Insulin With Metformin for Diabetes Ups Death Risk

In patients with diabetes mellitus (DM) who are receiving metformin, the addition of insulin compared with a sulfonylurea is associated with an increased risk of nonfatal cardiovascular outcomes and all-cause death, according to a new study reported in JAMA.

Christianne L. Roumie, MD, MPH, of the Veterans Health Administration-Tennessee Valley Healthcare System Geriatric Research Education Clinical Center and Vanderbilt University and colleagues gathered data from national Veterans Health Administration, Medicare, and National Death Index databases. Included were veterans with DM for whom treatment started with metformin and then insulin or sulfonylurea subsequently was added. The researchers compared the risk between therapies of a composite outcome of heart attack, stroke, or all-cause death.

Among 178,341 patients who received metformin monotherapy, insulin was added for 2948 and a sulfonylurea was added for 39,990. The authors performed additional propensity matched analysis on a subset of 2436 patients from the insulin group and 12,180 patients from the sulfonylurea group. Patients had received metformin for a median of 14 months before another therapy was added; median follow-up after this addition was 14 months.

The rate of all-cause death was higher in patients who received insulin. Heart attack and stroke rates were statistically similar.

The finding of a modestly increased risk of a composite of cardiovascular events and death in metformin users for whom insulin was added is consistent with the available clinical trial and observational data, noted the authors, who added that their findings suggest intensification of metformin with insulin among patients who could add a sulfonylurea offers no advantage in regard to risk of cardiovascular events and is associated with some risk.

“These findings require further investigation to understand risks associated with insulin use in these patients and call into question recommendations that insulin is equivalent to sulfonylureas for patients who may be able to receive an oral agent,” the authors stated.

For patients with preserved kidney function, DM treatment begins with metformin and lifestyle changes to achieve a glycated hemoglobin level of 7% or lower, according to American Diabetes Association and European Association for the Study of Diabetes recommendations. Background information in the study suggests that patients require a second agent to reach this goal, but there is no consensus about which medication to choose. Because a few trials have had promising results, there has been an increase in early initiation of insulin and its use as add-on therapy to metformin.

In an accompanying editorial, “Comparative Effectiveness Research and Outcomes of Diabetes Treatment,” Monika M. Safford, MD, of the University of Alabama at Birmingham, commented on comparative effectiveness research, such as the study conducted by Roumie and colleagues:

“Comparative effectiveness research is creating new challenges as it generates much needed new evidence. The very methods that make studies like that of Roumie et al novel also create barriers to interpretation that may make it more difficult to apply their results. Some of the creativity being brought to bear on advancing methods of analysis may also be needed to advance methods of communicating both methods and results to practicing clinicians, and perhaps more importantly, to the patients who are facing decisions that may (or may not) have profound implications for their health and well-being.”

The study and editorial appear in the June 11 issue of JAMA, a diabetes theme issue.