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Addition of insulin to metformin increased mortality risk in diabetes
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In patients with diabetes, intensification of a metformin regimen with insulin was associated with modestly increased risk for nonfatal cardiovascular events and all-cause mortality, according to recent findings.
Patients who added a sulfonylurea rather than insulin to metformin treatment did not experience increased risk for myocardial infarction or stroke.
In the retrospective cohort study, researchers utilized data from 178,341 adult patients with diabetes collected from national Veterans Health Administration, Medicare and National Death index databases. The patient population consisted of veterans treated between 2001 and 2008 whose initial intervention was metformin monotherapy. Patients identified for inclusion were subsequently prescribed an add-on regimen of insulin (n=2,948) or a sulfonylurea (n=39,990). The add-on therapy was started about 14 months after the start of metformin monotherapy, and the median follow-up took place 14 months after intensification.
The study’s primary outcome was defined as a composite of acute MI, stroke hospitalization and/or all-cause mortality. Secondary outcomes included CV disease deaths, with acute MI and stroke combined; all-cause death; and a composite of acute MI, stroke and CV death.
The researchers evaluated time to the composite using a propensity score-matched cohort, with each participant who added an insulin regimen matched to five who used intensification therapy with a sulfonylurea. Propensity score matching resulted in 2,436 insulin and 12,180 sulfonylurea add-on patients. The researchers compared the risk of composite outcome between the two therapies using marginal structural Cox proportional hazard models, adjusting for medications, cholesterol levels, HbA1c levels, creatinine levels, BP, BMI and comorbid conditions.
The investigators found that at the median follow-up of 14 months, the patients who added insulin had 172 events for the primary outcome vs. 634 events in the sulfonylurea add-on group (42.7 vs. 32.8 events per 1,000 person-years; adjusted HR=1.3; 95% CI, 1.07-1.38). There were statistically similar rates of acute MI, with 41 events in the insulin group vs. 229 in the sulfonylurea group (10.2 vs. 11.9 events per 1,000 person-years; adjusted HR=0.88; 95% CI, 0.59-1.3). The rates of all-cause mortality were 137 for the insulin add-on group and 444 for the sulfonylurea group (33.7 events vs. 22.7 events per 1,000 person-years; adjusted HR=1.44; 95% CI, 1.15-1.79). Of the secondary outcomes, there were 54 in the insulin group vs. 258 in the sulfonylurea group (22.8 vs. 22.5 events per 1,000 person-years; adjusted HR=0.98; 95% CI, 0.71-1.34).
According to study researcher Christianne L. Roumie, MD, MPH, of the Veterans Administration-Tennessee Valley Healthcare System Geriatric Research Education Clinical Center, these findings support previous clinical trial and observational data, which found no CV benefit in the addition of insulin to a metformin regimen vs. oral agents.
“Our study suggests that 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.” Roumie said in a press release.
“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,” she said.
Disclosure: The researchers report no relevant financial disclosures.
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