Guidelines advocate using metformin as initial pharmacologic therapy for lowering A1C in type 2 diabetes. “Despite these guidelines, relatively few studies have provided evidence for this recommendation, particularly with regard to outcomes other than A1C and glycemic control,” explains Niteesh K. Choudhry, MD, PhD. “Given that more agents are now available and the increasing use of newer drug classes, it’s important to clarify differences among the available therapies.” There has also been a shift toward focusing on the need to intensify treatment with a second oral agent or insulin to achieve A1C goals as part of patient-centric care. Various therapies come with different risks for short-term adverse events, but these differences have not been well assessed in clinical research.

Examining Effects

In a retrospective study published in JAMA Internal Medicine, Dr. Choudhry and colleagues sought to determine the effect of the initial oral glucose-lowering agent class on subsequent treatment intensification and several short-term adverse clinical events. Participants included more than 15,500 patients who were newly prescribed an oral glucose-lowering agent and then filled a second prescription for a drug in the same class with a dosage at or above the World Health Organization’s defined daily dose within 3 months of the end-of-day’s supply of the first prescription.

“We found that only about 40% of patients in our study started therapy with metformin,” says Dr. Choudhry. “Patients who were initially prescribed metformin were less likely to require treatment intensification than those who started taking other drugs like sulfonylureas, thiazolidinediones, or dipeptidyl peptidase 4 inhibitors. We also observed no real advantages for other agents with regard to short-term clinical outcomes.”

In addition, the study noted that sulfonylureas—which were the second most commonly prescribed initial class—were associated with a higher risk of cardiovascular events and emergency department visits for a diabetes-related problem, such as hypoglycemia. Overall, alternatives to metformin were not associated with a reduced risk of hypoglycemia, emergency department visits, or cardiovascular events.

Assessing Implications

Dr. Choudhry says the study provides useful information to help guide the selection of initial oral glucose-lowering agents. “Our research supports guideline recommendations to use metformin first when treating type 2 diabetes,” he says. “Our data suggests that using metformin first and then moving onto new agents may benefit patients, but what we really need are randomized control trials that directly compare all of the available oral diabetes treatment to determine which of these, when used as the first treatment patients are started on, achieves the best outcomes.”