SGLT2 inhibitor dapagliflozin prevents atherosclerotic and cardiac complications in experimental type 1 diabetes

Abstract

Introduction Cardiovascular disease (CVD) is two to five times more prevalent in diabetic patients and is the leading cause of death. Therefore, identification of novel therapeutic strategies that reduce the risk of CVD is a research priority. Clinical trials showed that reduction in the relative risk of heart failure by sodium-glucose cotransporter 2 inhibitors (SGLT2i) are partly beyond their glucose lowering effects, however, the molecular mechanisms are still elusive. Here we investigated the role of SGLT2i dapagliflozin (DAPA) in the prevention of diabetes-induced cardiovascular complications. Methods Type 1 diabetes was induced with streptozotocin (65 mg/bwkg, ip.) in adult, male Wistar rats. Following the onset of diabetes rats were treated for six weeks with DAPA (1 mg/bwkg/day, po.). Results DAPA decreased blood glucose levels (D: 37±2.7 vs. D+DAPA: 18±5.6 mmol/L; p<0.05) and prevented metabolic decline. Aortic intima-media thickening was mitigated by DAPA. DAPA abolished cardiac hypertrophy, and myocardial damage. Cardiac inflammation and fibrosis were also moderated after DAPA treatment. Conclusions These data support the preventive and protective role of SGLT2i in diabetes-associated cardiovascular disease. SGLT2i may provide novel therapeutic strategy to hinder the development of cardiovascular diseases in type 1 diabetes, thereby improve the outcomes.

Impact of Sodium–Glucose Cotransporter 2 (SGLT2) Inhibitors on Arterial Stiffness and Vascular Aging—What Do We Know So Far? (A Narrative Review)

“…In a recent study conducted by Hodrea et al [ 64 ], the group of investigators demonstrated that dapagliflozin ameliorates cardiac inflammation induced by diabetes mellitus similarly to the effect observed in type 2 diabetic rodent models by Aragón-Herrera et al [ 117 ] or Ye et al [ 118 ]. The anti-inflammatory and anti-fibrotic effect of dapagliflozin was also evidenced in the study proposed by the last mentioned investigators, dapagliflozin administration leading to decreased inflammasome activation and decreased levels of IL-1β [ 118 ].…”

“…Until the development of SGLT2 inhibitors, glucose-lowering agents had little or no impact on CVD progression in patients with diabetes mellitus [ 64 ]. Of all the agents in this class, dapagliflozin is the only one approved for the treatment of patients with type 1 diabetes in the European Union to date [ 64 ].…”

“…Until the development of SGLT2 inhibitors, glucose-lowering agents had little or no impact on CVD progression in patients with diabetes mellitus [ 64 ]. Of all the agents in this class, dapagliflozin is the only one approved for the treatment of patients with type 1 diabetes in the European Union to date [ 64 ]. Fibroblasts in the interstitial tubules are responsible for the synthesis of erythropoietin, the production of which is mediated by the hypoxia-inducible factor in the presence of oxygen [ 65 , 66 ].…”

Anti-inflammatory role of SGLT2 inhibitors as part of their anti-atherosclerotic activity: Data from basic science and clinical trials

“…Nevertheless, the molecular mechanisms are still unclear ( 42 ). This gap is mainly due to the absence of evidence showing SGLT2 expression in monocytes/macrophages and endothelial cells.…”

Safety profile of sodium glucose co-transporter 2 (SGLT2) inhibitors: A brief summary

“…SGLT2 inhibitors may indeed influence the blood lipid profiles. Many studies have investigated their role in atherosclerosis (41)(42)(43), triglyceride levels (44), and nonalcoholic fatty liver disease (45,46). A meta-analysis of 15 randomized trials (with a total of 7,578 patients with type 2 diabetes mellitus) found an increase in total cholesterol, lowdensity lipoprotein cholesterol, and high-density lipoprotein cholesterol, while a decrease in triglycerides with SGLT2 inhibitors compared to placebo or other oral glucose-lowering drugs.…”