Choosing a Second Diabetes Agent After Metformin: Glycemic, Cardiovascular, and Microvascular Outcomes

For patients with type 2 diabetes in whom metformin does not confer adequate control, which medication should be added next? In 2022, the multicenter GRADE trial became the first large, randomized trial to address this question.

GRADE researchers compared the effect of four diabetes medications on glycemic, microvascular, and cardiovascular outcomes in 5000 patients with type 2 diabetes (mean duration, 4 years) already taking metformin. Participants had relatively well-controlled diabetes at baseline (mean glycosylated hemoglobin [HbA_1c], 7.5%), and only 6% had prior cardiovascular (CV) disease. They were randomized to add a sulfonylurea (glimepiride), a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin), a glucagon-like peptide-1 (GLP-1…