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

Completed · Phase 3

Conditions studied: Type 2 Diabetes, Comparative Effectiveness of Glycemia-lowering Medications

In brief

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.

Key facts

Study ID

NCT01794143

Run by

GRADE Study Group

People needed

7850

Starts

2013-05-01

Expected to finish

2021-04-30

Last updated by the study team

2026-02-10

Who can join

Age: 30 and older. Sex: any. Healthy volunteers: not accepted.

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
• 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

Where it is running

• 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

Full record on ClinicalTrials.gov

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