A Comparative Effectiveness Study of Major Glycemia-lowering Medications for Treatment of Type 2 Diabetes
GRADE
Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study
2 other identifiers
interventional
7,850
1 country
36
Brief Summary
The GRADE Study is a pragmatic, unmasked clinical trial that will compare commonly used diabetes medications, when combined with metformin, on glycemia-lowering effectiveness and patient-centered outcomes.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_3 type-2-diabetes
Started May 2013
Longer than P75 for phase_3 type-2-diabetes
36 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
February 13, 2013
CompletedFirst Posted
Study publicly available on registry
February 18, 2013
CompletedStudy Start
First participant enrolled
May 1, 2013
CompletedPrimary Completion
Last participant's last visit for primary outcome
April 30, 2021
CompletedStudy Completion
Last participant's last visit for all outcomes
April 30, 2021
CompletedResults Posted
Study results publicly available
February 10, 2026
CompletedFebruary 10, 2026
January 1, 2026
8 years
February 13, 2013
October 23, 2025
January 23, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
Time to HbA1c>=7%, While Receiving Metformin and the Randomly Assigned Glucose-lowering Study Medication
The primary metabolic outcome is the time to primary failure defined as an HbA1c\>=7% (53mmol/mol), subsequently confirmed, after addition of randomly assigned glucose-lowering medication at baseline.
Quarterly for 4 to 7 years
HbA1c>=7%, While Receiving Metformin and the Randomly Assigned Glucose-lowering Study Medication
Number of participants who reached primary failure defined as an HbA1c\>=7% (53mmol/mol), subsequently confirmed, after addition of randomly assigned glucose-lowering medication at baseline.
Quarterly, 4-7 years
Secondary Outcomes (2)
Time to HbA1c>7.5%, While Receiving Metformin and the Randomly Assigned Glucose-lowering Study Medication.
Quarterly, 4-6 years
HbA1c>7.5%, While Receiving Metformin and the Randomly Assigned Glucose-lowering Study Medication.
Quarterly for 4 to 7 years
Study Arms (4)
Sulfonylurea (glimepiride)
ACTIVE COMPARATORSulfonylurea
DPP-4 inhibitor
ACTIVE COMPARATORDPP-4 inhibitor (sitagliptin)
GLP-1 receptor agonist
ACTIVE COMPARATORGLP-1 receptor agonist (liraglutide)
Insulin (glargine)
ACTIVE COMPARATORInsulin (glargine), Lantus
Interventions
Used in accordance with labeling and/or usual practice
Used in accordance with labeling and/or usual practice.
Used in accordance with labeling and/or usual practice.
Used in accordance with labeling and/or usual practice.
Eligibility Criteria
You may qualify if:
- Men or women diagnosed with diabetes at age ≥ 30 years (≥ 20 for American Indians)
- Duration of diagnosed diabetes \< 10 years
- HbA1c criteria (at final run-in visit, \~2 weeks prior to randomization): 6.8-8.5%
- Taking a daily dose of ≥ 1000 mg metformin for a minimum of 8 weeks at final run-in
- Willingness to administer daily subcutaneous injections, take a second diabetes drug after randomization, potentially initiate insulin and intensify insulin therapy if study metabolic goals are not met, perform self-monitoring of blood glucose
- Fluent in either English or Spanish
- A negative pregnancy test for all females of childbearing potential (i.e. pre-menopausal, and not surgically sterile)
- Provision of signed and dated informed consent prior to any study procedures
You may not qualify if:
- Suspected type 1 diabetes (lean with polyuria, polydipsia, and weight loss with little response to metformin) or "secondary" diabetes due to specific causes (e.g. previously diagnosed monogenic syndromes, pancreatic surgery, pancreatitis)
- Current or previous (within past 6 months) treatment with any diabetes drug/glucose-lowering medication other than metformin (limited use of no longer than seven days is allowed, for example during hospitalization)
- More than 10 years of treatment with metformin at time of randomization screening
- History of intolerance or allergy or other contraindications to any of the proposed study medications
- Resides in the same household with another GRADE study participant
- Current need for any specific glucose-lowering medications solely for other conditions, for example for polycystic ovary syndrome
- Symptomatic hyperglycemia requiring immediate therapy during screening or run-in, in the judgment of the physician
- A life-threatening event within 30 days prior to screening or currently planned major surgery
- Any major cardiovascular event in previous year, including history of myocardial infarction, stroke, or vascular procedure such as coronary artery or peripheral bypass grafting, stent placements (peripheral or coronary) or angioplasty.
