1. The addition of insulin to metformin was associated with an increased risk of all-cause mortality and an increased grouped risk of all-cause mortality and myocardial infarction (MI) or stroke relative to the addition of sulfonylureas.
2. The addition of insulin versus sulfonylureas to metformin did not differ in terms of rates of associated acute myocardial infarction (MI) or stroke alone.
Evidence Rating Level: 2 (Good)
Study Rundown: The American Diabetes Association recommends metformin for first-line treatment of diabetes for a goal of 7% HbA1c. Addition of second-line agents such as insulin or sulfonylureas is often needed to achieve this goal. Although clinical practice and research favors the use of insulin, patients prefer delaying insulin initiation. There is no consensus regarding the risk of cardiovascular events and deaths and all-cause death with insulin relative to sulfonylureas. This study evaluated this risk and found that addition of insulin to metformin increased the risk of all-cause mortality and increased the grouped risk of all-cause mortality and myocardial infarction (MI) or stroke but did not differ from sulfonylureas in rates of acute MI or stroke.
While this study provides information that could be useful in choosing second-line therapy for glycemic control, it is unlikely to change clinical practice without further corroboration. Unmeasured confounders including individual differences in treatment response can affect the results. Sample size for insulin treatment was significantly smaller than that for sulfonylureas making result interpretation challenging. The study population consisted mostly of white men, thus limiting the generalizability of the study results.
In-Depth [retrospective cohort]: This study used the Veterans’ Affairs database from 2001 to 2008 to select 2948 adult patients initiated on insulin following metformin and 39990 patients who were instead initiated on sulfonylureas. After matching for known/measured confounders, 2436 patients from the insulin group were compared to 12180 patients from the sulfonylurea group for the grouped primary outcome of acute myocardial infarction (MI), stroke and all-cause mortality and secondary outcomes including cardiovascular events (MI and stroke), and all-cause mortality. Follow-up period was 1 year for mortality events and 3 years for all other outcomes.
Insulin-metformin co-therapy increased the risk of the grouped primary outcome (acute MI, stroke, and all-cause mortality) relative to co-therapy with sulfonylureas (aHR 1.30; 95% CI, 1.07-1.58; p=0.009). Risk of all-cause deaths was also elevated in the insulin group relative to the sulfonylurea group (aHR 1.44; 95% CI, 1.15-1.79; p=0.001). There was no difference in rates of cardiovascular events (acute MI and stroke).
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