Preferred second line medication for diabetes treatment after metformin failure remains uncertain.
We compared time to acute myocardial infarction [AMI], stroke, or death in a cohort of metformin initiators who added insulin or a sulfonylurea.
Retrospective cohort constructed using national Veterans Health Administration, Medicare, and National Death Index databases.
Veterans initially treated with metformin from 2001 through 2008 who subsequently added either insulin or sulfonylurea. Each insulin intensifier was propensity score matched by characteristics to five sulfonylurea intensifiers. Patients were followed through September, 2011 for primary analyses or September, 2009 for cause of death analyses.
Main Outcome Measures
Risk of a composite outcome of AMI, stroke hospitalization or all-cause death was compared between therapies using marginal structural Cox proportional hazard models to adjust for baseline and time-varying demographics, medications, cholesterol, hemoglobin A1c, creatinine, blood pressure, body mass index, and co-morbidities.
Among 178,341 metformin monotherapy patients, 2,948 and 39,990 added insulin or sulfonylurea, respectively. Propensity score matching yielded 2,436 metformin+insulin and 12,180 metformin+sulfonylurea patients. At intensification, the median (interquartile range) time on metformin was 14 months (5, 30) and HbA1c was 8.1% (7.2, 9.9). There were 172 versus 634 events for the primary outcome among those who added insulin versus sulfonylureas respectively (42 versus 33 events per 1000 person-years, adjusted hazard ratio [aHR] 1.30, 95% confidence interval [CI] 1.07, 1.58, p=0.009). AMI and stroke rates were statistically similar 41 versus 229 (10.2 and 11.9 per 1000 person years, aHR 0.88,95% CI 0.59, 1.30, p=0.52), while all-cause death rates were137 versus 444, respectively (33.7 and 22.7 per 1000 person-years, aHR 1.44, 95% CI,1.15, 1.79, p=0.001). There were 54 versus 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=0.87).
Among patients with diabetes using metformin, the addition of insulin versus 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.