The longer-term effectiveness of pharmaceuticals to treat type 2 diabetes (T2D) beyond 6-12 months is unknown. GRADE will compare the effectiveness of the 4 most commonly used therapies over 4 to 7 years in 5047 participants with T2D for up to 10 years and treated with metformin alone. Participants were randomly assigned to receive metformin plus either the sulfonylurea glimepiride, the DPP-4 inhibitor sitagliptin, the incretin liraglutide or the basal insulin glargine. The goal is to determine which combination of diabetes medications achieves best glycemic control, has the fewest side effects, and is most beneficial for overall good health.
PRINCIPAL INVESTIGATOR(S)
ADDITIONAL INVESTIGATOR(S)
RESEARCH STAFF
Michael Backman, Ionut Bebu, Joel Bethepu, Nicole Butera, CJ Buys, Sandy Coppage, Naureen Elahi, Yuping Gao, Alokananda Ghosh, Michaela Gramzinski, Nisha Grover, Stephanie Hall, Erin Kazemi, Loree Lamour, Liz Legowski, Laura Lucs, Anna Murphy, Hannah Rapoport, Colleen Suratt, Jeff Weir
MAJOR PUBLICATIONS
Lachin JM. Sample size and power for a logrank test and Cox proportional hazards model with multiple groups and strata, or a quantitative covariate with multiple strata. Stat Med. 2013;32(25):4413-4425. PMCID:PMC3775959
Nathan DM, Buse JB, Kahn SE, Krause-Steinrauf H, Larkin ME, Staten M, Wexler D, Lachin JM, the GRADE Study Research Group. Rationale and design of the glycemia reduction approaches in diabetes: a comparative effectiveness study (GRADE). Diabetes Care. 2013;36(8):2254-2261. PMCID:PMC3714493
Lachin JM. Applications of the Wei-Lachin Multivariate One-Sided Test for Multiple Outcomes on Possibly Different Scales.(Research Article). PLoS ONE. 9(10) PMCID:PMC4201485
Lachin JM. Fallacies of last observation carried forward analyses. Clinical Trials. 13(2):161-168. PMCID:PMC4785044
Lachin JM, Bebu I. Application of the Wei–Lachin multivariate one-directional test to multiple event-time outcomes. Clinical Trials. 12(6):627-633. PMCID:PMC4562325
Devchand R, Nicols C, Gallivan JM, Tiktin M, Krause-Steinrauf H, Larkin M, Tuncer DM, the GRADE Research Group. Assessment of a National Diabetes Education Program diabetes management booklet: The GRADE experience. J Am Assoc Nurse Pract. 2017;29(5):255-263. PMCID:PMC5419861
Bebu I, Lachin JM. Properties of composite time to first event versus joint marginal analyses of multiple outcomes. Statistics In Medicine. 37(27):3918-3930. PMCID:PMC6615937
Behringer-Massera S, Browne T, George G, Duran Sally, Cherrington A, McKee MD, the GRADE Research Group. Facilitators and barriers to successful recruitment into a large comparative effectiveness trial: a qualitative study. J Comp Eff Res. 2019;8(10):815-826.
Larkin ME, Nathan DM, Bebu I, Krause-Steinrauf H, Herman WH, Higgins JM, Tiktin M, Cohen RM, Lund C, Bergenstal RM, Johnson ML, Arends V, and the GRADE Research Group. Rationale and Design for a GRADE Substudy of Continuous Glucose Monitoring. Diabetes Technology & Therapeutics. 21(12):682-690.
Wexler DJ, Krause-Steinrauf H, Crandall JP, Florez HJ, Hox SH, Kuhn A, Sood A, Underkofler C, Aroda VR, the GRADE Research Group. Baseline Characteristics of Randomized Participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Diabetes Care. 2019;11(43):2098-2107. PMCID:PMC6804613
ADDITIONAL PUBLICATIONS
Learn more at ClinicalTrials.gov
GRADE is a clinical trial comparing the effectiveness of 4 alternate randomly-assigned glucose-lowering therapies, in addition to metformin, in 5047 participants with type 2 diabetes over 4-7 years of follow-up to assess metabolic status, side effects, quality of life, beta cell function and micro- and macro-vascular complications.
GRADE will provide high quality evidence to guide physician decisions on the therapeutic assignments to the millions of patients with early (up to 10 years) of type 2 diabetes based on indices of effectiveness and safety over up to 7 years of treatment and follow-up. The principal outcomes to be assessed include the overall metabolic status and the durability of treatment to maintain adequate glycemic control, the evolution and progression of microvascular complications of diabetes that affect eyes, kidneys and nerves and of overt cardiovascular disease (myocardial infarction, stroke and congestive heart failure), and possibly mortality. The study will also assess the incidence of potential adverse effects, especially hypoglycemia and potentially pancreatitis and cancer. The study will also assess heterogeneity of outcomes in specific sub-populations defined by demographics (age, sex), diabetes factors (duration of T2D, family history) and various risk factors to provide patient-specific recommendations, so-called precision medicine.