Systematic Review or Meta-analysis Effects of glucose-lowering and multifactorial interventions on cardiovascular and mortality outcomes: a meta-analysis of randomized control trials

Introduction The effect of intensive glycaemic control alone or as part of a multifactorial intervention on cardiovascular and mortality outcomes is not fully understood. In addition, the interaction of duration of diabetes diagnosis on cardiovascular and mortality outcomes is unclear. Aim To quantify the effect of intensive treatment (i.e. intensive glucose lowering either alone or as part of a multifactorial intervention) on non-fatal myocardial infarction (MI), non-fatal stroke, cardiovascular disease (CV) mortality and all-cause mortality in patients with Type 2 diabetes. A secondary objective was to investigate the association between the treatment effect and trial-level characteristics such as average age, duration of Type 2 diabetes, the percentage male and the baseline event rate. Methods We searched MEDLINE, Embase and the Cochrane Central Register of Controlled Trials without language restrictions from inception to 13 May 2015. We included randomized controlled trials (RCTs) that evaluated intensive treatment in adult patients with Type 2 diabetes. The review was registered on PROSPERO (registration number 42014013860). We pooled rates across studies using random effects meta-analysis and investigated study-level covariate associations using Bayesian meta-regression. Results A total of 19 RCTs were included: 16 examined non-fatal MI (n = 79 595), 14 non-fatal stroke (n = 78 568), 18 cardiovascular mortality (n = 83 938) and 18 all-cause mortality (n = 84 266). There was evidence to suggest that compared with standard care, intensive treatment reduced the risk of non-fatal MI [risk ratio (RR) 0.90, 95% confidence interval (CI) 0.83–0.96], but not non-fatal stroke (RR 0.96, 95% CI 0.86–1.07), CV mortality (RR 1.00, 95% CI 0.90– 1.11) or all-cause mortality (RR 1.00, 95% CI 0.94–1.06). Compared with standard care, multifactorial interventions alone reduced non-fatal stroke (RR 0.53, 95% CI 0.32–0.0.87) but not non-fatal MI (RR 0.66, 95% CI 0.38–1.03), CV mortality (RR 0.72, 95% CI 0.46–1.14) or all-cause mortality (RR 0.82, 95% CI 0.64–1.05). There was no evidence to suggest that the effect of intensive treatment on cardiovascular and mortality outcomes was associated with mean age, mean duration of Type 2 diabetes and percentage of male patients across trials. There was evidence to suggest that the effectiveness of intensive treatment to reduce mortality outcomes increases as the baseline incidence of cardiovascular mortality [ratio of hazard = 0.82, 95% credible interval (CrI) 0.65–0.99] increased across trials, but not baseline incidence of non-fatal MI, non-fatal stroke and all-cause mortality. Intensive glucose-lowering and multifactorial interventions are predicted to have the desired beneficial effect of reducing CVD mortality in populations where the incidence rate is greater than about 6.3 CVD deaths per 1000 person-years or an average 10–year CVD risk of 6.3%. Conclusions Apart from non-fatal MIs, there was no evidence that intensive glucose-lowering and multifactorial interventions reduced or increased the risk of cardiovascular and mortality outcomes. Intensive glucose-lowering and multifactorial interventions are likely to be beneficial in populations with a higher baseline incidence of CV mortality, but there was no evidence of an association with the mean duration of Type 2 diabetes. Multifactorial interventions had a much greater impact on non-fatal MI and non-fatal strokes. (PROSPERO registration no.: 42014013860) Diabet. Med. 33, 280–289 (2016) Correspondence to: Samuel Seidu. E-mail: sis11@le.ac. uk 280 a 2015 The Authors. Diabetic Medicine a 2015 Diabetes UK DIABETICMedicine DOI: 10.1111/dme.12885