Adding insulin to metformin may increase risk for nonfatal CV events, all-cause mortality versus adding a sulfonylurea

Adding insulin to metformin as second-line therapy may increase risk for nonfatal cardiovascular events and all-cause mortality compared with adding a sulfonylurea, according to a recent study.

Researchers conducted a retrospective cohort study using the Veterans Health Administration, Medicare, and National Death Index databases to investigate the preferred second-line therapy after metformin failure. Included patients were veterans who initially received metformin from 2001 through 2008 and then added insulin or a sulfonylurea. Each patient who added insulin was matched with 5 patients who added a sulfonylurea. For the primary analyses, patients were followed through September 2011, while for the cause-of-death analyses, they were followed through September 2009. The study's primary composite outcome was acute myocardial infarction (AMI), stroke hospitalization, or all-cause death; secondary outcomes were cardiovascular disease events (AMI and stroke combined), all-cause deaths, and a composite including AMI, stroke, and cardiovascular death. The study was published in the June 11 Journal of the American Medical Association.

Ninety-five percent of the study patients were men, and 70% were white. Overall, 178,341 patients were initially receiving metformin monotherapy. Of these, 2,948 added insulin and 33,990 added a sulfonylurea. After propensity score matching, there were a total of 2,436 patients who added insulin and 12,180 who added a sulfonylurea. At the time the second drug was added, patients had been taking metformin for a median of 14 months (interquartile range, 5 to 30 months), and their median HbA1c level was 8.1% (interquartile range, 7.2% to 9.9%). Patients were followed for a median of 14 months (interquartile range, 6 to 29 months) after treatment intensification.

One hundred seventy-two primary outcome events occurred in the insulin group versus 634 in the sulfonylurea group (42.7 vs. 32.8 events per 1,000 person-years; adjusted hazard ratio, 1.30; P=0.009). No statistically significant difference was seen in AMI and stroke rates (10.2 vs. 11.9 events per 1,000 person-years; adjusted hazard ratio, 0.88; P=0.52) or in rates of the secondary outcome (22.8 vs. 22.5 events per 1,000 person-years; adjusted hazard ratio, 0.98; P=0.87). All-cause mortality rates did differ significantly according to second-line treatment (33.7 vs. 22.7 events per 1,000 person-years; adjusted hazard ratio, 1.44; P=0.001).

The authors noted that their study may have been missing some data on medication refills, that the sample size of patients receiving insulin was relatively small, and that most of the included patients were white men, among other limitations. However, they concluded that in diabetic patients receiving metformin, insulin added as second-line therapy versus a sulfonylurea was associated with increased risk for nonfatal cardiovascular outcomes as well as all-cause mortality. “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 wrote.