Title:
Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus.

Abstract:
Patients with type 2 diabetes mellitus (T2D) have an increased risk of cardiovascular disease and mortality compared to the background population. Observational studies report an association between reduced blood glucose and reduced risk of both micro- and macrovascular complications in patients with T2D. Our previous systematic review of intensive glycaemic control versus conventional glycaemic control was based on 20 randomised clinical trials that randomised 29 ,986 participants with T2D. We now report our updated review.
To assess the effects of targeted intensive glycaemic control compared with conventional glycaemic control in patients with T2D.
Trials were obtained from searches of The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL (all until December 2012).
We included randomised clinical trials that prespecified targets of intensive glycaemic control versus conventional glycaemic control targets in adults with T2D.
Two authors independently assessed the risk of bias and extracted data. Dichotomous outcomes were assessed by risk ratios (RR) and 95% confidence intervals (CI). Health-related quality of life and costs of intervention were assessed with standardized mean differences (SMD) and 95% Cl.
Twenty-eight trials with 34,912 T2D participants randomised 18,717 participants to intensive glycaemic control versus 16,195 participants to conventional glycaemic control. Only two trials had low risk of bias on all risk of bias domains assessed. The duration of the intervention ranged from three days to 12.5 years. The number of participants in the included trials ranged from 20 to 11,140. There were no statistically significant differences between targeting intensive versus conventional glycaemic control for all-cause mortality (RR 1.00, 95% CI 0.92 to 1.08; 34,325 participants, 24 trials) or cardiovascular mortality (RR 1.06, 95% CI 0.94 to 1.21; 34,177 participants, 22 trials). Trial sequential analysis showed that a 10% relative risk reduction could be refuted for all-cause mortality. Targeting intensive glycaemic control did not show a statistically significant effect on the risks of macrovascular complications as a composite outcome in the random-effects model, but decreased the risks in the fixed-effect model (random RR 0.91, 95% CI 0.82 to 1.02; and fixed RR 0.93, 95% CI 0.87 to 0.99; P = 0.02; 32,846 participants, 14 trials). Targeting intensive versus conventional glycaemic control seemed to reduce the risks of non-fatal myocardial infarction (RR 0.87, 95% CI 0.77 to 0.98; P = 0.02; 30,417 participants, 14 trials), amputation of a lower extremity (RR 0.65, 95% CI 0.45 to 0.94; P = 0.02; 11,200 participants, 11 trials), as well as the risk of developing a composite outcome of microvascular diseases (RR 0.88, 95% CI 0.82 to 0.95; P = 0.0008; 25,927 participants, 6 trials), nephropathy (RR 0.75, 95% CI 0.59 to 0.95; P = 0.02; 28,096 participants, 11 trials), retinopathy (RR 0.79, 95% CI 0.68 to 0.92; P = 0.002; 10,300 participants, 9 trials), and the risk of retinal photocoagulation (RR 0.77, 95% CI 0.61 to 0.97; P = 0.03; 11,212 participants, 8 trials). No statistically significant effect of targeting intensive glucose control could be shown on non-fatal stroke, cardiac revascularization, or peripheral revascularization. Trial sequential analyses did not confirm a reduction of the risk of non-fatal myocardial infarction but confirmed a 10% relative risk reduction in favour of intensive glycaemic control on the composite outcome of microvascular diseases. For the remaining microvascular outcomes, trial sequential analyses could not establish firm evidence for a 10% relative risk reduction. Targeting intensive glycaemic control significantly increased the risk of mild hypoglycaemia, but substantial heterogeneity was present; severe hypoglycaemia (RR 2.18, 95% CI 1.53 to 3.11; 28,794 participants, 12 trials); and serious adverse events (RR 1.06, 95% CI 1.02 to 1.10; P = 0.007; 24,280 participants, 11 trials). Trial sequential analysis for a 10% relative risk increase showed firm evidence for mild hypoglycaemia and serious adverse events and a 30% relative risk increase for severe hypoglycaemia when targeting intensive versus conventional glycaemic control. Overall health-related quality of life, as well as the mental and the physical components of health-related quality of life did not show any statistical significant differences.
Although we have been able to expand the number of participants by 16% in this update, we still find paucity of data on outcomes and the bias risk of the trials was mostly considered high. Targeting intensive glycaemic control compared with conventional glycaemic control did not show significant differences for all-cause mortality and cardiovascular mortality. Targeting intensive glycaemic control seemed to reduce the risk of microvascular complications, if we disregard the risks of bias, but increases the risk of hypoglycaemia and serious adverse events.