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

We appreciate the interest of John S Yudkin and Kasia J Lipska to our systematic review “Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials” (1).

As you correctly note, we have not presented the numbers needed to treat for the assessed outcomes. According to The Cochrane Collaboration, the preferred reporting of intervention effects is a relative measure (e.g., relative risk or odds ratio), as these estimates remain more stable across different risk groups (2). Therefore, we have reported the relative risk ratio for all outcomes in the systematic review (1). Furthermore, we also reported the absolute risk difference for the composite microvascular outcome and for retinopathy (1). We would have reported the numbers needed to treat based on these association measures if the assessed intervention had shown significant effects. Therefore, we did not perform this additional analysis as the uncertainty that intensive glycaemic control really reduce these outcomes may render it impossible to calculate 95% confidence interval on the numbers needed to treat.

As the trial sequential analysis makes evident, the trial sequential monitoring boundaries were not surpassed for the composite microvascular outcome (trial sequential analysis adjusted 95% confidence interval for the relative risk: 0.76 to 1.01) and retinopathy (trial sequential analysis adjusted 95% confidence interval for the relative risk: 0.55 to 1.15) still leaving the possibility for a harmful or neutral effect on these outcomes (1). Therefore, calculation of numbers needed to treat does not seem meaningful to us.

We are grateful for Drs. Yudkin and Lipska to point the readers’ attention to the notion that, apparently, insufficient evidence exists to support the view that glucose-lowering has a strong beneficial impact on microvascular outcomes in type 2 diabetes. In line with this, we believe that one of the key findings from our meta-analysis, using trial sequential analysis, was the apparent lack of firm evidence of benefit when targeting intensive versus standard glucose control on a composite microvascular outcome in patients with type 2 diabetes in usual care settings as outlined above (1). Retinal photocoagulation and cataract extraction (which we did not assess) are both important to the patient. However, the assessments of these outcomes are very prone to bias in trials without blinding (3).

1. Hemmingsen B, Lund SS, Gluud C, Vaag A, Almdal T, Hemmingsen C, et al. Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials. BMJ 2011;343:d6898.
2. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
3. Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman DG, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ 2008;336:601.