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During a period of standardized sodium intake, dapagliflozin therapy reduced blood pressure without clear changes in sodium excretion, indicating that neither natriuresis nor volume changes alone contribute to blood pressure-lowering effects. These research findings were published in Diabetes Care.
Researchers conducted a mechanistic, nonrandomized, open-label study to examine the effect of dapagliflozin on cumulative sodium excretion among patients with type 2 diabetes and preserved kidney function during a period of strictly controlled sodium intake. Investigators hypothesized that a sodium-glucose cotransporter 2 (SGLT2) inhibitor would increase urinary sodium excretion and affect both volume status and blood pressure.
The primary study outcome was the effect of dapagliflozin therapy on the change in 24-hour sodium excretion. The primary endpoint was defined as the change in average sodium excretion at baseline relative to the start of treatment.
Thirty-one patients were enrolled in the study; 17 of these patients began dapagliflozin therapy (10 mg once daily for 14 days plus or minus 1 day). Efficacy analyses were performed in 14 patients, while safety was assessed in all 17 patients who started treatment.
At baseline, mean 24-hour sodium excretion was 150 plus or minus 32 mmol every 24 hours. Dapagliflozin therapy did not significantly change the 24-hour sodium excretion (urinary 24-hour sodium change at start of treatment: -7.0 mmol/24 hours; 95% CI, -22.4 to 8.4; P =.34; change at end of treatment: 2.1 mmol/24 hours; 95% C, -28.8 to 33.0; P =.89). Mean 24-hour urinary sodium excretion from day -1 to day 1 trended toward an increase (27 mmol/24 hours; 95% CI, -10 to 63).
Conversely, mean baseline urinary glucose excretion was 1.9 plus or minus 2.2 mmol every 24 hours, which significantly increased during dapagliflozin treatment (change at start of treatment: 351 mmol/24 hours; 95% CI, 273-428; P <.0001; change at end of treatment: 322 mmol/24 hours; 95% CI, 231-413; P <.0001). Mean baseline 24-hour systolic blood pressure was significantly reduced during dapagliflozin treatment, from 128 plus or minus 10 mmHg to -6.1 mmHg at the start of treatment (95% CI, -9.1 to -3.1; P =.001) and -7.2 mmHg at the end of treatment (95% CI, -10.1 to -4.3; P <.001). This remained reduced during the follow-up period.
Mean plasma volume remained stable at the start of treatment, dipped slightly at the end of treatment, and significantly increased during the follow-up period compared with the end of treatment. Extracellular volume was significantly reduced at the start of treatment and did not change compared with the end of treatment during follow-up.
Similarly, mean intracellular volume did not significantly change over the course of dapagliflozin therapy at either the start or end of treatment, and change during follow-up as compared with the end of treatment was -0.3 L (95% CI, -0.7 to -0.0; P =.08).
Study limitations include the deliberate use of a homogenous cohort of people with type 2 diabetes and preserved kidney function, potentially limiting the generalizability of the findings, as well as the assessment of extra- and intracellular volumes by bioimpedance spectroscopy, which is not the gold standard method. Finally, the overall size of the study cohort was small, and the use of the open-label design does not allow for definitive conclusions.
“We have demonstrated that treatment with dapagliflozin lowers blood pressure without clear effects on sodium excretion in patients with type 2 diabetes and preserved kidney function,” the researchers concluded. “Together with the absence of prolonged changes in plasma volume, extracellular volume, and intracellular volume, this suggests that other nondiuretic-related effects cannot be ruled out in the [cardiovascular] protective effects conferred by SGLT2 inhibitors.”
Disclosure: This clinical trial was supported by AstraZeneca. Please see the original reference for a full list of authors’ disclosures.
Reference
Scholtes RA, Muskiet MHA, van Baar MJB, et al. Natriuretic effect of two weeks of dapagliflozin treatment in patients with type 2 diabetes and preserved kidney function during standardized sodium intake: results of the DAPASALT trial. Published online December 14, 2020. Diabetes Care. doi:10.2337/dc20-2604