- Plans for pregnancy during the course of the study for women of child-bearing potential
- History of or planning bariatric surgery, including banding procedures or surgical gastric and/or intestinal bypass (if banding removed, may be considered eligible after 1 year)
- History of congestive heart failure (NYHA 3 or greater)
- History of pancreatitis
- History of cancer, other than non-melanoma skin cancer, that required therapy in the 5 years prior to randomization
- Personal or family history of MEN-2 or family history of medullary thyroid cancer
- +13 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (36)
University of Alabama-Birmingham
Birmingham, Alabama, United States
Southwestern American Indian Center
Phoenix, Arizona, United States
Veterans Medical Research Foundation, San Diego (San Diego VA)
San Diego, California, United States
University of Colorado
Denver, Colorado, United States
Yale University School of Medicine
New Haven, Connecticut, United States
South Florida VA Foundation (Miami VA)
Miami, Florida, United States
Atlanta VA Medical Center
Decatur, Georgia, United States
Kaiser Permanente of Georgia
Duluth, Georgia, United States
Pacific Health Research and Education Institute (VA Pacific Islands)
Honolulu, Hawaii, United States
Indiana University School of Medicine
Indianapolis, Indiana, United States
University of Iowa
Iowa City, Iowa, United States
Pennington Biomedical Research Center
Baton Rouge, Louisiana, United States
MedStar Health Research Institute
Hyattsville, Maryland, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
University of Michigan
Ann Arbor, Michigan, United States
International Diabetes Center
Minneapolis, Minnesota, United States
University of Minnesota
Minneapolis, Minnesota, United States
Washington University School of Medicine
St Louis, Missouri, United States
University of Nebraska
Omaha, Nebraska, United States
University of New Mexico School of Medicine
Albuquerque, New Mexico, United States
State University of New York (SUNY)-Downstate Medical Center
Brooklyn, New York, United States
Columbia University Naomi Berrie Diabetes Center
New York, New York, United States
Mount Sinai St. Luke's Hospital
New York, New York, United States
Albert Einstein College of Medicine
The Bronx, New York, United States
Duke University Medical Center
Durham, North Carolina, United States
University of North Carolina Diabetes Care Center
Durham, North Carolina, United States
University of Cincinnati
Cincinnati, Ohio, United States
Case Western Reserve University School of Medicine
Cleveland, Ohio, United States
Kaiser Permanente Northwest
Portland, Oregon, United States
Oregon Health and Science University
Portland, Oregon, United States
Vanderbilt University Medical Center
Nashville, Tennessee, United States
Baylor Endocrine Center
Dallas, Texas, United States
University of Texas-Southwestern Medical Center
Dallas, Texas, United States
Baylor College of Medicine
Houston, Texas, United States
University of Texas Health Science Center
San Antonio, Texas, United States
Seattle Institute for Biomedical and Clinical Research
Seattle, Washington, United States
Related Publications (61)
Butera NM, Zeng D, Heiss G, Cai J. Modeling longitudinal change in biomarkers using data from a complex survey sampling design: An application to the Hispanic Community Health Study/Study of Latinos. Stat Med. 2023 Feb 28;42(5):632-655. doi: 10.1002/sim.9635. Epub 2023 Jan 11.
PMID: 36631123BACKGROUNDButera NM, Zeng D, Green Howard A, Gordon-Larsen P, Cai J. A doubly robust method to handle missing multilevel outcome data with application to the China Health and Nutrition Survey. Stat Med. 2022 Feb 20;41(4):769-785. doi: 10.1002/sim.9260. Epub 2021 Nov 16.
PMID: 34786739BACKGROUNDGhosh A, Chan W, Younes N, Davis BR. A Dynamic Risk Model for Multitype Recurrent Events. Am J Epidemiol. 2023 Apr 6;192(4):621-631. doi: 10.1093/aje/kwac213.
