Discussant Report from the ESC Congress 2013 – SAVOR TIMI 53 Trial

by Michel Komajda (pictured right) – DPP4 inhibitors are a new class of glucose lowering agents which act on the incretin pathway. 

SAVOR TIMI 53 was designed to :

1. Assess the cardiovascular safety of Saxagliptin 2,5mg-5mg/day added to background therapy compared to placebo
2. Determine if Saxagliptin was superior to placebo to reduce the occurrence of major cardiovascular events in type 2 diabetes mellitus.

This large trial enrolled # 16.500 elderly people with type 2 diabetes mellitus and either an established cardiovascular disease (80%) or multiple risk factors (20%).
More than 40% of the patients were under insulin and the mean duration of diabetes was close to 12 years.

The difference in Hb A,C level between the two arms was modest (0.2 or 0.3 units), but intensification of therapy was allowed in the control arm. Saxagliptin was associated with a lower rate of initiation of insulin therapy or diabetes mellitus treatment intensification.

Main result : Saxagliptin was not inferior to the control group for cardiovascular safety: the Hazard Ratio (HR)for MACE was 1.00 (0.89-1.12) and the HR for the secondary endpoint including unstable angina, heart failure or revascularization was 1.02 (0.94-1.11).

This good cardiovascular safety was observed in all the pre-specified subgroups and in particular in elderly people > 75 years.

A modest but significant increase in hospitalizations for heart failure was observed and this observation is intriguing since DPP4 inhibitors do not induce cardiac dysfunction or fluid retention and do not increase heart rate.

SAVOR TIMI 53 failed to demonstrate that Saxagliptin reduced the occurrence of MACE compared to placebo as was suggested by previous pooled analyses of short/mid-term trials.

The fact that most patients had severe cardiovascular disease and were in an advanced stage of diabetes mellitus together with the short follow-up period
(2 years), are potential explanations for the failure to demonstrate superiority.

Finally, SAVOR TIMI 53 provided reassuring information on non cardiovascular safety since no increase in infections, bone fractures, malignancies or pancreatitis was observed.

In conclusion, SAVOR  demonstrated the good cardiovascular and non cardiovascular safety of Saxagliptin in diabetic people at high cardiovascular risk.
The SAVOR results will need to be compared to those of the other forthcoming mega trials with DPP4 inhibitors such as TECOS or CAROLINA