American Diabetes Association
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Comparative effects of randomized second-line therapy for type 2 diabetes on a composite outcome incorporating glycemic control, body weight, and hypoglycemia: An analysis of the Glycemia Reduction Approaches in Type 2 Diabetes - A Comparative Effectiveness (GRADE) Study

posted on 2024-01-09, 20:32 authored by M. Sue Kirkman, Mark Tripputi, Heidi Krause-Steinrauf, Ionut Bebu, Hiba Abouassi, Henry Burch, Elizabeth Duran-Valdez, Hermes Florez, W. Timothy Garvey, Daniel S. Hsia, Maamoun Salam, Rodica Pop Busui

Background: The GRADE Study (5047 participants, mean follow-up 5.0 years) demonstrated differences in glycemic control over time among four randomized therapies added to metformin. Weight gain and hypoglycemia are also important outcomes for people with type 2 diabetes. We compared the effects of the four randomized GRADE medications on a composite outcome incorporating glycemic deterioration, weight gain, and hypoglycemia.

Methods: The composite outcome was time to first occurrence of any of: HbA1c >7.5%, confirmed; ≥5% weight gain; or severe or recurrent non-severe hypoglycemia. Secondary analyses examined individual components of the composite outcome, subgroup effects and potential mediators, and treatment satisfaction. Cumulative incidence was estimated using the Kaplan-Meier estimator. Cox proportional hazards models assessed pairwise group differences in risk of an outcome.

Results: Risk of reaching the composite outcome (events per 100 participant-treatment years, PTYs) was lowest with liraglutide (19/100 PTYs) followed by sitagliptin (26/100 PTYs), glargine (29/100 PTYs), and glimepiride (40/100 PTYs); all pairwise comparisons were statistically significant. Risk of weight gain and hypoglycemia had the same order, but risk of glycemic deterioration was lowest with glargine, followed by liraglutide, glimepiride, and sitagliptin. No significant heterogeneity in risk of composite outcome was detected across pre-specified covariates. Participants who reached the composite outcome had modestly but significantly lower treatment satisfaction.

Conclusions: Among common second-line drug classes for type 2 diabetes, liraglutide had the lowest and glimepiride the highest risk of reaching a composite outcome encompassing glycemic deterioration, weight gain, and hypoglycemia. These findings may inform decision-making regarding type 2 diabetes therapy.


The GRADE Study was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health under Award Number U01DK098246. The planning of GRADE was supported by a U34 planning grant from the NIDDK (U34-DK-088043). The American Diabetes Association supported the initial planning meeting for the U34 proposal. The National Heart, Lung, and Blood Institute and the Centers for Disease Control and Prevention also provided funding support. The Department of Veterans Affairs provided resources and facilities. Additional support was provided by grant numbers P30 DK017047, P30 DK020541, P30 DK020572, P30 DK072476, P30 DK079626, P30 DK092926, U54 GM104940, UL1 TR000170, UL1 TR000439, UL1 TR000445, UL1 TR001102, UL1 TR001108, UL1 TR001409, 2UL1TR001425, UL1 TR001449, UL1 TR002243, UL1 TR002345, UL1 TR002378, UL1 TR002489, UL1 TR002529, UL1 TR002535, UL1 TR002537, UL1 TR002541 and UL1 TR002548. Educational materials have been provided by the National Diabetes Education Program. Material support in the form of donated medications and supplies has been provided by Becton, Dickinson and Company, Bristol-Myers Squibb, Merck & Co., Inc., Novo Nordisk, Roche Diagnostics, and Sanofi. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The GRADE Study Research Group is deeply grateful to our participants whose loyal dedication made GRADE possible.


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