Used alone, oral antihyperglycemic drugs usually lower glycated hemoglobin (A1C) by 0.5-1.5%. Metformin is generally the drug of choice for initial treatment of type 2 diabetes. If metformin alone does not achieve the desired A1C goal, comorbidities or cost may determine the choice of a second drug: options include an SGLT2 inhibitor or a GLP-1 receptor agonist for patients with cardiovascular disease or chronic kidney disease, an SGLT2 inhibitor for patients with heart failure, or a sulfonylurea if cost is an issue. If glycemic control is not achieved with maximum doses of 2 drugs, insulin or another drug can be added.4

Two randomized, open-label, crossover studies in a total of 60 healthy adults found that the 3-drug combination tablet was bioequivalent to individual tablets of empagliflozin, linagliptin, and extended-release metformin taken together.5

No new efficacy trials were required for approval of Trijardy XR. Approval of the 3-drug combination was based on the results of earlier trials in which addition of empagliflozin/linagliptin to metformin reduced A1C significantly more than addition of either drug alone.

The labeling of Trijardy XR includes a long list of warnings and precautions about adverse effects, including lactic acidosis associated with metformin, acute pancreatitis with DPP-4 inhibitors, and euglycemic ketoacidosis with SGLT2 inhibitors. As might be expected with a 3-drug combination available in 4 different strengths, the dosing instructions for starting treatment are complex.