This study demonstrated that dapagliflozin improves vascular stiffness and cardiorenal markers in patients at cardiovascular risk regardless of diabetes status, providing mechanistic support for the universal cardiorenal protective effects of SGLT2 inhibitors.
We investigated the impact of 12 weeks of sodium-glucose cotransporter-2 inhibition (dapagliflozin 10 mg daily) on vascular stiffness, cardiac and kidney function, and neurohormonal pathways in participants at cardiovascular risk.
This randomized double-blind, parallel-group, placebo-controlled study enrolled 51 participants with at least 1 established cardiovascular condition or cardiovascular risk factor. Participants underwent 3 sequential assessments under clamped euglycemia (4-6 mmol/L): at baseline, at 1 week and 12 weeks of treatment. The primary outcome was vascular arterial stiffness, quantified as augmentation index and pulse-wave velocity. Secondary outcomes included: blood pressure, body fluid composition, noninvasive cardiac output monitoring, arterial vasodilatation tests, heart rate variability, echocardiography, iohexol-measured glomerular filtration rate, and natriuresis.
Dapagliflozin decreased vascular arterial stiffness, as measured by aortic augmentation index (placebo-adjusted change of -7.4±2.8%, P=0.01) after 12 weeks. Dapagliflozin acutely decreased extracellular fluid (-0.8±0.3 L, P=0.004), with sustained reductions in thoracic fluid content at 12 weeks (-3.3±1.5 kΩ-1, P=0.03). Reductions in measured glomerular filtration rate (-5.8±2.1 mL/min per 1.73m2, P=0.008) were accompanied by acute increases in proximal sodium excretion (5.1±2.2%, P=0.03), absolute fractional distal sodium reabsorption (4.4±2.1%, P=0.04), and urine adenosine (0.21±0.08 mmol/L per μmol Cr, P=0.01).
Dapagliflozin induced early cardiorenal changes in individuals at varying levels of cardiovascular risk in whom evidence of clinical protection is lacking. Clinical trials in lower-risk populations, particularly in the context of primary prevention, are needed to determine whether these effects of sodium-glucose cotransporter-2 inhibition translate into improved clinical cardiorenal outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04258371.
