The recent SAVOR-TIMI 53 (saxagliptin) and EXAMINE (alogliptin) trials recently reported the effects of the DPPIV inhibitor class of glucose lowering agents in people with diabetes. As required by the US FDA, both drugs were found not to increase cardiovascular risk, allowing the agents to be registered for use in that country. Good news, it would seem.

The spanner in the works is that neither drug was found to produce any cardiovascular benefit, and the SAVOR-TIMI trial suggested an increased risk of heart failure in people treated with the drug. The obvious question is therefore why should the drugs be used, even if they are registered?

The answer to this question is not straightforward, and there are many considerations.

Firstly, the studies were designed to minimise the glucose differences achieved by the drugs, and were successful in this: each trial had an average HbA1c difference between the arms of about 0.3%, less than half that achieved in earlier trials. As the primary mechanism of action is via glucose lowering, it is unrealistic to expect the drug to produce benefits if this effect has been minimised.

Second, the trials were also short term, and may need a longer period of exposure to generate benefits from a cardiovascular perspective.

Finally, the SAVOR-TIMI trial reported benefits on markers of kidney disease, raising the possibility that this may translate into longer term reductions in kidney failure and cardiovascular events.
Where to from here? Several additional trials of agents in this class will report their findings over the next couple of years, and should help to answer many of these questions. Until clear benefits are proven, the role of this class of drugs will remain uncertain.