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SAVOR-TIMI 53 sets new standard for cardiovascular outcome trials in diabetes

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Uncertainty persists regarding whether drugs that lower sugar reduce the risk of heart attack, with some concerns that diabetes drugs may actually raise the risks.

The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR-TIMI 53) trial was a large international clinical trial that randomized patients to the diabetes drug saxagliptin (Onglyza), a selective dipeptidyl peptidase 4 (DPP-4) inhibitor, or to placebo in order to determine the effect on heart attack risk. The study found no excess, or reduction, in the risk of the primary composite endpoint of heart attacks, stroke, or cardiovascular death, which was the primary safety goal of the study. An increase in hospitalization for heart failure in the saxagliptin arm was noted.

"This large cardiovascular outcome trial sets a new standard for examination of the safety of diabetes drugs," said trial co-principal investigator, Deepak L. Bhatt, MD, MPH, from the VA Boston Healthcare System and the TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.

"Saxagliptin demonstrated better control of glucose compared with placebo, reduced the need for insulin therapy, and prevented deterioration in protein spilling from the kidneys to the urine," added co-principal investigator Itamar Raz, MD, Hadassah Medical Center, Israel.

SAVOR-TIMI 53, a multicenter, randomized, double-blind, placebo-controlled Phase 4 trial conducted at 788 sites in 26 countries, included patients with type 2 diabetes mellitus, HbA1c levels between 6.5% and 12.0%, and either established or multiple risk factors for cardiovascular disease.

A total of 16,492 patients were randomized to receive either saxagliptin 5 mg daily (or 2.5 mg daily in patients with renal impairment) or matching placebo over a median follow-up of 2.1 years. Treatment with all other diabetes and cardiovascular medications was left to the discretion of the treating physician.

The primary endpoint of the study, a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal ischemic stroke occurred in 7.3% of the saxagliptin group compared with 7.2% of the placebo group (hazard ratio [HR] 1.00; P =0.99 for superiority and P <0.001 for non-inferiority).

The major secondary endpoint of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure, unstable angina or coronary revascularization was also balanced and occurred in 12.8% of the saxagliptin group and 12.4% of the placebo group (HR 1.02; P=0.66).

"The lack of any excess in heart attack risk is reassuring," commented Benjamin Scirica, MD MPH, TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA, "though the neutral findings are in contrast to the benefit observed in pooled analyses from smaller, prior studies of saxagliptin, and highlight the importance of adequately powered outcome studies with sufficient follow-up to assess more fully cardiovascular effects of therapy."

In terms of blood sugar control, patients treated with saxagliptin were more likely to achieve a glycated hemoglobin less than 7% at the end of treatment (36.2% vs. 27.9%; P<0.001).

However, significantly more patients in the saxagliptin group reported at least one hypoglycemic event compared with placebo (15.3% vs 13.4%; p<0.001), though there was no significant excess in the rate of hospitalization for hypoglycemia.

Additionally, more patients in the saxagliptin group were hospitalized for heart failure compared with the placebo group (3.5% vs 2.8%; HR 1.27; P=0.007).

"The increase in hospitalization for heart failure was not expected and deserves further study," stated study chairman Eugene Braunwald, MD, TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.

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