Hypoglycemia limits the glycemic control that can be achieved with insulin and sulfonylureas (SUs) , but we lack evidence from head-to-head studies to guide management. In the GRADE comparative effectiveness study, 5,047 patients with type 2 diabetes (T2DM) of <years’ duration, on metformin monotherapy with HbA1c 6.8-8.5%, were randomized to addition of the SU glimepiride, insulin glargine U-100, sitagliptin, or liraglutide, permitting a direct comparison over 5.0 ± 1.3 (mean ± SD) years of follow-up. Glimepiride was initiated at 1-2 mg/day, glargine at 10-20 units/day, and both were titrated according to algorithms based on self-monitored blood glucose levels. Over 4 years, adjudicated severe hypoglycemia occurred in 2.3% of those randomized to glimepiride vs. 1.4% with glargine, but was less frequent with liraglutide (0.9%) and sitagliptin (0.7%) , p=0.003. During GRADE, HbA1c was measured every 3 months, and if a HbA1c >7.5% was confirmed, “rescue treatment” with glargine and/or aspart was added. We examined management in participants who were unable to keep HbA1c ≤7.5% - whose primary study drug was insufficient - prior to their “rescue”. At 3 mo after randomization, hypoglycemic symptoms or a measured glucose <70 mg/dl within the previous 30 d was reported by 33% of those using glimepiride vs. 15% with glargine (p <0.001) . The mean dose of glimepiride at 3 mo (n=627) and 12 mo (n=337) was 3.4 and 4.2 mg/day, respectively [a 24% increase but considerably submaximal (8 mg) ]. In contrast, the dose of glargine at 3 mo (n=487) and 12 mo (n=337) was 26 and 37 units/day, respectively (a 44% increase, p <0.0vs. glimepiride) . The outcome of a confirmed HbA1c >7.5% was reached in 50% of those using glimepiride, vs. 39% with glargine (p<0.001) . Conclusions: In metformin-treated patients with T2DM, there was more hypoglycemia, less increase in drug dose, and less preservation of glycemic control, with addition of the SU glimepiride compared to glargine; increases in glimepiride dose might have been limited by hypoglycemia.


L.S. Phillips: Research Support; Abbott Diabetes, AbbVie Inc., Janssen Pharmaceuticals, Inc., Janssen Scientific Affairs, LLC, Pfizer Inc. Other Relationship; Cystic Fibrosis Foundation, Diasyst Inc. E.R. Seaquist: None. C. Baker: None. R.M. Bergenstal: Advisory Panel; Hygieia, Medtronic, Roche Diabetes Care, Zealand Pharma A/S. Consultant; Abbott Diabetes, Ascensia Diabetes Care, Bigfoot Biomedical, Inc., CeQur SA, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, Onduo LLC, Sanofi, United HealthCare Services, Inc. Research Support; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk, Sanofi. N.M. Butera: None. J.P. Crandall: Research Support; Abbott. R. Goland: None. S.H. Hox: None. D.S. Hsia: None. M.L. Johnson: Research Support; Abbott Diabetes, Dexcom, Inc., Insulet Corporation, Jaeb Center for Health Research, Lilly, Medtronic, Novo Nordisk, Sanofi. P. Raskin: None. W. Valencia: None. A.H. Waltje: None. N. Younes: None.


National Institute of Diabetes and Digestive and Kidney Diseases (U01DK098246, U34-DK-088043)

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