Comparative Effects of Glucose-Lowering Medications on Kidney Outcomes in Type 2 Diabetes
Authors: Wexler Deborah J. , de Boer Ian H. , Ghosh Alokananda , Younes Naji , Bebu Ionut , Inzucchi Silvio E. , McGill Janet B. , Mudaliar Sunder , Schade David , Steffes Michael W. , Tamborlane William V. , Tan Meng H. , Ismail-Beigi Faramarz ,   GRADE Research Group, Crandall Jill P. , McKee Melissa Diane , Beringher-Massera Stephanie , Brown-Friday Janet , Xhori Entila , Ballentine-Cargill Keisha , Duran Sally , Estrella Hayley , Gonzalez de la torre Susana , Lukin Jennifer , Phillips Lawrence , Burgess Elizabeth , Olson Darin , Rhee Mary , Wilson Peter , Raines Tasha Stephanie , Boers Johanna , Costello Julie , Maher-Albertelli Maxine , Mungara Radhika , Savoye Louise , White CarolAnn , Gullett Chona , Holloway Leah , Morehead Folayan , Person Saranjit , Sibymon Mabil , Tanukonda Sridhar , Adams Cynthia , Ross April , Balasubramanyam Ashok , Gaba Ruchi , Gonzalez Erica , Ideozu Adrienne , Jimenez Julizza , Montes Gabriela , Wright Charlyne , Hollander Priscilla , Roe Erin , Jackson Analyn , Smiley Ashley , Burt Polly , Estrada Lorie , Chionh Kris , Ismail-Beigi Faramarz , Falck-Ytter Corinna , Sayyed Kassem Laure , Sood Ajay , Tiktin Margaret , Cramer Bethany , Iacoboni Jacalyn , Kononets Maria V. , Kulow Tanya , Newman Cynthia , Stancil Katherine A. , Sanders Cristina , Tucker Lisa , Werner Amanda , Krol Adrienne , McPhee Gloria , Patel Christine , Colosimo Linda , Maxwell Audrey , Goland Robin , Pring James , Alfano Lucia , Kringas Patricia , Hausheer Camille , Tejada Jessica , Gumpel Kelly , Kirpitch Amanda , Schneier Harvey , Green Jennifer B. , AbouAssi Hiba , Chatterjee Ranee , Feinglos Mark N. , English Jones Jennifer , Khan Shubi A. , Kimpel Jeanne B. , Zimmer Ronna P. , Furst Mary , Satterwhite Barbara M. , Thacker Connie R , Evans Kreider Kathryn , Mariash Cary N , Mather Kieren J. , Ismail Heba M , Lteif Amale , Mullen Maureen , Hamilton Tonya , Patel Nick , Riera Gabriela , Jackson Marcia , Pirics Vivian , Howard Devin , Aguillar Danielle , Hurt Sloan , Bergenstal Richard , Carlson Anders , Martens Thomas , Johnson Mary , Hill Renae , Hyatt Jamie , Jensen Connie , Madden Marcia , Martin Dianna , Willis Holly , Konerza Wanda , Yang Shoua , Passi Rebecca , Kleeberger Kathleen , Fortmann Stephen , Herson Michael , Mularski Karen , Glauber Harry , Prihoda James , Ash Britt , Carlson Christina , Ramey Phyllis Anne , Schield Emily , Torgrimson-Ojerio Britta , Arnold Kathy , Kauffman Bryan , Panos Elease , Sahnow Samantha , Bays Kristi , Cook Jennifer , Gluth Jennifer , Ghioni Debra , Schell Katrina , Criscola Jennifer , Friason Camille , Jones Suzi , Nazarov Sergey , Barzilay Joshua , Rassouli Negah , Puttnam Rachel , Ojoawo Olubukola , Nelson Roslin , Curtis Michelle , Hollis Bonita , Sanders-Jones Cynthia , Stokes Kia , El-Haqq Zakiah , Kolli Abby , Tran Tu , Wexler Deborah , Larkin Mary , Meigs James , Chambers Brittany , Dushkin Amy , Rocchio Gianna , Yepes Mike , Steiner Barbara , Dulin Hilary , Cayford Melody , DeManbey