medwireNews: Findings from a US randomized controlled trial suggest that add-on treatment with the sodium-glucose cotransporter (SGLT)2 inhibitor dapagliflozin reduces levels of some vasoconstrictors and increases some vasodilators in people with type 2 diabetes.
The phase 4 study included 47 obese people with type 2 diabetes and glycated hemoglobin levels below 8% (64 mmol/mol) who were randomly assigned to receive 12 weeks of treatment with dapagliflozin 10 mg/day or placebo alongside ongoing standard therapy. The majority (85%) of participants were taking metformin, while 38% were on insulin, 38% on sulfonylureas, and 21% on pioglitazone.
Paresh Dandona and colleagues, from the State University of New York at Buffalo, report in Diabetes, Obesity and Metabolism that dapagliflozin treatment led to a reduction in systolic blood pressure (SBP), in accordance with previous studies.
Specifically, average SBP fell from 134 mmHg at baseline to 124 mmHg at week 12 in the dapagliflozin group, compared with a reduction from 136 to 133 mmHg in the placebo group, giving a significant between-group difference of 7 mmHg for the change in SBP. The team also observed “an acute fall” in average SBP 6 hours after the first dose of dapagliflozin in a subgroup of 13 participants with data collected at this timepoint.
In an analysis of fasting blood and 24-h urine samples taken at baseline and at week 12, Dandona et al found that mean levels of the vasoconstrictors angiotensin II and angiotensinogen decreased in the dapagliflozin arm, from 29.2 to 19.6 pg/mL and 7.23 to 5.88 µg/mL, respectively, but remained consistent in the placebo group. Average angiotensin II and angiotensinogen levels were also significantly lower in the dapagliflozin than the placebo arm at week 12.
Conversely, dapagliflozin-treated individuals experienced an increase in average levels of the vasodilators atrial natriuretic peptide (from 92 to 125 pg/mL) and cyclic guanosine monophosphate (from 73 to 109 pmol/mL), with significantly higher levels of both among dapagliflozin- versus placebo-treated patients at week 12. There were no changes in other vasoactive factors tested with dapagliflozin treatment, including the vasoconstrictors endothelin-1 and renin, and the vasodilators brain natriuretic peptide and cyclic adenosine monophosphate.
While these findings suggest that changes in some vasoactive mediators “may potentially contribute to [dapagliflozin’s] anti-hypertensive effects and its benefits in congestive cardiac failure,” the researchers note that there was no significant association between these changes and reductions in blood pressure in their study.
However, they say “[i]t is possible that the absence of such association is due to the relatively small sample size or due to the fact that blood pressure regulation is a complex process involving the effect of multiple mediators and factors.”
They conclude that “further and larger studies focused on changes in levels of […] vasoactive mediators following treatment with SGLT-2 inhibitors and their expression in relevant tissues are warranted to fully understand the blood pressure lowering mechanisms of these agents.”
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Diabetes Obes Metab 2021; doi:10.1111/dom.14377