Medical Grand Rounds

Diabetes medications and cardiovascular outcome trials: Lessons learned

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The US Food and Drug Administration’s current standards require that new diabetes medications demonstrate cardiovascular safety in large, long-term trials. New drugs that have been assessed in such trials are changing the management of type 2 diabetes.


  • Saxagliptin, alogliptin, and sitagliptin confer neither benefit nor harm for the composite outcome of cardiovascular death, myocardial infarction, or stroke. Saxagliptin and alogliptin carry warnings of increased risk of heart failure; sitagliptin was shown to not affect heart failure risk.
  • Liraglutide and semaglutide showed evidence of cardiovascular benefit; lixisenatide was noninferior to placebo.
  • Empagliflozin is now approved to reduce risk of cardiovascular death in patients with type 2 diabetes and atherosclerotic cardiovascular disease.
  • Canagliflozin decreased the composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes with or at risk of cardiovascular disease, but also increased the risk of amputation and did not significantly reduce the individual outcome of cardiovascular death.



Since 2008, the US Food and Drug Administration (FDA) has required new diabetes drugs to demonstrate cardiovascular safety, resulting in large and lengthy clinical trials. Under the new regulations, several dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated cardiovascular safety, with some demonstrating superior cardiovascular efficacy. In 2016, the SGLT-2 inhibitor empagliflozin became the first (and as of this writing, the only) diabetes drug approved by the FDA for a clinical outcome indication, ie, to reduce the risk of cardiovascular death.


Changing priorities

The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) was formed in 1990 as a collaborative effort across global regulatory agencies and coordinated by the World Health Organization to universalize criteria for drug development. The ICH standards for type 2 diabetes drug development included the following requirements for patient exposure to investigational products to satisfy new drug application requirements:

  • 1,500 individuals total (including single-dose exposure)
  • 300–600 patients for 6 months
  • 100 patients for 1 year.

Thus, just 250 patient-years of exposure were needed for approval of a drug that patients might take for decades. These standards were unlikely to reveal rare, serious complications and had no ability to assess clinical outcomes efficacy for either microvascular or macrovascular disease complications.

When the ICH regulatory standards were set in the early 1990s, only insulin and sulfonyl­ureas were available in the United States. (Metformin had been available outside the United States since the 1950s.) Since 1990, the prevalence of type 2 diabetes in the United States has increased from around 2% to now over 10% of the US adult population. This increase, along with the known increased risk of atherosclerotic cardiovascular disease and heart failure associated with diabetes, created a sense of urgency for developing new therapies. With a burgeoning population with or at risk of diabetes, new drugs were needed and were rapidly developed.

Since 1995, when metformin was approved in the United States, a new class of antihyperglycemic medication has been approved about once every 2 years, so that by 2008, 12 classes of medications had become available for the treatment of type 2 diabetes. This extraordinary rate of drug development has now yielded more classes of medications to treat type 2 diabetes than we presently have for the treatment of hypertension.

This proliferation of new treatments resolved much of the pressure of the unmet medical need, over a period of increasing awareness of the cardiovascular complications of type 2 diabetes, along with numerous examples of adverse cardiovascular effects observed with some of the drugs. In this context, the FDA (and in parallel the European Medicines Agency) made paradigm-shifting changes in the requirements for the development of new type 2 diabetes drugs, requiring large-scale randomized clinical outcome data to assess cardiovascular safety of the new drugs. In December 2008, the FDA published a Guidance for Industry,1 recommending that sponsors of new drugs for type 2 diabetes demonstrate that therapy would not only improve glucose control, but also that it would, at a minimum, not result in an unacceptable increase in cardiovascular risk.1 To better assess new diabetes drugs, the requirement for patient-years of exposure to the studied drug was increased by over 60-fold from 250 patient-years to more than 15,000.


The incretin system, a regulator of postprandial glucose metabolism, is an attractive target for glycemic control, as it promotes early satiety and lowers blood glucose.

After a meal, endocrine cells in the distal small intestine secrete the incretin hormones GLP-1 and gastric inhibitory polypeptide (GIP), among others, which reduce gastric motility, stimulate the pancreas to augment glucose-appropriate insulin secretion, and decrease postprandial glucagon release. GLP-1 also interacts with the satiety center of the hypothalamus, suppressing appetite. GLP-1 and GIP are rapidly inactivated by the circulating protease DPP-4. Injectable formulations of GLP-1 receptor agonists that are resistant to DPP-4 degradation have been developed.

Novel diabetes drugs: Findings of cardiovascular outcome studies

Ten incretin modulators are now available in the United States. The 4 available DPP-4 inhibitors are all once-daily oral medications, and the 6 GLP-1 receptor agonists are all injectable (Table 1).

Small studies in humans and animals suggest that DPP-4 inhibitors and GLP-1-receptor agonists may have multiple favorable effects on the cardiovascular system independent of their glycemic effects. These include reducing myocardial infarct size,2–5 improving endothelial function,6 reducing inflammation and oxidative stress,7 reducing atherosclerotic plaque volume,8 improving left ventricular function, 9,10 and lowering triglyceride levels.11 However, large clinical trials are needed to determine clinical effectiveness.


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