Arginine or Hypertonic Saline-Stimulated Copeptin to Diagnose AVP Deficiency.

Journal

The New England journal of medicine
ISSN: 1533-4406
Titre abrégé: N Engl J Med
Pays: United States
ID NLM: 0255562

Informations de publication

Date de publication:
16 Nov 2023
Historique:
medline: 15 11 2023
pubmed: 15 11 2023
entrez: 15 11 2023
Statut: ppublish

Résumé

Distinguishing between arginine vasopressin (AVP) deficiency and primary polydipsia is challenging. Hypertonic saline-stimulated copeptin has been used to diagnose AVP deficiency with high accuracy but requires close sodium monitoring. Arginine-stimulated copeptin has shown similar diagnostic accuracy but with a simpler test protocol. However, data are lacking from a head-to-head comparison between arginine-stimulated copeptin and hypertonic saline-stimulated copeptin in the diagnosis of AVP deficiency. In this international, noninferiority trial, we assigned adult patients with polydipsia and hypotonic polyuria or a known diagnosis of AVP deficiency to undergo diagnostic evaluation with hypertonic-saline stimulation on one day and with arginine stimulation on another day. Two endocrinologists independently made the final diagnosis of AVP deficiency or primary polydipsia with use of clinical information, treatment response, and the hypertonic-saline test results. The primary outcome was the overall diagnostic accuracy according to prespecified copeptin cutoff values of 3.8 pmol per liter after 60 minutes for arginine and 4.9 pmol per liter once the sodium level was more than 149 mmol per liter for hypertonic saline. Of the 158 patients who underwent the two tests, 69 (44%) received the diagnosis of AVP deficiency and 89 (56%) received the diagnosis of primary polydipsia. The diagnostic accuracy was 74.4% (95% confidence interval [CI], 67.0 to 80.6) for arginine-stimulated copeptin and 95.6% (95% CI, 91.1 to 97.8) for hypertonic saline-stimulated copeptin (estimated difference, -21.2 percentage points; 95% CI, -28.7 to -14.3). Adverse events were generally mild with the two tests. A total of 72% of the patients preferred testing with arginine as compared with hypertonic saline. Arginine-stimulated copeptin at a value of 3.0 pmol per liter or less led to a diagnosis of AVP deficiency with a specificity of 90.9% (95% CI, 81.7 to 95.7), whereas levels of more than 5.2 pmol per liter led to a diagnosis of primary polydipsia with a specificity of 91.4% (95% CI, 83.7 to 95.6). Among adult patients with polyuria polydipsia syndrome, AVP deficiency was more accurately diagnosed with hypertonic saline-stimulated copeptin than with arginine-stimulated copeptin. (Funded by the Swiss National Science Foundation; CARGOx ClinicalTrials.gov number, NCT03572166.).

Sections du résumé

BACKGROUND BACKGROUND
Distinguishing between arginine vasopressin (AVP) deficiency and primary polydipsia is challenging. Hypertonic saline-stimulated copeptin has been used to diagnose AVP deficiency with high accuracy but requires close sodium monitoring. Arginine-stimulated copeptin has shown similar diagnostic accuracy but with a simpler test protocol. However, data are lacking from a head-to-head comparison between arginine-stimulated copeptin and hypertonic saline-stimulated copeptin in the diagnosis of AVP deficiency.
METHODS METHODS
In this international, noninferiority trial, we assigned adult patients with polydipsia and hypotonic polyuria or a known diagnosis of AVP deficiency to undergo diagnostic evaluation with hypertonic-saline stimulation on one day and with arginine stimulation on another day. Two endocrinologists independently made the final diagnosis of AVP deficiency or primary polydipsia with use of clinical information, treatment response, and the hypertonic-saline test results. The primary outcome was the overall diagnostic accuracy according to prespecified copeptin cutoff values of 3.8 pmol per liter after 60 minutes for arginine and 4.9 pmol per liter once the sodium level was more than 149 mmol per liter for hypertonic saline.
RESULTS RESULTS
Of the 158 patients who underwent the two tests, 69 (44%) received the diagnosis of AVP deficiency and 89 (56%) received the diagnosis of primary polydipsia. The diagnostic accuracy was 74.4% (95% confidence interval [CI], 67.0 to 80.6) for arginine-stimulated copeptin and 95.6% (95% CI, 91.1 to 97.8) for hypertonic saline-stimulated copeptin (estimated difference, -21.2 percentage points; 95% CI, -28.7 to -14.3). Adverse events were generally mild with the two tests. A total of 72% of the patients preferred testing with arginine as compared with hypertonic saline. Arginine-stimulated copeptin at a value of 3.0 pmol per liter or less led to a diagnosis of AVP deficiency with a specificity of 90.9% (95% CI, 81.7 to 95.7), whereas levels of more than 5.2 pmol per liter led to a diagnosis of primary polydipsia with a specificity of 91.4% (95% CI, 83.7 to 95.6).
CONCLUSIONS CONCLUSIONS
Among adult patients with polyuria polydipsia syndrome, AVP deficiency was more accurately diagnosed with hypertonic saline-stimulated copeptin than with arginine-stimulated copeptin. (Funded by the Swiss National Science Foundation; CARGOx ClinicalTrials.gov number, NCT03572166.).

