Glycemia Reduction in Type 2 Diabetes - Glycemic Outcomes

GRADE Study Research Group; David M Nathan; John M Lachin; Ashok Balasubramanyam; Henry B Burch; John B Buse; Nicole M Butera; Robert M Cohen; Jill P Crandall; Steven E Kahn; Heidi Krause-Steinrauf; Mary E Larkin; Neda Rasouli; Margaret Tiktin; Deborah J Wexler; Naji Younes

doi:10.1056/NEJMoa2200433

Glycemia Reduction in Type 2 Diabetes - Glycemic Outcomes

N Engl J Med. 2022 Sep 22;387(12):1063-1074. doi: 10.1056/NEJMoa2200433.

Authors

Collaborators

GRADE Study Research Group:
J P Crandall, M D McKee, S Behringer-Massera, J Brown-Friday, E Xhori, K Ballentine-Cargill, S Duran, H Estrella, S Gonzalez de la Torre, J Lukin, L S Phillips, E Burgess, D Olson, M Rhee, P Wilson, T S Raines, J Boers, J Costello, M Maher-Albertelli, R Mungara, L Savoye, C A White, C Gullett, L Holloway, F Morehead, S Person, M Sibymon, S Tanukonda, C Adams, A Ross, A Balasubramanyam, R Gaba, E Gonzalez Hattery, A Ideozu, J Jimenez, G Montes, C Wright, P Hollander, E Roe, A Jackson, A Smiley, P Burt, L Estrada, K Chionh, F Ismail-Beigi, C Falck-Ytter, L Sayyed Kassem, A Sood, M Tiktin, T Kulow, C Newman, K A Stancil, B Cramer, J Iacoboni, M V Kononets, C Sanders, L Tucker, A Werner, A Maxwell, G McPhee, C Patel, L Colosimo, A Krol, R Goland, J Pring, L Alfano, P Kringas, C Hausheer, J Tejada, K Gumpel, A Kirpitch, H Schneier, J B Green, H AbouAssi, R Chatterjee, M N Feinglos, J English Jones, S A Khan, J B Kimpel, R P Zimmer, M Furst, B M Satterwhite, C R Thacker, K Evans Kreider, C N Mariash, K J Mather, H M Ismail, A Lteif, M Mullen, T Hamilton, N Patel, G Riera, M Jackson, V Pirics, D Aguillar, D Howard, S Hurt, R Bergenstal, A Carlson, T Martens, M Johnson, R Hill, J Hyatt, C Jensen, M Madden, D Martin, H Willis, W Konerza, S Yang, K Kleeberger, R Passi, S Fortmann, M Herson, K Mularski, H Glauber, J Prihoda, B Ash, C Carlson, P A Ramey, E Schield, B Torgrimson-Ojerio, K Arnold, B Kauffman, E Panos, S Sahnow, K Bays, K Berame, J Cook, D Ghioni, J Gluth, K Schell, J Criscola, C Friason, S Jones, S Nazarov, J Barzilay, N Rassouli, R Puttnam, B Ojoawo, R Nelson, M Curtis, B Hollis, C Sanders-Jones, K Stokes, Z El-Haqq, A Kolli, T Tran, D Wexler, M E Larkin, J Meigs, B Chambers, A Dushkin, G Rocchio, M Yepes, B Steiner, H Dulin, M Cayford, K Chu, A DeManbey, M Hillard, K Martin, N Thangthaeng, L Gurry, R Kochis, E Raymond, V Ripley, C Stevens, J Park, V Aroda, A Ghazi, M Magee, A Ressing, A Loveland, M Hamm, M Hurtado, A Kuhn, J Leger, L Manandhar, F Mwicigi, O Sanchez, T Young, R Garg, V Lagari-Libhaber, H J Florez, W M Valencia, J Marks, S Casula, L Oropesa-Gonzalez, L Hue, A Cuadot, R Nieto-Martinez, A K Riccio Veliz, M Gutt, Y J Kendal, B Veciana, A Ahmann, D Aby-Daniel, F Joarder, V Morimoto, C Sprague, D Yamashita, N Cady, N Rivera-Eschright, P Kirchhoff, B Morales Gomez, J Adducci, A Goncharova, S H Hox, H Petrovitch, M Matwichyna, V Jenkins, L Broadwater, R R Ishii, N O Bermudez, D S Hsia, W T Cefalu, F L Greenway, C Waguespack, E King, G Fry, A Dragg, B Gildersleeve, J Arceneaux, N Haynes, A Thomassie, M Pavlionis, B Bourgeois, C Hazlett, S Mudaliar, R Henry, S Boeder, J Pettus, E Diaz, D Garcia-Acosta, S Maggs, C DeLue, A Stallings, E Castro, S Hernandez, J Krakoff, J M Curtis, T Killean, M Khalid, E Joshevama, K Tsingine, T Karshner, J Albu, F X Pi-Sunyer, S Frances, C Maggio, E Ellis, J Bastawrose, X Gong, M A Banerji, P August, M Lee, D Lorber, N M Brown, D H Josephson, L L Thomas, M Tsovian, A Cherian, M H Jacobson, M M Mishko, M S Kirkman, J B Buse, J Dostou, S Machineni, L Young, K Bergamo, A Goley, J Kerr, J F Largay, S Guarda, J Cuffee, D Culmer, R Fraser, H Almeida, S Coffer, E Debnam, L Kiker, S Morton, K Josey, G Fuller, W T Garvey, A L Cherrington, D Dyer, McR Lawson, O Griffith, A Agne, S McCullars, R M Cohen, J Craig, M C Rogge, K Burton, K Kersey, C Wilson, S Lipp, M B Vonder Meulen, C Adkins, T Onadeko, N Rasouli, C Baker, E Schroeder, M Razzaghi, C Lyon, R Penaloza, C Underkofler, R Lorch, S Douglass, S Steiner, W I Sivitz, E Cline, L K Knosp, J McConnell, T Lowe, W H Herman, R Pop-Busui, M H Tan, C Martin, A Waltje, A Katona, L Goodhall, R Eggleston, S Kuo, S Bojescu, S Bule, N Kessler, E LaSalle, K Whitley, E R Seaquist, A Bantle, T Harindhanavudhi, A Kumar, B Redmon, J Bantle, M Coe, M Mech, A Taddese, L Lesne, S Smith, C Desouza, L Kuechenmeister, V Shivaswamy, S Burbach, M G Rodriguez, K Seipel, A Alfred, A L Morales, J Eggert, G Lord, W Taylor, R Tillson, D S Schade, A Adolphe, M Burge, E Duran-Valdez, J Martinez, A Bancroft, S Kunkel, F Ali Jamaleddin Ahmad, D Hernandez McGinnis, B Pucchetti, E Scripsick, A Zamorano, R A DeFronzo, E Cersosimo, M Abdul-Ghani, C Triplitt, D Juarez, R I Garza, H Verastiqui, K Wright, C Puckett, P Raskin, C Rhee, S Abraham, L F Jordan, S Sao, L Morton, O Smith, L Osornio Walker, L Schnurr-Breen, R Ayala, R B Kreymer, D Sturgess, K M Utzschneider, S E Kahn, L Alarcon-Casas Wright, E J Boyko, E C Tsai, D L Trence, S Trikudanathan, B N Fattaleh, B K Montgomery, K M Atkinson, A Kozedub, T Concepcion, C Moak, N Prikhodko, S Rhothisen, T A Elasy, S Martin, L Shackelford, R Goidel, N Hinkle, C Lovell, J Myers, J Lipps Hogan, J B McGill, M Salam, T Schweiger, S Kissel, C Recklein, M J Clifton, W Tamborlane, A Camp, B Gulanski, S E Inzucchi, K Pham, M Alguard, P Gatcomb, K Lessard, M Perez, L Iannone, E Magenheimer, A Montosa, H B Burch, A A Bremer, J Fradkin, D M Nathan, J M Lachin, H Krause-Steinrauf, N Younes, I Bebu, N Butera, C J Buys, A Fagan, Y Gao, A Ghosh, M R Gramzinski, S D Hall, E Kazemi, E Legowski, H Liu, C Suratt, M Tripputi, A Arey, M Backman, J Bethepu, C Lund, P Mangat Dhaliwal, P McGee, E Mesimer, L Ngo, M Steffes, J Seegmiller, A Saenger, V Arends, D Gabrielson, T Conner, S Warren, J Day, J Huminik, A Scrymgeour, E Z Soliman, Y Pokharel, Z M Zhang, C Campbell, J Hu, L Keasler, S Hensley, Y Li, R Mihalcea, D J Min, V Perez-Rosas, L Prosser, K Resnicow, W Ye, H Shao, P Zhang, J Luchsinger, D Sanchez, S Assuras, E Groessl, F Sakha, H Chong, N Hillery, B M Everett, I Abdouch, G Bahtiyar, P Brantley, F E Broyles, G Canaris, P Copeland, J J Craine, W L Fein, A Gliwa, L Hope, M S Lee, R Meiners, V Meiners, H O'Neal, J E Park, A Sacerdote, E Sledge Jr, L Soni, J Steppel-Reznik, A Turchin, B Brooks-Worrell, C S Hampe, J P Palmer, A Shojaie, J Higgins, L Fischer, S Golden, J Gonzalez, A Naik, E Walker, L Doner Lotenberg, H Sharp, J M Gallivan, J Lim, D M Tuncer

