Blood glucose reduction by diabetic drugs with minimal hypoglycaemia risk for cardiovascular outcomes: Evidence from Meta-regression Analysis of Randomized Controlled Trials

AIM: To investigate the effects of blood glucose control with antihyperglycemic agents with minimal hypoglycemia 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 hypoglycemia risk were comprehensively searched 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 92400 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 (median, 0.27-0.86%) for participants given antihyperglycemic 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 each of the following possible confounding factors including age, sex, baseline HbA1c, duration of follow-up, difference in achieved systolic blood pressure, difference in achieved body weight, or risk difference in hypoglycemia. Lowering HbA1c by 1% conferred a significant risk reduction of 30% (95% CI, 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 hypoglycemic hazard significantly reduced the risk of MACE. The MACE reduction seems to be associated with HbA1c reduction in a linear relationship.