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

Bianca Hemmingsen; Søren Lund; Christian Nyfeldt Gluud; Allan Vaag; Thomas Almdal; Christina Hemmingsen; Jørn Wetterslev

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, Søren Lund, Christian Nyfeldt Gluud, Allan Vaag, Thomas Almdal, Christina Hemmingsen, Jørn Wetterslev

252 Citations (Scopus)

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 Published and unpublished trials in all languages were included, irrespective of predefined outcomes.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%.

Original language	English
Journal	B M J
Volume	343
Pages (from-to)	d6898
ISSN	0959-8146
DOIs	https://doi.org/10.1136/bmj.d6898
Publication status	Published - 3 Dec 2011

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10.1136/bmj.d6898

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@article{51750c1ccbdd43ae9b53444edd501ac5,

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

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%.",

author = "Bianca Hemmingsen and S{\o}ren Lund and Gluud, {Christian Nyfeldt} and Allan Vaag and Thomas Almdal and Christina Hemmingsen and J{\o}rn Wetterslev",

year = "2011",

month = dec,

day = "3",

doi = "10.1136/bmj.d6898",

language = "English",

volume = "343",

pages = "d6898",

journal = "The BMJ",

issn = "0959-8146",

publisher = "BMJ Publishing Group",

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TY - JOUR

T1 - Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials

AU - Hemmingsen, Bianca

AU - Lund, Søren

AU - Gluud, Christian Nyfeldt

AU - Vaag, Allan

AU - Almdal, Thomas

AU - Hemmingsen, Christina

AU - Wetterslev, Jørn

PY - 2011/12/3

Y1 - 2011/12/3

N2 - 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%.

AB - 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%.

U2 - 10.1136/bmj.d6898

DO - 10.1136/bmj.d6898

M3 - Journal article

SN - 0959-8146

VL - 343

SP - d6898

JO - The BMJ

JF - The BMJ

ER -

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

Abstract

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