Canagliflozin Improves a Left Ventricular Diastolic Dysfunction without Affecting Baroreflex Sensitivity in Type 2 Diabetes

In type 2 diabetes, there is no effective treatment for gradual progression of left ventricular (LV) diastolic dysfunction and reduced baroreflex sensitivity (BRS), which is a sensitive measure of cardiovascular (CV) autonomic function. Here we prospectively evaluated the effect of Canagliflozin, sodium-glucose cotransporter (SGLT) 2 inhibitor, on LV diastolic dysfunction and BRS at the same time. 37 type 2 diabetic patients with high risks of CV disease were enrolled. All participants were evaluated LV function, BRS, HbA1c, Hb, BNP and t-PA-PAI-1 complex before and after 3 months of the additional treatment with Canagliflozin. Multiple-linear regression was used to assess individual and cumulative effects of δearly diastolic velocity/basal septal diastolic velocity (E/e’) and δLV mass index. UMIN000025964 for Clinical Trials Registry. Characteristics of the subjects are age 64.2 ± 8.1 years (mean±SD), HbA1c 7.9±0.7%, diabetes duration 13.5 ± 8.1 years, complicated CV disease 32.4%. E/e’ ratio (13.7 ± 3.5 to 12.1 ± 2.8, p = 0.001), LV mass index (82.0 ± 15.8 to 77.3 ± 16.4 g/m², p = 0.003), HbA1c (7.9 ± 0.7 to 7.1 ± 0.6%, p = 0.000), and t-PA-PAI-1 complex (27.0 ± 15.8 to 19.4 ± 7.0 ng/mL, p =0.002) were decreased and Hb (13.9 ± 1.2 to 14.7 ± 1.4 g/dL, p =0.000) was increased. The level of BRS (10.7 ± 8.5 to 10.2 ± 7.3 msec/mmHg, p = 0.721) and BNP (15.1 ± 10.7 to 13.5 ± 10.1 pg/dL, p = 0.062) did not show any differences. Interestingly, δE/e` were negatively correlated with baseline E/e` and δHb (r=-0.618, p=0.000; r=-0.496, p=0.002, respectively). Multiple regression model still revealed that δE/e` were related to baseline E/e` (β=-0.581, p=0.007) and δHb (β=-0.406, p=0.009) independently of age, sex, and baseline SBP (R-squared 0.469). Canagliflozin improved LV diastolic dysfunction without reducing BRS in type 2 diabetic patients with high CV disease risk. Our results suggest that greater increase of Hb is a surrogate marker of improvement of diastolic function.