Clinical Implications of Cardiovascular Outcome Trials in Type 2 Diabetes: From DCCT to EMPA-REG

Clin Ther. 2016 Jun;38(6):1279-1287. doi: 10.1016/j.clinthera.2016.03.035. Epub 2016 Apr 20.


Cardiovascular disease is a major threat to people with diabetes. Attempts have long been made to lower cardiovascular risk by means of glucose-lowering treatment. Initially, it seemed that was an option, but subsequent trials could not verify the original observations and there was concern that some glucose-lowering drugs can actually cause cardiovascular harm. This led medical product agencies in the United States and Europe to require major outcomes trials before accepting new glucose-lowering drugs. The least requirement was noninferiority compared with existing treatment modalities. A large number of such trials have been performed or are ongoing, including >100,000 patients. The drug classes investigated are basal insulin, glucagon-like peptide-1 agonists, dipeptidyl peptidase 4 inhibitors, and sodium-glucose cotransporter-2 (SGLT2) inhibitors. This commentary discusses these trials and their outcomes, the reasons why several of them ended with neutral results (noninferiority), and that the likelihood for showing cardiovascular benefit was minor or even nonexistent. The surprising and highly rewarding impact of the SGLT2 inhibitor empagliflozin is described and potential mechanisms for cardiovascular benefits are discussed.

Keywords: cardiovascular events; clinical trials; diabetes; glucose-lowering drugs; prognosis.

MeSH terms

  • Benzhydryl Compounds / therapeutic use
  • Cardiovascular Diseases / etiology
  • Cardiovascular Diseases / prevention & control*
  • Clinical Trials as Topic
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use
  • Glucagon-Like Peptide 1 / agonists
  • Glucosides / therapeutic use
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Insulin / therapeutic use
  • Risk Factors
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors


  • Benzhydryl Compounds
  • Dipeptidyl-Peptidase IV Inhibitors
  • Glucosides
  • Hypoglycemic Agents
  • Insulin
  • SLC5A2 protein, human
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors
  • Glucagon-Like Peptide 1
  • empagliflozin