SAVOR-TIMI 53 raises bar for CV outcome trials in diabetes.

When added to standard care in patients with type 2 diabetes at high CV risk, saxagliptin neither reduced nor increased risk for ischemic events, according to results from the SAVOR-TIMI 53 trial.

Saxagliptin (Onglyza, AstraZeneca and Bristol-Myers Squibb) was also shown to improve glycemic control, but was associated with a small increase in the rate of hospitalization for HF.

The multicenter, randomized, double blind, placebo-controlled, phase 4 trial was designed to determine whether saxagliptin was noninferior to placebo when added to background therapy, for the composite endpoint of CV death, nonfatal MI or nonfatal ischemic stroke, Deepak L. Bhatt, MD, MPH, professor of medicine at Harvard Medical School and Chief Medical Editor of Cardiology Today’s Intervention, said at an ESC Congress 2013 press conference.

During a mean follow-up of 2.1 years, the primary endpointoccurred in 7.3% of patients assigned saxagliptin compared with 7.2% assigned placebo (HR=1.00; 95% CI, 0.89-1.12;P=.99 for superiority; P<.001 for noninferiority). An on-treatment analysis yielded similar results (HR=1.03; 95% CI, 0.91-1.17).

The major secondary endpoint, a composite of CV death, MI, stroke and hospitalization for unstable angina, coronary revascularization or HF, occurred in 12.8% of patients assigned saxagliptin compared with 12.4% assigned placebo (HR=1.02; 95% CI, 0.94-1.11). Of note, the saxagliptin group had more hospitalizations for HF (3.5% vs. 2.8%; HR=1.27; 95% CI, 1.07-1.51). In addition, a prespecified secondary endpoint of all-cause mortality occurred in 4.9% of patients assigned saxagliptin compared with 4.2% assigned placebo (HR=1.11; 95% CI, 0.96-1.27).

“The high risk of hospitalization for HF was unexpected, but it was a predefined adjudicated endpoint. Therefore, it does merit further evaluation given the history of other diabetic agents and HF,” Bhatt said. “Additional analyses are ongoing and preliminary data suggest that the risk is highest in those with elevated baseline clinical risk for HF, such as a history of prior HF and/or elevated BNP levels at baseline.”

Fewer patients assigned saxagliptin required the addition or increase of any new antidiabetic medications (23.7% vs. 29.3%; HR=0.77; 95% CI, 0.73-0.82) or the initiation of insulin therapy for more than 3 months (5.5% vs. 7.8%; HR=0.7; 95% CI, 0.62-0.79). Reductions in blood glucose were also greater with saxagliptin, with mean reductions in HbA1c of 0.5% at 2 years in the saxagliptin group compared with 0.2% in the placebo group (P<.001). More patients assigned saxagliptin achieved or maintained goal HbA1c <7% (40% vs. 30.3%; P<.001). About 15% of patients in the saxagliptin group reported at least one hypoglycemic event compared with 13.4% of patients in the placebo group (P<.001). Hospitalization for hypoglycemia was infrequent and similar between groups (0.6% vs. 0.5%; P=.33).

Additionally, saxagliptin was associated with reduced development and progession of microalbuminuria.

“It is very encouraging that within such a short time, 2 years of follow-up, that saxagliptin has demonstrated a beneficial effect on the kidney,” researcherItamar Raz, MD, head of the diabetes unit, department of medicine, Haddassah University Medical Center, Jerusalem, told Cardiology Today.

Rates of pancreatitis were similar with saxagliptin and placebo (0.3% for both; P=.77). Five cases of pancreatic cancer were reported in the saxagliptin group compared with 12 in the placebo group. The incidence of other prespecified safety endpoints were balanced, Bhatt said.

Premature discontinuation of the study drug occurred more in the placebo group (20.8% vs. 18.4%; P<.001).

“There is still a great need to bring patients to HbA1c target and we know today that we only have 50% to 60% of diabetes patients at target. [Saxagliptin] is a safe drug that was not shown to do CV harm, as was shown in the primary and secondary endpoint results,” Raz said.

In The New England Journal of Medicine study, the researchers acknowledged “there remains a strong clinical need to identify antihyperglycemic agents that are, at a minimum, safe and that can potentially reduce cardiovascular complications.”

Saxagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. – by Katie Kalvaitis

Source: Endocrine Today.



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