Comparative Effectiveness of Glycemia-lowering Medications, Type 2 Diabetes
Conditions
Keywords
Treatment of Type 2 diabetes, Comparative effectiveness research, Clinical trial, Patient-centered outcomes
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.
Interventions
DRUGSulfonylurea (glimepiride)
Used in accordance with labeling and/or usual practice.
DRUGDPP-4 inhibitor (sitagliptin)
Used in accordance with labeling and/or usual practice
DRUGGLP-1 receptor agonist (liraglutide)
Used in accordance with labeling and/or usual practice.
DRUGInsulin (glargine)
Used in accordance with labeling and/or usual practice.
Sponsors
GRADE Study Group
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Heart, Lung, and Blood Institute (NHLBI)
Centers for Disease Control and Prevention
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Men or women diagnosed with diabetes at age ≥ 30 years (≥ 20 for American Indians) 2. Duration of diagnosed diabetes \< 10 years 3. HbA1c criteria (at final run-in visit, \~2 weeks prior to randomization): 6.8-8.5% 4. Taking a daily dose of ≥ 1000 mg metformin for a minimum of 8 weeks at final run-in 5. 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 6. Fluent in either English or Spanish 7. A negative pregnancy test for all females of childbearing potential (i.e. pre-menopausal, and not surgically sterile) 8. Provision of signed and dated informed consent prior to any study procedures
Exclusion criteria
1. 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) 2. 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) 3. More than 10 years of treatment with metformin at time of randomization screening 4. History of intolerance or allergy or other contraindications to any of the proposed study medications 5. Resides in the same household with another GRADE study participant 6. Current need for any specific glucose-lowering medications solely for other conditions, for example for polycystic ovary syndrome 7. Symptomatic hyperglycemia requiring immediate therapy during screening or run-in, in the judgment of the physician 8. A life-threatening event within 30 days prior to screening or currently planned major surgery 9. 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. 10. Plans for pregnancy during the course of the study for women of child-bearing potential 11. 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) 12. History of congestive heart failure (NYHA 3 or greater) 13. History of pancreatitis 14. History of cancer, other than non-melanoma skin cancer, that required therapy in the 5 years prior to randomization 15. Personal or family history of MEN-2 or family history of medullary thyroid cancer 16. Estimated GFR (eGFR) \<30 ml/min/1.73 m2 or end stage renal disease requiring renal replacement therapy 17. History of severe liver disease or acute hepatitis or ALT \> 3 times upper limit of normal 18. Current alcoholism or excessive alcohol intake 19. Previous organ transplant 20. 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) 21. Treatment with atypical antipsychotics 22. 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 23. Clinically or medically unstable with expected survival \<1 year 24. Unwillingness to permit sites to contact the PCP to communicate information about the study and the participant's data 25. No non-study PCP or inability to identify such a PCP (who will provide non-study care) by the time of final run-in 26. Participation in another interventional clinical trial 27. Previous randomization in the GRADE study 28. In the opinion of the principal investigator (PI), any other factor, including language barrier, likely to limit compliance with the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to HbA1c>=7%, While Receiving Metformin and the Randomly Assigned Glucose-lowering Study Medication | Quarterly for 4 to 7 years | 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. |
| HbA1c>=7%, While Receiving Metformin and the Randomly Assigned Glucose-lowering Study Medication | Quarterly, 4-7 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to HbA1c>7.5%, While Receiving Metformin and the Randomly Assigned Glucose-lowering Study Medication. | Quarterly, 4-6 years | The secondary metabolic outcome is time to HbA1c\>7.5% (58 mmol/mol), confirmed, after addition of randomly assigned glucose-lowering medication at baseline. |
| HbA1c>7.5%, While Receiving Metformin and the Randomly Assigned Glucose-lowering Study Medication. | Quarterly for 4 to 7 years | 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. |
Countries
United States
Contacts
STUDY_CHAIRDavid M Nathan, MD
Massachusetts General Hospital
Participant flow
Pre-assignment details
During a run-in period of 6 to 14 weeks before randomization, the metformin dose was increased to a minimum of 1000 mg per day, with a target maximal dose (one that could be taken without unacceptable side effects) of 2000 mg per day. Of the 7,850 participants consented for study run-in, 5,047 were randomized into the trial.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 57.0 years STANDARD_DEVIATION 9.9 |
| HbA1c | 7.5 % STANDARD_DEVIATION 0.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 34 Participants |
| Race (NIH/OMB) Asian | 47 Participants |
| Race (NIH/OMB) Black or African American | 271 Participants |
| Race (NIH/OMB) More than one race | 319 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 28 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 19 Participants |
| Race (NIH/OMB) White | 3314 Participants |
| Sex: Female, Male Female | 1837 Participants |
| Sex: Female, Male Male | 811 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 42 / 1,263 | 43 / 1,254 | 27 / 1,262 | 41 / 1,268 | 0 / 7,850 |
| other Total, other adverse events | 0 / 1,263 | 0 / 1,254 | 0 / 1,262 | 0 / 1,268 | 0 / 7,850 |
| serious Total, serious adverse events | 259 / 1,263 | 315 / 1,254 | 204 / 1,262 | 272 / 1,268 | 1 / 7,850 |
Outcome results
None listed