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Review
. 2011 Nov 24:343:d6898.
doi: 10.1136/bmj.d6898.

Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials

Bianca Hemmingsen  1 , Søren S Lund, Christian Gluud, Allan Vaag, Thomas Almdal, Christina Hemmingsen, Jørn Wetterslev
Affiliations
Review

Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials

Bianca Hemmingsen et al. BMJ. .

Abstract

Objective: To assess the effect of targeting intensive glycaemic control versus conventional glycaemic control on all cause mortality and cardiovascular mortality, non-fatal myocardial infarction, microvascular complications, and severe hypoglycaemia in patients with type 2 diabetes.

Design: Systematic review with meta-analyses and trial sequential analyses of randomised trials.

Data sources: Cochrane Library, Medline, Embase, Science Citation Index Expanded, LILACS, and CINAHL to December 2010; hand search of reference lists and conference proceedings; contacts with authors, relevant pharmaceutical companies, and the US Food and Drug Administration.

Study selection: Randomised clinical trials comparing targeted intensive glycaemic control with conventional glycaemic control in patients with type 2 diabetes. Published and unpublished trials in all languages were included, irrespective of predefined outcomes.

Data extraction: Two reviewers independently assessed studies for inclusion and extracted data related to study methods, interventions, outcomes, risk of bias, and adverse events. Risk ratios with 95% confidence intervals were estimated with fixed and random effects models.

Results: Fourteen clinical trials that randomised 28,614 participants with type 2 diabetes (15,269 to intensive control and 13,345 to conventional control) were included. Intensive glycaemic control did not significantly affect the relative risks of all cause (1.02, 95% confidence interval 0.91 to 1.13; 28,359 participants, 12 trials) or cardiovascular mortality (1.11, 0.92 to 1.35; 28,359 participants, 12 trials). Trial sequential analyses rejected a relative risk reduction above 10% for all cause mortality and showed insufficient data on cardiovascular mortality. The risk of non-fatal myocardial infarction may be reduced (relative risk 0.85, 0.76 to 0.95; P=0.004; 28,111 participants, 8 trials), but this finding was not confirmed in trial sequential analysis. Intensive glycaemic control showed a reduction of the relative risks for the composite microvascular outcome (0.88, 0.79 to 0.97; P=0.01; 25,600 participants, 3 trials) and retinopathy (0.80, 0.67 to 0.94; P=0.009; 10,793 participants, 7 trials), but trial sequential analyses showed that sufficient evidence had not yet been reached. The estimate of an effect on the risk of nephropathy (relative risk 0.83, 0.64 to 1.06; 27,769 participants, 8 trials) was not statistically significant. The risk of severe hypoglycaemia was significantly increased when intensive glycaemic control was targeted (relative risk 2.39, 1.71 to 3.34; 27,844 participants, 9 trials); trial sequential analysis supported a 30% increased relative risk of severe hypoglycaemia.

Conclusion: Intensive glycaemic control does not seem to reduce all cause mortality in patients with type 2 diabetes. Data available from randomised clinical trials remain insufficient to prove or refute a relative risk reduction for cardiovascular mortality, non-fatal myocardial infarction, composite microvascular complications, or retinopathy at a magnitude of 10%. Intensive glycaemic control increases the relative risk of severe hypoglycaemia by 30%.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that SSL, AV, and TA have reported equity in Novo Nordisk A/S; SSL and AV have received fees from Novo Nordisk A/S for speaking; TA is employed at Steno Diabetes Center, Gentofte, Denmark; AV and SSL were employed at Steno Diabetes Center at the time the review was written. Steno Diabetes Center is an academic institution owned by Novo Nordisk A/S. CH has been employed at Novo Nordisk after completion of the data extraction.

Figures

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Fig 1 Flow diagram of identification of randomised trials for inclusion
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Fig 2 Forest plot for all cause mortality
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Fig 3 Trial sequential analysis of all cause mortality. Heterogeneity adjusted required information size of 46 677 participants calculated on basis of proportion of mortality of 8.4% in conventional glucose control group, relative risk reduction of 10%, α=5%, β=20%, and I2=30%. Actually accrued No of participants was 28 149, 60% of required information size. Dashed red cumulative Z curve does not cross solid blue trial sequential monitoring boundaries for benefit or harm, but boundaries for futility (blue inner wedge boundaries) are crossed. Horizontal dotted green lines illustrate traditional level of statistical significance (P=0.05)
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Fig 4 Forest plot for cardiovascular mortality
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Fig 5 Trial sequential analysis for cardiovascular mortality. Heterogeneity adjusted required information size of 129 468 participants calculated on basis of proportion of cardiovascular mortality of 4.1% in conventional glucose control group, relative risk reduction of 10%, α=5%, a β=20%, and I2=46%. Actually accrued No of participants was 28 149, 22% of required information size. Dashed red cumulative Z curve does not cross solid blue trial sequential monitoring boundaries for benefit or harm. Horizontal dotted green lines illustrate the traditional level of statistical significance (P=0.05)
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Fig 6 Forest plot for non-fatal myocardial infarction
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Fig 7 Trial sequential analysis for non-fatal myocardial infarction. Heterogeneity adjusted required information size of 63 446 participants calculated on basis of proportion of non-fatal myocardial infarction of 4.5% in conventional glucose control group, relative risk reduction of 10%, α=5%, β=20%, and I2=0%. Actually accrued No of participants was 27 958, 44% of required information size. Dashed red cumulative Z curve does not cross solid blue trial sequential monitoring boundaries for benefit or harm. Horizontal dotted green lines illustrate the traditional level of statistical significance (P=0.05)
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Fig 8 Forest plot for composite microvascular outcome
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Fig 9 Trial sequential analysis for composite microvascular outcome. Heterogeneity corrected required information size of 43 703 participants calculated on basis of proportion of composite microvascular outcome of 11.1% in conventional glucose control group, relative risk reduction of 10%, α=5%, β=20%, and I2=45%. Dashed red cumulative Z curve does not cross solid blue trial sequential monitoring boundaries for benefit or harm. Horizontal dotted green lines illustrate the traditional level of statistical significance (P=0.05)
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Fig 10 Forest plot for retinopathy
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Fig 11 Trial sequential analysis for retinopathy. Heterogeneity corrected required information size of 43 960 participants calculated on basis of proportion of retinopathy of 14.3% in conventional glucose control group, relative risk reduction of 10%, α=5%, β=20%, and I2=59%. Actually accrued No of participants was 10 793, 25% of required information size. Dashed red cumulative Z curve does not cross solid blue trial sequential monitoring boundaries for benefit or harm. Horizontal dotted green lines illustrate the traditional level of statistical significance (P=0.05)
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Fig 12 Forest plot for nephropathy
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Fig 13 Forest plot for severe hypoglycaemia
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Fig 14 Trial sequential analysis for severe hypoglycaemia. Heterogeneity adjusted required information size of 36 937 participants calculated on basis of proportion of severe hypoglycaemia of 2.9% in conventional glucose control group, relative risk reduction of 30%, α=5%, β=20%, and I2=73%. Cumulative Z curve crosses trial sequential monitoring boundary, showing sufficient evidence reached for 30% increase in relative risk with targeted intensive glycaemic control. Horizontal dotted green lines illustrate the traditional level of statistical significance (P=0.05)
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