 for all databases.

Selection criteria: We included all randomised controlled trials (RCTs) that had defined different glycaemic targets in the treatment arms, studied patients with type 1 diabetes, and had a follow-up duration of at least one year.

Data collection and analysis: Two review authors independently extracted data, assessed studies for risk of bias, with differences resolved by consensus. Overall study quality was evaluated by the 'Grading of Recommendations Assessment, Development, and Evaluation' (GRADE) system. Random-effects models were used for the main analyses and the results are presented as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes.

Main results: We identified 12 trials that fulfilled the inclusion criteria, including a total of 2230 patients. The patient populations varied widely across studies with one study only including children, one study only including patients after a kidney transplant, one study with newly diagnosed adult patients, and several studies where patients had retinopathy or microalbuminuria at baseline. The mean follow-up duration across studies varied between one and 6.5 years. The majority of the studies were carried out in the 1980s and all trials took place in Europe or North America. Due to the nature of the intervention, none of the studies could be carried out in a blinded fashion so that the risk of performance bias, especially for subjective outcomes such as hypoglycaemia, was present in all of the studies. Fifty per cent of the studies were judged to have a high risk of bias in at least one other category.Under intensive glucose control, the risk of developing microvascular complications was reduced compared to conventional treatment for a) retinopathy: 23/371 (6.2%) versus 92/397 (23.2%); RR 0.27 (95% CI 0.18 to 0.42); P < 0.00001; 768 participants; 2 trials; high quality evidence; b) nephropathy: 119/732 (16.3%) versus 211/743 (28.4%); RR 0.56 (95% CI 0.46 to 0.68); P < 0.00001; 1475 participants; 3 trials; moderate quality evidence; c) neuropathy: 29/586 (4.9%) versus 86/617 (13.9%); RR 0.35 (95% CI 0.23 to 0.53); P < 0.00001; 1203 participants; 3 trials; high quality evidence. Regarding the progression of these complications after manifestation, the effect was weaker (retinopathy) or possibly not existent (nephropathy: RR 0.79 (95% CI 0.37 to 1.70); P = 0.55; 179 participants with microalbuminuria; 3 trials; very low quality evidence); no adequate data were available regarding the progression of neuropathy. For retinopathy, intensive glucose control reduced the risk of progression in studies with a follow-up duration of at least two years (85/366 (23.2%) versus 154/398 (38.7%); RR 0.61 (95% CI 0.49 to 0.76); P < 0.0001; 764 participants; 2 trials; moderate quality evidence), while we found evidence for an initial worsening of retinopathy after only one year of intensive glucose control (17/49 (34.7%) versus 7/47 (14.9%); RR 2.32 (95% CI 1.16 to 4.63); P = 0.02; 96 participants; 2 trials; low quality evidence).Major macrovascular outcomes (stroke and myocardial infarction) occurred very rarely, and no firm evidence could be established regarding these outcome measures (low quality evidence).We found that intensive glucose control increased the risk for severe hypoglycaemia, however the results were heterogeneous and only the 'Diabetes Complications Clinical Trial' (DCCT) showed a clear increase in severe hypoglycaemic episodes under intensive treatment. A subgroup analysis according to the baseline haemoglobin A1c (HbA1c) of participants in the trials (low quality evidence) suggests that the risk of hypoglycaemia is possibly only increased for patients who started with relatively low HbA1c values (< 9.0%). Several of the included studies also showed a greater weight gain under intensive glucose control, and the risk of ketoacidosis was only increased in studies using insulin pumps in the intensive treatment group (very low quality evidence).Overall, all-cause mortality was very low in all studies (moderate quality evidence) except in one study investigating renal allograft as treatment for end-stage diabetic nephropathy. Health-related quality of life was only reported in the DCCT trial, showing no statistically significant differences between the intervention and comparator groups (moderate quality evidence). In addition, only the DCCT published data on costs, indicating that intensive glucose therapy control was highly cost-effective considering the reduction of potential diabetes complications (moderate quality evidence).

Authors' conclusions: Tight blood sugar control reduces the risk of developing microvascular diabetes complications. The evidence of benefit is mainly from studies in younger patients at early stages of the disease. Benefits need to be weighed against risks including severe hypoglycaemia, and patient training is an important aspect in practice. The effects of tight blood sugar control seem to become weaker once complications have been manifested. However, further research is needed on this issue. Furthermore, there is a lack of evidence from RCTs on the effects of tight blood sugar control in older patient populations or patients with macrovascular disease. There is no firm evidence for specific blood glucose targets and treatment goals need to be individualised taking into account age, disease progression, macrovascular risk, as well as the patient's lifestyle and disease management capabilities.