Andrea , Hillard Mallory , Martin Kimberly , Thangthaeng Nopporn , Gurry Lindsey , Kochis Raquel , Raymond Elyse , Ripley Valerie , Stevens Christine , Park Jean , Aroda Vanita , Ghazi Adline , Magee Michelle , Ressing Ann , Loveland Amy , Hamm Mia , Hurtado Maria , Kuhn Alexander , Leger Jayme L. , Manandhar Lumanti , Mwicigi Florence , Sanchez Osirelis , Young Theresa , Garg Rajesh , Lagari-Libhaber Victoria , Florez Hermes J , Valencia Willy M , Mark Jennifer , Casula Sabina , Oropesa-Gonzalez Lisset , Hue Lisa , Cuadot Alain , Nieto-Martinez Ramfis , Riccio Veliz Ana K , Gutt Miriam , Kendal Yvette J , Veciana Bertha , Ahmann Andrew , Aby-Daniel Diana , Joarder Farahnaz , Morimoto Victoria , Sprague Carol , Yamashita Daisuke , Cady Nancy , Rivera-Eschright Nadia , Kirchhoff Patricia , Morales Gonzalez Brianna , Adducci Joseph , Goncharova Alina , Hox Sophia H , Petrovich Helen , Matwichyna Michael , Jenkins Victoria , Broadwater L , Ishii Renée R. , Bermudez Nina O. , Hsia Daniel S. , Cefalu William T. , Greenway Frank L. , Waguespack Celeste , King Erin , Fry Greta , Dragg Amber , Gildersleeve Bethany , Arceneaux Jennifer , Haynes Natalie , Thomassie Amy , Pavlionis Mallory , Bourgeois Brandi , Hazlett Claire , Mudaliar Sunder , Robert Henry , Boeder Schafer , Pettus Jeremy , Diaz Elsa , Garcia-Acosta Daneila , Maggs Sarah , DeLue Catherine , Stallings Andrea , Castro Erick , Hernandez Sylvia , Krakoff Jonathan , Curtis Jeffrey M. , Killean Tina , Khalid Meshall , Joshevama Erica , Diaz Enrique , Martin Denelle , Tsingine Kaylee , Karshner Tracey , Albu Jeanine , Pi-Sunyer F. Xavier , Frances Sylvaine , Maggio Carol , Ellis Emily , Bastawrose Joseph , Gong Xiuqun , Banerji Mary Ann , August Phyllis , Lee Melissa , Lorber Daniel , Necole M. Brown , Josephson Debra H. , Thomas Lorraine L. , Tsovian Maria , Cherian Ajini , Jacobson Marlo H. , Mishko Motria M. , Kirkman Sue M. , Buse John B. , Dostou Jeanine , Machineni Sriram , Young Laura , Bergamo Katherine , Goley April , Kerr Jeffrey , Largay Joseph F. , Guarda Sonia , Cuffee Juanita , Culmer Dawn , Fraser Rachael , Almeida Hope , Coffer Samantha , Debnam Elizabeth , Kiker Lauren , Morton Sarah , Josey Kim , Fuller Gail , Garvey W. Timothy , Cherrington Andrea L. , Dyer Dana , Lawson Mary Catherine Robertson , Griffith Olivia , Agne April , McCullars Steve , Cohen Robert M. , Craig Jacqueline , Rogge M. Colleen , Burton Kathryn , Kersey Kimberly , Wilson Carla , Lipp Sonia , Vonder Meulen Mary Beth , Adkins Connie , Onadeko Tolu , Rasouli Neda , Baker Chelsea , Schroeder Emily , Razzaghi Mitra , Lyon Corey , Penaloza Richard , Underkofler Chantal , Lorch Rebecca , Douglass Sarah , Steiner Stephanie , Sivitz William , Cline Erin , Knosp Laura K , McConnell Jennifer , Lowe Tamara , Herman William H. , Pop-Busui Rodica , Tan Meng H. , Martin Catherine , Waltje Andrea , Katona Aimee , Goodhall Lynn , Eggleston Rebecca , Kuo Shihchen , Bojescu Stefana , Bule Stephanie , Kessler Nancy , LaSalle Elizabeth , Whitley Kelly , Seaquist Elizabeth R. , Bantle Anne , Harindhanavudhi Tasma , Kumar Anjali , Redmon Bruce , Bantle John , Coe Mary , Mech Michael , Taddese Abdisa , Lesne Lesia , Smith Shannon , Desouza Cyrus , Kuechenmeister Lisa , Shivaswamv Vijay , Burbach Susan , Rodriguez Maria Grace , Seipel Kris , Alfred Alissa , Morales Ana Laura , Eggert Jenna , Lord Grace , Taylor William , Tillson Renee , Schade David S. , Adolphe Allen , Burge Mark , Duran-Valdez Elizabeth , Martinez Janae , Bancroft Anna , Kunkel Susan , Jamaleddin Ahmad Fadi Ali , Hernandez McGinnis Doris , Pucchetti Benjamin , Scripsick Elizabeth , Zamorano Amy , DeFronzo Ralph A. , Cersosimo Eugenio , Abdul-Ghani Muhammad , Triplitt Curtis , Juarez Deanna , Garza Rosa Irene , Verastiqui Hector , Wright Kathryn , Puckett Curtiss , Raskin Philip , Rhee Chanhaeng , Abraham Soma , Jordan Lin Fan , Sao Serey , Morton Luisa , Smith Oralenda , Osornio Walker Laura , Schnurr-Breen Laura , Ayala Rosa Irene , Kreymer Robert Brian , Sturgess Daytheon , Utzschneider Kristina M , Kahn Steven E. , Alarcon-Casas Wright Lorena , Boyko Edward J. , Tsiai Elaine C. , Trence Dace L. , Trikudanathan Subblaxmi , Fattaleh Basma N. , Montgomery Brenda K , Atkinson Karen M. , Kozedub Alexandra , Concepcion Tessa , Moak Cameron , Prikhodko Nina , Rhothisen Samantha , Elasy Tom A. , Martin Stephanie , Shackelford Laura , Goidel Rita , Hinkle Nina , Lovell Cynthia , Myers Janet , Lipps Hogan Janie , McGill Janet B. , Salam Maamoun , Schweiger Toni , Kissel Sarah , Recklein Carol , Clifton Mary Jane , Tamborlane William , Camp Anne , Gulanski Barbara , Inzucchi Silvio E , Pham Kim , Alguard Michele , Gatcomb Patricia , Lessard Katarzyna , Perez Magalys , Iannone Lynne , Magenheimer Elizabeth , Montosa Abmaridel , Cefalu William T , Fradkin Judith , Burch Henry B. , Bremer Andrew , Nathan David M. , Lachin John M. , Krause-Steinrauf Heidi , Younes Naji , Bebu Ionut , Butera Nicole , Buys CJ , Fagan Anna , Gao Yuping , Ghosh Alokananda , Gramzinski Michaela R. , Hall Stephanie D. , Kazemi Erin , Legowski Elizabeth , Liu Haiyin , Suratt Colleen E. , Tripputi Mark , Arey Alyssa , Backman Michael , Bethepu Joel , Lund Claire , Mangat Dhaliwal Pam , McGee Paula , Mesimer Emily , Ngo Lisa , Steffes Michael , Seegmiller Jesse , Saenger Amy , Arends Valerie , Gabrielson Deanna , Conner Todd , Warren Stuart , Day Jolene , Huminik Jeffrey , Scrymgeour Alexandra , Soliman Elsayed Z. , Pokharel Yashashwi , Zhang Zhu-Ming , Campbell Charles , Hu Julie , Keasler Lisa , Hensley Susan , Li Yabing , Mihalcea Rada , Min Do June , Perez-Rosas Veronica , Prosser Lisa , Resnicow Kenneth , Ye Wen , Shao Hui , Zhang Ping , Luchsinger Jose , Sanchez Danurys , Assuras Stephanie , Groessl Erik , Sakha Fatema , Chong Helen , Hillery Naomi , Abdouch Ivan , Bahityar Gul , Brantley Paula , Broyles Frances E. , Canaris Gay , Copeland Paul , Craine Jeri J. , Fein Warren L. , Gliwa Agnieska , Hope Lisel M. , Lee Melissa S. , Meiners Rebecca , Meiners Vaughn , O'Neal Hollis , Park James E. , Sacerdote Alan , Sledge Edward , Soni Lisa , Steppel-Reznik Jeanne , Turchin Alexander 
Published: May 2023

Importance

Type 2 diabetes (T2D) is the leading cause of kidney disease in the US. It is not known whether glucose-lowering medications differentially affect kidney function.

Objective

To evaluate kidney outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) trial comparing 4 classes of glucose-lowering medications added to metformin for glycemic management in individuals with T2D.

Design, Setting, and Participants

A randomized clinical trial was conducted at 36 sites across the US. Participants included adults with T2D for less than 10 years, a hemoglobin A1clevel between 6.8% and 8.5%, and estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m2who were receiving metformin treatment. A total of 5047 participants were enrolled between July 8, 2013, and August 11, 2017, and followed up for a mean of 5.0 years (range, 0-7.6 years). Data were analyzed from February 21, 2022, to March 27, 2023.

Interventions

Addition of insulin glargine, glimepiride, liraglutide, or sitagliptin to metformin, with the medication combination continued until the HbA1cwas greater than 7.5%; thereafter, insulin was added to maintain glycemic control.

Main Outcomes and Measures

Chronic eGFR slope (change in eGFR between year 1 and trial end) and a composite kidney disease progression outcome (albuminuria, dialysis, transplant, or death due to kidney disease). Secondary outcomes included incident eGFR less than 60 mL/min/1.73 m2, 40% decrease in eGFR to less than 60 mL/min/1.73 m2, doubling of urine albumin-to-creatinine ratio (UACR) to 30 mg/g or greater, and progression of Kidney Disease Improving Global Outcomes stage. Analyses were intention-to-treat.

Results

Of the 5047 participants, 3210 (63.6%) were men. Baseline characteristics were mean (SD) age 57.2 (10.0) years; HbA1c7.5% (0.5%); diabetes duration, 4.2 (2.7) years; body mass index, 34.3 (6.8); blood pressure 128.3/77.3 (14.7/9.9) mm Hg; eGFR 94.9 (16.8) mL/min/1.73 m2; and median UACR, 6.4 (IQR 3.1-16.9) mg/g; 2933 (58.1%) were treated with renin-angiotensin-aldosterone inhibitors. Mean chronic eGFR slope was −2.03 (95% CI, −2.20 to −1.86) mL/min/1.73 m2per year for patients receiving sitagliptin; glimepiride, −1.92 (95% CI, −2.08 to −1.75) mL/min/1.73 m2per year; liraglutide, −2.08 (95% CI, −2.26 to −1.90) mL/min/1.73 m2per year; and insulin glargine, −2.02 (95% CI, −2.19 to −1.84) mL/min/1.73 m2per year (P = .61). Mean composite kidney disease progression occurred in 135 (10.6%) patients receiving sitagliptin; glimepiride, 155 (12.4%); liraglutide, 152 (12.0%); and insulin glargine, 150 (11.9%) (P = .56). Most of the composite outcome was attributable to albuminuria progression (98.4%). There were no significant differences by treatment assignment in secondary outcomes. There were no adverse kidney events attributable to medication assignment.

Conclusions and Relevance

In this randomized clinical trial, among people with T2D and predominantly free of kidney disease at baseline, no significant differences in kidney outcomes were observed during 5 years of follow-up when a dipeptidyl peptidase 4 inhibitor, sulfonylurea, glucagonlike peptide 1 receptor agonist, or basal insulin was added to metformin for glycemic control.

Trial Registration

ClinicalTrials.gov Identifier:NCT01794143