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Role of Glycosuria in SGLT2 Inhibitor-Induced Cardiorenal Protection: A Mechanistic Analysis of the CREDENCE Trial

Ele Ferrannini1, Anna Solini2, Simona Baldi3

  • 1CNR Institute of Clinical Physiology, Pisa, Italy.

Diabetes
|November 8, 2023
PubMed

Insights

Sodium-glucose cotransporter 2 (SGLT2) inhibitors like canagliflozin increase urinary glucose excretion (glycosuria). Higher glycosuria levels in patients with type 2 diabetes and chronic kidney disease correlated with significantly reduced cardiorenal events.

Area of Science:

  • Nephrology
  • Cardiology
  • Endocrinology

Background:

  • Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiorenal outcomes in patients with type 2 diabetes and chronic kidney disease.
  • The precise mechanisms driving these protective effects are not fully understood.
  • Glycosuria, or elevated glucose in urine, is a known effect of SGLT2 inhibitors.

Purpose of the Study:

  • To investigate if elevated glycosuria induced by SGLT2 inhibitors contributes to their cardiorenal benefits.
  • To assess the association between glycosuria levels and cardiorenal outcomes in patients treated with canagliflozin.

Main Methods:

  • Analysis of data from the CREDENCE trial, including approximately 2,600 patients with type 2 diabetes, chronic kidney disease, and albuminuria.
  • Measurement of urine glucose, creatinine, and ketones at baseline and after 1 year of treatment with canagliflozin or placebo.
  • Statistical assessment using Cox proportional hazards models to evaluate the association between glycosuria and primary/secondary endpoints.

Main Results:

  • Canagliflozin significantly increased fractional urinary glucose excretion from 3% to 30% after 1 year.
  • Patients in the top quartile of urine glucose to creatinine ratio with canagliflozin showed significantly reduced risk for the primary composite endpoint (HR 0.42).
  • Similar protective associations were observed for hospitalized heart failure and all-cause mortality, persisting after risk factor adjustments.

Conclusions:

  • Elevated glycosuria is strongly associated with reduced cardiorenal events in patients with type 2 diabetes and chronic kidney disease treated with canagliflozin.
  • This suggests that drug-induced glycosuria may be a key mechanism mediating the cardiorenal protective effects of SGLT2 inhibitors.
  • The findings highlight the clinical significance of monitoring glycosuria in patients receiving SGLT2 inhibitor therapy.

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