Insulin growth factor axis and cardio-renal risk in diabetic kidney disease: an analysis from the CREDENCE trial

BACKGROUND: The insulin-like growth factors (IGF) play a crucial role in regulating cellular proliferation, apoptosis, and key metabolic pathways. The ratio of IGF-1 to IGF binding protein-3 (IGFBP-3) is an important factor in determining IGF-1 bioactivity. We sought to investigate the association o...

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Autores principales: Mohebi, Reza, Liu, Yuxi, Hansen, Michael K., Yavin, Yshai, Sattar, Naveed, Pollock, Carol A., Butler, Javed, Jardine, Meg, Masson, Serge, Heerspink, Hiddo J. L., Januzzi Jr, James L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10339517/
https://www.ncbi.nlm.nih.gov/pubmed/37438734
http://dx.doi.org/10.1186/s12933-023-01916-2
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author Mohebi, Reza
Liu, Yuxi
Hansen, Michael K.
Yavin, Yshai
Sattar, Naveed
Pollock, Carol A.
Butler, Javed
Jardine, Meg
Masson, Serge
Heerspink, Hiddo J. L.
Januzzi Jr, James L.
author_facet Mohebi, Reza
Liu, Yuxi
Hansen, Michael K.
Yavin, Yshai
Sattar, Naveed
Pollock, Carol A.
Butler, Javed
Jardine, Meg
Masson, Serge
Heerspink, Hiddo J. L.
Januzzi Jr, James L.
author_sort Mohebi, Reza
collection PubMed
description BACKGROUND: The insulin-like growth factors (IGF) play a crucial role in regulating cellular proliferation, apoptosis, and key metabolic pathways. The ratio of IGF-1 to IGF binding protein-3 (IGFBP-3) is an important factor in determining IGF-1 bioactivity. We sought to investigate the association of IGF-1 and IGFBP-3 with cardio-renal outcomes among persons with type 2 diabetes. METHODS: Samples were available from 2627 individuals with type 2 diabetes and chronic kidney disease that were randomized to receive canagliflozin or placebo and were followed up for incident cardio-renal events. Primary outcome was defined as a composite of end-stage kidney disease, doubling of the serum creatinine level, or renal/cardiovascular death. IGF-1 and IGFBP-3 were measured at baseline, Year-1 and Year-3. Elevated IGF-1 level was defined according to age-specific cutoffs. Cox proportional hazard regression was used to investigate the association between IGF-1 level, IGFBP-3, and the ratio of IGF-1/IGFBP-3 with clinical outcomes. RESULTS: Elevated IGF-1 was associated with lower glomerular filtration rate at baseline. Treatment with canagliflozin did not significantly change IGF-1 and IGFBP-3 concentrations by 3 years (p-value > 0.05). In multivariable models, elevated IGF-1 (above vs below age-specific cutoffs) was associated with the primary composite outcome (incidence rate:17.8% vs. 12.7% with a hazard ratio [HR]: 1.52; 95% confidence interval CI 1.09–2.13;P: 0.01), renal composite outcome (HR: 1.65; 95% CI 1.14–2.41; P: 0.01), and all-cause mortality (HR: 1.52; 95% CI 1.00–2.32; P; 0.05). Elevations in log IGFBP-3 did not associate with any clinical outcomes. Increase in log IGF-1/IGFBP-3 ratio was also associated with a higher risk of the primary composite outcome (HR per unit increase: 1.57; 95% CI 1.09–2.26; P; 0.01). CONCLUSIONS: These results further suggest potential importance of IGF biology in the risk for cardio-renal outcomes in type 2 diabetes. SGLT2 inhibition has no impact on the biology of IGF despite its significant influence on outcomes. Trial registration: CREDENCE; ClinicalTrials.gov Identifier: NCT02065791. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12933-023-01916-2.
