Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE)

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.

The BSC is the prime awardee and funds all study sites through sub-awards. The BSC serves as the Coordinating Center (CoC) for the GRADE Study and substudies responsible for organizing the Research Group, its committees, and working groups. The CoC provides biostatistical design, data processing and management, data analysis and interpretation of results, preparation of reports, presentations, and publications. The CoC monitors protocol performance and coordinates communication among the clinical sites, laboratories and other service cores, and the Executive Committee and DSMB. The CoC collaborates with the Research Group members in the preparation of publications, providing design and statistical support.

VISIT STUDY WEBSITE

PRINCIPAL INVESTIGATOR(S)

John Lachin, ScD

ADDITIONAL INVESTIGATOR(S)

Heidi Krause-Steinrauf, MS

Naji Younes, PhD

RESEARCH STAFF

Ionut Bebu, Nicole Butera, Yuping Gao, Alokananda Ghosh, Michaela Gramzinski, Stephanie Hall, Erin Kazemi, Loree Lamour, Liz Legowski, Anna Murphy, Sam Rosin, Jason Stonewall, Colleen Suratt, Mark Tripputi, Jeff Weir

MAJOR PUBLICATIONS

Wexler DJ, deBoer IH, Ghosh A, Younes N, Bebu I, Inzucchi SE, McGill JB, Mudaliar S, Schade D, Steffes MW, Tamborlane WV, Tan MH, Ismail-Beigi F for the GRADE Research Group. Comparative effects of glucose-lowering medications on kidney outcomes in type 2 diabetes: The GRADE Randomized Clinical Trial. JAMA IM. 2023 May 22; doi:10.1001/jamainternmed.20231487. PMID: 37213109; PubMed Central PMCID: PMC10203973.

The GRADE Study Research Group. Glycemia Reduction in Type 2 Diabetes — Glycemic Outcomes. N Engl J Med. Sept 22, 2022; 387(12):1063-1074; doi: htps://doi 10.1056/NEJMoa2200433. PubMed PMID: 36129996; PubMed Central PMID/PMCID: PMC9829320

The GRADE Study Research Group. Glycemia Reduction in Type 2 Diabetes — Microvascular and Cardiovascular Outcomes. N Engl J Med. Sept 22, 2022; 387(12):1075-1088; doi: https://10.1056/NEJMoa2200436. PubMed PMID: 36129997; PubMed Central PMID/PMCID:PMC9832916

Wexler DJ, Krause-Steinrauf H, Crandall JP, Florez HJ, Hox SH, Kuhn A, Underkofler C, Aroda VR, and the GRADE Research Group. Baseline Characteristics of Randomized Participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Diabetes Care. 2019; 43(11):2098-2107 doi: 10.2337/dc19-0901. Epub Aug 7 2019; PubMed PMID: 31391203; PubMed Central PMCID: PMC6804613

Nathan DM, Buse JB, Kahn SE, Krause-Steinrauf H, Larkin ME, Staten M, Wexler D, Lachin JM; GRADE Study Research Group. Rationale and design of the glycemia reduction approaches in diabetes: a comparative effectiveness study (GRADE). Diabetes Care. 2013; 36(8):2254-61. doi: 10.2337/dc13-0356. PubMed PMID: 23690531; PubMed Central PMCID: PMC3714493

ADDITIONAL PUBLICATIONS

Hollander PA, Krause-Steinrauf H, Butera NM, Kazemi EJ, Ahmann AJ, Fattaleh BN, Johnson ML, Killean T, Lagari VS, Larkin ME, Legowski EA, Rasouli N, Willis HJ, Martin CL; for the GRADE Research Group. The Use of Rescue Insulin in the Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study (GRADE). Diabetes Care. 2023 Sep 26:dc230516. doi: 10.2337/dc23-0516. Epub ahead of print. PMID: 37756542.

