The SGLT2 Inhibitor Dapagliflozin Significantly Improves the Peripheral Microvascular Endothelial Function in Patients with Uncontrolled Type 2 Diabetes Mellitus

Abstract

Objective Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular events and decrease the body fat mass in patients with type 2 diabetes mellitus (T2DM). We examined whether or not the SGLT2-inhibitor dapagliflozin can improve the endothelial function associated with a reduction in abdominal fat mass. Methods We prospectively recruited patients with uncontrolled [hemoglobin A1c (HbA1c) >7.0%] T2DM who were not being treated by SGLT2 inhibitors. Patients were treated with add-on dapagliflozin (5 mg/day) or non-SGLT2 inhibitor medicines for 6 months to improve their HbA1c. We measured the peripheral microvascular endothelial function as assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) and calculated the natural logarithmic transformed value of the RH-PAT index (LnRHI). We then investigated changes in the LnRHI and abdominal fat area using computed tomography (CT). Results The subjects were 54 patients with uncontrolled T2DM (72.2% men) with a mean HbA1c of 8.1%. The HbA1c was significantly decreased in both groups, with no significant difference between the groups. Dapagliflozin treatment, but not non-SGLT2 inhibitor treatment, significantly increased the LnRHI. The changes in the LnRHI were significantly greater in the dapagliflozin group than in the non-SGLT2 inhibitor group. Dapagliflozin treatment, but not non-SGLT2 inhibitor treatment, significantly decreased the abdominal visceral fat area, subcutaneous fat area (SFA), and total fat area (TFA) as assessed by CT and significantly increased the plasma adiponectin levels. The percentage changes in the LnRHI were significantly correlated with changes in the SFA, TFA, systolic blood pressure, and adiponectin. Conclusion Add-on treatment with dapagliflozin significantly improves the glycemic control and endothelial function associated with a reduction in the abdominal fat mass in patients with uncontrolled T2DM.

Keywords: endothelial function; fat mass; sodium-glucose co-transporter 2 inhibitor; type 2 diabetes.

Figure 1.

Percentage changes in the peripheral microvasular endothelial function as assessed by an RH-PAT examination in dapagliflozin therapy and non-SGLT2 inhibitor therapy. Bar graphs depict the changes in the natural logarithmic transformation of reactive hyperemia index (LnRHI) values (mean and standard error) in patients with dapagliflozin therapy (n=27) or non-sodium-glucose co-transporter 2 (SGLT2) inhibitor therapy (n=27). Percentage increase in LnRHI=[(LnRHI after 6 months of therapy)-(LnRHI at enrollment)]×100/ (LnRHI at enrollment). With regard to the inter-group comparison, the changes in the LnRHI in patients with dapagliflozin therapy were significantly greater than those in the patients with non-SGLT2 inhibitor therapy (unpaired t-test, p=0.03). Six months of dapagliflozin therapy significantly increased the LnRHI compared with the baseline (paired t-test, *p<0.01).

Figure 2.

Pie charts of the proportion of patients with an improved endothelial function who received dapagliflozin therapy and non-SGLT2 inhibitor therapy. The proportion of patients with an improved endothelial function was 74.1% in the dapagliflozin group and 40.7% in the non-SGLT2 inhibitor group (p=0.013). LnRHI: natural logarithmic transformation of the reactive hyperemia index, SGLT2-I: sodium-glucose co-transporter 2 inhibitor