Making the metformin GRADE


I’m sure we’d all agree that for most patients with type 2 diabetes (T2DM), metformin is the first-line therapeutic agent to use. The guidelines support this choice, too.1,2 What would you add if your patient was no longer controlled with just this medication? The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) is seeking to answer this, among other questions. This NIH-funded, randomized clinical trial is investigating which one of four FDA-approved drugs for T2DM is more effective than the others, when used in combination with metformin.3  Study participants will be randomized to metformin, along with: a sulfonylurea (glimepiride), a DPP-4 inhibitor (sitagliptin), a GLP-1 receptor agonist (liraglutide), or a long-acting insulin (glargine). These individuals will then be followed for up to 7 years.

Forty-five sites across the US are presently recruiting and enrolling participants. To date, 2201 individuals have been randomized, and the goal is a total of 5000 participants. Some of the inclusion criteria includes: adults over 30 years of age, T2DM for less than 10 years, never on metformin/ only on metformin, HbA1c 6.8 - 8.5%. Participants will undergo 4 follow-up visits per year for 4-7 years.

“What differentiates GRADE from previous studies is that it will perform a head-to-head comprehensive comparison of the most commonly used drugs over a long period of time,” said David M. Nathan, MD, of Massachusetts General Hospital, Boston, a co-principal investigator along with John Lachin, ScD, of The George Washington University, Washington, DC. Dr. Nathan also noted, “In addition to determining which medications control blood glucose levels most effectively over time, we hope to examine individual factors that are associated with better or worse response to the different medications. This should provide understanding of how to personalize the treatment of diabetes.” 4

I am one of the sub-investigators at the University of California, San Diego and VA San Diego study site, working with the team led by Robert Henry, MD, and urge you to learn more and discuss with your patients who are interested about this practical, crucial, and potentially paradigm-changing clinical study. For more information about this study, please visit: or


1. American Diabetes Association. Standards of Care 2015. Diabetes Care. 2015;38(Suppl 1):S1-S93.

2. Handelsman Y, et al. American Association of Clinical Endocrinologists and American College of Endocrinology. Clinical Practice Guidelines for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2015;21(Suppl 1):1-87.

3. Nathan DM, et al. GRADE Study Research Group. Rationale and design of the Glycemia Reduction Approaches in Diabetes: a comparative effective study (GRADE). Diabetes Care. 2013;36(8):2254-2261.

4. National Institutes of Health. NIH begins recruitment for long-term study of diabetes drug efficacy. June, 3, 2013. Accessed August 29, 2015.

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