SAVOR-TIMI 53: Saxagliptin does not alter CV risk in type 2 diabetes mellitus

Presented at the ESC congress 2013 by:   Deepak BHATT (Newton, US)

Background

It is unclear whether drugs that lower blood sugar levels decrease risk of a heart attack, of possibly enhance the risk.
Saxagliptin is a selective dipeptidyl peptidase 4 (DPP-4) inhibitor. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR-TIMI 53) study is a phase 4 trial that investigates whether saxagliptin (daily 5 mg, or 2.5 mg at renal failure) can lower risk of cardiovascular events when used alone, or in combination with other diabetic medication. Follow-up was on average 2.1 years.

Main results

• No difference was seen in the risk of the primary composite endpoint of non-fatal myocardial infarction, stroke or cardiovascular death (7.3% vs. 7.2%, HR: 1.00, 95%CI: 0.89-1.12, P<0.001 for non-inferiority, P=0.99 for superiority) between patients who received saxagliptin or placebo.
• The main secondary endpoint of CV mortality, MI, stroke or hospitalization for heart failure, unstable angina or coronary revascularization occurred in 12.8% of patients in the saxagliptin arm and in 12.4% of patients in the placebo group (HR: 1.02, 95%CI: 0.94-1.11, P<0.001 for non-inferiority, P=0.66 for superiority).
• More patients treated with saxagliptin had HbA1c>7% at the end of treatment (36.2% vs. 27.9%, P<0.001).
• More patients on saxagliptin than on placebo reported at least one hypoglycaemic event (15.3% VS. 13.4%, p<0.001), although this did not lead to an increased number of hospitalizations for hypoglycaemia.
• More patients in the saxagliptin group were hospitalized for heart failure than in the placebo group (3.5% vs. 2.8%, HF: 1.27, P=0.007).

Conclusion

When applied in standard care in patients with T2DM with an increased CV risk, saxagliptin does not lower, nor increases the risk of the primary composite endpoint of CV mortality, MI or ischaemic stroke. Saxagliptin does seem to improve glycaemic control. Hypoglycaemia occurred more often after saxagliptin use, but this did not lead to hospitalisation.
The SAVOR-TIMI 53 trial emphasises the importance of conducting large-scale studies with clinically relevant cardiovascular outcomes, for the evaluation of diabetic drugs.
Further research is needed into the relation between HbA1c and cardiovascular outcomes. Studies that test the effect of Dpp-4 inhibitors on an intermediate term do not show a benefit with regard to CV outcomes, but a study with 10 years of follow-up might show benefits of lowering HbA1c and limiting progression of microalbuminuria.

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