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May 23, 2022Diabetes Obesity and MetabolismOpen Access

Mediators of ertugliflozin effects on heart failure and kidney outcomes among patients with type 2 diabetes mellitus

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Why the study?

SGLT2 inhibitors reduce hospitalization for heart failure and composite kidney outcomes, but the mediators underlying these benefits remain unknown.

Does ertugliflozin reduce hospitalization for heart failure and composite kidney outcomes in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease?

Population

Patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease from the VERTIS CV trial

Comparison

Ertugliflozin vs placebo

Design

Mediation analysis of a randomized controlled trial

Key result

Markers of volume status and haemoconcentration, particularly haemoglobin, mediated 63.3% of the effect of ertugliflozin on reducing the risk of hospitalization for heart failure in patients with type 2 diabetes.

Authors

MSMatthew W. SegarAKAhmed A. KolkailahRFRobert Frederich

Discussion

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Overview

Reinforces ertugliflozin use in T2D with ASCVD; extends prior SGLT2i trials by identifying volume and hematopoiesis mediators.

Study Design

Type

RCT (n=8,246)

Blinding

Double-blind

Randomization

1:1:1

Multicenter

Yes

Structured PICO

Does ertugliflozin reduce hospitalization for heart failure and composite kidney outcomes in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease?

P
Population
8,246 patients aged 40 years or older with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease, randomized to ertugliflozin or placebo.
I
Intervention
Ertugliflozin
C
Comparator
Placebo
O
Outcome
First hospitalization for heart failure (HHF) and composite kidney outcomecomposite

Main Result

Effect estimate: 63.33% mediation (95% CI 26.08-231.35)

The cardioprotective and renoprotective effects of ertugliflozin in patients with type 2 diabetes appear to be primarily mediated by changes in markers of volume status and hemoconcentration.

Limitations

  • Mediation analyses do not assess causation or mechanistic relations, only associations.
  • Mediation could only be assessed for measured biomarkers; unmeasured biomarkers like beta-hydroxybutyrate or natriuretic peptides were not included.
  • Ejection fraction was not systematically assessed, preventing evaluation of differences in mediators between heart failure subtypes.
  • The interaction between different mediators could not be fully assessed to evaluate the exact interplay contributing to improved outcomes.

Cite This Study

Segar et al. (2022) conducted an RCT in Type 2 diabetes mellitus and established atherosclerotic cardiovascular disease (n=8,246). Ertugliflozin vs. Placebo was evaluated on Percentage mediation of ertugliflozin's effect on hospitalization for heart failure by average change in haemoglobin (63.33% mediation, 95% CI 26.08-231.35). Markers of volume status and haemoconcentration, particularly haemoglobin, mediated 63.3% of the effect of ertugliflozin on reducing the risk of hospitalization for heart failure in patients with type 2 diabetes.

synapsesocial.com/papers/6a7845247ecc675f86aee666https://doi.org/10.1111/dom.14769
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