Sulfonylureas, thiazolidinediones, and dipeptidyl peptidase 4 (DPP-4) inhibitors do not differ in reducing hemoglobin A1c (HbA1c) levels or the risk for kidney disorders in patients with type 2 diabetes who have received first-line metformin, according to study results published in JAMA Network Open.

Researchers conducted a retrospective analysis of 3 cohort studies to determine whether second-line treatment options such as sulfonylureas, DPP-4 inhibitors, and thiazolidinediones were associated with reduced HbA1c levels in patients with type 2 diabetes who received metformin as first-line therapy. In a meta-analysis, the investigators also sought to determine whether any second-line treatment was associated with a lower risk for myocardial infarction, kidney disorders, and/or eye disorders.

Using open-source analytical tools and a common data model, researchers assessed medical data of 246,558,805 patients from multiple countries who received metformin therapy for type 2 diabetes with at least 1 recorded HbA1c level. Within 90 days after metformin prescription, patients were prescribed sulfonylureas, DPP-4 inhibitors, or thiazolidinediones.

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Each drug was primarily examined for its ability to lower HbA1c levels to ≤7% of total hemoglobin; researchers discovered no significant difference between the 3 treatment options with regard to this measure, or for the risk for kidney disorders. However, compared with DPP-4 inhibitors, sulfonylureas were associated with a slightly increased risk for myocardial infarction (hazard ratio 1.12; 95% CI, 1.02-1.24) and eye disorders (hazard ratio 1.15; 95% CI, 1.11-1.19).

The researchers noted several limitations of this study, including data quality issues caused by discrepancies inherent in large healthcare databases.

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“Two-way comparisons among DPP-4 [inhibitors], sulfonylureas, and thiazolidinediones for a difference in lowering HbA1c levels to 7% of total hemoglobin or less in patients with type 2 diabetes treated with metformin as a first-line therapy were inconclusive after meta-analysis as well as after empirical calibration,” concluded the researchers. However, secondary outcomes “support preferring DPP-4 inhibitors over sulfonylureas as second-line therapies, in agreement with the February 2017 recommendation from the American Association of Clinical Endocrinologists and American College of Endocrinology….”


Vashisht R, Jung K, Schuler A, et al. Association of hemoglobin A1c levels with use of sulfonylureas, dipeptidyl peptidase 4 inhibitors, and thiazolidinediones in patients with type 2 diabetes treated with metformin: Analysis from the observational health data sciences and informatics initiative [published online August 24, 2018]. JAMA Network Open. doi:10.1001/jamanetworkopen.2018.1755