• GRADE Study Research Group, David M Nathan, John M Lachin, Ionut Bebu, Henry B Burch, John B Buse, Andrea L Cherrington, Stephen P Fortmann, Jennifer B Green, Steven E Kahn, M Sue Kirkman, Heidi Krause-Steinrauf, Mary E Larkin, Lawrence S Phillips, Rodica Pop-Busui, Michael Steffes, Margaret Tiktin, Mark Tripputi, Deborah J Wexler, and Naji Younes.
• 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).
• N. Engl. J. Med. 2022 Sep 22; 387 (12): 107510881075-1088.

BackgroundData 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.MethodsWe 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.ResultsDuring 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.ConclusionsIn 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 ClinicalTrials.gov number, NCT01794143.).Copyright © 2022 Massachusetts Medical Society.

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