eprintid: 10074175
rev_number: 20
eprint_status: archive
userid: 608
dir: disk0/10/07/41/75
datestamp: 2019-05-20 13:42:58
lastmod: 2021-10-04 00:12:57
status_changed: 2019-05-20 13:42:58
type: article
metadata_visibility: show
creators_name: Idzerda, NMA
creators_name: Stefansson, BV
creators_name: Pena, MJ
creators_name: Sjostrom, DC
creators_name: Wheeler, DC
creators_name: Heerspink, HJL
title: Prediction of the effect of dapagliflozin on kidney and heart failure outcomes based on short-term changes in multiple risk markers
ispublished: inpress
divisions: UCL
divisions: B02
divisions: C10
divisions: D17
divisions: G93
keywords: clinical trial, dapagliflozin, diabetic kidney disease, heart failure, risk markers
note: Copyright © The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.
abstract: BACKGROUND: Besides improving glucose control, sodium-glucose co-transporter 2 inhibition with dapagliflozin reduces blood pressure, body weight and urinary albumin:creatinine ratio (UACR) in patients with type 2 diabetes (T2DM). The parameter response efficacy (PRE) score was developed to predict how short-term drug effects on cardiovascular risk markers translate into long-term changes in clinical outcomes. We applied the PRE score to clinical trials of dapagliflozin to model the effect of the drug on kidney and heart failure (HF) outcomes in patients with T2DM and impaired kidney function. METHODS: The relationships between multiple risk markers and long-term outcome were determined in a background population of patients with T2DM with a multivariable Cox model. These relationships were then applied to short-term changes in risk markers observed in a pooled database of dapagliflozin trials (n = 7) that recruited patients with albuminuria to predict the drug-induced changes to kidney and HF outcomes. RESULTS: A total of 132 and 350 patients had UACR >200 mg/g and >30 mg/g at baseline, respectively, and were selected for analysis. The PRE score predicted a risk change for kidney events of -40.8% [95% confidence interval (CI) -51.7 to -29.4) and -40.4% (95% CI -48.4 to -31.1) with dapagliflozin 10 mg compared with placebo for the UACR >200 mg/g and >30 mg/g subgroups. The predicted change in risk for HF events was -27.3% (95% CI -47.7 to -5.1) and -21.2% (95% CI -35.0 to -7.8), respectively. Simulation analyses showed that even with a smaller albuminuria-lowering effect of dapagliflozin (10% instead of the observed 35% in both groups), the estimated kidney risk reduction was still 26.5 and 26.8%, respectively. CONCLUSIONS: The PRE score predicted clinically meaningful reductions in kidney and HF events associated with dapagliflozin therapy in patients with diabetic kidney disease. These results support a large long-term outcome trial in this population to confirm the benefits of the drug on these endpoints.
date: 2019-04-21
date_type: published
official_url: https://doi.org/10.1093/ndt/gfz064
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1653087
doi: 10.1093/ndt/gfz064
pii: 5475769
lyricists_name: Wheeler, David
lyricists_id: DWHEE12
actors_name: Flynn, Bernadette
actors_id: BFFLY94
actors_role: owner
full_text_status: public
publication: Nephrology Dialysis Transplantation
event_location: England
issn: 1460-2385
citation:        Idzerda, NMA;    Stefansson, BV;    Pena, MJ;    Sjostrom, DC;    Wheeler, DC;    Heerspink, HJL;      (2019)    Prediction of the effect of dapagliflozin on kidney and heart failure outcomes based on short-term changes in multiple risk markers.                   Nephrology Dialysis Transplantation        10.1093/ndt/gfz064 <https://doi.org/10.1093/ndt%2Fgfz064>.    (In press).    Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10074175/1/Wheeler_gfz064.pdf