From:  Reframing SGLT2 inhibition as systematic metabolic stress modulation across the cardiovascular-renal-metabolic axis

 Summary of extra-glycemic systemic effects contributing to cardiometabolic benefits of SGLT2 inhibitors.

Physiological domainMechanismMagnitude of effectClinical implication
Weight reductionCaloric loss via glucosuria2–3 kg average weight reductionImproved cardiometabolic risk profile
Visceral adiposityReduction in ectopic fat depositionReduced visceral and hepatic fatLower metabolic syndrome burden
Blood pressureNatriuresis and plasma volume reductionAbout 3–5 mmHg systolic BP reductionAdjunct antihypertensive effect
Uric acid reductionIncreased renal urate excretionSignificant uric acid loweringPotential reduction in CV and renal risk
Liver metabolismImproved hepatic steatosis and inflammationReduced liver fat content and ALT/AST levelsEmerging therapy for MASLD
Mitochondrial efficiencyKetone body utilization and metabolic shiftImproved myocardial energeticsPotential antiarrhythmic and HF benefit
Insulin sensitivityReduced glucotoxicity and lipotoxicityImproved metabolic homeostasisDelay progression of T2DM
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BP: blood pressure; ALT: alanine aminotransferase; AST: aspartate aminotransferase; CV: cardiovascular; MASLD: metabolic dysfunction-associated steatotic liver disease; HF: heart failure; T2DM: type 2 diabetes mellitus.