PMID: 36549905BACKGROUNDLachin JM, Bebu I. Closed testing of each group versus the others combined in a multiple group analysis. Clin Trials. 2020 Feb;17(1):77-86. doi: 10.1177/1740774519879932. Epub 2019 Oct 24.
PMID: 31647326BACKGROUNDBebu I, Lachin JM. Properties of composite time to first event versus joint marginal analyses of multiple outcomes. Stat Med. 2018 Nov 30;37(27):3918-3930. doi: 10.1002/sim.7849. Epub 2018 Jun 28.
PMID: 29956365BACKGROUNDLachin JM, Bebu I. Application of the Wei-Lachin multivariate one-directional test to multiple event-time outcomes. Clin Trials. 2015 Dec;12(6):627-33. doi: 10.1177/1740774515601027. Epub 2015 Sep 2.
PMID: 26336199BACKGROUNDLachin JM. Applications of the Wei-Lachin multivariate one-sided test for multiple outcomes on possibly different scales. PLoS One. 2014 Oct 17;9(10):e108784. doi: 10.1371/journal.pone.0108784. eCollection 2014.
PMID: 25329662BACKGROUNDLachin JM. Fallacies of last observation carried forward analyses. Clin Trials. 2016 Apr;13(2):161-8. doi: 10.1177/1740774515602688. Epub 2015 Sep 22.
PMID: 26400875BACKGROUNDPop-Busui R, Rosin SP, Butera NM, Krause-Steinrauf H, Abou Assi H, Garg RK, Inzucchi SE, Katona A, McGill JB, Mudaliar S, Schade DS, Seaquist ER, Tiktin M, Soliman EZ, Green JB; GRADE Research Group. Differences in Prevalence and Incidence of Electrocardiogram Abnormalities and Cardiovascular Autonomic Neuropathy Among Randomized Glucose-Lowering Treatments in Early Type 2 Diabetes: The Glycemia Reduction Approaches in Diabetes (GRADE) Cohort. Diabetes Care. 2025 Nov 1;48(11):1960-1970. doi: 10.2337/dc25-1087.
PMID: 40986645RESULTPresley CA, Butera NM, Krause-Steinrauf H, Desouza CV, Hollander PA, Hoogendoorn CJ, Lagari VS, Legowski EA, Martin CL, Rasouli N, Gonzalez JS, Cherrington AL. Lack of Association of Emotional Distress With Insulin Initiation in the GRADE Randomized Diabetes Comparative Effectiveness Trial. Sci Diabetes Self Manag Care. 2025 Aug;51(4):382-393. doi: 10.1177/26350106251361363. Epub 2025 Aug 1.
PMID: 40751289RESULTHsia DS, Younes N, Ghosh A, Kazemi EJ, Krause-Steinrauf H, Buse JB, Baker C, Brown-Friday J, Diaz E, Diner J, Groessl EJ, Legowski EA, Mariash CN, Waltje AH, Wexler DJ, Martin CL; GRADE Research Group. Association of Hospitalizations With Randomized Glycemia-Lowering Treatment in GRADE. Diabetes Care. 2025 Jul 1;48(7):1288-1294. doi: 10.2337/dc24-2839.
PMID: 40424051RESULTLuchsinger JA, Rosin SP, Kazemi EJ, Younes N, Suratt CE, Fattaleh BN, Florez HJ, Gonzalez JS, Hollander P, Hox SH, Kuo S, Lee MS, Martens T, Pop-Busui R, Seaquist ER, Waltje AH, Barzilay JI; GRADE Research Group. Glucose-Lowering Medications, Glycemia, and Cognitive Outcomes: The GRADE Randomized Clinical Trial. JAMA Intern Med. 2025 Jul 1;185(7):778-787. doi: 10.1001/jamainternmed.2025.1189.
PMID: 40388190RESULTWexler DJ, Garvey WT, Ghosh A, Kazemi EJ, Krause-Steinrauf H, Ahmann AJ, Brown-Friday J, Casula S, Cherrington AL, Elasy TA, Fortmann SP, Krakoff JA, Mudaliar S, Tiktin M, Younes N; GRADE Study Research Group. Weight Gain Was Associated With Worsening Glycemia and Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes Independent of Diabetes Medication in the GRADE Randomized Controlled Trial. Diabetes Care. 2025 Jun 1;48(6):935-944. doi: 10.2337/dc24-2825.
