ADA – Saxagliptin Lowers Glucose, Reduces Cardiovascular Events

Major adverse cardiovascular events were 55% less common with saxagliptin than with placebo or metformin, Robert Wolf, M.D., of Bristol-Myers Squibb in Princeton, N.J., and colleagues found.

Notably, saxagliptin yielded lower major adverse cardiovascular event rates in nearly all high-risk groups compared with controls, they reported at the American Diabetes Association meeting.

These findings were reassuring, said Dr. Wolf, whose group had gone looking for signals of cardiovascular harm in the pooled data from all phase II and III saxagliptin studies. If confirmed prospectively, a cardioprotective effect “would be a very important advance,” he said. “There’s not definitive proof that any diabetes drug provides cardiovascular benefit for hard clinical endpoints.”

Rather, in 2007, results of a study of rosiglitazone (Avandia) ignited concerns that some agents were increasing cardiovascular event rates atop the already elevated cardiovascular risk of diabetes. Since then, the FDA’s bar has risen for scrutiny of cardiovascular safety in new diabetes drugs, Dr. Wolf said. So, the researchers analyzed adverse events reported by the 4,607 patients in the eight randomized, double-blind phase II or III clinical trials of saxagliptin in Type 2 diabetes.
Over the 3,758 patient-years of saxagliptin exposure in these studies, the researchers found no increased risk of cardiovascular events in the overall population, the individual studies, or in subgroups of patients with higher risk characteristics.

Despite similar cardiovascular risk factor rates between treatment groups, the incidence of major adverse cardiovascular events — the composite of cardiovascular death, nonfatal MI, and nonfatal stroke — among saxagliptin-treated patients overall was half that among controls (0.7% versus 1.4%).

Acute cardiovascular events — revascularization procedures and reversible and irreversible ischemic events — were likewise less common with saxagliptin (1.1% versus 1.8%).

Saxagliptin was also associated with lower rates of both overall and cardiovascular-specific mortality compared with controls (0.3% versus 1.0% and 0.2% versus 0.8%, respectively).

In patient populations expected to be at elevated risk, the major adverse cardiovascular event incidence was lower with saxagliptin for all subgroups except older adults.

The rates compared with controls were:

• 9.2% versus 46.3% in those with a history of cardiovascular disease
• 7.0% versus 15.8% in those with at least one cardiovascular risk factor beyond diabetes
• 9.1% versus 18.4% in those with at least two cardiovascular risk factors in addition to diabetes
• 8.8% versus 22.5% in those with a history of hypertension
• 8.0% versus 13.2% in those with a history of high cholesterol levels
• 7.7% versus 22.5% for men
• 11.4% versus 9.9% among those age 65 and older

This study appeared to exclude the possibility of excess cardiovascular harm with the experimental agent but could not prove the potential cardiovascular benefit, Dr. Wolf cautioned.

Further prospective study is needed to test this hypothesis, and a phase III/IV study to do so is being designed for enrollment after FDA approval of the drug, he said.

The companies codeveloping saxagliptin — Bristol-Myers Squibb and AstraZeneca — have submitted a new drug application to the FDA, with news expected in July.

Wolf R, et al “Evaluation of CV risk in the saxagliptin clinical trials” ADA 2009; Abstract LB-8.

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FACT:
ADA – Factors Affecting Benefit or Harm of Intensive Glucose Control in Type 2 Diabetes: Intensive control is appropriate in the first 15 years after diagnosis of Type 2 diabetes.
Initiation of Intensive Control After 16-20 Years – No Benefit; Initiation After 20 Year.
See This Week’s Item 1

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