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Early changes in renal function do not appear to mediate cardiovascular risk with dapagliflozin plus semaglutide: a

Muneera O AlTaweel1,2, Saleh Al Makhloof2,3, Ahmad K AlKhayyal2,4

  • 1Department of Cardiac Sciences, King Abdulaziz Hospital, MNGHA, Al-Ahsa, Saudi Arabia.

Expert Review of Cardiovascular Therapy
|July 31, 2026
PubMed
Abstract

Insights

Combination therapy with dapagliflozin and semaglutide did not significantly reduce heart failure or myocardial infarction events. Early changes in estimated glomerular filtration rate (eGFR) did not mediate these outcomes, suggesting further research is needed.

Area of Science:

  • Cardiology
  • Nephrology
  • Endocrinology

Background:

  • Cardiovascular-kidney-metabolic (CKM) syndrome encompasses heart failure (HF), myocardial infarction (MI), kidney disease, diabetes, and obesity.
  • SGLT2 inhibitors and GLP-1 receptor agonists offer cardiovascular and renal benefits, but their combined mechanisms are unclear.
  • Investigating the role of early estimated glomerular filtration rate (ΔeGFR) changes in mediating treatment effects is crucial.

Purpose of the Study:

  • To assess if early ΔeGFR mediates the association between dapagliflozin plus semaglutide combination therapy and HF/MI-related outcomes.
  • To evaluate the effectiveness of combination therapy compared to dapagliflozin alone in managing CKM syndrome components.
  • To explore the underlying mechanisms of dual SGLT2 inhibitor and GLP-1 receptor agonist treatment.

Main Methods:

  • Retrospective cohort study of 376 adult patients prescribed dapagliflozin with or without semaglutide.
  • Utilized inverse probability of treatment weighting (IPTW) and causal mediation analysis.
  • Follow-up duration ranged from 90 to 365 days to assess treatment-outcome associations and ΔeGFR mediation.

Main Results:

  • Combination therapy showed no statistically significant difference in HF/MI-related clinical status compared to dapagliflozin alone (adjusted RR 0.787; p=0.516).
  • Early ΔeGFR demonstrated minimal mediation of treatment effects (indirect RR 1.013).
  • IPTW analyses corroborated these findings, indicating neutral effects (composite RR 1.12).

Conclusions:

  • Early ΔeGFR changes provided little evidence for mediating HF/MI risk differences between combination therapy and monotherapy.
  • The study's secondary findings are exploratory due to the lack of independent outcome adjudication.
  • Larger prospective studies are required to validate these findings and further elucidate treatment mechanisms.
Keywords:
Dapagliflozincardiovascular-kidney-metabolic syndromeeGFRheart failuremediation analysismyocardial infarctionpropensity score weightingsemaglutide

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