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Conflict of interest statement

Birgit Fullerton: none known.

Klaus Jeitler: participation in the preparation of a report for the Institute for Quality and Efficiency in Health Care on the benefits of long‐term blood glucose lowering to near‐normal levels in patients with type 2 diabetes mellitus (Nutzenbewertung einer langfristigen normnahen Blutzuckersenkung bei Patienten mit Diabetes mellitus Typ 2).

Mirjam Seitz: none known.

Karl Horvath: has received payments (congress fees, travel expenses and accomodation) from Roche, Novartis, Sanofi Aventis and Novo Nordisk to attend annual meetings of the Austrian Diabetes Association; has received payments (congress fees, travel expenses and accomodation) from Novartis and Aventis to attend annual meetings of the EASD; has received financial compensation as a speaker from Novartis, Eli Lilly, Medtronic, The Styrian Health Insurance Company and The Styrian Medical Association; participation in the preparation of a report for the Institute for Quality and Efficiency in Health Care on the benefits of long‐term blood glucose lowering to near‐normal levels in patients with type 2 diabetes mellitus (Nutzenbewertung einer langfristigen normnahen Blutzuckersenkung bei Patienten mit Diabetes mellitus Typ 2).

Andrea Berghold: none known.

Andrea Siebenhofer: participation in the preparation of a report for the Institute for Quality and Efficiency in Health Care on the benefits of long‐term blood glucose lowering to near‐normal levels in patients with type 2 diabetes mellitus (Nutzenbewertung einer langfristigen normnahen Blutzuckersenkung bei Patienten mit Diabetes mellitus Typ 2).

