Cardiovascular-Kidney Effects of Dapagliflozin in Patients at Cardiovascular Risk With or Without Type 2 Diabetes: Results of a Randomized, Double-Blind, Placebo-Controlled Trial

BACKGROUND: 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. METHODS: 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. RESULTS: 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 1.73m 2 , 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). CONCLUSIONS: 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.