Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes

Alessandro Doria; Andrzej T Galecki; Cathie Spino; Rodica Pop-Busui; David Z Cherney; Ildiko Lingvay; Afshin Parsa; Peter Rossing; Ronald J Sigal; Maryam Afkarian; Ronnie Aronson; M Luiza Caramori; Jill P Crandall; Ian H de Boer; Thomas G Elliott; Allison B Goldfine; J Sonya Haw; Irl B Hirsch; Amy B Karger; David M Maahs; Janet B McGill; Mark E Molitch; Bruce A Perkins; Sarit Polsky; Marlon Pragnell; William N Robiner; Sylvia E Rosas; Peter Senior; Katherine R Tuttle; Guillermo E Umpierrez; Amisha Wallia; Ruth S Weinstock; Chunyi Wu; Michael Mauer; PERL Study Group

doi:10.1056/NEJMoa1916624

Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes

N Engl J Med. 2020 Jun 25;382(26):2493-2503. doi: 10.1056/NEJMoa1916624.

Authors

Alessandro Doria¹, Andrzej T Galecki¹, Cathie Spino¹, Rodica Pop-Busui¹, David Z Cherney¹, Ildiko Lingvay¹, Afshin Parsa¹, Peter Rossing¹, Ronald J Sigal¹, Maryam Afkarian¹, Ronnie Aronson¹, M Luiza Caramori¹, Jill P Crandall¹, Ian H de Boer¹, Thomas G Elliott¹, Allison B Goldfine¹, J Sonya Haw¹, Irl B Hirsch¹, Amy B Karger¹, David M Maahs¹, Janet B McGill¹, Mark E Molitch¹, Bruce A Perkins¹, Sarit Polsky¹, Marlon Pragnell¹, William N Robiner¹, Sylvia E Rosas¹, Peter Senior¹, Katherine R Tuttle¹, Guillermo E Umpierrez¹, Amisha Wallia¹, Ruth S Weinstock¹, Chunyi Wu¹, Michael Mauer¹; PERL Study Group

Collaborators

PERL Study Group:
Alessandro Doria, Michael Mauer, Ronnie Aronson, Maria Luiza Caramori, Jill P Crandall, Ian H de Boer, John H Eckfeldt, Thomas G Elliott, Michael Flessner, Andrzej T Galecki, Allison B Goldfine, Irl B Hirsch, Amy B Karger, Ildiko Lingvay, David M Maahs, Janet B McGill, Mark E Molitch, Helen Nickerson, Afshin Parsa, Bruce A Perkins, Sarit Polsky, Rodica Pop-Busui, Marlon Pragnell, Sylvia E Rosas, Peter Rossing, Peter Senior, Ronald J Sigal, Catherine Spino, Katherine R Tuttle, Guillermo E Umpierrez, Donna DiFranco, Massimo Pietropaolo, Yi-Miau Tsai, Chunyi Wu, William Robiner, Sylvia Rosas, Enrico Cagliero, Michael Thompson, Ruth S Weinstock, Christina Gjerlev-Poulsen, Maria Lajer, Frederik Persson, Sascha Pilemann-Lyberg, Signe A Winther, Mary Frohauer, San Thida, Peter Gottlieb, David Maahs, Viral Shah, Emily Schroeder, Michael McDermott, Lynn Ang, Frank C Brosius 3rd, Nazanene H Esfandiari, Kara Mizokami-Stout, Rachel Perlman, Arti Bhan, Davida Kruger, Wenyu Huang, Amisha Wallia, Matthew K Abramowitz, Valentin Anghel, Erika Brutsaert, Nithya Mani, Divya Rajasekaran, Carol Levy, Melissa Katz, Naina Sinha, Gregory Nobuyuki, Bill Miyawaki, Shayan Shirazian, Ulrich K Schubart, David Cherney, Lorraine L Lipscombe, Andrew Advani, Ronald Goldenberg, Amy Riek, Maamoun Salam, Julie McKeen, Peter Senior, Rose Yeung, J Sonya Haw, Bruce W Bode, Darin Olson, Maryam Afkarian, Dace L Trence, Grace Lee, Ildiko Lingvay, Radica Alicic

Affiliation

¹ From the Research Division, Joslin Diabetes Center, and the Department of Medicine, Harvard Medical School, Boston (A.D., A.B.G., S.E.R.); the Division of Geriatrics, Institute of Gerontology (A.T.G., C.W.), the Department of Biostatistics, School of Public Health (A.T.G., C.S.), Statistical Analysis of Biomedical and Educational Research (SABER) (C.S.), and the Department of Internal Medicine, Metabolism, Endocrinology, and Diabetes (R.P.-B.), University of Michigan, Ann Arbor; the Departments of Medicine, Physiology, and Pharmacology and Toxicology (D.Z.C.) and the Division of Endocrinology and Metabolism (B.A.P.), University of Toronto, the Division of Nephrology, University Health Network (D.Z.C.), LMC Diabetes and Endocrinology (R.A.), and Lunenfeld-Tanenbaum Research Institute, Sinai Health System (B.A.P.), Toronto, the Departments of Medicine, Cardiac Sciences, and Community Health Sciences, Faculties of Medicine and Kinesiology, University of Calgary, Calgary, AB (R.J.S.), BCDiabetes, Vancouver (T.G.E.), and the Division of Endocrinology, University of Alberta, Edmonton (P.S.) - all in Canada; the Departments of Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD (A.P.); Steno Diabetes Center, and the Department of Clinical Medicine, University Copenhagen, Copenhagen (P.R.); the Division of Nephrology, Department of Medicine, University of California, Davis (M.A.), and the Department of Pediatrics and Stanford Diabetes Research Center, Stanford University, Palo Alto (D.M.M.) - both in California; the Departments of Medicine and Pediatrics (M.L.C., W.N.R.. M.M.) and Laboratory Medicine and Pathology (A.B.K.), University of Minnesota, Minneapolis; the Division of Endocrinology and Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine (J.P.C.), and JDRF (Juvenile Diabetes Research Foundation) (M.P.), New York; the Department of Medicine (I.H.B., I.B.H.) and the Nephrology Division (K.R.T.), University of Washington, and the Institute of Translational Health Sciences, Kidney Research Institute (K.R.T.), Seattle, and Providence Health Care, Spokane (K.R.T.) - both in Washington; the Department of Medicine, Emory University, Atlanta (J.S.H., G.E.U.); the Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis (J.B.M.); the Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago (M.E.M., A.W.); the Barbara Davis Center for Diabetes, University of Colorado, Aurora (S.P.); and the Department of Medicine, State University of New York Upstate Medical University, Syracuse (R.S.W.).

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. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.).

Publication types

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

MeSH terms

Adult
Aged
Allopurinol / adverse effects
Allopurinol / therapeutic use*
Diabetes Mellitus, Type 1 / blood
Diabetes Mellitus, Type 1 / drug therapy*
Diabetes Mellitus, Type 1 / physiopathology
Diabetic Nephropathies / prevention & control*
Double-Blind Method
Enzyme Inhibitors / adverse effects
Enzyme Inhibitors / therapeutic use*
Female
Glomerular Filtration Rate / drug effects*
Humans
Male
Middle Aged
Renin-Angiotensin System
Treatment Failure
Uric Acid / blood*
Xanthine Oxidase / antagonists & inhibitors*

Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes

Authors

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Abstract

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