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Relationship between baseline HbA1c and risk of severe hypoglycaemia.
1.1
1.1. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 1 Retinopathy.
1.2
1.2. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 2 Manifestation of retinopathy.
1.3
1.3. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 3 Progression of retinopathy, random effects model.
1.4
1.4. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 4 Progression of retinopathy, random effects model, all studies, Steno 1 after 2 years.
1.5
1.5. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 5 Progression of retinopathy, random effects model, stratified by follow‐up duration.
1.6
1.6. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 6 Progression of retinopathy, fixed‐effect model, stratified by follow‐up duration.
1.7
1.7. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 7 Progression of retinopathy, random effects model, stratified by follow‐up duration, OR.
1.8
1.8. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 8 Manifestation of nephropathy, random‐effects model, RR.
1.9
1.9. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 9 Manifestation of nephropathy, random‐effects model, alternative measure in Oslo 1987.
1.10
1.10. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 10 Manifestation of nephropathy, fixed‐effect model, RR.
1.11
1.11. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 11 Manifestation of nephropathy, random‐effects model, OR.
1.12
1.12. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 12 Progression of nephropathy, random‐effects model, RR.
1.13
1.13. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 13 Progression of nephropathy, fixed‐effect model, RR.
1.14
1.14. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 14 Progression of nephropathy, random‐effects model, OR.
1.15
1.15. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 15 Manifestation of neuropathy, random‐effects model, RR.
1.16
1.16. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 16 Manifestation of neuropathy, fixed‐effect model, RR.
1.17
1.17. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 17 Manifestation of neuropathy, random‐effects model, OR.
1.18
1.18. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 18 Severe hypoglycaemia, random‐effects model, RR.
1.19
1.19. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 19 Severe hypoglycaemia, assistance of other person.
1.20
1.20. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 20 Severe hypoglycaemia, coma or hospital admission.
1.21
1.21. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 21 Severe hypoglycaemia, random‐effects model, RR, without DCCT.
1.22
1.22. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 22 Severe hypoglycaemia, stratified by baseline HbA1c.
1.23
1.23. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 23 Severe hypoglycaemia, random‐effects model, RR, without Bucharest‐Düsseldorf.
1.24
1.24. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 24 Severe hypoglycaemia, random‐effects model, RR, without DCCT and Bucharest‐Düsseldorf.
1.25
1.25. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 25 Severe hypoglycaemia, stratified by baseline HbA1c, without Bucharest‐Düsseldorf.
1.26
1.26. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 26 Severe hypoglycaemia, coma or hospital admission, without Bucharest‐Düsseldorf.
1.27
1.27. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 27 Severe hypoglycaemia, stratified by baseline HbA1c, fixed‐effect model.
1.28
1.28. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 28 Severe hypoglycaemia, stratified by baseline HbA1c, OR.
1.29
1.29. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 29 Ketoacidosis.
1.30
1.30. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 30 Ketoacidosis, CSII.
1.31
1.31. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 31 Ketoacidosis, MI.
1.32
1.32. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 32 Ketoacidosis, MI or CSII.
1.33
1.33. Analysis
Comparison 1 Intensive glucose control versus conventional glucose control, Outcome 33 All‐cause mortality.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Bucharest‐Düsseldorf 1984 {published and unpublished data}
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DCCT1 1993 {published data only (unpublished sought but not used)}
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    1. Albers JW, Herman WH, Pop‐Busui R, Martin CL, Cleary P, Waberski B. Subclinical neuropathy among Diabetes Control and Complications Trial participants without diagnosable neuropathy at trial completion: Possible predictors of incident neuropathy?. Diabetes Care 2007;30(10):2613‐8. - PMC - PubMed
    1. Albers JW, Kenny DJ, Brown M, Greene D, Cleary PA, Lachin JM, et al. Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Annals of Neurology 1995;38(6):869‐80. - PubMed
    1. Carter RE, Lackland DT, Cleary PA, Yim E, Lopes‐Virella MF, Gilbert GE, et al. Intensive treatment of diabetes is associated with a reduced rate of peripheral arterial calcification in the Diabetes Control and Complications Trial. Diabetes Care 2007;30(10):2646‐8. - PMC - PubMed
    1. Herman WH, Eastman RC. The effects of treatment on the direct costs of diabetes. Diabetes Care 1998;21 Suppl 3:C19‐C21. - PubMed
    1. Kilpatrick ES, Rigby AS, Atkin SL. Insulin resistance, the metabolic syndrome, and complication risk in type 1 diabetes: "Double diabetes" in the Diabetes Control and Complications Trial. Diabetes Care 2007;30(3):707‐12. - PubMed
Holman 1983 {published data only}
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Linn 1996 {published data only}
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MCSG 1995 {published data only}
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MDCCT 1994 {published data only}
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Oslo 1987 {published data only}
    1. Amthor KF, Dahl‐Jorgensen K, Berg TJ, Skard Heier M, Sandvik L, Aagenaes O, et al. The effect of 8 years of strict glycaemic control on peripheral nerve function in IDDM patients: The Oslo study. Diabetologia 1994;37(6):579‐84. - PubMed
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    1. Brinchmann‐Hansen O, Dahl‐Jorgensen K, Hanssen KF, Sandvik L. Oscillatory potentials, macular recovery time, and diabetic retinopathy through 3 years of intensified insulin treatment. Ophthalmology 1988;95(10):1358‐66. - PubMed
    1. Brinchmann‐Hansen O, Dahl‐Jørgensen K, Hanssen KF, Sandvik L. The response of diabetic retinopathy to 41 months of multiple insulin injections, insulin pumps, and conventional insulin therapy. Archives of Ophthalmology 1988;106(9):1242‐6. - PubMed
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Steno 1 1983 {published data only}
    1. Deckert T, Lauritzen T, Parvig HH, Christiansen JS, Steno Study Group. Effect of two years of strict metabolic functions in long term insulin‐dependent diabetes. Diabetic Nephropathy 1984;3:6‐10.
    1. Feldt‐Rasmussen B, Mathiesen ER, Jensen T, Lauritzen T, Deckert T. Effect of improved metabolic control on loss of kidney function in type 1 (insulin‐dependent) diabetic patients: an update of the Steno studies. Diabetologia 1991;34(3):164‐70. - PubMed
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Steno 2 1986 {published data only}
    1. Feldt‐Rasmussen B, Mathiesen ER, Deckert T. Effect of two years of strict metabolic control on progression of incipient nephropathy in insulin‐dependent diabetes. Lancet 1986;2(8519):1300‐4. - PubMed
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Verrillo 1988 {published data only}
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Wysocki 2003 {published data only}
    1. Hershey T, Bhargava N, Sadler M, White NH, Craft S. Conventional versus intensive diabetes therapy in children with type 1 diabetes: effects on memory and motor speed. Diabetes Care 1999;22(8):1318‐24. - PubMed
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References to studies excluded from this review