PMID: 40267365RESULTUtzschneider KM, Tripputi M, Butera NM, Mari A, Rosin SP, Banerji MA, Bergenstal RM, Brown N, Carlson AL, DeFronzo RA, Gramzinski MR, Harindhanavudhi T, Kozedub A, Sivitz WI, Steffes MW, Balasubramanyam A, Rasouli N; GRADE Research Group. Differential Treatment Effects on beta-Cell Function Using Model-Based Parameters in Type 2 Diabetes: Results From the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Diabetes Care. 2025 Apr 1;48(4):623-631. doi: 10.2337/dc24-2419.
PMID: 39998948RESULTNathan DM. Response to Comment on Nathan et al. Relationship Between Average Glucose Levels and HbA1c Differs Across Racial Groups: A Substudy of the GRADE Randomized Trial. Diabetes Care 2024;47:2155-2163. Diabetes Care. 2025 Mar 1;48(3):e34-e35. doi: 10.2337/dci24-0095. No abstract available.
PMID: 39977640RESULTEhrmann D, Krause-Steinrauf H, Uschner D, Wen H, Hoogendoorn CJ, Crespo-Ramos G, Presley C, Arends VL, Cohen RM, Garvey WT, Martens T, Willis HJ, Cherrington A, Gonzalez JS; GRADE Research Group. Differential associations of somatic and cognitive-affective symptoms of depression with inflammation and insulin resistance: cross-sectional and longitudinal results from the Emotional Distress Sub-Study of the GRADE study. Diabetologia. 2025 Jul;68(7):1403-1415. doi: 10.1007/s00125-025-06369-8. Epub 2025 Feb 14.
PMID: 39951058RESULTSeaquist ER, Phillips LS, Ghosh A, Baker C, Bergenstal RM, Crandall JP, Goland RS, Gramzinski MR, Hox SH, Hsia DS, Johnson ML, Lachin JM, Raskin P, Valencia WM, Waltje AH, Younes N; GRADE Research Group. Glycemia reduction in type 2 diabetes-Hypoglycemia outcomes: A randomized clinical trial. PLoS One. 2024 Nov 15;19(11):e0309907. doi: 10.1371/journal.pone.0309907. eCollection 2024.
PMID: 39546502RESULTNathan DM, Herman WH, Larkin ME, Krause-Steinrauf H, Abou Assi H, Ahmann AJ, Brown-Friday J, Hsia DS, Harindhanavudhi T, Johnson M, Arends VL, Butera NM, Rosin SP, Lachin JM, Younes N; GRADE Study Research Group. Relationship Between Average Glucose Levels and HbA1c Differs Across Racial Groups: A Substudy of the GRADE Randomized Trial. Diabetes Care. 2024 Dec 1;47(12):2155-2163. doi: 10.2337/dc24-1362.
PMID: 39312277RESULTGonzalez JS, Bebu I, Krause-Steinrauf H, Hoogendoorn CJ, Crespo-Ramos G, Presley C, Naik AD, Kuo S, Johnson ML, Wexler D, Crandall JP, Bantle AE, Arends V, Cherrington AL; GRADE Research Group. Differential Effects of Type 2 Diabetes Treatment Regimens on Diabetes Distress and Depressive Symptoms in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Diabetes Care. 2024 Apr 1;47(4):610-619. doi: 10.2337/dc23-2459.
PMID: 38416773RESULTGreen JB, Everett BM, Ghosh A, Younes N, Krause-Steinrauf H, Barzilay J, Desouza C, Inzucchi SE, Pokharel Y, Schade D, Scrymgeour A, Tan MH, Utzschneider KM, Mudaliar S; GRADE Study Research Group. Cardiovascular Outcomes in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study). Circulation. 2024 Mar 26;149(13):993-1003. doi: 10.1161/CIRCULATIONAHA.123.066604. Epub 2024 Feb 12.
