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Publication Briefs

Cardiovascular Outcomes after Addition of Insulin Versus Sulfonylureas in Veterans with Diabetes Taking Metformin

Diabetes and its complications represent an enormous healthcare burden and result in nearly 200,000 deaths annually. The first choice of medications for most patients with diabetes is metformin. If control of diabetes is not achieved after adding metformin to diet and exercise, then a second medicine is needed. However, the optimal choice of second medication is unknown. This retrospective cohort study compared time to a combined outcome of acute myocardial infarction (AMI), stroke, or death among Veterans with diabetes that were initially treated with metformin, and subsequently added either insulin or sulfonylurea. Among 178,341 Veterans on metformin monotherapy, 2,948 and 39,990 added insulin or sulfonylurea, respectively. Propensity score matching on baseline covariates yielded 2,436 metformin+insulin and 12,180 metformin+sulfonylurea patients. Covariates examined in this study included demographics, healthcare use, physiologic variables (e.g., blood pressure, creatinine, body mass index), smoking, and presence of comorbidities.


  • Compared to those who added a sulfonylurea, Veterans with diabetes who added insulin to metformin therapy had a 30% higher risk of the combined outcome of heart attack, stroke, and all-cause mortality. Although new heart attacks and strokes occurred at similar rates in both groups, mortality was higher in patients who added insulin.
  • Although sulfonylurea use predominated as add-on therapy, there was increasing use of insulin intensification over the study years (increasing by an average of 17% per year). Reasons may include a growing prevalence of obesity and insulin resistance, emphasis on metrics such as glycemic targets, increasing comfort with newer analog insulins, and/or the benefit in microvascular outcome prevention.
  • Veterans had been on metformin for an average of 14 months, with a hemoglobin A1c of 8.1% at the time of addition of the second medication. At one year, median HbA1c declined to 7% among metformin+ insulin users and 6.9% among metformin+ sulfonylurea users.


  • Residual confounding from difficult to measure factors, such as patient frailty or diabetes severity, remains possible.
  • Veterans may not receive all their healthcare or medications in VA facilities, resulting in missing events or medications; this was partially addressed through Medicare and Medicaid data.
  • Veterans who added insulin comprised only 7% of intensifiers. This resulted in a relatively small sample size and limited the precision of some estimates.


  • Intensification of metformin with insulin among those who could add a sulfonylurea (HbA1c <10%) offers no advantage on risk of cardiovascular events and is associated with some risk.

All authors are part of the GRECC (Geriatric Research Education and Clinical Center) at the VA Tennessee Valley Healthcare System.

PubMed Logo Roumie C, Greevy R, Grijalva C, Hung A, Liu X, Murff H, Elasy T, Griffin M. Association between Intensification of Metformin Treatment with Insulin versus Sulfonylureas and Cardiovascular Events and All-Cause Mortality among Patients with Diabetes. JAMA. June 11, 2014;311(22):2288-96.

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What are HSR Publication Briefs?

HSR requires notification by HSR-funded investigators about all articles accepted for publication. These journal articles are reviewed by HSR and publication briefs or summaries are written for a select number of articles that are then forwarded to VHA Central Office leadership to keep them informed about important findings or information. Articles to be summarized are selected by HSR based on timeliness of the findings, interest of leadership, or potential impact on the organization. Publication briefs are written for only a small number of HSR published articles. Visit the HSR citations database for a complete listing of HSR articles and presentations.

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