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Type 2 DiabetesPhase 3GRADENCT01794143

A Comparative Effectiveness Study of Major Glycemia-lowering Medications for Treatment of Type 2 Diabetes

A Phase 3 study testing Sulfonylurea (glimepiride), DPP-4 inhibitor (sitagliptin) and GLP-1 receptor agonist (liraglutide) in people with Type 2 Diabetes and Comparative Effectiveness of Glycemia-lowering Medications, run by GRADE Study Group at 36 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 30 years and older
What is being tested?
Sulfonylurea (glimepiride), DPP-4 inhibitor (sitagliptin) and GLP-1 receptor agonist (liraglutide)
Could I receive a placebo?
No, everyone receives an active treatment
How many people
7,850 participants
Where
36 sitesUnited States
Study dates
May 2013to 30 Apr 2021
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 30 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 28Show fewer
  • 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
  • Estimated GFR (eGFR) <30 ml/min/1.73 m2 or end stage renal disease requiring renal replacement therapy
  • History of severe liver disease or acute hepatitis or ALT > 3 times upper limit of normal
  • Current alcoholism or excessive alcohol intake
  • Previous organ transplant
  • Treatment with oral or systemic glucocorticoids (other than short-term treatment, for example for poison ivy) or disease likely to require periodic or regular glucocorticoid therapy (inhaled steroids are allowed)
  • Treatment with atypical antipsychotics
  • History of hemolytic anemia, chronic transfusion requirement, or other condition rendering HbA1c results unreliable as indicator of chronic glucose levels, or hematocrit <35 for males and <33 for females
  • Clinically or medically unstable with expected survival <1 year
  • Unwillingness to permit sites to contact the PCP to communicate information about the study and the participant's data
  • No non-study PCP or inability to identify such a PCP (who will provide non-study care) by the time of final run-in
  • Participation in another interventional clinical trial
  • Previous randomization in the GRADE study
  • In the opinion of the principal investigator (PI), any other factor, including language barrier, likely to limit compliance with the protocol

Trial locations and contacts

36 sites in 1 country.

36 sites in 1 country

United States36 sites

  • University of New Mexico School of Medicine

    Albuquerque, New Mexico

  • University of Michigan

    Ann Arbor, Michigan

  • Pennington Biomedical Research Center

    Baton Rouge, Louisiana

  • University of Alabama-Birmingham

    Birmingham, Alabama

  • Massachusetts General Hospital

    Boston, Massachusetts

  • State University of New York (SUNY)-Downstate Medical Center

    Brooklyn, New York

  • University of Cincinnati

    Cincinnati, Ohio

  • Case Western Reserve University School of Medicine

    Cleveland, Ohio

  • Baylor Endocrine Center

    Dallas, Texas

  • University of Texas-Southwestern Medical Center

    Dallas, Texas

  • Atlanta VA Medical Center

    Decatur, Georgia

  • University of Colorado

    Denver, Colorado

  • Kaiser Permanente of Georgia

    Duluth, Georgia

  • Duke University Medical Center

    Durham, North Carolina

  • University of North Carolina Diabetes Care Center

    Durham, North Carolina

  • Pacific Health Research and Education Institute (VA Pacific Islands)

    Honolulu, Hawaii

  • Baylor College of Medicine

    Houston, Texas

  • MedStar Health Research Institute

    Hyattsville, Maryland

  • Indiana University School of Medicine

    Indianapolis, Indiana

  • University of Iowa

    Iowa City, Iowa

  • South Florida VA Foundation (Miami VA)

    Miami, Florida

  • International Diabetes Center

    Minneapolis, Minnesota

  • University of Minnesota

    Minneapolis, Minnesota

  • Vanderbilt University Medical Center

    Nashville, Tennessee

  • Yale University School of Medicine

    New Haven, Connecticut

  • Columbia University Naomi Berrie Diabetes Center

    New York, New York

  • Mount Sinai St. Luke's Hospital

    New York, New York

  • University of Nebraska

    Omaha, Nebraska

  • Southwestern American Indian Center

    Phoenix, Arizona

  • Kaiser Permanente Northwest

    Portland, Oregon

  • Oregon Health and Science University

    Portland, Oregon

  • University of Texas Health Science Center

    San Antonio, Texas

  • Veterans Medical Research Foundation, San Diego (San Diego VA)

    San Diego, California

  • Seattle Institute for Biomedical and Clinical Research

    Seattle, Washington

  • Washington University School of Medicine

    St Louis, Missouri

  • Albert Einstein College of Medicine

    The Bronx, New York

Other trials in United States

About this study

Official title: Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study

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.