Crespo-Ramos G, Bebu I, Krause-Steinrauf H, Hoogendoorn CJ, Fang R, Ehrmann D, Presley C, Naik AD, Katona A, Walker EA, Cherrington A, Gonzalez JS, GRADE Research Group. Emotional Distress and Cardiovascular Disease Risk among Participants enrolled in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study. Diabetes Research And Clinical Practice, 2023 Jun 30; doi: 10.1016/j.diabres.2023.110808. PMID: 37394014;

Luchsinger JA, Kazemi EJ, Sanchez DL, Larkin ME, Valencia WM, DeSouza C, Carlson AL, Pop-Busui R, Seaquist ER, Florez, HJ, Barzilay J, and the GRADE Research Group. BMI, insulin sensitivity, and cognition in early type 2 diabetes: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study. 2023;31(7):1812–24; doi: 10.1002/oby.23785. PMID: 37368512;

Cherrington AL, Krause-Steinrauf H, Aroda V, Buse JB, Fattaleh B, Fortmann SP, Hall S, Hox SH, Kuhn S, Killean T, Loveland A, Phillips LS, Uy Jackson A, Waltje A, McKee MD and the GRADE Research Group. Use of comprehensive recruitment strategies in glycemia reduction approaches in diabetes: A comparative effectiveness study (GRADE) multi-center clinical trial. Clinical Trials. 2023 Jun 17; doi: 10.1177/17407745231175919. PMID: 37329282; PMCID: PMC10524662

Gulanski BI, Butera NM, Krause-Steinrauf H, Lichtman JH, Harindhanavudhi T, Green JB, Suratt CE, AbouAssi H, DeSouza C, Ahmann AJ, Wexler DJ, Aroda VR and the GRADE Research Group. Higher burden of cardiometabolic and socioeconomic risk factors in women with type 2 diabetes: an analysis of the Glycemic Reduction Approaches in Diabetes (GRADE) baseline cohort. BMJ Open Diabetes Res Care. 2023;11:e003159; doi: 10.1136/bmjdrc-2022-003159. PMID: 37094945; PubMed Central PMCID: PMC10151943.

Seegmiller JC, Schmit DJ, Arends VL, Steffes MW, Kahn SE, Younes N, and the GRADE Research Group. Assessment of circulating insulin using liquid chromatography – mass spectrometry during insulin glargine treatment in type 2 diabetes: Implications for estimating insulin sensitivity and ꞵ-cell function. Diabetes Obes Metab. 2023; 1-10. March 30; doi: 10.1111/dom.15072. PubMed PMID: 36999229; PubMedCentral PMCID: PMC10239335

Gonzalez JS, Krause-Steinrauf H, Bebu I, Crespo-Ramos G, Hoogendoorn CJ, Naik AD, Waltje A, Walker E, Ehrmann D, Brown-Friday J, Cherrington A; GRADE Research Group. Emotional Distress, Self-Management, and Glycemic Control among Participants enrolled in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study. Diabetes Res Clin Pract. 2023 Feb;196:110229. doi: 10.1016/j.diabres.2022.110229. Epub 2022 Dec 20. PMID: 36549506; PubMed Central PMCID: PMC9974790.

Aroda VR, Krause-Steinrauf K, Kazemi EJ, Buse JB, Gulanski BI, Florez HJ, Ahmann AJ, Loveland A, Kuhn A, Lonier JY, Wexler DJ, and the GRADE Research Group. Clinical and Metabolic Characterization of Adults With Type 2 Diabetes by Age in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) Cohort. Diabetes Care. July 13, 2022; doi: https://doi.org/10.2337/dc21-2659. PubMed Central PMID/PMCID: PMC9375440

Florez HJ, Ghosh A, Pop-Busui R, Hox, SH, Underkofler C, McKee MD, Park J, Rhee MK, Killean T, Krause-Steinrauf H, Aroda VR, Wexler DJ, and the GRADE Research Group. Differences in Complications, Cardiovascular Risk Factor, and Diabetes Management among participants enrolled at Veterans Affairs (VA) and Non-VA Medical Centers in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Diabetes Research and Clinical Practice 2021 Dec 28 :109188; doi: https:/doi.org/10.1016/j.diabres.2021.109188. PubMed PMID: 34971663; PubMed Central PMID/PMCID: PMC8917078

