Long-term effects of ipragliflozin on blood pressure in patients with type 2 diabetes: Insights from the randomized PROTECT study

Background: /Aims Although previous reports have shown that sodium-glucose cotransporter-2 (SGLT2) inhibitors have a blood pressure (BP) lowering effect, relevant long-term data is limited. This study aimed to evaluate the effect of the SGLT2 inhibitor ipragliflozin on BP, and associations between BP reduction and changes in cardiometabolic variables in patients with type 2 diabetes. Methods This was a sub-analysis of the PROTECT (Prevention of atherosclerosis by SGLT2 inhibitor: multicenter, randomized controlled study) trial, a multicenter, randomized, open-label, blinded-endpoint study to assess if ipragliflozin delays carotid intima-media thickness progression in patients with type 2 diabetes. Participants were randomized to ipragliflozin and control groups. The primary endpoint of the present sub-analysis was the trajectory of systolic BP, which was measured in a routine clinical setting at baseline and at 3, 6, 12 and 24 months. Correlations between systolic BP changes and cardiometabolic variables during the follow-up period were also evaluated. Results A total of 232 patients with well-balanced baseline characteristics were included in each study group. During the 24-month follow-up, systolic BP was consistently lower in the ipragliflozin group than the control group. Throughout the 24-month observation period, mean systolic BP was lower in the ipragliflozin group by 3.6 mm Hg (95% confidence interval, 0.7 to 6.5 mm Hg) across several subgroups. Changes in systolic BP correlated significantly with changes in body mass index particularly in the ipragliflozin group, while no significant correlations between changes in systolic BP and carotid intima-media thickness, estimated glomerular filtration rate, or N-terminal pro-B-type natriuretic peptide were observed from baseline to 24 months. Conclusions Ipragliflozin treatment was associated with BP reduction throughout the 24-month follow-up period as compared to control treatment. BP reduction correlated with weight loss, which might be a major mechanism for the BP lowering effect of SGLT2 inhibitors. Trial registration University Hospital Medical Information Network Clinical Trial Registry; UMIN000018440 and Japan Registry of Clinical Trials; jRCTs071180041 and jRCT1071220089.