Azar 1999 {published data only}
    1. Azar ST, Kanaan N. Intensive insulin therapy compared with conventional insulin therapy does not reduce depressive symptoms in parents of children with type 1 diabetes. Diabetes Care 1999;22(8):1372‐3. - PubMed
Bangstad 1992 {published data only}
    1. Bangstad HJ, Kofoed‐Enevoldsen A, Dahl‐Jørgensen K, Hanssen KF. Glomerular charge selectivity and the influence of improved blood glucose control in type 1 (insulin‐dependent) diabetic patients with microalbuminuria. Diabetologia 1992;35(12):1165‐9. - PubMed
Barr 2001 {published data only}
    1. Barr CC. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive insulin therapy, by The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. New England Journal of Medicine 2000;342:381‐9. Survey of Ophthalmology 2001;45(5):459‐60. - PubMed
Beck‐Nielsen 1990 {published data only}
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Biesenbach 1988 {published data only}
    1. Biesenbach G, Grafinger P, Kaiser W, Stuby U, Zazgornik J. [Metabolic control in labile type I diabetes with conventional insulin therapy, basal bolus insulin therapy using pens and continuous subcutaneous insulin infusion with the pump]. [German]. Medizinische Klinik 1988;83(12):398‐401. - PubMed
Bougneres 1993 {published data only}
    1. Bougneres PF, Landais P, Mairesse AM, Jais JP, Jos J, Peyraud J, et al. Improvement of diabetic control and acceptability of a three‐injection insulin regimen in diabetic adolescents. A multicenter controlled study. Diabetes Care 1993;16(1):94‐102. - PubMed
Christensen 1987 {published data only}
    1. Christensen CK, Christiansen JS, Schmitz A, Christensen T, Hermansen K, Mogensen CE. Effect of continuous subcutaneous insulin infusion on kidney function and size in IDDM patients: a 2 year controlled study. The Journal of Diabetic Complications 1987;1(3):91‐5. - PubMed
Christiansen 1987 {published data only}
    1. Christiansen JS, Ingerslev J, Bernvil SS, Christensen CK, Hermansen K, Schmitz A. Near normoglycemia for 1 year has no effect on platelet reactivity, factor VIII, and von Willebrand factor in insulin‐dependent diabetes mellitus: a controlled trial. The Journal of Diabetic Complications 1987;1(3):100‐6. - PubMed
Ciavarella 1985 {published data only}
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Crepaldi 1989 {published data only}
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de Beaufort 1989 {published data only}
    1. Beaufort CE, Houtzagers CMGJ, Bruining GJ, Aarsen RSR, Boer NC, Grose WFA, et al. Continuous subcutaneous insulin infusion (CSII) versus conventional injection therapy in newly diagnosed diabetic children: Two‐year follow‐up of a randomized, prospective trial. Diabetic Medicine 1989;6(9):766‐71. - PubMed
Ditzel 1987 {published data only}
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Dzien 1988 {published data only}
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Edelmann 1987 {published data only}
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Eschwege 1979 {published data only}
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Franklin 2006 {published data only}
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Goicolea 1987 {published data only}
    1. Goicolea Opacua I, Hernandez Colau I, Cortazar Galarza A, Vazquez Garcia JA. [Comparison of metabolic control between the continuous subcutaneous insulin infusion pump and augmented conventional treatment. Effects after 12 months]. [Spanish]. Medicina Clinica 1987;88(16):617‐20. - PubMed
Itoh 1990 {published data only}
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Kaufman 2005 {published data only}
    1. Kaufman FR. Intensive management of type 1 diabetes in young children. Lancet 2005;365(9461):737‐8. - PubMed
Kordella 2005 {published data only}
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Kritz 1983 {published data only}
    1. Kritz H, Hagmuller G, Lovett R, Irsigler K. Implanted constant basal rate insulin infusion devices for Type 1 (insulin‐dependent) diabetic patients. Diabetologia 1983;25(2):78‐81. - PubMed
KROC 1988 {published data only}
    1. The Kroc Collaborative Study Group. Diabetic retinopathy after two years of intensified insulin treatment. Follow‐up of the Kroc Collaborative Study. JAMA 1988;260(1):37‐41. - PubMed
Levy 1984 {published data only}
    1. Levy I, Bergua M, Esmatjes E, Halperin I, Figuerola D. [Unstable type I diabetes mellitus: comparative study between intensive conventional treatment and continuous subcutaneous infusion of insulin]. [Spanish]. Medicina Clinica 1984;83(13):525‐8. - PubMed
Malmberg 1997 {published data only}
    1. Malmberg K, Ryden L, Hamsten A, Herlitz J, Waldenstrom A, Wedel H. Mortality prediction in diabetic patients with myocardial infarction: experiences from the DIGAMI study.[Erratum appears in Cariovasc Res 1997 Dec;36(3):460]. Cardiovascular Research 1997;34(1):248‐53. - PubMed
Montanya 1997 {published data only}
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Nosadini 1988 {published data only}
    1. Nosadini R, Velussi M, Fioretto P, Doria A, Avogaro A, Trevisan R, et al. Frequency of hypoglycaemic and hyperglycaemic‐ketotic episodes during conventional and subcutaneous continuous insulin infusion therapy in IDDM. Diabetes, Nutrition & Metabolism ‐ Clinical & Experimental 1988;1(4):289‐96.
Perlman 1984 {published data only}
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