Brooks-Worrell B, Hampe CS, Hattery EG, Palomino B, Zangeneh SZ, Utzschneider K, Kahn SE, Larkin ME, Johnson ML, Mather KJ, Younes N, Rasouli N, Desouza C, Cohen RM, Park JY, Florez HJ, Valencia WM; GRADE Beta-cell Ancillary Study Network, Shojaie A, Palmer JP, Balasubramanyam A. Islet autoimmunity is highly prevalent and associated with diminished beta cell function in patients with type 2 diabetes in the GRADE study. Diabetes. 2022 Jan 21; 71(6):1261-1271. doi: 10.2337/db21-0590. PubMed PMID: 35061024; PubMed Central PMID/PMCID: PMC9375448

Nathan DM, Krause-Steinrauf H, Braffett BH, Arends VL, Younes N, McGee P, Lund C, Johnson M, Lorenzi G, Gao X, Steffes MW, Lachin JM, the GRADE Research Group, and the DCCT/EDIC Research Group. Comparison of central laboratory HbA1c measurements obtained from a capillary collection versus a standard venous whole blood collection in the GRADE and EDIC studies. PLOSOne. 2021 Nov 15; 16(11); e0257154; doi: 10.1371/journal.pone.0257154. PubMed PMID: 34780485; PubMed Central PMID/PMCID: PMC8592405

Luchsinger JA, Younes N, Manly JJ, Barzilay J, Valencia W, Larkin ME, Falck-Ytter C, Krause-Steinrauf H, Pop-Busui R, Florez H, Seaquist E, and the GRADE Research Group. Association of glycemia, lipids, and blood pressure with cognitive performance in people with type 2 diabetes in the glycemia reduction approaches in diabetes: A comparative effectiveness study. Diabetes Care 2021; doi: 10.2337/dc20-2858. PubMed PMID: 34285097; PubMed Central PMID/PMCID: PMC8740937

Barzilay J, Ghosh A, Pop-Busui R, Ahmann A, Balasubramanyam A, Banerji MA, Cohen RM, Green J, Ismail-Beigi F, Martin CL, Seaquist E, Luchsinger JA, and the GRADE Research Group. The Cross-Sectional Association of Cognition with Diabetic Peripheral and Autonomic Neuropathy: The GRADE Study. J. Diabetes Complicat. 2021; doi: 10.1016/j.jdiacomp.2021.108047. PubMed PMID: 34556408; PubMed Central PMID/PMCID: PMC8608739

Cherrington A, Krause-Steinrauf H, Bebu I, Naik A, Walker E, Golden S, Gonzalez J, and the GRADE Research Group. Study of emotional distress in a comparative effectiveness trial of diabetes treatments: Rationale and design. Contemporary Clinical Trials. 2021 Aug; 107:106366.; doi: 10.1016/j.cct.2021.106366. Epub 2021 Mar 22. PubMed PMID: 33766761 ; PubMed Central PMID/PMCID: PMC8667624

Utzschneider KM, Younes N, Rasouli N, Barzilay JI, Banerji MA, Cohen RM, Gonzalez EV, Ismail-Beigi F, Mather KJ, Raskin P, Wexler DJ, Lachin JM, Kahn SE, and The GRADE Research Group. Shape of the OGTT glucose response curve: Relationship with β-cell function and differences by sex, race, and BMI in adults with early type 2 diabetes treated with metformin. BMJ Open Diab Res Care 2021;9(1):e002264; doi: 10.1136/bmjdrc-2021-002264. PubMed PMID: 34531242 PubMed Central PMID/PMCID: PMC8449940

Larkin M, 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 Technol Ther. 2019; 21(12):682-690. doi: 10.1089/dia.2019.0202. PubMed PMID: 31393176; PubMed Central PMCID: PMC7207016.