PMID: 38344820RESULTHampe CS, Shojaie A, Brooks-Worrell B, Dibay S, Utzschneider K, Kahn SE, Larkin ME, Johnson ML, Younes N, Rasouli N, Desouza C, Cohen RM, Park JY, Florez HJ, Valencia WM, Stempel R, Palmer JP, Balasubramanyam A. GAD65Abs Are Not Associated With Beta-Cell Dysfunction in Patients With T2D in the GRADE Study. J Endocr Soc. 2024 Feb 8;8(3):bvad179. doi: 10.1210/jendso/bvad179. eCollection 2024 Jan 16.
PMID: 38333889RESULTHsia DS, Younes N, Krause-Steinrauf H, Kassem LS; GRADE Research Group. The incidence of retinopathy in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness study (GRADE). J Diabetes Complications. 2024 Mar;38(3):108692. doi: 10.1016/j.jdiacomp.2024.108692. Epub 2024 Feb 5.
PMID: 38354481RESULTGarvey WT, Cohen RM, Butera NM, Kazemi EJ, Younes N, Rosin SP, Suratt CE, Ahmann A, Hollander PA, Krakoff J, Martin CL, Seaquist E, Steffes MW, Lachin JM; GRADE Research Group. Association of Baseline Factors With Glycemic Outcomes in GRADE: A Comparative Effectiveness Randomized Clinical Trial. Diabetes Care. 2024 Apr 1;47(4):562-570. doi: 10.2337/dc23-1782.
PMID: 38285957RESULTBanerji MA, Buse JB, Younes N, Krause-Steinrauf H, Ghazi A, Lee M, Park J, Pop-Busui R, Underkofler C, Fortmann SP; GRADE Research Group. Mortality in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Diabetes Care. 2024 Apr 1;47(4):589-593. doi: 10.2337/dc23-1356.
PMID: 38252886RESULTCherrington AL, Bebu I, Krause-Steinrauf H, Hoogendoorn CJ, Crespo-Ramos G, Presley C, Naik AD, Balasubramanyam A, Gramzinski MR, Killean T, Arends VL, Gonzalez JS; GRADE Research Group. Does Emotional Distress Predict Worse Glycemic Control Over Time? Results From the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Diabetes Care. 2024 Apr 1;47(4):620-628. doi: 10.2337/dc23-0642.
PMID: 38252848RESULTHoogendoorn CJ, Krause-Steinrauf H, Uschner D, Wen H, Presley CA, Legowski EA, Naik AD, Golden SH, Arends VL, Brown-Friday J, Krakoff JA, Suratt CE, Waltje AH, Cherrington AL, Gonzalez JS; GRADE Research Group. Emotional Distress Predicts Reduced Type 2 Diabetes Treatment Adherence in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Diabetes Care. 2024 Apr 1;47(4):629-637. doi: 10.2337/dc23-1401.
PMID: 38227900RESULTRasouli N, Younes N, Ghosh A, Albu J, Cohen RM, DeFronzo RA, Diaz E, Sayyed Kassem L, Luchsinger JA, McGill JB, Sivitz WI, Tamborlane WV, Utzschneider KM, Kahn SE; GRADE Research Group. Longitudinal Effects of Glucose-Lowering Medications on beta-Cell Responses and Insulin Sensitivity in Type 2 Diabetes: The GRADE Randomized Clinical Trial. Diabetes Care. 2024 Apr 1;47(4):580-588. doi: 10.2337/dc23-1070.
PMID: 38211595RESULTKirkman MS, Tripputi M, Krause-Steinrauf H, Bebu I, AbouAssi H, Burch H, Duran-Valdez E, Florez H, Garvey WT, Hsia DS, Salam M, Pop-Busui R; GRADE Research Group. 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 Diabetes: A Comparative Effectiveness Study (GRADE). Diabetes Care. 2024 Apr 1;47(4):594-602. doi: 10.2337/dc23-1332.
PMID: 38194519RESULTUtzschneider KM, Younes N, Butera NM, Balasubramanyam A, Bergenstal RM, Barzilay J, DeSouza C, DeFronzo RA, Elasy T, Krakoff J, Kahn SE, Rasouli N, Valencia WM, Sivitz WI; GRADE Research Group. Impact of Insulin Sensitivity and beta-Cell Function Over Time on Glycemic Outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE): Differential Treatment Effects of Dual Therapy. Diabetes Care. 2024 Apr 1;47(4):571-579. doi: 10.2337/dc23-1059.
