Longitudinal Effects of Glucose-Lowering Medications on β-Cell Responses and Insulin Sensitivity in Type 2 Diabetes: The GRADE Randomized Clinical Trial
Authors: Neda Rasouli, Naji Younes, Alokananda Ghosh, Jeanine Albu, Robert M. Cohen, Ralph A. DeFronzo, Elsa Diaz, Laure Sayyed Kassem, José A. Luchsinger, Janet B. McGill, William I. Sivitz, William V. Tamborlane, Kristina M. Utzschneider, Steven E. Kahn, 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, E. Diaz, D. Martin, 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. Diner, 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, M.C.R. 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, K. 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, M. Mullen, 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, J. Fradkin, H.B. Burch, A.A. Bremer, 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, L. Resnicow, W. Ye, H. Shao, P. Zhang, J. Luchsinger, D. Sanchez, S. Assuras, E. Groessl, F. Sakha, H. Chong, N. Hillery, 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, L. Soni, J. Steppel-Reznik, A. Turchin
Journal: Diabetes Care (2024)

OBJECTIVE To compare the long-term effects of glucose-lowering medications (insulin glargine U-100, glimepiride, liraglutide, and sitagliptin) when added to metformin on insulin sensitivity and β-cell function. RESEARCH DESIGN AND METHODS In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) cohort with type 2 diabetes (n = 4,801), HOMA2 was used to estimate insulin sensitivity (HOMA2-%S) and fasting β-cell function (HOMA2-%B) at baseline and 1, 3, and 5 years on treatment. Oral glucose tolerance test β-cell responses (C-peptide index [CPI] and total C-peptide response [incremental C-peptide/incremental glucose over 120 min]) were evaluated at the same time points. These responses adjusted for HOMA2-%S in regression analysis provided estimates of β-cell function. RESULTS HOMA2-%S increased from baseline to year 1 with glargine and remained stable thereafter, while it did not change from baseline in the other treatment groups. HOMA2-%B and C-peptide responses were increased to variable degrees at year 1 in all groups but then declined progressively over time. At year 5, CPI was similar between liraglutide and sitagliptin, and higher for both than for glargine and glimepiride [0.80, 0.87, 0.74, and 0.64 (nmol/L)/(mg/dL) * 100, respectively; P &amp;lt; 0.001], while the total C-peptide response was greatest with liraglutide, followed in descending order by sitagliptin, glargine, and glimepiride [1.54, 1.25, 1.02, and 0.87 (nmol/L)/(mg/dL) * 100, respectively, P &amp;lt; 0.001]. After adjustment for HOMA2-%S to obtain an estimate of β-cell function, the nature of the change in β-cell responses reflected those in β-cell function. CONCLUSIONS The differential long-term effects on insulin sensitivity and β-cell function of four different glucose-lowering medications when added to metformin highlight the importance of the loss of β-cell function in the progression of type 2 diabetes.