Being tested
Sulfonylurea (glimepiride), DPP-4 inhibitor (sitagliptin), GLP-1 receptor agonist (liraglutide), Insulin (glargine)
Keywords
Treatment of Type 2 diabetes, Comparative effectiveness research, Clinical trial, Patient-centered outcomes
Medical subject headings
Diabetes Mellitus, Type 2

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Sulfonylurea (glimepiride)Drug

    Also called Glimepiride

    Used in accordance with labeling and/or usual practice.

  • DPP-4 inhibitor (sitagliptin)Drug

    Also called Sitagliptin

    Used in accordance with labeling and/or usual practice

  • GLP-1 receptor agonist (liraglutide)Drug

    Also called Liraglutide

    Used in accordance with labeling and/or usual practice.

  • Insulin (glargine)Drug

    Also called Lantus

    Used in accordance with labeling and/or usual practice.

Study groups in NCT01794143
Study groupRoleWhat they receive
Sulfonylurea (glimepiride)Active comparatorSulfonylurea
Receives: Drug: Sulfonylurea (glimepiride)
DPP-4 inhibitorActive comparatorDPP-4 inhibitor (sitagliptin)
Receives: Drug: DPP-4 inhibitor (sitagliptin)
GLP-1 receptor agonistActive comparatorGLP-1 receptor agonist (liraglutide)
Receives: Drug: GLP-1 receptor agonist (liraglutide)
Insulin (glargine)Active comparatorInsulin (glargine), Lantus
Receives: Drug: Insulin (glargine)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Quarterly for 4 to 7 years

  2. 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.

    Measured: Quarterly, 4-7 years

Secondary outcomes (2)

  1. Time to HbA1c>7.5%, While Receiving Metformin and the Randomly Assigned Glucose-lowering Study Medication.

    The secondary metabolic outcome is time to HbA1c>7.5% (58 mmol/mol), confirmed, after addition of randomly assigned glucose-lowering medication at baseline.

    Measured: Quarterly, 4-6 years

  2. HbA1c>7.5%, While Receiving Metformin and the Randomly Assigned Glucose-lowering Study Medication.

    Number of participants who reached primary failure defined as an HbA1c>7.5% (58 mmol/mol), confirmed, after addition of randomly assigned glucose-lowering medication at baseline.

    Measured: Quarterly for 4 to 7 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Feb 2013 (estimated)
  2. Study startMay 2013
  3. Primary completion30 Apr 2021
  4. Study completion30 Apr 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
7,850 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01794143
Sponsor's protocol ID
GRADE
Other IDs
1U01DK098246-01
Acronym
GRADE
Status last verified
Jan 2026
First submitted
13 Feb 2013
Last updated
10 Feb 2026
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 36631123

  • Butera 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.

    PubMed 34786739

  • Ghosh 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.

    PubMed 36549905

  • Lachin 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.

    PubMed 31647326

  • Bebu 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.

    PubMed 29956365

  • Lachin 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.

    PubMed 26336199

  • Lachin 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.

    PubMed 25329662

  • Lachin JM. Fallacies of last observation carried forward analyses. Clin Trials. 2016 Apr;13(2):161-8. doi: 10.1177/1740774515602688. Epub 2015 Sep 22.

    PubMed 26400875

  • Pop-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.

    PubMed 40986645

  • Presley 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.

    PubMed 40751289

  • Hsia 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.

    PubMed 40424051

  • Luchsinger 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.

    PubMed 40388190

  • Wexler 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.

    PubMed 40267365

  • Utzschneider 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.

    PubMed 39998948

  • Nathan 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.

    PubMed 39977640

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Sulfonylurea (glimepiride), DPP-4 inhibitor (sitagliptin) and GLP-1 receptor agonist (liraglutide) in people with Type 2 Diabetes and Comparative Effectiveness of Glycemia-lowering Medications, run by GRADE Study Group at 36 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 36 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 10 Feb 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Time to HbA1c>=7%, While Receiving Metformin and the Randomly Assigned Glucose-lowering Study Medication (time frame: Quarterly for 4 to 7 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01794143, which also lists 61 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Feb 2026.

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