Prevention of cardiovascular disease through reduction of glycaemic exposure in type 2 diabetes: A perspective on glucose-lowering interventions

Diabetes Obes Metab. 2018 Feb;20(2):238-244. doi: 10.1111/dom.13033. Epub 2017 Jul 25.


Type 2 diabetes is a leading cause of cardiovascular disease (CVD). Observational studies have consistently shown an association between glycaemic level and risk of major adverse cardiovascular events (MACE); however, intervention studies have provided limited evidence supporting a reduction in the cardiovascular burden of diabetes through intensive glucose control. In the present review, we aimed to examine the concept of cumulative glycaemic exposure with regard to protection against CVD in diabetes. We address how we can move from a binary approach in trials, to a more quantitative approach based on differences in cumulative glycaemic exposure. We plotted the association between differing glycaemic exposures between study arms and the hazard ratio for MACE in randomized controls trials comparing intensive with conventional glycaemic control in type 2 diabetes. We found a strikingly strong correlation between differential exposure and cardiovascular risk reduction. Similar results were obtained for trials comparing antidiabetes drugs with placebo. The results suggest that a minimum study duration and a minimum gain in glycated haemoglobin (HbA1c) reduction are necessary to drive a relevant risk reduction in CVD risk, and we provide a quantitative perspective in that respect. The present analysis underlines that the duration of the intensification of glycemic control, and the amplitude of the resulting reduction in HbA1c, are important notions for clinical decision-making.

Keywords: antidiabetic drug; cardiovascular disease; clinical trial; glycaemic control; randomised trial; systematic review.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Cardiovascular Diseases / complications
  • Cardiovascular Diseases / epidemiology
  • Cardiovascular Diseases / prevention & control*
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetic Angiopathies / epidemiology
  • Diabetic Angiopathies / prevention & control*
  • Diabetic Cardiomyopathies / epidemiology
  • Diabetic Cardiomyopathies / prevention & control*
  • Evidence-Based Medicine*
  • Glycated Hemoglobin A / analysis
  • Humans
  • Hyperglycemia / prevention & control*
  • Hypoglycemia / chemically induced
  • Hypoglycemia / prevention & control
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / therapeutic use*
  • Meta-Analysis as Topic
  • Proportional Hazards Models
  • Randomized Controlled Trials as Topic
  • Risk


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