Longitudinal Effects of Glucose-Lowering Medications on β-Cell Responses and Insulin Sensitivity in Type 2 Diabetes: The GRADE Randomized Clinical Trial
Author:
Rasouli Neda1ORCID, Younes Naji2, Ghosh Alokananda2, Albu Jeanine3, Cohen Robert M.4, DeFronzo Ralph A.5ORCID, Diaz Elsa6, Sayyed Kassem Laure7, Luchsinger José A.8ORCID, McGill Janet B.9, Sivitz William I.10ORCID, Tamborlane William V.11ORCID, Utzschneider Kristina M.12ORCID, Kahn Steven E.12ORCID, , Crandall J.P., McKee M.D., Behringer-Massera S., Brown-Friday J., Xhori E., Ballentine-Cargill K., Duran S., Estrella H., Gonzalez de la torre S., Lukin J., Phillips L.S., Burgess E., Olson D., Rhee M., Wilson P., Raines T.S., Boers J., Costello J., Maher-Albertelli M., Mungara R., Savoye L., White C.A., Gullett C., Holloway L., Morehead F., Person S., Sibymon M., Tanukonda S., Adams C., Ross A., Balasubramanyam A., Gaba R., Gonzalez Hattery E., Ideozu A., Jimenez J., Montes G., Wright C., Hollander P., Roe E., Jackson A., Smiley A., Burt P., Estrada L., Chionh K., Ismail-Beigi F., Falck-Ytter C., Sayyed Kassem L., Sood A., Tiktin M., Kulow T., Newman C., Stancil K.A., Cramer B., Iacoboni J., Kononets M.V., Sanders C., Tucker L., Werner A., Maxwell A., McPhee G., Patel C., Colosimo L., Krol A., Goland R., Pring J., Alfano L., Kringas P., Hausheer C., Tejada J., Gumpel K., Kirpitch A., Schneier H., Green J.B., AbouAssi H., Chatterjee R., Feinglos M.N., English Jones J., Khan S.A., Kimpel J.B., Zimmer R.P., Furst M., Satterwhite B.M., Thacker C.R., Evans Kreider K., Mariash C.N., Mather K.J., Ismail H.M., Lteif A., Mullen M., Hamilton T., Patel N., Riera G., Jackson M., Pirics V., Aguillar D., Howard D., Hurt S., Bergenstal R., Carlson A., Martens T., Johnson M., Hill R., Hyatt J., Jensen C., Madden M., Martin D., Willis H., Konerza W., Yang S., Kleeberger K., Passi R., Fortmann S., Herson M., Mularski K., Glauber H., Prihoda J., Ash B., Carlson C., Ramey P.A., Schield E., Torgrimson-Ojerio B., Arnold K., Kauffman B., Panos E., Sahnow S., Bays K., Berame K., Cook J., Ghioni D., Gluth J., Schell K., Criscola J., Friason C., Jones S., Nazarov S., Barzilay J., Rassouli N., Puttnam R., Ojoawo B., Nelson R., Curtis M., Hollis B., Sanders-Jones C., Stokes K., El-Haqq Z., Kolli A., Tran T., Wexler D., Larkin M.E., Meigs J., Chambers B., Dushkin A., Rocchio G., Yepes M., Steiner B., Dulin H., Cayford M., Chu K., DeManbey A., Hillard M., Martin K., Thangthaeng N., Gurry L., Kochis R., Raymond E., Ripley V., Stevens C., Park J., Aroda V., Ghazi A., Magee M., Ressing A., Loveland A., Hamm M., Hurtado M., Kuhn A., Leger J., Manandhar L., Mwicigi F., Sanchez O., Young T., Garg R., Lagari-Libhaber V., Florez H.J., Valencia W.M., Marks J., Casula S., Oropesa-Gonzalez L., Hue L., Cuadot A., Nieto-Martinez R., Riccio Veliz A.K., Gutt M., Kendal Y.J., Veciana B., Ahmann A., Aby-Daniel D., Joarder F., Morimoto V., Sprague C., Yamashita D., Cady N., Rivera-Eschright N., Kirchhoff P., Morales Gomez B., Adducci J., Goncharova A., Hox S.H., Petrovitch H., Matwichyna M., Jenkins V., Broadwater L., Ishii R.R., Bermudez N.O., Hsia D.S., Cefalu W.T., Greenway F.L., Waguespack C., King E., Fry G., Dragg A., Gildersleeve B., Arceneaux J., Haynes N., Thomassie A., Pavlionis M., Bourgeois B., Hazlett C., Mudaliar S., Henry R., Boeder S., Pettus J., Diaz E., Garcia-Acosta D., Maggs S., DeLue C., Stallings A., Castro E., Hernandez S., Krakoff J., Curtis J.M., Killean T., Khalid M., Joshevama E., Diaz E., Martin D., Tsingine K., Karshner T., Albu J., Pi-Sunyer F.X., Frances S., Maggio C., Ellis E., Bastawrose J., Gong X., Banerji M.A., August P., Lee M., Lorber D., Brown N.M., Josephson D.H., Thomas L.L., Tsovian M., Cherian A., Jacobson M.H., Mishko M.M., Kirkman M.S., Buse J.B., Diner J., Dostou J., Machineni S., Young L., Bergamo K., Goley A., Kerr J., Largay J.F., Guarda S., Cuffee J., Culmer D., Fraser R., Almeida H., Coffer S., Debnam E., Kiker L., Morton S., Josey K., Fuller G., Garvey W.T., Cherrington A.L., Dyer D., Lawson M.C.R., Griffith O., Agne A., McCullars S., Cohen R.M., Craig J., Rogge M.C., Burton