ABSTRACT: Hypoglycemia and acute metabolic complications (AMCs; ketoacidosis, hyperosmolarity, and coma) are glycemic outcomes that have high cost and high morbidity; these outcomes must be taken into consideration when choosing initial second-line therapy after metformin. We conducted a retrospective cohort study analyzing national administrative data from adults with type 2 diabetes mellitus who started a second-line diabetes medication (sulfonylureas [SFUs], thiazolidinediones [TZDs], glucagon-like peptide 1 [GLP-1] agonists, dipeptidyl peptidase 4 [DPP-4] inhibitors, basal insulin, or sodium-glucose contransporter 2 [SGLT-2] inhibitors) between April 1, 2011 and September 30, 2015 (N=43,288) and compared rates of hypoglycemia and AMCs. Most patients (24,506 [56.6%]) were prescribed sulfonylurea as second-line treatment, followed by DPP-4 inhibitors (7953 [18.4%]), GLP-1 agonists (3854 [8.9%]), basal insulin (2542 [5.9%]), SGLT-2 inhibitors (2537 [5.9%), and TZDs (1896 [4.4%]). Baseline rates of hypoglycemia varied more than 5-fold across initial second-line antidiabetic medication classes, and rates of AMCs varied 7-fold. Compared with patients taking an SFU, lower adjusted rates of hypoglycemia were associated with taking a DPP-4 inhibitor (63% lower rate; incidence rate ratio [IRR], 0.37; 95% CI, 0.25 to 0.57), SGLT-2 inhibitor (54% lower; IRR, 0.46; 95% CI, 0.22 to 0.94), or TZD (79% lower; IRR, 0.21; 95% CI, 0.08 to 0.56) but not a glucagon-like peptide 1 agonist or basal insulin. For AMCs, only initiation of a DPP-4 inhibitor (43% lower rate; IRR, 0.57; 95% CI, 0.41 to 0.81) was associated with a lower adjusted rate compared with SFU. Use of SGLT-2 inhibitors was not associated with a substantially increased rate of acute metabolic complications compared with SFU. Special attention still needs to be paid to glycemic outcomes when choosing a second-line diabetes therapy following metformin.
