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

Reza Mohebi; Yuxi Liu; Michael K Hansen; Yshai Yavin; Naveed Sattar; Carol A Pollock; Javed Butler; Meg Jardine; Serge Masson; Hiddo J L Heerspink; James L Januzzi Jr

doi:10.1186/s12933-023-01916-2

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

Cardiovasc Diabetol. 2023 Jul 12;22(1):176. doi: 10.1186/s12933-023-01916-2.

Authors

Reza Mohebi¹, Yuxi Liu¹, Michael K Hansen², Yshai Yavin², Naveed Sattar³, Carol A Pollock⁴, Javed Butler^{5

6}, Meg Jardine^{7

8

9}, Serge Masson¹⁰, Hiddo J L Heerspink¹¹, James L Januzzi Jr^{12

13}

Affiliations

¹ Cardiology Division, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
² Janssen Research Development, LLC, Spring House, Montgomery, PA, USA.
³ BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
⁴ Kolling Institute, Royal North Shore Hospital University of Sydney, Sydney, NSW, Australia.
⁵ University of Mississippi Medical Center, Jackson, MS, USA.
⁶ Baylor Scott & White Institute, Dallas, TX, USA.
⁷ The George Institute for Global Health, UNSW Sydney, Sydney, NSW, Australia.
⁸ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.
⁹ Concord Repatriation General Hospital, Sydney, NSW, Australia.
¹⁰ Roche Diagnostics International, Rotkreuz, Switzerland.
¹¹ Department Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, The Netherlands.
¹² Cardiology Division, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA. jjanuzzi@partners.org.
¹³ Heart Failure and Biomarker Trials, Baim Institute for Clinical Research, Boston, MA, USA. jjanuzzi@partners.org.

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.

Keywords: Canagliflozin; Chronic kidney disease; Diabetes mellitus; IGF-1.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Canagliflozin
Diabetes Mellitus, Type 2* / diagnosis
Diabetes Mellitus, Type 2* / drug therapy
Diabetic Nephropathies* / diagnosis
Humans
Insulin
Insulin-Like Growth Factor Binding Protein 3
Insulin-Like Growth Factor I

Substances

Insulin
Insulin-Like Growth Factor I
Insulin-Like Growth Factor Binding Protein 3
Canagliflozin

Associated data

ClinicalTrials.gov/NCT02065791