Intensive Care Medicine

, Volume 43, Issue 1, pp 1–15 | Cite as

Glycemic control, mortality, and hypoglycemia in critically ill patients: a systematic review and network meta-analysis of randomized controlled trials

  • Tomohide YamadaEmail author
  • Nobuhiro Shojima
  • Hisashi Noma
  • Toshimasa Yamauchi
  • Takashi Kadowaki



It is unclear whether tight glycemic control is warranted in all critically ill adults. We employed network meta-analysis to examine the risk of mortality and hypoglycemia associated with different glycemic control targets in critically ill adults.


Electronic databases were searched up to 2016 for randomized controlled trials comparing various insulin regimens in critically ill adults with hyperglycemia. Two reviewers independently extracted information and evaluated quality with the Cochrane risk-of-bias tool. Four glycemic control groups were compared: tight (blood glucose: 4.4 < 6.1 mmol/l), moderate (6.1 < 7.8 mmol/l), mild (7.8 < 10.0 mmol/l), and very mild (10.0 to < 12.2 mmol/l). Network meta-analysis was performed by a frequentist approach with multivariate random effects meta-analysis.


Thirty-six randomized trials (17,996 patients) were identified. Compared with very mild control, tight control did not reduce the risk of short-term mortality [relative risk (RR) 0.94 (95 % CI 0.83–1.07, p = 0.36)], and neither did mild control [RR 0.88 (0.73–1.06), p = 0.18] or moderate control [RR 1.1 (0.66–1.84), p = 0.72]. However, severe hypoglycemia (<2.2 mmol/l) was more frequent with tight control than very mild control [RR 5.49 (3.22–9.38), p < 0.001] or mild control [RR 4.47 (2.5–8.03), p < 0.001]. Stratified analyses (cause of death, ICU type, time period, or diabetes) did not find significant between-group differences. Ranking analysis revealed the following hierarchy for avoiding death (highest to lowest rank): mild control, tight control, and very mild control.


Network meta-analysis showed no mortality benefit of tight glycemic control in critically ill patients, but fivefold more hypoglycemia versus mild or very mild control.


Glycemic control Hypoglycemia Mortality Meta-analysis 



There was no acknowledgment in this research.

Compliance with ethical statement


T.Yamada was funded by Japan Diabetes Society, Banyu Foundation, KAKENHI (Grants-in-Aid for Scientific Research), Japan Foundation for Applied Enzymology, and Japan Association for Diabetes Education and Care. We declare that these funds have not influenced this research.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Conflicts of interest

No potential conflicts of interest relevant to this article were reported.

Supplementary material

134_2016_4523_MOESM1_ESM.pptx (4.3 mb)
Supplementary Figure 1. Flowchart of study selection. Supplementary Figure 2. Summary of the risk of bias: our judgements about the risk of bias for each item in each study. Blue low risk of bias, Yellow unclear risk of bias, Red high risk of bias. Supplementary Figure 3a. Rankogram for short-term mortality. The plot presents the ranking probabilities and their uncertainty. Supplementary Figure 3b. Hierarchy of outcomes for short-term mortality according to surface under the cumulative ranking curve (SUCRA) values. As the SUCRA value becomes higher, the efficacy (no short-term mortality) decreases. Supplementary figure 4. Network plot comparing the different treatment strategies. Nodes and edges are weighted according to the number of studies with the respective interventions. Supplementary Figure 5a. Rankogram for hypoglycemia. The plot presents the ranking probabilities and their uncertainty. Supplementary Figure 5b. Hierarchy of outcomes for hypoglycemia according to surface under the cumulative ranking curve (SUCRA) values. As the SUCRA value becomes higher, the safety (no hypoglycemia) decreases. Supplementary Figure 6. Comparison of various glycemic targets by using the mixed treatment comparison model stratified by the presence of diabetes. Supplementary Figure 7. Comparison of various glycemic targets using the mixed treatment comparison model with stratification by the cause of death (sepsis mortality, cardiovascular mortality, respiratory mortality, or neurological mortality). Supplementary Figure 8. Hierarchy of mortality outcomes according to the surface under the cumulative ranking curve (SUCRA). Mortality increases as the SUCRA value becomes higher. Supplementary Figure 9. Direct comparison meta-analysis between tight control and very mild control. Supplementary Figure 10. Direct comparison meta-analysis between tight control and mild control. Supplementary Figure 11. Funnel plots and the results of Begg’s test and Egger’s test. Supplementary Figure 12a. Direct comparison meta-analysis between tight control and very mild (or mild) control in patients with diabetes. Supplementary Figure 12b. Direct comparison meta-analysis between tight control and very mild (or mild) control in patients without diabetes.Supplementary Figure13. Meta-regression analysis of the relation between diabetes and the relative risk of short-term mortality with tight glycemic control versus mild and very mild control (PPTX 4424 kb)
134_2016_4523_MOESM2_ESM.docx (26 kb)
Supplementary Table 1. Terms used to search the electronic databases. Supplementary Table 2. Type of ICU and cause of death in all trials included in the network meta-analysis (DOCX 26 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2016

Authors and Affiliations

  • Tomohide Yamada
    • 1
    Email author
  • Nobuhiro Shojima
    • 1
  • Hisashi Noma
    • 2
  • Toshimasa Yamauchi
    • 1
  • Takashi Kadowaki
    • 1
  1. 1.Department of Diabetes and Metabolic Diseases, Graduate School of MedicineUniversity of TokyoTokyoJapan
  2. 2.Department of Data ScienceThe Institute of Statistical MathematicsTokyoJapan

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