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Glycemia Reduction in Type 2 Diabetes — Microvascular and Cardiovascular Outcomes | NEJM –

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Original ArticleFree Preview

The members of the GRADE Study Research Group are listed in the Supplementary Appendix, available at
Data are lacking on the comparative effectiveness of commonly used glucose-lowering medications, when added to metformin, with respect to microvascular and cardiovascular disease outcomes in persons with type 2 diabetes.
We assessed the comparative effectiveness of four commonly used glucose-lowering medications, added to metformin, in achieving and maintaining a glycated hemoglobin level of less than 7.0% in participants with type 2 diabetes. The randomly assigned therapies were insulin glargine U-100 (hereafter, glargine), glimepiride, liraglutide, and sitagliptin. Prespecified secondary outcomes with respect to microvascular and cardiovascular disease included hypertension and dyslipidemia, confirmed moderately or severely increased albuminuria or an estimated glomerular filtration rate of less than 60 ml per minute per 1.73 m2 of body-surface area, diabetic peripheral neuropathy assessed with the Michigan Neuropathy Screening Instrument, cardiovascular events (major adverse cardiovascular events [MACE], hospitalization for heart failure, or an aggregate outcome of any cardiovascular event), and death. Hazard ratios are presented with 95% confidence limits that are not adjusted for multiple comparisons.
During a mean 5.0 years of follow-up in 5047 participants, there were no material differences among the interventions with respect to the development of hypertension or dyslipidemia or with respect to microvascular outcomes; the mean overall rate (i.e., events per 100 participant-years) of moderately increased albuminuria levels was 2.6, of severely increased albuminuria levels 1.1, of renal impairment 2.9, and of diabetic peripheral neuropathy 16.7. The treatment groups did not differ with respect to MACE (overall rate, 1.0), hospitalization for heart failure (0.4), death from cardiovascular causes (0.3), or all deaths (0.6). There were small differences with respect to rates of any cardiovascular disease, with 1.9, 1.9, 1.4, and 2.0 in the glargine, glimepiride, liraglutide, and sitagliptin groups, respectively. When one treatment was compared with the combined results of the other three treatments, the hazard ratios for any cardiovascular disease were 1.1 (95% confidence interval [CI], 0.9 to 1.3) in the glargine group, 1.1 (95% CI, 0.9 to 1.4) in the glimepiride group, 0.7 (95% CI, 0.6 to 0.9) in the liraglutide group, and 1.2 (95% CI, 1.0 to 1.5) in the sitagliptin group.
In participants with type 2 diabetes, the incidences of microvascular complications and death were not materially different among the four treatment groups. The findings indicated possible differences among the groups in the incidence of any cardiovascular disease. (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) 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., Ionut Bebu, Ph.D., Henry B. Burch, M.D., John B. Buse, M.D., Andrea L. Cherrington, M.D., Stephen P. Fortmann, M.D., Jennifer B. Green, M.D., Steven E. Kahn, M.B., Ch.B., M. Sue Kirkman, M.D., Heidi Krause-Steinrauf, M.S., Mary E. Larkin, R.N., Lawrence S. Phillips, M.D., Rodica Pop-Busui, M.D., Ph.D., Michael Steffes, M.D., Margaret Tiktin, D.N.P., Mark Tripputi, Ph.D., 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 our 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., I.B., H.K.-S., M. Tripputi, 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 Division of Endocrinology and Metabolism, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill (J.B.B., M.S.K.), and the Department of Medicine, Duke Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham (J.B.G.) — both in North Carolina; the University of Alabama, Birmingham (A.L.C.); Kaiser Permanente Center for Health Research, Portland, OR (S.P.F.); the Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, Veterans Affairs (VA) Puget Sound Health Care System, University of Washington, Seattle (S.E.K.); the Atlanta VA Medical Center, Decatur, GA (L.S.P.); the Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor (R.P.-B.); the Advanced Research and Diagnostic Laboratory, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis (M.S.); and the Louis Stokes Cleveland VA Medical Center, Case Western Reserve University, Cleveland (M. Tiktin).
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; 387:1075-1088
DOI: 10.1056/NEJMoa2200436

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