Cardiovascular outcome trials of glucose-lowering drugs or strategies in type 2 diabetes

Lancet. 2014 Jun 7;383(9933):2008-17. doi: 10.1016/S0140-6736(14)60794-7.

Abstract

Few trials of glucose-lowering drugs or strategies in people with type 2 diabetes have investigated cardiovascular outcomes, even though most patients die from cardiovascular causes despite the beneficial effects of lipid-reducing and blood pressure-lowering treatments. The evidence-based reduction in risk of microvascular disease with glucose lowering has resulted in guidelines worldwide recommending optimisation of glycosylated haemoglobin, but no trial results have shown unequivocal cardiovascular risk reduction with glucose lowering. However, results of the post-trial follow-up of the UK Prospective Diabetes Study, and of a meta-analysis of the four glucose-lowering outcome trials completed to date, suggest about a 15% cardiovascular relative risk reduction per 1% decrement in HbA1c. The 2008 US Food and Drug Administration industry guidance for licensing of antidiabetic drugs greatly increased the number of cardiovascular outcome trials in diabetes, but most trials opted for non-inferiority designs aiming primarily to show absence of cardiovascular toxicity in the shortest possible time. This unintended consequence of the new regulations has meant that the potential long-term benefits, and the possible risks of new therapies, are not being assessed effectively. Also, essential head-to-head trials of therapies for this complex progressive disease, to answer issues such as how best to achieve and maintain optimum glycaemia without promoting weight gain or hypoglycaemia, are not being undertaken. In this Series paper, we summarise randomised controlled cardiovascular outcome trials in type 2 diabetes, provide an overview of ongoing trials and their limitations, and speculate on how future trials could be made more efficient and effective.

Publication types

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

MeSH terms

  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetic Angiopathies / drug therapy*
  • Follow-Up Studies
  • Forecasting
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Randomized Controlled Trials as Topic
  • Treatment Outcome

Substances

  • Hypoglycemic Agents