Research Funding Agreement tra Janssen Research & Development, LLC e CNR IFC-studio CREDENCE (DSB.AD003.080)

Thematic area

Biomedical sciences

Project area

Structure responsible for the research project

Institute of clinical physiology (IFC)

Project manager

GIORGIO IERVASI
Phone number: 0503152016
Email: iervasi@ifc.cnr.it

Abstract

Background
The striking relative risk reductions in cardiovascular mortality and hospitalization for heart failure in
the EMPA-REG OUTCOME (1), CANVAS (2) and DECLARE (3) trials in type 2 diabetic patients at
high CVD risk have been accompanied by unexpected reductions in nephropathy progression.
In the CREDENCE trial (4) in patients with type 2 diabetes and kidney disease, the risk of kidney failure
and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median
follow-up of 2.62 years.As there is general consensus that the SGLT2i-induced reductions in HbA1c, body weight, and blood pressure cannot quantitatively account for the degree of cardiovascular and renal protection observed in
these CVOT trials (5), explanatory hypotheses cluster around two areas: hemodynamic (6) and metabolic
changes (7). The metabolic hypothesis hinges upon ketone bodies, which rise during SGLT2 inhibition
as a consequence of a shift from carbohydrate to fatty substrate utilization (8,9). In a recent study using
CANVAS plasma samples, there has emerged evidence that baseline plasma metabolite levels that mark
whole-body lipolysis (FFA and glycerol), cytosolic redox s

Goals

As a logical follow up to the above findings, we propose to use samples from CREDENCE to confirm
and extend the notion that (a) the redox balance is associated with, and predictive of, CV (5,10,11) and
renal (5,12) events in a complex fashion, and (b) changes in the redox state induced by interventions can
influence these hard outcomes. There are many aspects of this paradigm that the availability of a large
number of prospectively collected measurements can help elucidate, including the striking coherence
between cardiovascular and renal outcomes. In addition, the possibility of measuring these markers in
the urine as well as the plasma in patients with various degrees of renal dysfunction provides a unique
opportunity to further clarify the role of the kidney in regulating the supply of these biomarkers to bodily
tissues under basal conditions (ie, before any intervention) and in response to SGLT2 inhibition, which
selectively changes their circulating levels

Start date of activity

16/12/2020

Keywords

Relation of circulating metabolites to renal and CV outcomes in CREDENCE

Last update: 29/11/2024