Canagliflozin and Myocardial Fibrosis

Overview

Recently, large clinical intervention studies have demonstrated the cardiovascular protective effects on of sodium-glucose cotransporter 2 inhibitors (SGLT2i) such as empagliflozin, dapagliflozin, and canagliflozin in reduction of cardiovascular and all-cause mortality, coincident with a significant reduction in heart failure hospitalizations. Therefore, SGLT2i had been recommended as a therapeutic drug for diabetic patients to reduce the occurrence of cardiovascular events. However, the mechanism of these benefits remains unclear at the present time. Myocardial fibrosis is not only an important physiopathological mechanism of heart failure, but also has been shown to be closely associated with the risk of heart failure-related hospitalization and death, especially in patients with T2D. However, whether SGLT2i can exert cardioprotective effects by improving myocardial fibrosis remains to be further investigated. In recent years, the development of cardiac magnetic resonance (CMR) technology enables to detect focal and diffuse fibrosis in myocardial tissue, which makes it possible to systematically explore the role of SGLT2i on myocardial fibrosis. Although several studies including EMPA-HEART, SUGAR-DM-HF have explored the effects of SGLT2i on cardiac structure and function, these studies didn't reach consistent results. In addition, more scarce studies have investigated the effects of SGLT2i on both focal and diffuse fibrosis. At present, whether SGLT2i treatment can change the relevant indicators of myocardial fibrosis in people with diabetes and cardiovascular risk factors has not yet been reported. In addition, previous studies mainly focus on empagliflozin and dapagliflozin, and studies on canagliflozin are still very scarce. Therefore, this study intends to explore the effects of canagliflozin on myocardial fibrosis and other structures and functions of the heart in patients with type 2 diabetes mellitus and high cardiovascular risk factors.

According to the International Federation for Diabetes, diabetes now affects approximately 9.3% of the population worldwide, and the prevalence over the next two decades will continue to increase, reaching 552 million by 2030. In particular, type 2 diabetes (T2D) can cause macrovascular and microvascular complications, for example, T2D can increase the risks of ischemic stroke by 72% and stable angina by 62%. In addition, the incidence of heart failure in T2D patients is 9-22%, 2-4 times that of the general population. A significant breakthrough in contemporary cardiology was the finding that sodium-glucose-cotransporter-2 (SGLT2) inhibitors are associated with a lower risk of heart failure (HF) Hospitalization in patients with or at high risk of CV disease. In the EMPAREG OUTCOME Trial, Empagliflozin reduced cardiovascular death and hospitalisation for heart failure (HF) by 38% and 35%, respectively, with an almost immediate beneficial effect despite only a modest difference in glycaemic control, comparing two study arms over 94 weeks. The reductions in CV death were not accounted for by the reductions in atherothrombotic outcomes, as the rates of myocardial infarction and stroke remained unchanged with therapy. The proposed theory that HF is the outcome most sensitive to SGLT2 inhibition was confirmed in the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program and Dapagliflozin DECLARE-TIMI 58 trials. More recently, the EMPEROR trial showed that SGLT2 inhibition reduces the risk of hospitalisation for HF in patients regardless of the presence or absence of diabetes. The mechanisms by which SGLT2 inhibitors cause the reduction in HF risks and cardiovascular mortality are yet unknown. Myocardial fibrosis is not only an important physiopathological mechanism of heart failure, but also has been shown to be closely associated with the risk of heart failure-related hospitalization and death, especially in patients with T2D. However, whether SGLT2i can exert cardioprotective effects by improving myocardial fibrosis remains to be further investigated. In recent years, the development of cardiac magnetic resonance (CMR) technology enables to detect focal and diffuse fibrosis in myocardial tissue, which makes it possible to systematically explore the role of SGLT2i on myocardial fibrosis. At present, relevant studies have explored the effects of SGLT2i on cardiac structure and function. For example, there have been several related studies on left ventricular structure and function, but no consistent conclusions have been drawn: for example, the EMPA-HEART study showed that empagliflozin can reduce left ventricular mass; DAPA-HEART The LVH and SUGAR-DM-HF studies clarified the effect of dapagliflozin in reducing left ventricular mass and end-systolic volume; the REFORM study did not find that dapagliflozin had any effect on left ventricular weight. plastic effect. In addition, only the EMPA-HEART study investigated the effect of SGLT2i on both focal and diffuse fibrosis, and found that empagliflozin significantly improved diffuse fibrosis in people with diabetes and coronary heart disease. However, the SUGAR-DM-HF study did not observe changes in diffuse fibrosis with empagliflozin intervention in people with diabetes or prediabetes with reduced ejection fraction. At present, whether SGLT2i treatment can change the relevant indicators of myocardial fibrosis in people with diabetes and cardiovascular risk factors has not yet been reported. In addition, previous studies mainly focus on empagliflozin and dapagliflozin, and studies on canagliflozin are still very scarce. Therefore, this study intends to explore the effects of canagliflozin on myocardial fibrosis and other structures and functions of the heart in patients with type 2 diabetes mellitus and high cardiovascular risk factors.