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Aim: To clarify the importance of HbA1c reduction and antidiabetic drug use in preventing major adverse cardiovascular events (MACE) for patients with type 2 diabetes (T2D). Materials and Methods: We conducted an updated systematic review of contemporary large randomized controlled trials assessing the relative efficacy and safety of antidiabetic drugs with less hypoglycaemia risk in adult T2D patients. Mixed‐effects meta‐regression was performed to examine the associations of HbA1c reduction with subsequent risk of macrovascular and microvascular events. We evaluated the potential mediating role of HbA1c reduction in the relationship between antidiabetic drugs and MACE. Results: Eighteen placebo‐controlled trials comprising 155 610 participants were included. The effects of treatment differed among antidiabetic drug classes for most adverse outcomes with high heterogeneity (I2: 63.7%‐95.8%). Mean HbA1c reduction was lowest with dipeptidyl peptidase‐4 inhibitors (0.30%), followed by sodium‐glucose co‐transporter‐2 inhibitors (0.46%), and was highest with glucagon‐like peptide‐1 receptor agonists (0.58%) and thiazolidinediones (0.60%). Lower relative risks of MACE were significantly associated with larger reductions in achieved HbA1c (β −0.3182; 95% CI: −0.5366 to −0.0998; P =.0043), even after adjusting for drug classes. When considering HbA1c lowering as a mediator to be controlled, beneficial effects owing to specific antidiabetic treatment for MACE were not observed (χ2 = 1.4494; P =.6940). The proportion mediated by HbA1c reduction was 50.0%‐63.5% for these antidiabetic agents. Conclusions: The main benefits of antidiabetic agents might result from the reduction in blood sugar levels and are generally independent of drugs used. Risk reduction in MACE was proportional to the magnitude of HbA1c decrease conferred by antidiabetic agents with less hypoglycaemic hazard. [ABSTRACT FROM AUTHOR]

Aims: To investigate the effects of blood glucose control with antihyperglycaemic agents with minimal hypoglycaemia risk on cardiovascular outcomes in patients with type 2 diabetes (T2D). Materials and methods: Randomized controlled trials (RCTs) comparing the relative efficacy and safety of antidiabetic drugs with less hypoglycaemia risk were comprehensively researched in MEDLINE, Embase and the Cochrane Library up to January 27, 2018. Mixed‐effects meta‐regression analysis was conducted to explore the relationship between haemoglobin A1c (HbA1c) reduction and the risk of major adverse cardiovascular events (MACE), myocardial infarction, stroke, cardiovascular death, all‐cause death, and hospitalization for heart failure. Results: Ten RCTs comprising 92 400 participants with T2D were included and provided information on 9773 MACE during a median follow‐up of 2.6 years. The mean HbA1c concentration was 0.42% lower (range, 0.27%‐0.86%) for participants given antihyperglycaemic agents than those given placebo. The meta‐regression analysis demonstrated that HbA1c reduction was significantly associated with a decreased risk of MACE (β value, −0.39 to −0.55; P < 0.02) even after adjusting for possible confounding factors including age, sex, baseline HbA1c, duration of follow‐up, difference in achieved systolic blood pressure, difference in achieved body weight, and risk difference in hypoglycaemia. Lowering HbA1c by 1% conferred a significant risk reduction of 30% (95% confidence interval, 17%‐40%) for MACE. By contrast, the meta‐regression analysis for trials using conventional agents failed to demonstrate a significant relationship between achieved HbA1c difference and MACE risk (P > 0.74). Conclusions: Compared with placebo, newer T2D agents with less hypoglycaemic hazard significantly reduced the risk of MACE. The MACE reduction appears to be associated with HbA1c reduction in a linear relationship. [ABSTRACT FROM AUTHOR]