• Seth A Berkowitz, Alexis A Krumme, Jerry Avorn, Troyen Brennan, Olga S Matlin, Claire M Spettell, Edmund J Pezalla, Gregory Brill, William H Shrank, and Niteesh K Choudhry.
• Division of Pharmacoepidemiology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts2Division of General Internal Medicine, Massachusetts General Hospital, Boston.
• JAMA Intern Med. 2014 Dec 1; 174 (12): 1955-62.

ImportanceAlthough many classes of oral glucose-lowering medications have been approved for use, little comparative effectiveness evidence exists to guide initial selection of therapy for diabetes mellitus.ObjectiveTo determine the effect of initial oral glucose-lowering agent class on subsequent need for treatment intensification and 4 short-term adverse clinical events.Design, Setting, And ParticipantsThis study was a retrospective cohort study of patients who were fully insured members of Aetna (a large national health insurer) who had been prescribed an oral glucose-lowering medication from July 1, 2009, through June 30, 2013. Individuals newly prescribed an oral glucose-lowering agent who filled a second prescription for a medication in the same class and with a dosage at or above the World Health Organization's defined daily dose within 90 days of the end-of-day's supply of the first prescription were studied. Individuals with interim prescriptions for other oral glucose-lowering medications were excluded.ExposuresInitiation of treatment with metformin, a sulfonylurea, a thiazolidinedione, or a dipeptidyl peptidase 4 inhibitor.Main Outcomes And MeasuresTime to addition of a second oral agent or insulin, each component separately, hypoglycemia, other diabetes-related emergency department visits, and cardiovascular events.ResultsA total of 15 516 patients met the inclusion criteria, of whom 8964 (57.8%) started therapy with metformin. In unadjusted analyses, use of medications other than metformin was significantly associated with an increased risk of adding a second oral agent only, insulin only, and a second agent or insulin (P < .001 for all). In propensity score and multivariable-adjusted Cox proportional hazards models, initiation of therapy with sulfonylureas (hazard ratio [HR], 1.68; 95% CI, 1.57-1.79), thiazolidinediones (HR, 1.61; 95% CI, 1.43-1.80), and dipeptidyl peptidase 4 inhibitors (HR, 1.62; 95% CI, 1.47-1.79) was associated with an increased hazard of intensification. Alternatives to metformin were not associated with a reduced risk of hypoglycemia, emergency department visits, or cardiovascular events.Conclusions And RelevanceDespite guidelines, only 57.8% of individuals began diabetes treatment with metformin. Beginning treatment with metformin was associated with reduced subsequent treatment intensification, without differences in rates of hypoglycemia or other adverse clinical events. These findings have significant implications for quality of life and medication costs.

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