Comparative Effects of Randomized Second-line Therapy for Type 2 Diabetes on a Composite Outcome Incorporating Glycemic Control, Body Weight, and Hypoglycemia: An Analysis of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE)
Author:
Kirkman M. Sue1ORCID, Tripputi Mark2, Krause-Steinrauf Heidi2ORCID, Bebu Ionut2ORCID, AbouAssi Hiba3, Burch Henry4, Duran-Valdez Elizabeth5, Florez Hermes67, Garvey W. Timothy8ORCID, Hsia Daniel S.9ORCID, Salam Maamoun10, Pop-Busui Rodica11ORCID, , 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., Golden S., Gonzalez J., Naik A., Walker E.
Affiliation:
1. 1University of North Carolina at Chapel Hill, Chapel Hill, NC 2. 2The Biostatistics Center, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Rockville, MD 3. 3Duke University Medical Center, Durham, NC 4. 4National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Rockville, MD 5. 5University of New Mexico, Albuquerque, NM 6. 6Department of Medicine, University of Miami, Miami, FL 7. 8Medical University of South Carolina, Charleston, SC 8. 9University of Alabama at Birmingham, Birmingham, AL 9. 10Pennington Biomedical Research Center, Baton Rouge, LA 10. 11Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO 11. 12Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI
Abstract
OBJECTIVE
In Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) (5,047 participants, mean follow-up 5.0 years), differences in glycemic control were demonstrated over time among four randomized therapies added to metformin. Weight gain and hypoglycemia are also important outcomes for people with type 2 diabetes. We compared the effects of the four randomized GRADE medications on a composite outcome incorporating glycemic deterioration, weight gain, and hypoglycemia.
RESEARCH DESIGN AND METHODS
The composite outcome was time to first occurrence of any of the following: HbA1c >7.5%, confirmed; ≥5% weight gain; or severe or recurrent nonsevere hypoglycemia. Secondary analyses included examination of individual components of the composite outcome, subgroup effects and potential mediators, and treatment satisfaction. Cumulative incidence was estimated with the Kaplan-Meier estimator. Cox proportional hazards models were used to assess pairwise group differences in risk of an outcome.
RESULTS
Risk of reaching the composite outcome (events per 100 participants per treatment year [PTYs]) was lowest with liraglutide (19 per 100 PTYs) followed by sitagliptin (26 per 100 PTYs), glargine (29 per 100 PTYs), and glimepiride (40 per 100 PTYs); all pairwise comparisons were statistically significant. The order was the same for risk of weight gain and hypoglycemia, but risk of glycemic deterioration was lowest with glargine, followed by liraglutide, glimepiride, and sitagliptin. No significant heterogeneity in risk of composite outcome was detected across prespecified covariates. Participants who reached the composite outcome had modestly but significantly lower treatment satisfaction.
CONCLUSIONS
Among participants treated with common second-line drug classes for type 2 diabetes, the liraglutide group had the lowest and glimepiride the highest risk of reaching a composite outcome encompassing glycemic deterioration, weight gain, and hypoglycemia. These findings may inform decision-making regarding type 2 diabetes therapy.
Funder
Centers for Disease Control and Prevention National Institute of Diabetes and Digestive and Kidney Diseases National Heart, Lung, and Blood Institute American Diabetes Association
Publisher
American Diabetes Association
Reference21 articles.
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