PMID: 38190619RESULTCherrington AL, Tripputi MT, Younes N, Herman WH, Katona A, Groessl EJ, Craig J, Gonzalez JS, Garg R, Casula S, Kuo S, Florez HJ; GRADE Research Group. Impact of Glucose-Lowering Medications on Health-Related Quality of Life in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Diabetes Care. 2024 Apr 1;47(4):603-609. doi: 10.2337/dc23-1648.
PMID: 38190625RESULTHollander 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; GRADE Research Group. The Use of Rescue Insulin in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Diabetes Care. 2024 Apr 1;47(4):638-645. doi: 10.2337/dc23-0516.
PMID: 37756542RESULTCrespo-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 Res Clin Pract. 2023 Sep;203:110808. doi: 10.1016/j.diabres.2023.110808. Epub 2023 Jun 30.
PMID: 37394014RESULTLuchsinger JA, Kazemi EJ, Sanchez DL, Larkin ME, Valencia WM, Desouza C, Carlson AL, Pop-Busui R, Seaquist ER, Florez HJ, Barzilay J; GRADE Research Group. BMI, insulin sensitivity, and cognition in early type 2 diabetes: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study. Obesity (Silver Spring). 2023 Jul;31(7):1812-1824. doi: 10.1002/oby.23785.
PMID: 37368512RESULTCherrington AL, Krause-Steinrauf H, Aroda V, Buse JB, Fattaleh B, Fortmann SP, Hall S, Hox SH, Kuhn A, Killean T, Loveland A, Phillips LS, Jackson AU, Waltje A, McKee MD; GRADE Research Group. Use of comprehensive recruitment strategies in the glycemia reduction approaches in diabetes: A comparative effectiveness study (GRADE) multi-center clinical trial. Clin Trials. 2023 Oct;20(5):546-558. doi: 10.1177/17407745231175919. Epub 2023 Jun 17.
PMID: 37329282RESULTWexler DJ, de Boer IH, Ghosh A, Younes N, Bebu I, Inzucchi SE, McGill JB, Mudaliar S, Schade D, Steffes MW, Tamborlane WV, Tan MH, Ismail-Beigi F; GRADE Research Group. Comparative Effects of Glucose-Lowering Medications on Kidney Outcomes in Type 2 Diabetes: The GRADE Randomized Clinical Trial. JAMA Intern Med. 2023 Jul 1;183(7):705-714. doi: 10.1001/jamainternmed.2023.1487.
PMID: 37213109RESULTGulanski BI, Butera NM, Krause-Steinrauf H, Lichtman JH, Harindhanavudhi T, Green JB, Suratt CE, AbouAssi H, Desouza C, Ahmann AJ, Wexler DJ, Aroda VR; 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 Apr;11(2):e003159. doi: 10.1136/bmjdrc-2022-003159.
PMID: 37094945RESULTSeegmiller JC, Schmit DJ, Arends VL, Steffes MW, Kahn SE, Younes N; 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 beta-cell function. Diabetes Obes Metab. 2023 Jul;25(7):1995-2004. doi: 10.1111/dom.15072. Epub 2023 Apr 24.
PMID: 36999229RESULTGonzalez 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: 36549506RESULTGRADE Study Research Group; Nathan DM, Lachin JM, Bebu I, Burch HB, Buse JB, Cherrington AL, Fortmann SP, Green JB, Kahn SE, Kirkman MS, Krause-Steinrauf H, Larkin ME, Phillips LS, Pop-Busui R, Steffes M, Tiktin M, Tripputi M, Wexler DJ, Younes N. Glycemia Reduction in Type 2 Diabetes - Microvascular and Cardiovascular Outcomes. N Engl J Med. 2022 Sep 22;387(12):1075-1088. doi: 10.1056/NEJMoa2200436.
