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Heterogeneous cardiovascular effects of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes: a causal forest

Yuichiro Mori1, Toshiaki Komura2, Motohiko Adomi3

  • 1Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

European Journal of Preventive Cardiology
|September 1, 2025
PubMed
Abstract

Insights

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) offer benefits beyond traditional cardiovascular disease (CVD) risk scores. Individual patient factors, not just CVD risk, better predict SGLT2i effectiveness in reducing adverse outcomes.

Area of Science:

  • Cardiology
  • Pharmacology
  • Data Science

Background:

  • Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are increasingly used for cardiovascular risk reduction.
  • Evidence is limited regarding optimal patient selection for SGLT2i, particularly in those without high cardiovascular disease (CVD) risk.

Purpose of the Study:

  • To investigate the heterogeneity in SGLT2i effectiveness across different CVD risk profiles.
  • To identify patient characteristics that predict benefit from SGLT2i beyond conventional CVD risk scores.

Main Methods:

  • A target trial emulation framework compared SGLT2i with dipeptidyl peptidase 4 inhibitors (DPP4i) in Japanese working-age adults (2015-2023).
  • A composite outcome of all-cause death, myocardial infarction, stroke, or heart failure over three years was assessed.
  • Machine-learning causal forest models were used to evaluate heterogeneity in treatment effect and its correlation with CVD risk.

Main Results:

  • SGLT2i use was associated with a decreased risk of the primary composite outcome (3-year risk difference, +0.38 percentage points).
  • The causal forest analysis revealed significant heterogeneity in SGLT2i effectiveness, with benefit weakly correlated with CVD risk score (r=0.287).
  • Among individuals with low CVD risk, 91.0% were predicted to benefit, characterized by higher blood pressure, BMI, and fasting glucose levels.

Conclusions:

  • The cardioprotective effects of SGLT2i are heterogeneous.
  • Individual patient characteristics, rather than overall CVD risk score, are stronger predictors of SGLT2i benefit.
  • This highlights the need to consider individual factors for SGLT2i therapy selection beyond standard risk stratification.
Keywords:
Cardiovascular diseaseDiabetesHeterogeneous treatment effectsSGLT2 inhibitorsTarget trial emulation

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