Effects of glucose-lowering agents on vascular outcomes in type 2 diabetes: a critical reappraisal

Diabetes Metab. 2014 Jun;40(3):176-85. doi: 10.1016/j.diabet.2014.03.004. Epub 2014 Apr 30.


Type 2 diabetes mellitus (T2DM) is strongly associated with cardiovascular complications, especially coronary artery disease. Numerous epidemiological studies have shown a close relationship between major cardiovascular events and glycaemia, and several pathophysiological mechanisms have been described that explain how hyperglycaemia induces vascular damage. However, randomized controlled trials investigating either an intensive glucose-lowering strategy vs standard care or the addition of a new glucose-lowering agent vs a placebo have largely failed to demonstrate any clinical benefits in terms of cardiovascular morbidity or mortality. This lack of evidence has led some people to contest the clinical efficacy of lowering blood glucose in patients with T2DM, despite its positive effects on microvascular complications. This article analyzes the various reasons that might explain such discrepancies. There are still strong arguments in favour of targeting hyperglycaemia while avoiding other counterproductive effects, such as hypoglycaemia and weight gain, and of integrating the glucose-lowering approach within a global multi-risk strategy to reduce the burden of cardiovascular disease in T2DM.

Keywords: Cardiovascular disease; Evidence-based medicine; Microangiopathy; Outcome; Type 2 diabetes.

Publication types

  • Review

MeSH terms

  • Blood Glucose / drug effects
  • Coronary Artery Disease / blood
  • Coronary Artery Disease / etiology
  • Coronary Artery Disease / prevention & control*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / physiopathology
  • Diabetic Angiopathies / blood
  • Diabetic Angiopathies / etiology
  • Diabetic Angiopathies / prevention & control*
  • Glycated Hemoglobin / drug effects
  • Humans
  • Hyperglycemia / drug therapy*
  • Hypoglycemia / chemically induced*
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / therapeutic use*
  • Microcirculation / drug effects
  • Randomized Controlled Trials as Topic
  • Weight Gain / drug effects


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