Implications of Removing Rosiglitazone's Black Box Warning and Restricted Access Program on the Uptake of Thiazolidinediones and Dipeptidyl Peptidase-4 Inhibitors Among Patients with Type 2 Diabetes.

backgroundMedications are increasingly being approved with limited, short-term evidence regarding safety. Regulatory safety concerns may emerge for these drugs but later may be reversed if additional evidence suggests no warning is indicated.

objectiveTo describe trends over time in the initiation of rosiglitazone and pioglitazone-both in the thiazolidinedione (TZD) class-and medications from the dipeptidyl peptidase-4 (DPP-4) inhibitor class before and after the FDA removed a black box warning and restricted access program for rosiglitazone regarding an increased risk of myocardial infarction.

methodsThis retrospective study evaluated initiation of TZDs and DPP-4 inhibitors using 2001-2015 administrative claims data from a U.S. commercially insured population. Patients were aged 18-64 years and were new users of either a TZD or DPP-4 inhibitor. Among all patients who were new users of either a TZD or a DPP-4 inhibitor during each quarter-year (Q), the percentage of patients who initiated rosiglitazone, pioglitazone, and DPP-4 inhibitors were calculated.

resultsThere were 630,977 patients eligible for the study. During 2007, rosiglitazone initiators decreased from 39.1% to 8.0% in 2007 Q4 when the black box warning was implemented. During 2010, rosiglitazone initiators decreased from 7.6% to 1.0%, as safety evidence accumulated and the restricted access program requirement was announced. Rosiglitazone initiation remained below 1.0%, even after regulatory restrictions were removed in November 2013. Pioglitazone initiation decreased from 46.4% in 2010 Q1 to 14.8% in 2011 Q4 and remained relatively constant between 14.5% and 17.8% after regulatory restrictions for rosiglitazone were removed. After DPP-4 inhibitors first became available in 2006 Q3, initiation of this medication class increased rapidly, stayed relatively constant between 42.8% and 45.5% in 2009, and then quickly rose and remained above 80% from 2012 through 2015.

conclusionsThis case study provides some evidence that adding and later reversing drug safety warnings-particularly those with restricted access requirements-may affect the uptake of the targeted product into the population when multiple clinically relevant treatment alternatives are available (such as type 2 diabetes). Once a treatment falls out of favor, removal of safety warnings and/or restricted access programs may not lead to increased use. DISCLOSURES: This project was not directly supported by any funding. Hickson was supported by the National Heart, Lung, and Blood Institute through a National Research Service Award (NRSA) training grant (4T32HL007055-41) as a postdoctoral research fellow with the Cardiovascular Disease Epidemiology Program at The University of North Carolina at Chapel Hill (UNC-CH). Cole was supported by a NRSA Predoctoral Traineeship from the Agency for Healthcare Research and Quality sponsored by The Cecil G. Sheps Center for Health Services Research, UNC-CH (grant no. T32-HS000032) and a predoctoral fellowship from the American Foundation for Pharmaceutical Education. Unrelated to this project, Cole was a part-time employee of Truven Health Analytics/IBM Watson Health. Dusetzina has nothing to disclose.