The Effect of SGLT2 Inhibitors on Carotid IMT in Patients with Type 2 Diabetes Mellitus: The PROTECT Study

The PROTECT study enrolled 488 patients with type 2 diabetes from 39 sites in Japan between September 2015 and June 2018. Of the patients who met the criteria, 482 were split into 2 groups of 241 and randomized to receive either ipragliflozin 50 mg/day (ipragliflozin group) or a non-SGLT2 inhibitor (control group), with the maximum dosage of ipragliflozin limited to 100mg. In both groups, a total of 232 patients were included in the analysis, and IMT data were available for 197 and 204 patients, respectively.

The patient backgrounds were similar between the two groups, with a median age of 68 years, about 70% male, a median duration of diabetes of about 8 years, and an HbA1c of about 7.3%. About 40% of all patients were receiving secondary preventive treatment for cardiovascular disease, and about 80% were prescribed antihypertensive medication at baseline, about 66% were prescribed statins, and about 85% were prescribed hypoglycemic medication.

The mean IMT of the common carotid artery decreased from 0.818 mm to 0.814 mm from baseline to 24 months in the ipragliflozin group and from 0.841 mm to 0.836 mm in the control group, with no difference between the two groups in the 24 months change set as the primary endpoint (corrected ipragliflozin and difference in the control group -0.0002 [95%CI -0.0193-0.0189] p=0.985).

The primary endpoint assessment showed no significant differences between the two groups in any of the following subgroups: age, gender, duration of diabetes, HbA1c, metformin, and DPP-4 inhibitor use, BMI, eGFR, mean baseline IMT, hypertension, and history of atherosclerotic cardiovascular disease. On the other hand, when divided by statin use, the results suggested a possible benefit of ipragliflozin in patients not using statins (-0.032 [95%CI -0.065-0.002]).

In terms of glucose-related measures, the difference in change in HbA1c from baseline to 24 months was greater in the ipragliflozin group (-0.31% [95%CI -0.44--0.19] p<0.001) and even during the fasting glucose (the adjusted group difference -12.47 mg/dL [95%CI -18.39--6.55] p<0.001). Systolic and diastolic blood pressure were lower in the ipragliflozin group than in the control group, but the corrected difference between groups was not significant.

The ipragliflozin group showed a significantly greater decrease in BMI at 24 months compared to the control group (adjusted group difference -0.90 [95%CI -1.12--0.67] p<0.001), but not in the eGFRs (adjusted group difference -0.92 [95%CI -2.10-0.27] p=0.130).

With regard to adverse events, all-cause mortality occurred in 4 patients in the ipragliflozin group and 5 in the control group, cardiovascular death in 1 and 2 patients, respectively, nonfatal MI in 0 and 1 patient, nonfatal stroke in 2 and 3 patients, heart failure in 3 patients in both groups, and urinary tract/genital tract infection in 3 and 2 patients, respectively.

Dr. Tanaka summarized, "In patients with type 2 diabetes, treatment with ipragliflozin over 24 months did not inhibit the progression of carotid IMT compared to controls. This suggests that the cardiovascular benefit of SGLT2 inhibitors may not be an anti-atherosclerotic effect within this treatment period."

The 86^th Annual Scientific Meeting of the Japanese Circulation Society