CardioExchange Archive

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For many years critics have bemoaned the absence of outcome studies for the many diabetes drugs used to lower blood glucose levels. Now, finally, two large trials with different drugs have been presented at the European Society of Cardiology meeting in Amsterdam and published simultaneously in The New England Journal of Medicine. The good news is that the drugs appear safe. Both trials turned up no evidence for the adverse cardiovascular events that some had feared. The bad news is that neither drug appeared to improve cardiovascular outcomes, though cardiovascular disease is the cause of death in most people with diabetes.

SAVOR-TIMI 53

A total of 16,492 people with type 2 diabetes at high risk for a cardiovascular event were studied in SAVOR-TIMI 53. Participants were randomized to the DPP-4 inhibitor saxagliptin (Onglyza, Bristol-Myers Squibb and AstraZeneca) or placebo.

• The primary endpoint (composite of CV death, MI, or ischemic stroke) occurred in 7.3% of the saxagliptin group and 7.2% in the placebo group (hazard ratio 1.0, CI 0.89-1.12, p=0.99 for superiority, p<0.001 for noninferiority).

• An important secondary endpoint, the composite of CV death, MI, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure occurred in 12.8% of the treatment group versus 12.4% of the placebo group (HR 1.02, CI 0.94-1.11, p=0.66).

• There was an excess of hospitalization in the saxagliptin group compared with the placebo group: 3.5% versus 2.8% (HR1.27, CI 1.07-1.51, p=0.007).

“Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes,” the investigators wrote.

Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE)

In the EXAMINE trial, 5,380 people with a recent acute coronary syndrome (ACS) were randomized to alogliptin (Nesina, Takeda Pharmaceuticals) or placebo.

• The primary endpoint (a composite of death from CV causes, nonfatal MI, or nonfatal stroke) occurred in 11.3% of the alogliptin group versus 11.8% of the placebo group (HR 0.96, p<0.001 for noninferiority)

• As expected, alogliptin therapy resulted in a significant reduction in glycated hemoglobin levels, but there were no significant differences in hypoglycemia, cancer, pancreatitis, or initiation of dialysis.

The authors of both studies said that the relatively short duration of their studies meant that they were unable to rule out possible benefits associated with longer-term usage of the study drugs.

These trials represent the first round of FDA-mandated cardiovascular outcomes trials for diabetes drugs, a major result of the rosiglitazone controversy. In an accompanying perspective in NEJM, William Hiatt, Sanjay Kaul, and Robert Smith, all members of the FDA advisory committees that debated the fate of rosiglitazone, discuss the complicated recent history of diabetes drugs at the FDA. After all the serious concerns raised about the cardiovascular safety of rosiglitazone, they write that it now appears that rosiglitazone, along, now, with saxagliptin and alogliptin, “appear to be relatively safe” from a cardiovascular standpoint.

“It is disappointing, however, that neither intensive glycemic control nor the use of specific diabetes medications is associated with any suggestion of cardiovascular benefit. Thus the evidence does not support the use of glycated hemoglobin as a valid surrogate for assessing either the cardiovascular risks or the cardiovascular benefits of diabetes therapy.”

They suggest that the FDA might reconsider its requirement that all diabetes drugs be forced to demonstrate their cardiovascular safety. These trials might only be necessary when warranted by clinical or preclinical problems. “The optimal approach to the reduction of cardiovascular risk in diabetes should focus on aggressive management of the standard cardiovascular risk factors rather than on intensive glycemic control.”