CV Safety of Diabetes Drugs on ADA 2015 Program

Anne L. Peters, MD


June 04, 2015

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Hi. I am Dr Anne Peters, and today I want to provide updates on cardiovascular outcomes trials of three DPP-4 inhibitors and one GLP-1 receptor agonist.

The basic news is that none of these trials found a worsening or an improvement in cardiovascular outcomes. The drugs were similar to placebo in terms of the primary outcomes. The one deviation is the SAVOR-TIMI trial of saxagliptin, which showed an increase in rates of congestive heart failure requiring hospitalization.

Drilling Down Into the Details

The two trials that have the longest follow-up are the EXAMINE[1] and SAVOR-TIMI[2] trials. EXAMINE enrolled approximately 5500 individuals who had recently suffered acute coronary syndrome. They were very sick individuals. They received either alogliptin or placebo, and the study found no difference in terms of the cardiovascular outcomes. The SAVOR-TIMI trial compared saxagliptin and placebo in approximately 16,500 individuals who were at high risk for cardiovascular events but who had not experienced any recent cardiovascular events. As mentioned, SAVOR-TIMI showed no difference in rates of cardiovascular endpoints, but it did find an increased risk for congestive heart failure requiring hospitalization.

The US Food and Drug Administration was concerned enough about these findings that they held a special hearing on April 14, 2015, to discuss these trials and decide whether the findings warrant a change in labeling of these drugs. The panel decided not to change the alogliptin label but to change the label on saxagliptin to reflect this added risk for congestive heart failure with the drug. The precise wording on the label will be determined within the next few weeks to months.

TECOS and ELIXA Results Reported

Very recently, we have heard news about the TECOS trial,[3] the large cardiovascular outcomes trial of sitagliptin. The full results will be presented at the American Diabetes Association (ADA) meeting in June. However, the manufacturer has reported that sitagliptin was found to be noninferior to placebo in terms of rates of major cardiovascular events and congestive heart failure. Thus, sitagliptin appears to be safe in terms of cardiovascular outcomes and congestive heart failure.

Finally, the ELIXA study[4] showed no difference in cardiovascular outcomes with lixisenatide, a GLP-1 receptor agonist. I personally had hoped to see an improvement in cardiovascular outcomes with the GLP-1 receptor agonist, but according to the data that have been released, there was no difference between the lixisenatide-treated patients and the placebo-treated patients in either their main cardiovascular outcome or in rate of congestive heart failure. This is also a study that will be more fully reported at the ADA Scientific Sessions in June.

We will learn more of the details of these trials at the ADA meeting, but for now, cardiovascular safety for DPP-4 inhibitors looks pretty good, except for the risk for congestive heart failure seen with saxagliptin. In addition, the first cardiovascular outcomes study on GLP-1 receptor agonists is encouraging in terms of not increasing cardiovascular risk.


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