Effects of the SGLT2 Inhibition on Cardiac Remodeling in Streptozotocin-Induced Diabetic Rats, a Model of Type 1 Diabetes Mellitus

Abstract

Clinical trials have shown that sodium glucose co-transporter 2 (SGLT2) inhibitors improve clinical outcomes in diabetes mellitus (DM) patients. As most studies were performed in Type 2 DM, the cardiovascular effects of SGLT2 inhibition still require clarification in Type 1 DM. We analyzed the effects of SGLT2 inhibitor dapagliflozin on cardiac remodeling in rats with streptozotocin-induced diabetes, an experimental model of Type 1 DM. Methods: Male Wistar rats were assigned into four groups: control (C, n = 14); control treated with dapagliflozin (C + DAPA, n = 14); diabetes (DM, n = 20); and diabetes treated with dapagliflozin (DM + DAPA, n = 20) for 8 weeks. Dapagliflozin dosage was 5 mg/kg/day. Statistical analyses: ANOVA and Tukey or Kruskal–Wallis and Dunn. Results: DM + DAPA presented decreased blood pressure and glycemia and increased body weight compared to DM (C 507 ± 52; C + DAPA 474 ± 50; DM 381 ± 52 *; DM + DAPA 430 ± 48 # g; * p < 0.05 vs. C; # p < 0.05 vs. C + DAPA and DM + DAPA). DM echocardiogram presented left ventricular and left atrium dilation with impaired systolic and diastolic function. Cardiac changes were attenuated by dapagliflozin. Myocardial hydroxyproline concentration and interstitial collagen fraction did not differ between groups. The expression of Type III collagen was lower in DM and DM + DAPA than their controls. Type I collagen expression and Type I-to-III collagen ratio were lower in DM + DAPA than C + DAPA. DM + DAPA had lower lipid hydroperoxide concentration (C 275 ± 42; C + DAPA 299 ± 50; DM 385 ± 54 *; DM + DAPA 304 ± 40 # nmol/g tissue; * p < 0.05 vs. C; # p < 0.05 vs. DM) and higher superoxide dismutase and glutathione peroxidase activity than DM. Advanced glycation end products did not differ between groups. Conclusion: Dapagliflozin is safe, increases body weight, decreases glycemia and oxidative stress, and attenuates cardiac remodeling in an experimental rat model of Type 1 diabetes mellitus.

The influence of dapagliflozin on cardiac remodeling, myocardial function and metabolomics in type 1 diabetes mellitus rats

“…Dapagliflozin reduced blood glucose and body weight loss. This long-term result is in accordance with a previous study in which dapagliflozin was administered for 8 weeks in Type 1 DM rats [ 22 ]. Although the reduced glycemia and better cell environment may be crucial for body mass preservation, the mechanisms involved in this effect are not clear, especially considering that a major action of SGLT2 inhibitors is to decrease renal glucose reabsorption.…”

“…We have previously observed that short-term administration of SGLT2 inhibitor dapagliflozin is safe, and reduces glycemia, cardiac remodeling and oxidative stress in rats with Type 1 DM [ 22 ]. Several mechanisms have been proposed to explain the effects of SGLT2 inhibition in clinical trials.…”

Effect of pharmacological treatment on outcomes of heart failure with preserved ejection fraction: an updated systematic review and network meta-analysis of randomized controlled trials

“…SGLT2i inhibitors can reduce EAT abnormalities, reduce water and sodium retention, and reduce the risk of HFpEF combined with atrial fibrillation. (iv) Anti-myocardial fibrosis and inhibition of ventricular remodeling: SGLT2 inhibitors can reduce the release of inflammatory factors, thereby reducing myocardial fibrosis [ 41 , 42 ]. SGLT2 inhibitors can also reverse LV remodeling by reducing Na + and NHE-1 receptor activity in cardiomyocytes to slow myocardial fibrosis and cardiac hypertrophy [ 43 ].…”

Sodium-Glucose Cotransporter 2 Inhibitors: A Scoping Review of the Positive Implications on Cardiovascular and Renal Health and Dynamics for Clinical Practice

“…The same drug was also tested in Black and Tan Brachyury (BTBR) mice by Moy et al, which are bred for insulin resistance [ 32 ], and was found to limit the fibrotic impact and pathological remodeling of the left ventricle implicating SGLT2i as the potential for improving heart function [ 33 ]. Among a type I diabetic rat model induced by streptozotocin, dapagliflozin had a lower type I-to-type III collagen ratio and the most common type of collage found in the myocardium [ 34 ] with lesser reactive oxygen species concentrations in tissues [ 35 ]. Findings correlate with improved myocardial tissue health and thereby can be associated with a likely potential benefit in reducing harmful cardiac changes with SGLT2i use.…”