Utzschneider K, Younes N, Rasouli N, Barzilay J, Banerji MA, Cohen R, Gonzalez E, Mather K, Ismail-Beigi F, Raskin P, Wexler D, Lachin J, Kahn S, and the GRADE Research Group. Association of glycemia with insulin sensitivity and β-cell function in adults with early type 2 diabetes on metformin alone. Journal of Diabetes and its Complications 2021; doi: https://doi.org/10.1016/j.jdiacomp.2021.107912. PubMed PMID: 33752962; PubMed Central PMID/PMCID: PMC8048071

Barzilay JI, Younes N, Pop-Busui R, Florez H, Seaquist E, Falck-Ytter C, Luchsinger JA, and the GRADE Research Group. The cross-sectional association of renal dysfunction with tests of cognition in middle-aged adults with early type 2 diabetes: The GRADE Study. J Diabetes Complications. 2021 Mar; 35(3):107805; doi: 10.1016/j.jdiacomp.2020.107805. Epub 2020 Nov 26. PubMed PMID: 33288412; PubMed Central PMCID: PMC7870547

Rasouli N, Younes N, Utzschneider KM, Inzucchi SE, Balasubramanyam A, Cherrington AL, Ismail-Beigi F, Cohen RM, Olson DE, DeFronzo RA, Herman WH, Lachin JM, Kahn SE, and the GRADE Research Group. Association of Baseline Characteristics With Insulin Sensitivity and β-Cell Function in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study Cohort. 2021 Feb;44(2):340-349; doi: 10.2337/dc20-1787. Epub 2020 Dec 17. PubMed PMID: 33334808; PubMed Central PMCID: PMC7818323

Mather KJ, Bebu I, Baker C, Cohen RM, Crandall JP, DeSouza C, Green JB, Kirkman MS, Krause-Steinrauf H, Larkin M, Pettus J, Seaquist ER, Soliman EZ, Schroeder EB, Wexler DJ, Pop-Busui R, and the GRADE Research Group. Prevalence of microvascular and macrovascular disease in the Glycemia Reduction Approaches in Diabetes - A Comparative Effectiveness (GRADE) Study cohort. Diabetes Res Clin Pract 2020;165:108235. doi: 10.1016/j.diabres.2020.108235. Epub 2020 May 23. PubMed PMID: 32450102; PubMed Central PMCID: PMC7416515

Sivitz WI, Phillips LS, Wexler DJ, Fortmann SP, Camp AW, Tiktin M, Perez M, Craig J, Hollander PA, Cherrington A, Aroda VR, Tan MH, Krakoff J, Rasouli N, Butera NM, Younes N, and the GRADE Research Group. Optimization of Metformin in the GRADE Cohort: Effect on Glycemia and Body Weight. Diabetes Care 2020 May;43(5):940-7; doi: 10.2337/dc19-1769. PubMed PMID: 32139384; PubMed Central PMCID: PMC7171946.

Behringer-Massera S, Browne T, George G, Duran S, Cherrington A, McKee MD, and 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. Epub 2019 Aug 1. doi: 10.2217/cer-2019-0010. PubMed PMID: 31368793; PubMed Central PMCID: PMC7333580

Devchand R, Nicols C, Gallivan JM, Tiktin M, Krause-Steinrauf H, Larkin M, Tuncer DM, and 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. doi: 10.1002/2327-6924.12445. PubMed PMID: 28213915; PubMed Central PMCID: PMC5419861 .

GRADE is a clinical trial comparing the effectiveness of 4 randomly-assigned glucose-lowering therapies (insulin glargine, glimepiride, liraglutide, sitagliptin) plus metformin in 5047 participants with type 2 diabetes over 4-7 yrs of follow-up on metabolic status, side effects, quality of life, ꞵ-cell function and vascular complications.

GRADE will provide high quality evidence to guide physician decisions on the therapeutic assignments to the millions of patients with early onset (up to 10 years) 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 cardiovascular disease (myocardial infarction, stroke and 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, race/ethnicity), diabetes factors (duration of T2D, family history) and various risk factors to provide patient-specific recommendations, so-called precision medicine.

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