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The members of the GRADE Study Research Group are listed in the Supplementary Appendix, available at
The comparative effectiveness of glucose-lowering medications for use with metformin to maintain target glycated hemoglobin levels in persons with type 2 diabetes is uncertain.
Download a PDF of the Research Summary.
In this trial involving participants with type 2 diabetes of less than 10 years’ duration who were receiving metformin and had glycated hemoglobin levels of 6.8 to 8.5%, we compared the effectiveness of four commonly used glucose-lowering medications. We randomly assigned participants to receive insulin glargine U-100 (hereafter, glargine), the sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or sitagliptin, a dipeptidyl peptidase 4 inhibitor. The primary metabolic outcome was a glycated hemoglobin level, measured quarterly, of 7.0% or higher that was subsequently confirmed, and the secondary metabolic outcome was a confirmed glycated hemoglobin level greater than 7.5%.
A total of 5047 participants (19.8% Black and 18.6% Hispanic or Latinx) who had received metformin for type 2 diabetes were followed for a mean of 5.0 years. The cumulative incidence of a glycated hemoglobin level of 7.0% or higher (the primary metabolic outcome) differed significantly among the four groups (P<0.001 for a global test of differences across groups); the rates with glargine (26.5 per 100 participant-years) and liraglutide (26.1) were similar and lower than those with glimepiride (30.4) and sitagliptin (38.1). The differences among the groups with respect to a glycated hemoglobin level greater than 7.5% (the secondary outcome) paralleled those of the primary outcome. There were no material differences with respect to the primary outcome across prespecified subgroups defined according to sex, age, or race or ethnic group; however, among participants with higher baseline glycated hemoglobin levels there appeared to be an even greater benefit with glargine, liraglutide, and glimepiride than with sitagliptin. Severe hypoglycemia was rare but significantly more frequent with glimepiride (in 2.2% of the participants) than with glargine (1.3%), liraglutide (1.0%), or sitagliptin (0.7%). Participants who received liraglutide reported more frequent gastrointestinal side effects and lost more weight than those in the other treatment groups.
All four medications, when added to metformin, decreased glycated hemoglobin levels. However, glargine and liraglutide were significantly, albeit modestly, more effective in achieving and maintaining target glycated hemoglobin levels. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE number, NCT01794143.)
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Supported by a grant (U01DK098246) from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH); a U34 planning grant (U34-DK-088043) for the planning of the trial from the NIDDK; funding for the initial planning meeting regarding the U34 proposal from the American Diabetes Association; the National Heart, Lung, and Blood Institute; the Centers for Disease Control and Prevention; resources and facilities from the Department of Veterans Affairs; grants (P30 DK017047, P30 DK020541-44, P30 DK020572, P30 DK072476, P30 DK079626, P30 DK092926, U54 GM104940, UL1 TR000170, UL1 TR000439, UL1 TR000445, UL1 TR001102, UL1 TR001108, UL1 TR001409, 2UL1TR001425, UL1 TR001449, UL1 TR002243, UL1 TR002345, UL1 TR002378, UL1 TR002489, UL1 TR002529, UL1 TR002535, UL1 TR002537, UL1 TR002541, and UL1 TR002548) from the NIH; educational materials from the National Diabetes Education Program; and donated medications and supplies from Becton Dickinson, Bristol Myers Squibb, Merck , Novo Nordisk, Roche Diagnostics, and Sanofi.
Disclosure forms provided by the authors are available with the full text of this article at
The members of the writing committee (David M. Nathan, M.D., John M. Lachin, Sc.D., Ashok Balasubramanyam, M.D., Henry B. Burch, M.D., John B. Buse, M.D., Nicole M. Butera, Ph.D., Robert M. Cohen, M.D., Jill P. Crandall, M.D., Steven E. Kahn, M.B., Ch.B., Heidi Krause-Steinrauf, M.S., Mary E. Larkin, R.N., Neda Rasouli, M.D., Margaret Tiktin, D.N.P., Deborah J. Wexler, M.D., and Naji Younes, Ph.D.) assume responsibility for the overall content and integrity of this article.
The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
A data sharing statement provided by the authors is available with the full text of this article at
We thank the participants, whose loyal dedication made this trial possible.
From the Massachusetts General Hospital Diabetes Center, Harvard Medical School, Boston (D.M.N., M.E.L., D.J.W.); the Biostatistics Center, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, George Washington University, Rockville (J.M.L., N.M.B., H.K.-S., N.Y.), and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (H.B.B.) — both in Maryland; the Section of Endocrinology, Diabetes, and Metabolism, Baylor College of Medicine, Houston (A.B.); the Division of Endocrinology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill (J.B.B.); the Cincinnati Veterans Affairs (VA) Medical Center, University of Cincinnati College of Medicine, Cincinnati (R.M.C.); the Division of Endocrinology and Diabetes and the Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, Bronx, NY (J.P.C.); the Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, VA Puget Sound Health Care System, University of Washington, Seattle (S.E.K.); the Division of Endocrinology, Metabolism, and Diabetes, University of Colorado School of Medicine, and the VA Eastern Colorado Health Care System — both in Aurora (N.R.); and the Louis Stokes Cleveland VA Medical Center, Case Western Reserve University, Cleveland (M.T.).
Dr. Lachin can be contacted at or at the George Washington University Biostatistics Center–GRADE Coordinating Center, 6110 Executive Blvd., Ste. 750, Rockville, MD 20852.

The members of the GRADE Study Research Group are listed in the Supplementary Appendix, available at

The members of the GRADE Study Research Group are listed in the Supplementary Appendix, available at
September 22, 2022
N Engl J Med 2022; 387:1063-1074
DOI: 10.1056/NEJMoa2200433

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