Sodium-glucose co-transporter-2 (SGLT2) inhibitors like empagliflozin, dapagliflozin, and canagliflozin have become established treatments for managing hyperglycemia. These medications are recognized not only for their glucose-lowering effects but also for contributing to weight reduction. Beyond glycemic control, SGLT2 inhibitors exert osmotic diuretic and natriuretic effects, leading to a decrease in plasma volume and a reduction in both systolic and diastolic blood pressure. These multifaceted actions are increasingly understood to be the basis for the cardiovascular and renal advantages observed with this drug class. Notably, SGLT2 inhibition is also associated with an initial decrease in estimated glomerular filtration rate and a significant reduction in albuminuria, mirroring observations from preclinical studies. These findings suggest a mechanism involving proximal tubular natriuresis, which subsequently activates renal tubuloglomerular feedback via increased sodium and chloride delivery to the macula densa, resulting in afferent vasoconstriction.
The effectiveness of SGLT2 inhibitors in lowering glucose and promoting weight loss may be less pronounced in individuals with chronic kidney disease, particularly when estimated glomerular filtration rate is reduced. Despite this, landmark trials such as EMPA-REG OUTCOME have demonstrated substantial benefits. Empagliflozin, for example, was linked to a significant 30% decrease in cardiovascular mortality, overall mortality, and hospitalizations for heart failure, even with only minor differences in hemoglobin A1c levels between treatment groups. Importantly, beyond the expected increase in mycotic genital infections, patients treated with empagliflozin experienced fewer serious adverse events, including a reduced risk of acute kidney injury. The compelling results from EMPA-REG OUTCOME have influenced clinical guidelines, with some now recommending SGLT2 inhibitors with proven cardiovascular benefits as a priority for patients with type 2 diabetes mellitus who have not reached their glycemic targets and have existing atherosclerotic cardiovascular disease.
As further research and cardiorenal protection trials progress, the sodium-related physiological effects of SGLT2 inhibitors and the clinical implications of natriuresis will remain a central focus. The impact on critical outcomes such as blood pressure management, heart failure progression, kidney protection strategies, and overall mortality continues to be a key area of investigation, solidifying the importance of understanding sodium glucose co-transporters in therapeutic interventions.
