Canagliflozin and iron metabolism in the CREDENCE trial.

anemia cardiovascular chronic kidney disease iron deficiency sodium-glucose cotransporter 2 inhibitors

Journal

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
ISSN: 1460-2385
Titre abrégé: Nephrol Dial Transplant
Pays: England
ID NLM: 8706402

Informations de publication

Date de publication:
20 Sep 2024
Historique:
medline: 21 9 2024
pubmed: 21 9 2024
entrez: 20 9 2024
Statut: aheadofprint

Résumé

Studies in patients with heart failure have indicated that sodium-glucose cotransporter 2 (SGLT2) inhibitors increase iron use and enhance erythropoiesis. In this post-hoc analysis of the CREDENCE trial, we evaluated the effects of canagliflozin on iron metabolism in patients with chronic kidney disease (CKD) and whether the effects of canagliflozin on hemoglobin and cardiorenal outcomes were modified by iron deficiency. We measured serum iron, total iron binding capacity (TIBC), transferrin saturation (TSAT) and ferritin at baseline and 12 months. The effects of canagliflozin, relative to placebo, on iron markers were assessed with analysis of covariance. Interactions between baseline iron deficiency, defined as TSAT < 20%, and the effects of canagliflozin on hemoglobin and cardiorenal outcomes were evaluated with mixed effect models and Cox regression models, respectively. Of 4401 participants randomized in CREDENCE, 2416 (54.9%) had iron markers measured at baseline, of whom 924 (38.2%) were iron deficient. Canagliflozin, compared to placebo, increased TIBC by 2.1% (95%CI 0.4-3.8; p = 0.014) and decreased ferritin by 11.5% (95%CI 7.1-15.7; p < 0.001) with no clear effect on serum iron or TSAT. Canagliflozin increased hemoglobin over the trial duration by 7.3 g/L (95% CI 6.2-8.5; p < 0.001) and 6.7 g/L (95% CI 5.2- 8.2; p < 0.001) in patients with and without iron deficiency, respectively (p-interaction = 0.38). The relative effect of canagliflozin on the primary outcome of doubling of serum creatinine, kidney failure or death due to cardiovascular disease or kidney failure (HR 0.70, 95%CI 0.56-0.87) was consistent regardless of iron deficiency (p-interaction 0.83), as were effects on other cardiovascular and mortality outcomes (all p-interactions ≥ 0.10). Iron deficiency is highly prevalent in patients with type 2 diabetes and CKD. Canagliflozin increased TIBC and decreased ferritin in patients with T2D and CKD, suggesting increased iron utilization, and improved hemoglobin levels and clinical outcomes regardless of iron deficiency.

Sections du résumé

BACKGROUND AND HYPOTHESIS OBJECTIVE
Studies in patients with heart failure have indicated that sodium-glucose cotransporter 2 (SGLT2) inhibitors increase iron use and enhance erythropoiesis. In this post-hoc analysis of the CREDENCE trial, we evaluated the effects of canagliflozin on iron metabolism in patients with chronic kidney disease (CKD) and whether the effects of canagliflozin on hemoglobin and cardiorenal outcomes were modified by iron deficiency.
METHODS METHODS
We measured serum iron, total iron binding capacity (TIBC), transferrin saturation (TSAT) and ferritin at baseline and 12 months. The effects of canagliflozin, relative to placebo, on iron markers were assessed with analysis of covariance. Interactions between baseline iron deficiency, defined as TSAT < 20%, and the effects of canagliflozin on hemoglobin and cardiorenal outcomes were evaluated with mixed effect models and Cox regression models, respectively.
RESULTS RESULTS
Of 4401 participants randomized in CREDENCE, 2416 (54.9%) had iron markers measured at baseline, of whom 924 (38.2%) were iron deficient. Canagliflozin, compared to placebo, increased TIBC by 2.1% (95%CI 0.4-3.8; p = 0.014) and decreased ferritin by 11.5% (95%CI 7.1-15.7; p < 0.001) with no clear effect on serum iron or TSAT. Canagliflozin increased hemoglobin over the trial duration by 7.3 g/L (95% CI 6.2-8.5; p < 0.001) and 6.7 g/L (95% CI 5.2- 8.2; p < 0.001) in patients with and without iron deficiency, respectively (p-interaction = 0.38). The relative effect of canagliflozin on the primary outcome of doubling of serum creatinine, kidney failure or death due to cardiovascular disease or kidney failure (HR 0.70, 95%CI 0.56-0.87) was consistent regardless of iron deficiency (p-interaction 0.83), as were effects on other cardiovascular and mortality outcomes (all p-interactions ≥ 0.10).
CONCLUSIONS CONCLUSIONS
Iron deficiency is highly prevalent in patients with type 2 diabetes and CKD. Canagliflozin increased TIBC and decreased ferritin in patients with T2D and CKD, suggesting increased iron utilization, and improved hemoglobin levels and clinical outcomes regardless of iron deficiency.

Identifiants

DOI: 10.1093/ndt/gfae198 PMID: 39304530
pubmed: 39304530
pii: 7762979
doi: 10.1093/ndt/gfae198
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.

Auteurs

Akihiko Koshino (A)

Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Department of Nephrology and Rheumatology, Kanazawa University, Ishikawa, Japan.
ORCID: 0000-0002-9432-2427

Hiddo J L Heerspink (HJL)

Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
The George Institute for Global Health, UNSW Sydney, Sydney, Australia.
ORCID: 0000-0002-3126-3730

Niels Jongs (N)

Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Sunil V Badve (SV)

The George Institute for Global Health, UNSW Sydney, Sydney, Australia.
Department of Nephrology, St George Hospital, Sydney, Australia.
Faculty of Medicine, University of New South Wales, Sydney, Australia.

Clare Arnott (C)

The George Institute for Global Health, UNSW Sydney, Sydney, Australia.
Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.
ORCID: 0000-0001-9370-9913

Bruce Neal (B)

The George Institute for Global Health, UNSW Sydney, Sydney, Australia.
School of Public Health, Imperial College London, UK.

Meg Jardine (M)

The George Institute for Global Health, UNSW Sydney, Sydney, Australia.
NHMRC Clinical Trials Centre University of Sydney NSW, Australia.
Concord Repatriation General Hospital, Sydney, Australia.

Kenneth W Mahaffey (KW)

Stanford Center for Clinical Research, Stanford University School of Medicine, Stanford, CA, USA.

Carol Pollock (C)

Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Australia.
Royal North Shore Hospital, St Leonards, New South Wales, Australia.
ORCID: 0000-0001-7167-6495

Vlado Perkovic (V)

The George Institute for Global Health, UNSW Sydney, Sydney, Australia.
Faculty of Medicine, University of New South Wales, Sydney, Australia.

Michael K Hansen (MK)

Janssen Research & Development, LLC, Spring House, PA, USA.

Stephan J L Bakker (SJL)

Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Takashi Wada (T)

Department of Nephrology and Rheumatology, Kanazawa University, Ishikawa, Japan.

Brendon L Neuen (BL)

The George Institute for Global Health, UNSW Sydney, Sydney, Australia.
Royal North Shore Hospital, St Leonards, New South Wales, Australia.
ORCID: 0000-0001-9276-8380

Classifications MeSH