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Relationships of SGLT2 inhibition, circulating metabolites, and cancer: A Mendelian randomization study

Wenhui Li1, Hui Zhou2, Xiaolei Wang2

  • 1The Second Clinical Medical School, Beijing University of Chinese Medicine, Beijing, China.

Medicine
|May 4, 2026
PubMed

Insights

Sodium-glucose cotransporter 2 (SGLT2) inhibition shows a causal link to various cancers, influencing risk through specific circulating metabolites like fatty acids and triglycerides.

Area of Science:

  • Metabolic pathways
  • Oncology
  • Genetic epidemiology

Background:

  • The impact of sodium-glucose cotransporter 2 (SGLT2) inhibition on cancer development is debated.
  • Understanding the interplay between SGLT2 inhibition, metabolic changes, and cancer risk is crucial.

Purpose of the Study:

  • To investigate the causal relationship between SGLT2 inhibition and cancer risk.
  • To explore the mediating role of circulating metabolites in this association.
  • To utilize Mendelian randomization for robust causal inference.

Main Methods:

  • Employed a two-sample, two-step Mendelian randomization approach.
  • Utilized genetic variants as instrumental variables for SGLT2 inhibition.
  • Analyzed associations between SGLT2 inhibition, cancer types, and specific circulating metabolites.

Main Results:

  • SGLT2 inhibition was linked to increased risks of lung, colorectal, skin, and basal cell carcinoma, but decreased risk of brain cancer.
  • Specific metabolites mediated these effects: polyunsaturated and omega-6 fatty acids for colorectal cancer; acetone for skin cancer; various triglycerides for brain cancer.
  • Established causal effects of SGLT2 inhibition on circulating metabolite levels.

Conclusions:

  • SGLT2 inhibition exerts causal effects on cancer risk, partly mediated by alterations in circulating metabolites.
  • Findings highlight the complex relationship between metabolic regulation, SGLT2 inhibition, and oncogenesis.
  • Suggests potential for targeted metabolic interventions in cancer prevention or treatment related to SGLT2 inhibition.
Keywords:
Mendelian randomizationSGLT2 inhibitioncancercirculating metabolites

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