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

Mohebi, R. et al. (2023) Insulin growth factor axis and cardio-renal risk in diabetic kidney disease: an analysis from the CREDENCE trial. Cardiovascular Diabetology, 22, 176. (doi: 10.1186/s12933-023-01916-2) (PMID:37438734) (PMCID:PMC10339517)

Abstract

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.

• Item Type: Articles
• Keywords: IGF-1, canagliflozin, chronic kidney disease, diabetes mellitus.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sattar, Professor Naveed
• Authors: Mohebi, R., Liu, Y., Hansen, M. K., Yavin, Y., Sattar, N., Pollock, C. A., Butler, J., Jardine, M., Masson, S., Heerspink, H. J. L., and Januzzi Jr, J. L.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Cardiovascular Diabetology
• Publisher: BioMed Central
• ISSN: 1475-2840
• ISSN (Online): 1475-2840
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Cardiovascular Diabetology 22: 176
• Publisher Policy: Reproduced under a Creative Commons License