PMID: 36129997RESULTGRADE Study Research Group; Nathan DM, Lachin JM, Balasubramanyam A, Burch HB, Buse JB, Butera NM, Cohen RM, Crandall JP, Kahn SE, Krause-Steinrauf H, Larkin ME, Rasouli N, Tiktin M, Wexler DJ, Younes N. Glycemia Reduction in Type 2 Diabetes - Glycemic Outcomes. N Engl J Med. 2022 Sep 22;387(12):1063-1074. doi: 10.1056/NEJMoa2200433.
PMID: 36129996RESULTAroda 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
RESULTFlorez 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; 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 Res Clin Pract. 2022 Feb;184:109188. doi: 10.1016/j.diabres.2021.109188. Epub 2021 Dec 28.
PMID: 34971663RESULTBrooks-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):1261-71. doi: 10.2337/db21-0590. Online ahead of print.
PMID: 35061024RESULTNathan DM, Krause-Steinrauf H, Braffett BH, Arends VL, Younes N, McGee P, Lund C, Johnson M, Lorenzi G, Gao X, Steffes MW, Lachin JM; GRADE Research Group; 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. PLoS One. 2021 Nov 15;16(11):e0257154. doi: 10.1371/journal.pone.0257154. eCollection 2021.
PMID: 34780485RESULTLuchsinger JA, Younes N, Manly JJ, Barzilay J, Valencia W, Larkin ME, Falck-Ytter C, Krause-Steinrauf H, Pop-Busui R, Florez H, Seaquist E; GRADE Research Group; GRADE Research Group Investigators:. 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 (GRADE). Diabetes Care. 2021 Oct;44(10):2286-2292. doi: 10.2337/dc20-2858. Epub 2021 Jul 20.
PMID: 34285097RESULTBarzilay JI, Ghosh A, Busui RP, Ahmann A, Balasubramanyam A, Banerji MA, Cohen RM, Green J, Ismail-Beigi F, Martin CL, Seaquist E, Luchsinger JA; GRADE Research Group. The cross-sectional association of cognition with diabetic peripheral and autonomic neuropathy-The GRADE study. J Diabetes Complications. 2021 Dec;35(12):108047. doi: 10.1016/j.jdiacomp.2021.108047. Epub 2021 Sep 15.
PMID: 34556408RESULTCherrington AL, Krause-Steinrauf H, Bebu I, Naik AD, Walker E, Golden SH, Gonzalez JS; GRADE Research Group. Study of emotional distress in a comparative effectiveness trial of diabetes treatments: Rationale and design. Contemp Clin Trials. 2021 Aug;107:106366. doi: 10.1016/j.cct.2021.106366. Epub 2021 Mar 22.
PMID: 33766761RESULTUtzschneider 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; GRADE Research Group. Shape of the OGTT glucose response curve: relationship with beta-cell function and differences by sex, race, and BMI in adults with early type 2 diabetes treated with metformin. BMJ Open Diabetes Res Care. 2021 Sep;9(1):e002264. doi: 10.1136/bmjdrc-2021-002264.
PMID: 34531242RESULTUtzschneider KM, Younes N, Rasouli N, Barzilay J, Banerji MA, Cohen RM, Gonzalez EV, Mather KJ, Ismail-Beigi F, Raskin P, Wexler DJ, Lachin JM, Kahn SE; GRADE Research Group. Association of glycemia with insulin sensitivity and beta-cell function in adults with early type 2 diabetes on metformin alone. J Diabetes Complications. 2021 May;35(5):107912. doi: 10.1016/j.jdiacomp.2021.107912. Epub 2021 Mar 17.
PMID: 33752962RESULTBarzilay JI, Younes N, Pop-Busui R, Florez H, Seaquist E, Falck-Ytter C, Luchsinger JA; 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.
PMID: 33288412RESULTRasouli 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; GRADE Research Group. Association of Baseline Characteristics With Insulin Sensitivity and beta-Cell Function in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study Cohort. Diabetes Care. 2021 Feb;44(2):340-349. doi: 10.2337/dc20-1787. Epub 2020 Dec 17.
PMID: 33334808RESULTMather 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; 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 Jul;165:108235. doi: 10.1016/j.diabres.2020.108235. Epub 2020 May 23.
PMID: 32450102RESULTSivitz 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; GRADE Research Group. Optimization of Metformin in the GRADE Cohort: Effect on Glycemia and Body Weight. Diabetes Care. 2020 May;43(5):940-947. doi: 10.2337/dc19-1769. Epub 2020 Mar 5.