Identifiants

DOI: 10.1056/NEJMoa2306263 PMID: 37966286
pubmed: 37966286
doi: 10.1056/NEJMoa2306263
doi:

Banques de données

ClinicalTrials.gov
['NCT03572166']

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

1877-1887

Subventions

Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
ID : P2BSP3-181720
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
ID : SNF-162608
Organisme : Schweizerische Akademie der Medizinischen Wissenschaften
ID : none
Organisme : Fundação de Amparo à Pesquisa do Estado de Minas Gerais
ID : FAPEMIG-APQ-01521-21
Organisme : NIHR Cambridge Biomedical Research Centre
ID : none
Organisme : Thermo Fisher Scientific
ID : Copeptin measurement

Informations de copyright

Copyright © 2023 Massachusetts Medical Society.

Auteurs

Julie Refardt (J)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.
ORCID: 0000-0002-3040-4685

Cihan Atila (C)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.
ORCID: 0000-0002-5442-7304

Irina Chifu (I)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.

Emanuele Ferrante (E)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.

Zoran Erlic (Z)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.
ORCID: 0000-0001-6953-9133

Juliana B Drummond (JB)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.

Rita Indirli (R)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.

Roosmarijn C Drexhage (RC)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.

Clara O Sailer (CO)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.
ORCID: 0000-0001-6439-8191

Andrea Widmer (A)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.

Susan Felder (S)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.

Andrew S Powlson (AS)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.

Nina Hutter (N)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.

Deborah R Vogt (DR)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.

Mark Gurnell (M)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.

Beatriz S Soares (BS)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.

Johannes Hofland (J)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.

Felix Beuschlein (F)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.

Martin Fassnacht (M)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.
ORCID: 0000-0001-6170-6398

Bettina Winzeler (B)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.
ORCID: 0000-0001-8305-2700

Mirjam Christ-Crain (M)

From the Departments of Endocrinology, Diabetology, and Metabolism (J.R., C.A., C.O.S., A.W., S.F., N.H., B.W., M.C.-C.) and Clinical Research (J.R., C.A., C.O.S., A.W., S.F., N.H., D.R.V., B.W., M.C.-C.), University Hospital Basel, University of Basel, Basel, and the Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich (Z.E., F.B.), and the LOOP Zurich-Medical Research Center (F.B.), Zurich - all in Switzerland; the Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands (J.R., R.C.D., J.H.); the Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg (I.C., M.F.), and Central Laboratory, University Hospital Würzburg (M.F.), Würzburg, and Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig Maximilians Universität München, Munich (F.B.) - all in Germany; the Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.F., R.I.), and the Department of Clinical Sciences and Community Health, University of Milan (R.I.) - both in Milan; the Department of Internal Medicine, Medical School of the Federal University of Minas Gerais, Belo Horizonte, Brazil (J.B.D., B.S.S.); and Wellcome-MRC Institute of Metabolic Science, University of Cambridge and Addenbrooke's Hospital, Cambridge Biomedical Campus (A.S.P., M.G.) and Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals (M.G.) - both in Cambridge, United Kingdom.

Classifications MeSH