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spelling pubmed-103395172023-07-14 Insulin growth factor axis and cardio-renal risk in diabetic kidney disease: an analysis from the CREDENCE trial Mohebi, Reza Liu, Yuxi Hansen, Michael K. Yavin, Yshai Sattar, Naveed Pollock, Carol A. Butler, Javed Jardine, Meg Masson, Serge Heerspink, Hiddo J. L. Januzzi Jr, James L. Cardiovasc Diabetol Research BACKGROUND: The insulin-like growth factors (IGF) play a crucial role in regulating cellular proliferation, apoptosis, and key metabolic pathways. The ratio of IGF-1 to IGF binding protein-3 (IGFBP-3) is an important factor in determining IGF-1 bioactivity. We sought to investigate the association of IGF-1 and IGFBP-3 with cardio-renal outcomes among persons with type 2 diabetes. METHODS: Samples were available from 2627 individuals with type 2 diabetes and chronic kidney disease that were randomized to receive canagliflozin or placebo and were followed up for incident cardio-renal events. Primary outcome was defined as a composite of end-stage kidney disease, doubling of the serum creatinine level, or renal/cardiovascular death. IGF-1 and IGFBP-3 were measured at baseline, Year-1 and Year-3. Elevated IGF-1 level was defined according to age-specific cutoffs. Cox proportional hazard regression was used to investigate the association between IGF-1 level, IGFBP-3, and the ratio of IGF-1/IGFBP-3 with clinical outcomes. RESULTS: Elevated IGF-1 was associated with lower glomerular filtration rate at baseline. Treatment with canagliflozin did not significantly change IGF-1 and IGFBP-3 concentrations by 3 years (p-value > 0.05). In multivariable models, elevated IGF-1 (above vs below age-specific cutoffs) was associated with the primary composite outcome (incidence rate:17.8% vs. 12.7% with a hazard ratio [HR]: 1.52; 95% confidence interval CI 1.09–2.13;P: 0.01), renal composite outcome (HR: 1.65; 95% CI 1.14–2.41; P: 0.01), and all-cause mortality (HR: 1.52; 95% CI 1.00–2.32; P; 0.05). Elevations in log IGFBP-3 did not associate with any clinical outcomes. Increase in log IGF-1/IGFBP-3 ratio was also associated with a higher risk of the primary composite outcome (HR per unit increase: 1.57; 95% CI 1.09–2.26; P; 0.01). CONCLUSIONS: These results further suggest potential importance of IGF biology in the risk for cardio-renal outcomes in type 2 diabetes. SGLT2 inhibition has no impact on the biology of IGF despite its significant influence on outcomes. Trial registration: CREDENCE; ClinicalTrials.gov Identifier: NCT02065791. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12933-023-01916-2. BioMed Central 2023-07-12 /pmc/articles/PMC10339517/ /pubmed/37438734 http://dx.doi.org/10.1186/s12933-023-01916-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Mohebi, Reza
Liu, Yuxi
Hansen, Michael K.
Yavin, Yshai
Sattar, Naveed
Pollock, Carol A.
Butler, Javed
Jardine, Meg
Masson, Serge
Heerspink, Hiddo J. L.
Januzzi Jr, James L.
Insulin growth factor axis and cardio-renal risk in diabetic kidney disease: an analysis from the CREDENCE trial
title Insulin growth factor axis and cardio-renal risk in diabetic kidney disease: an analysis from the CREDENCE trial
title_full Insulin growth factor axis and cardio-renal risk in diabetic kidney disease: an analysis from the CREDENCE trial
title_fullStr Insulin growth factor axis and cardio-renal risk in diabetic kidney disease: an analysis from the CREDENCE trial
title_full_unstemmed Insulin growth factor axis and cardio-renal risk in diabetic kidney disease: an analysis from the CREDENCE trial
title_short Insulin growth factor axis and cardio-renal risk in diabetic kidney disease: an analysis from the CREDENCE trial
title_sort insulin growth factor axis and cardio-renal risk in diabetic kidney disease: an analysis from the credence trial
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10339517/
https://www.ncbi.nlm.nih.gov/pubmed/37438734
http://dx.doi.org/10.1186/s12933-023-01916-2
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