PMID: 32139384RESULTWexler DJ, Krause-Steinrauf H, Crandall JP, Florez HJ, Hox SH, Kuhn A, Sood A, Underkofler C, Aroda VR; GRADE Research Group. Baseline Characteristics of Randomized Participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Diabetes Care. 2019 Nov;42(11):2098-2107. doi: 10.2337/dc19-0901. Epub 2019 Aug 7.
PMID: 31391203RESULTLarkin ME, Nathan DM, Bebu I, Krause-Steinrauf H, Herman WH, Higgins JM, Tiktin M, Cohen RM, Lund C, Bergenstal RM, Johnson ML, Arends V; GRADE Research Group. Rationale and Design for a GRADE Substudy of Continuous Glucose Monitoring. Diabetes Technol Ther. 2019 Dec;21(12):682-690. doi: 10.1089/dia.2019.0202. Epub 2019 Sep 4.
PMID: 31393176RESULTBehringer-Massera S, Browne T, George G, Duran S, Cherrington A, McKee MD; GRADE Research Group. Facilitators and barriers to successful recruitment into a large comparative effectiveness trial: a qualitative study. J Comp Eff Res. 2019 Jul;8(10):815-826. doi: 10.2217/cer-2019-0010. Epub 2019 Aug 1.
PMID: 31368793RESULTDevchand R, Nicols C, Gallivan JM, Tiktin M, Krause-Steinrauf H, Larkin M, Tuncer DM; GRADE Research Group. Assessment of a National Diabetes Education Program diabetes management booklet: The GRADE experience. J Am Assoc Nurse Pract. 2017 May;29(5):255-263. doi: 10.1002/2327-6924.12445. Epub 2017 Feb 18.
PMID: 28213915RESULTNathan 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 Aug;36(8):2254-61. doi: 10.2337/dc13-0356. Epub 2013 May 20.
PMID: 23690531RESULTLi JH, Szczerbinski L, Tripputi M, Liu H, Nam S, Mujica E, Emmanouilidou A, Wangden TY, Citko-Rojewska A, Konopka P, Czajkowski M, Huerta-Chagoya A, Vora M, Leong A, Meigs JB, Ng MY, Loos RJF, Pigeyre M, Gerstein HC, Moura FA, Lai YP, Bhatt DL, Marston NA, Ruff CT, Sabatine MS, Dawed AY, Pearson ER, Satin LS, den Hoed M, Kretowski A, Kahn SE, Younes N, Mercader JM, Florez JC. Common genetic variants near SLC2A2 and glycemic response to glimepiride in the GRADE comparative effectiveness clinical trial. medRxiv [Preprint]. 2025 Oct 8:2025.10.07.25336827. doi: 10.1101/2025.10.07.25336827.
PMID: 41282760DERIVEDNatale P, Green SC, Tunnicliffe DJ, Pellegrino G, Toyama T, Strippoli GF. Glucagon-like peptide 1 (GLP-1) receptor agonists for people with chronic kidney disease and diabetes. Cochrane Database Syst Rev. 2025 Feb 18;2(2):CD015849. doi: 10.1002/14651858.CD015849.pub2.
PMID: 39963952DERIVEDEl-Damanawi R, Stanley IK, Staatz C, Pascoe EM, Craig JC, Johnson DW, Mallett AJ, Hawley CM, Milanzi E, Hiemstra TF, Viecelli AK. Metformin for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 2024 Jun 4;6(6):CD013414. doi: 10.1002/14651858.CD013414.pub2.
PMID: 38837240DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- GRADE Project Director
- Organization
- George Washington University
Study Officials
- STUDY CHAIR
David M Nathan, MD
Massachusetts General Hospital
Publication Agreements
- PI is Sponsor Employee
- No
- Restrictive Agreement
- No
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
February 13, 2013
First Posted
February 18, 2013
Study Start
May 1, 2013
Primary Completion
April 30, 2021
Study Completion
April 30, 2021
Last Updated
February 10, 2026
Results First Posted
February 10, 2026
Record last verified: 2026-01