All the Scientific resources on ESC Congress 365
By Deepak Bhatt
Other authors: Dr. Benjamin M. Scirica, USA; Prof. Eugene Braunwald, USA; Prof. Itamar Raz, Israel; on behalf of the SAVOR-TIMI 53 Steering Committee and Investigators
Worldwide projections estimate that the prevalence of Type 2 diabetes mellitus(T2DM) will increase to more than 400 million people by 2030, largely due to a dramatic increase in the developing world. Despite decades of clinical research, no particular strategy or anti-diabetic agent has been shown to reduce cardiovascular (i.e., macrovascular) risk. In addition, there remains a concern regarding the cardiovascular (CV) safety of anti-diabetic drugs. Therefore a strong clinical need exists for antidiabetic agents that are safe and effectively reduce CV risk. Saxagliptin, a DPP-4 inhibitor, improves glycemic control by potentiating endogenous glucagon-like peptide (GLP)-1 concentrations, which augment insulin secretion and decrease glucagon release.
SAVOR-TIMI 53 is a phase 4, randomized, double-blind, placebo-controlled, trial designed to evaluate the safety and efficacy of saxagliptin during long-term treatment of ~16,500 patients with T2DM. Eligible patients with HbA1c >=6.5% and <12.0% on any background antidiabetic treatment (except incretin therapy) and history of established cardiovascular disease (history of coronary, cerebral, or peripheral artery disease) or multiple cardiovascular risk factors, were randomized 1:1 to saxagliptin 5mg qd (2.5mg in subjects with moderate/severe renal dysfunction) or matching placebo, stratified by qualifying disease state. The primary end point is the composite of CV death, non-fatal myocardial infarction, or non-fatal ischemic stroke. Major secondary end points include expanded MACE and total death. CV endpoints are prospectively adjudicated by a blinded events committee. The targeted number of primary endpoint events (n=1040) was accrued in January, 2013. Trial registration - NCT01107886 (www.clinicaltrials.gov).
Between May, 2010 and December, 2011, 16,497 subjects with T2DM and established cardiovascular disease (78% of the population) or multiple cardiovascular risks factors alone (22%) were randomized at 779 sites in 26 countries. The mean age was 65 years, 67% of patients were male, and the median duration of T2DM at randomization was 11.9 years. Database lock is anticipated to occur in June, allowing presentation of final results at ESC.
1040 primary endpoint events provides 85% power to identify a 17% relative reduction of the primary endpoint with saxagliptin vs. placebo, and 98% power to test for non-inferiority of saxagliptin vs. placebo (reject the upper limit of 95% CI for a hazard ratio <1.3 at a one-sided α of 0.025). SAVOR-TIMI 53 is testing the hypothesis that treatment with saxagliptin is safe and reduces cardiovascular events in T2DM patients with established cardiovascular disease or multiple cardiac risk factors.
DPP4 inhibitors are a new class of glucose lowering agents which act on the incretin pathway.
SAVOR TIMI 53 was designed to :
- Assess the cardiovascular safety of Saxagliptin 2,5mg-5mg/day added to background therapy compared to placebo
- 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.