Affiliation

¹ 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.).

Abstract

Background: 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.

Methods: 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%.

Results: 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.

Conclusions: 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 ClinicalTrials.gov number, NCT01794143.).

Publication types

Comparative Study
Randomized Controlled Trial
Research Support, N.I.H., Extramural

MeSH terms

Blood Glucose* / analysis
Comparative Effectiveness Research
Diabetes Mellitus, Type 2* / blood
Diabetes Mellitus, Type 2* / drug therapy
Dipeptidyl-Peptidase IV Inhibitors / adverse effects
Dipeptidyl-Peptidase IV Inhibitors / therapeutic use
Drug Therapy, Combination
Glucagon-Like Peptide-1 Receptor / agonists
Glucagon-Like Peptide-1 Receptor / therapeutic use
Glycated Hemoglobin* / analysis
Humans
Hypoglycemic Agents* / adverse effects
Hypoglycemic Agents* / therapeutic use
Insulin Glargine / adverse effects
Insulin Glargine / therapeutic use
Liraglutide / adverse effects
Liraglutide / therapeutic use
Metformin / adverse effects
Metformin / therapeutic use
Sitagliptin Phosphate / adverse effects
Sitagliptin Phosphate / therapeutic use
Sulfonylurea Compounds / adverse effects
Sulfonylurea Compounds / therapeutic use
Treatment Outcome

Substances

Blood Glucose
Dipeptidyl-Peptidase IV Inhibitors
Glucagon-Like Peptide-1 Receptor
Glycated Hemoglobin A
Hypoglycemic Agents
Sulfonylurea Compounds
Insulin Glargine
glimepiride
Liraglutide
Metformin
Sitagliptin Phosphate

Associated data

ClinicalTrials.gov/NCT01794143

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding