Serum urate lowering with allopurinol and kidney function in type 1 diabetes

A. Doria, A. T. Galecki, C. Spino, R. Pop-Busui, D. Z. Cherney, I. Lingvay, A. Parsa, P. Rossing, R. J. Sigal, M. Afkarian, R. Aronson, M. L. Caramori, J. P. Crandall, I. H. De Boer, T. G. Elliott, A. B. Goldfine, J. S. Haw, I. B. Hirsch, A. B. Karger, D. M. MaahsJ. B. McGill, M. E. Molitch, B. A. Perkins, S. Polsky, M. Pragnell, W. N. Robiner, S. E. Rosas, P. Senior, K. R. Tuttle, G. E. Umpierrez, A. Wallia, R. S. Weinstock, C. Wu, M. Mauer

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

BACKGROUND: Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease. METHODS: In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m2 of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed. RESULTS: A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m2 in the allopurinol group and 67.3 ml per minute per 1.73 m2 in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m2 (95% confidence interval [CI], -1.9 to 1.9; P = 0.99). The mean decrease in the iohexol-based GFR was -3.0 ml per minute per 1.73 m2 per year with allopurinol and -2.5 ml per minute per 1.73 m2 per year with placebo (between-group difference, -0.6 ml per minute per 1.73 m2 per year; 95% CI, -1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups. CONCLUSIONS: We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease.

Original languageEnglish (US)
Pages (from-to)2493-2503
Number of pages11
JournalNew England Journal of Medicine
Volume382
Issue number26
DOIs
StatePublished - Jun 25 2020

Bibliographical note

Funding Information:
data and safety monitoring committee from Merck and Pfizer, and grant support, paid to Northwestern University, from No-vartis and Novo Nordisk; Dr. Perkins, receiving consulting fees from Boehringer Ingelheim; Dr. Polsky, receiving grant support from Dexcom, Daisome Pharmaceuticals, Eli Lilly, Lexicon Pharmaceuticals, and Sanofi US Services, and grant support and advisory board fees from Medtronic MiniMed; Dr. Rosas, receiving grant support and advisory board fees from Bayer HealthCare Pharmaceuticals, grant support from Gilead Sciences, Idorsia, Ironwood Pharmaceuticals, and Janssen Pharmaceuticals, and advisory board fees from Reata Pharmaceuticals; Dr. Senior, receiving advisory board fees from Abbott Canada, AstraZeneca Canada, Boehringer Ingelheim, Eli Lilly, Janssen Biotech, Merck, and Sanofi Pasteur, grant support, paid to the University of Alberta, from Allergan, and grant support, paid to the University of Alberta, and advisory board fees from Novo Nordisk; Dr. Tuttle, receiving consulting fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Gilead Sciences, Goldfinch Bio, and Novo Nordisk and honoraria from Bayer; Dr. Wallia, receiving grant support from Novo Nordisk; and Dr. Weinstock, receiving grant support, paid to the Research Foundation of SUNY, from Boehringer Ingelheim, Dexcom, Diasome Pharmaceuticals, Eli Lilly, Insulet, Medtronic MiniMed, Mylan Pharmaceuticals, Oramed Pharmaceuticals, and Tolerion and consulting fees from InsuLogix. No other potential conflict of interest relevant to this article was reported.

Funding Information:
Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171. Supported by grants from the NIDDK (R03-DK-094484, R34-DK-097808, UC4-DK-101108, P30-DK-036836, and P30-DK-020572), the JDRF (17-2012-377), the National Center for Advancing Translational Sciences (UL1-TR-002494, UL1-TR-001422, UL1-TR-002556, UL1-TR-002319, and UL1-TR-001105), and the National Institute on Aging (Claude Pepper Center grant number, P30-AG-024824). Dr. Doria reports receiving grant support, paid to Joslin Diabetes Center, from Sanofi-Aventis US; Dr. Pop-Busui, receiving grant support, paid to the University of Michigan, from Astra-Zeneca and consulting fees from Bayer, Boehringer Ingelheim, and Novo Nordisk; Dr. Lingvay, receiving advisory board fees and consulting fees from AstraZeneca, advisory board fees from Boehringer Ingelheim, consulting fees from Eli Lilly, Intarcia Therapeutics, Janssen Global Services, Target Pharma Solutions, and Valeritas Holdings, grant support, paid to her institution, from Mylan Pharmaceuticals and Pfizer, grant support, paid to the University of Texas Southwestern, advisory board fees, consulting fees, and travel support from Novo Nordisk, and advisory board fees from Sanofi US Services; Dr. Rossing, receiving advisory board fees from Astellas Pharma, Boehringer Ingelheim, and Sanofi US Services, advisory board fees and fees for serving on a steering committee from AstraZeneca, Bayer HealthCare, and Novo Nordisk, consulting fees from Eli Lilly, and fees for serving on a steering committee from Gilead Sciences; Dr. Aronson, receiving grant support and consulting fees from Astra-Zeneca Canada, Becton Dickinson Technologies, Boehringer Ingelheim, Eli Lilly, Janssen Global Services, Novo Nordisk, and Sanofi US Services, grant support from Bausch Health, Bayer, Dexcom, Insulet, Kowa American, Medpace, Tandem Diabetes Care, Xeris Pharmaceuticals, and Zealand Pharma, and consulting fees from Gilead Sciences, HTL-STREFA, and Merck; Dr. Caramori, receiving advisory board fees and presentation fees, paid to her institution, from Bayer; Dr. Crandall, receiving grant support from Abbott Diabetes Care; Dr. de Boer, receiving advisory fees from Boehringer Ingelheim, George Clinical, Goldfinch Bio, and Ironwood Pharmaceuticals; Dr. Goldfine, being employed by Novartis; Dr. Hirsch, receiving consulting fees from Abbott Diabetes Care, Bigfoot Biomedical, and Roche Diabetes Care and grant support, paid to the University of Washington, from Medtronic MiniMed; Dr. Karger, receiving grant support, paid to the University of Minnesota, from Kyowa Kirin and Siemens; Dr. Maahs, receiving consulting fees from Abbott Diabetes Care, grant support, paid to Stanford University, from Dexcom and Tandem Diabetes Care, and advisory board fees from Eli Lilly, Medtronic USA, Novo Nordisk, and Sanofi Pasteur; Dr. Molitch, receiving consulting fees and fees for serving as an expert witness from Janssen Biotech, fees for serving on a data and safety monitoring committee from Merck and Pfizer, and grant support, paid to Northwestern University, from No-vartis and Novo Nordisk; Dr. Perkins, receiving consulting fees from Boehringer Ingelheim; Dr. Polsky, receiving grant support from Dexcom, Daisome Pharmaceuticals, Eli Lilly, Lexicon Pharmaceuticals, and Sanofi US Services, and grant support and advisory board fees from Medtronic MiniMed; Dr. Rosas, receiving grant support and advisory board fees from Bayer HealthCare Pharmaceuticals, grant support from Gilead Sciences, Idorsia, Ironwood Pharmaceuticals, and Janssen Pharmaceuticals, and advisory board fees from Reata Pharmaceuticals; Dr. Senior, receiving advisory board fees from Abbott Canada, Astra Zeneca Canada, Boehringer Ingelheim, Eli Lilly, Janssen Biotech, Merck, and Sanofi Pasteur, grant support, paid to the University of Alberta, from Allergan, and grant support, paid to the University of Alberta, and advisory board fees from Novo Nordisk; Dr. Tuttle, receiving consulting fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Gilead Sciences, Goldfinch Bio, and Novo Nordisk and honoraria from Bayer; Dr. Wallia, receiving grant support from Novo Nordisk; and Dr. Weinstock, receiving grant support, paid to the Research Foundation of SUNY, from Boehringer Ingelheim, Dexcom, Diasome Pharmaceuticals, Eli Lilly, Insulet, Medtronic MiniMed, Mylan Pharmaceuticals, Oramed Pharmaceuticals, and Tolerion and consulting fees from InsuLogix. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank the patients for participating in this long and demanding trial; the data and safety monitoring board members (Linda Fried, Ananda Basu, Melanie Blank, Tom Greene, Lawrence Holzman, Charity G. Moore Patterson, and John Sedor); NIH officers Teresa Jones, Robert Star, and Michael Flessner and regulatory program specialist Catherine Carr for guidance; the staff of Green Mountain Pharmaceuticals and Belmar Pharmacy (Lakewood, CO) for preparing and distributing allopurinol and placebo; all the research coordinators (Daphne Adelman, Gayatri Anupindi, Cathy Bagne, Mary Bates, Karen Belanger, Emily Boone, Jane Bulger, Leslie Cham, Jing H. Chao, Mary Ann Clearwaters, Mary Jane Clifton, Hector Com, Kristie DeHaan, Tineke Dineen, Amy Dunlop, Sara Eischen, C. Marcelo Falappa, Lestat Feliciano, Birgit Fink, Benjamin Flagg, Victoria Gage, Jason Gensler, Anne Goodling, Monica Hartmuller, Jessie Arman Hermann, Madeleine Hermans, Xinli Huang, Karen Hyams, Marla Inducil, Lone Jelstrup, Florence John, Yvette Kowalski, Vesta Lai, Lee-Ann Langkaas, Diane Larsen, Virginia Leone, Camilla Le-vister, Dawn Lum, Caroline Lyster, Maria Maione, Elaine Massaro, Jennifer McCance, Christine Mendonca, Sara R. Meyers, Joan Milton, Cindy A. Murphy, Andrej Orszag, Cynthia Plunkett, Carmyn Polk, Laurentiu Pop, Frederik Persson, Danielle Powell, Chinmaya Rajderkar, Clementina Ramos Garrido, Carol Recklein, Marilyn Richardson, Nicole Robinson, Lauri Schafer, Michelle Smith, Anna-Kay Thompson, Lindsey Towers, Josephine Tse, Joanie Tsougrianis, Victoria Tully, Sara Vecchi, Katherine Wilder, Tanisha Wilma, and Brittany Williams); Trudy Strand and Debra Conboy for leading the team of coordinators; Donna DiFranco, Glen Feak, Vasundhara Goplani, Eric Henricks, Lisa Holloway, Navasuja Kumar, Brooke Kilyanek, Ariane Nguyen, and Yi-Miau Tsai for work at the data coordinating center; Theresa Christiansen for serving as the trial pharmacologist; Massimo Pietropaolo for serving as the trial medical monitor; Annie Lukkari, Catherine Leiendecker Foster, and the staff of the Advanced Research and Diagnostic Laboratory at the University of Minnesota for laboratory measurements; and Geert Molenberghs and Rod Little for comments and suggestions on the statistical analytic approaches.

Funding Information:
The rationale and design of this double-blind, multicenter, randomized, placebo-controlled clinical trial of allopurinol have been published previously.22 The trial, which was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and JDRF (previously known as the Juvenile Diabetes Research Foundation), was conducted at 16 sites in the United States, Canada, and Denmark. The first author served as the sponsor-investigator (according to the Food and Drug Administration, a person who initiates and conducts an investigation and under whose immediate direction the investigational drug is administered or dispensed). Members of the steering committee designed the trial, supervised its conduct, and were responsible for reporting the results. Analyses were performed by the trial statistical team, which comprised three authors. Five of the authors wrote the initial draft of the manuscript, and all the authors contributed to revisions. The decision to submit the manuscript for publication was made jointly by all the authors, who also vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol (available with the full text of this article at NEJM.org). The iohexol that was used for assessing the iohexol-based GFR was donated by GE Healthcare, which had no role in the trial design or conduct or in the data collection or analysis but which reviewed the manuscript to ensure that no confidential information was disclosed.

Funding Information:
Supported by grants from the NIDDK (R03-DK-094484, R34-DK-097808, UC4-DK-101108, P30-DK-036836, and P30-DK-020572), the JDRF (17-2012-377), the National Center for Advancing Translational Sciences (UL1-TR-002494, UL1-TR-001422, UL1-TR-002556, UL1-TR-002319, and UL1-TR-001105), and the National Institute on Aging (Claude Pepper Center grant number, P30-AG-024824).

Publisher Copyright:
Copyright © 2020 Massachusetts Medical Society.

PubMed: MeSH publication types

  • Journal Article
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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