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Original Investigation |

Association Between Intensification of Metformin Treatment With Insulin vs Sulfonylureas and Cardiovascular Events and All-Cause Mortality Among Patients With Diabetes

Christianne L. Roumie, MD, MPH1,2; Robert A. Greevy, PhD1,3; Carlos G. Grijalva, MD, MPH1,4; Adriana M. Hung, MD, MPH1,2; Xulei Liu, MD, MS1,3; Harvey J. Murff, MD, MPH1,2; Tom A. Elasy, MD, MPH1,2; Marie R. Griffin, MD, MPH1,2,4
[+] Author Affiliations
1Veterans Health Administration–Tennessee Valley Healthcare System Geriatric Research Education Clinical Center, HSR&D Center, Nashville, Tennessee
2Department of Medicine, Vanderbilt University, Nashville, Tennessee
3Department of Biostatistics, Vanderbilt University, Nashville, Tennessee
4Department of Health Policy, Vanderbilt University, Nashville, Tennessee
JAMA. 2014;311(22):2288-2296. doi:10.1001/jama.2014.4312.
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Importance  Preferred second-line medication for diabetes treatment after metformin failure remains uncertain.

Objective  To compare time to acute myocardial infarction (AMI), stroke, or death in a cohort of metformin initiators who added insulin or a sulfonylurea.

Design, Setting, and Participants  Retrospective cohort constructed with national Veterans Health Administration, Medicare, and National Death Index databases. The study population comprised veterans initially treated with metformin from 2001 through 2008 who subsequently added either insulin or sulfonylurea. Propensity score matching on characteristics was performed, matching each participant who added insulin to 5 who added a sulfonylurea. Patients were followed through September 2011 for primary analyses or September 2009 for cause-of-death analyses.

Main Outcomes and Measures  Risk of a composite outcome of AMI, stroke hospitalization, or all-cause death was compared between therapies with marginal structural Cox proportional hazard models adjusting for baseline and time-varying demographics, medications, cholesterol level, hemoglobin A1c level, creatinine level, blood pressure, body mass index, and comorbidities.

Results  Among 178 341 metformin monotherapy patients, 2948 added insulin and 39 990 added a sulfonylurea. Propensity score matching yielded 2436 metformin + insulin and 12 180 metformin + sulfonylurea patients. At intensification, patients had received metformin for a median of 14 months (IQR, 5-30), and hemoglobin A1c level was 8.1% (IQR, 7.2%-9.9%). Median follow-up after intensification was 14 months (IQR, 6-29 months). There were 172 vs 634 events for the primary outcome among patients who added insulin vs sulfonylureas, respectively (42.7 vs 32.8 events per 1000 person-years; adjusted hazard ratio [aHR], 1.30; 95% CI, 1.07-1.58; P = .009). Acute myocardial infarction and stroke rates were statistically similar, 41 vs 229 events (10.2 and 11.9 events per 1000 person-years; aHR, 0.88; 95% CI, 0.59-1.30; P = .52), whereas all-cause death rates were 137 vs 444 events, respectively (33.7 and 22.7 events per 1000 person-years; aHR, 1.44; 95% CI, 1.15-1.79; P = .001). There were 54 vs 258 secondary outcomes: AMI, stroke hospitalizations, or cardiovascular deaths (22.8 vs 22.5 events per 1000 person-years; aHR, 0.98; 95% CI, 0.71-1.34; P = .87).

Conclusions and Relevance  Among patients with diabetes who were receiving metformin, the addition of insulin vs a sulfonylurea was associated with an increased risk of a composite of nonfatal cardiovascular outcomes and all-cause mortality. These findings require further investigation to understand risks associated with insulin use in these patients.

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Figure 2.
Cumulative Incidence of Cardiovascular Events and Mortality

A, Cumulative incidence of cardiovascular disease (acute myocardial infarction, stroke) or death among a propensity score–matched cohort of patients taking metformin + sulfonylurea vs patients taking metformin + insulin. All follow-up is through September 30, 2011. Events are the composite of cardiovascular disease or all-cause death that occurred in the 12 months between each point. B, Cumulative incidence of fatal and nonfatal cardiovascular events (acute myocardial infarction, stroke, or cardiovascular deaths) among a propensity score–matched cohort of patients taking metformin + sulfonylurea vs patients taking metformin + insulin. All follow-up is through September 30, 2009. Events are the composite of fatal and nonfatal cardiovascular events that occurred in the 12 months between each point.

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