K., Kersey K., Wilson C., Lipp S., Vonder Meulen M.B., Adkins C., Onadeko T., Rasouli N., Baker C., Schroeder E., Razzaghi M., Lyon C., Penaloza R., Underkofler C., Lorch R., Douglass S., Steiner S., Sivitz W.I., Cline E., Knosp L.K., McConnell J., Lowe T., Herman W.H., Pop-Busui R., Tan M.H., Martin C., Waltje A., Katona A., Goodhall L., Eggleston R., Kuo S., Bojescu S., Bule S., Kessler N., LaSalle E., Whitley K., Seaquist E.R., Bantle A., Harindhanavudhi T., Kumar A., Redmon B., Bantle J., Coe M., Mech M., Taddese A., Lesne K., Smith S., Desouza C., Kuechenmeister L., Shivaswamy V., Burbach S., Rodriguez M.G., Seipel K., Alfred A., Morales A.L., Eggert J., Lord G., Taylor W., Tillson R., Schade D.S., Adolphe A., Burge M., Duran-Valdez E., Martinez J., Bancroft A., Kunkel S., Ali Jamaleddin Ahmad F., Hernandez McGinnis D., Pucchetti B., Scripsick E., Zamorano A., DeFronzo R.A., Cersosimo E., Abdul-Ghani M., Triplitt C., Juarez D., Mullen M., Garza R.I., Verastiqui H., Wright K., Puckett C., Raskin P., Rhee C., Abraham S., Jordan L.F., Sao S., Morton L., Smith O., Osornio Walker L., Schnurr-Breen L., Ayala R., Kreymer R.B., Sturgess D., Utzschneider K.M., Kahn S.E., Alarcon-Casas Wright L., Boyko E.J., Tsai E.C., Trence D.L., Trikudanathan S., Fattaleh B.N., Montgomery B.K., Atkinson K.M., Kozedub A., Concepcion T., Moak C., Prikhodko N., Rhothisen S., Elasy T.A., Martin S., Shackelford L., Goidel R., Hinkle N., Lovell C., Myers J., Lipps Hogan J., McGill J.B., Salam M., Schweiger T., Kissel S., Recklein C., Clifton M.J., Tamborlane W., Camp A., Gulanski B., Inzucchi S.E., Pham K., Alguard M., Gatcomb P., Lessard K., Perez M., Iannone L., Magenheimer E., Montosa A., Fradkin J., Burch H.B., Bremer A.A., Nathan D.M., Lachin J.M., Krause-Steinrauf H., Younes N., Bebu I., Butera N., Buys C.J., Fagan A., Gao Y., Ghosh A., Gramzinski M.R., Hall S.D., Kazemi E., Legowski E., Liu H., Suratt C., Tripputi M., Arey A., Backman M., Bethepu J., Lund C., Mangat Dhaliwal P., McGee P., Mesimer E., Ngo L., Steffes M., Seegmiller J., Saenger A., Arends V., Gabrielson D., Conner T., Warren S., Day J., Huminik J., Scrymgeour A., Soliman E.Z., Pokharel Y., Zhang Z.M., Campbell C., Hu J., Keasler L., Hensley S., Li Y., Mihalcea R., Min D.J., Perez-Rosas V., Prosser L., Resnicow L., Ye W., Shao H., Zhang P., Luchsinger J., Sanchez D., Assuras S., Groessl E., Sakha F., Chong H., Hillery N., Abdouch I., Bahtiyar G., Brantley P., Broyles F.E., Canaris G., Copeland P., Craine J.J., Fein W.L., Gliwa A., Hope L., Lee M.S., Meiners R., Meiners V., O’Neal H., Park J.E., Sacerdote A., Sledge E., Soni L., Steppel-Reznik J., Turchin A.
Affiliation:
1. 1Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine, and VA Eastern Colorado Health Care System, Aurora, CO 2. 2The Biostatistics Center, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Rockville, MD 3. 3Icahn School of Medicine, Mount Sinai Morningside, New York, NY 4. 4Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati College of Medicine and Cincinnati VA Medical Center, Cincinnati, OH 5. 5University of Texas Health Science Center, San Antonio, TX 6. 6VA San Diego Healthcare System, San Diego, CA 7. 7Department of Endocrinology, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH 8. 8Departments of Medicine and Epidemiology, Columbia University Irving Medical Center, New York, NY 9. 9Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO 10. 10Department of Internal Medicine, University of Iowa, Iowa City, IA 11. 11Yale School of Medicine, New Haven, CT 12. 12Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle
Abstract
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 < 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 < 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.
Funder
National Institute of Diabetes and Digestive and Kidney Diseases Centers for Disease Control and Prevention The American Diabetes Association The National Heart, Lung, and Blood Institute
Publisher
American Diabetes Association
Cited by
3 articles.
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