Blood glucose reduction by diabetic drugs with minimal hypoglycaemia risk for cardiovascular outcomes: Evidence from meta-regression analysis of randomized controlled trials

Diabetes Obes Metab. 2018 Sep;20(9):2131-2139. doi: 10.1111/dom.13342. Epub 2018 May 29.


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.

Keywords: dipeptidyl peptidase-4 inhibitor; glucagon-like peptide-1 agonist; major adverse cardiovascular events; sodium-glucose cotransporter-2 inhibitor; thiazolidinedione; type 2 diabetes.

Publication types

  • Meta-Analysis

MeSH terms

  • Blood Glucose / drug effects*
  • Cardiovascular Diseases / etiology*
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Glycated Hemoglobin / drug effects
  • Humans
  • Hypoglycemia / chemically induced
  • Hypoglycemia / complications*
  • Hypoglycemic Agents / therapeutic use*
  • Randomized Controlled Trials as Topic
  • Regression Analysis
  • Risk Factors
  • Treatment Outcome


  • Blood Glucose
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • hemoglobin A1c protein, human