The effects of sodium‐glucose cotransporter 2 inhibitors on left ventricular function: current evidence and future directions

Abstract

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a unique class of oral anti-hyperglycaemic medications that act to reduce glucose reabsorption in the renal proximal tubules, thereby enhancing urinary glucose excretion. Large randomized placebo-controlled trials in people with diabetes at high cardiovascular risk have demonstrated that SGLT2 inhibitors reduce heart failure hospitalization within months of commencing therapy. These findings are of considerable interest, as diabetes is associated with an increased risk of both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. In addition, left ventricular (LV) hypertrophy and impaired diastolic function is thought to be more prevalent in people with diabetes. Although many hypotheses have been proposed, the underlying mechanisms through which SGLT2 inhibitors reduce the risk of heart failure in people with diabetes are not fully understood. Given the rapid reduction in heart failure hospitalization, it is conceivable that the benefits of SGLT2 inhibitors are due to favourable haemodynamic and metabolic effects on LV function. Several clinical studies have been conducted to investigate the effect of SGLT2 inhibitors on LV structure and function and have found that LV mass index and diastolic function improve following SGLT2 inhibitor therapy in people with type 2 diabetes. If these findings are confirmed in future studies utilizing novel cardiac imaging modalities and large randomized controlled trials, then this will bring new hope for the prevention and management of heart failure with preserved ejection fraction, for which no current treatments have been shown to reduce mortality. At the present time, SGLT2 inhibitors are indicated for the treatment of type 2 diabetes; however, the results of ongoing trials in participants with heart failure but without diabetes are eagerly awaited. The purpose of this review is to summarize current knowledge regarding the effects of SGLT2 inhibitors on LV function, particularly the findings from clinical studies, proposed biological mechanisms, and future directions.

The risk of new-onset atrial fibrillation in patients with type 2 diabetes mellitus treated with sodium glucose cotransporter 2 inhibitors versus dipeptidyl peptidase-4 inhibitors

“…[18] SGTL2i has been shown to reduce blood sugar levels, blood pressure, body weight, albuminuria, lipid pro le, arterial stiffness, and endothelial function via an insulin-independent mechanism in T2DM patients. [19] Moreover, SGLT2i has been shown to have impressive cardioprotective and renoprotective effects. The main mechanisms of their cardioprotective effects are improvements in cardiac cell metabolism and ventricular loading conditions, inhibition of Na + /H + exchange in myocardial cells, alterations in adipokine and cytokine production, and reductions in cardiac cell necrosis and cardiac brosis.…”

Effects of Luseogliflozin on Left Ventricular Diastolic Function in Patients with Type 2 Diabetes and Established Cardiovascular Disease.

“…Some studies showed that SGLT2 inhibitors reduced all-cause mortality [30], and other meta-analyses and systematic reviews suggested that SGLT2 inhibitors protect against CVD and death in diverse subsets of the patients with T2DM regardless of CVD history [31]. Several mechanisms through which SGLT2 inhibitors have improved cardiovascular events have been studied; however, it is unclear which mechanism is most crucial [15]. The potential effects of SGLT2 inhibitors on LV structure and function are multifaceted, and these effects may be due to effects on systemic hemodynamics and metabolism [32].…”

“…Therefore, SGLT2 inhibitors may reduce the activation of the re ex sympathetic nervous system or implicate other neurohormonal pathways that affect the heart [34,35]. The signi cant effects of SGLT2 inhibitors on cardiovascular outcomes may also be attributed to the anti-oxidative, anti-in ammatory, or anti-apoptotic properties of SGLT2 inhibitors as shown in experimental models [15,36,37]. However, whether such effects seen in such preclinical studies affect humans remains to be determined.…”

“…However, it has not been still fully clari ed why SGLT2 inhibitors could prevent cardiovascular events [14,15]. Moreover, the bene ts of SGLT2 inhibitors in patients with HFpEF have been controversial in clinical trials and animal studies [16,17].…”

Antihyperglycemic drugs that improve cardiovascular outcomes and a model of diabetic cardiomyopathy

“…Indeed, SGLT2is appear to have a positive impact upon left ventricular mass in the earlier phases of DMCM and improved ventricular performance (reviewed in ref 13). The ventricular remodeling and progression from HFpEF to HFrEF appear to be characterized by ischemic heart disease and ischemia/reperfusion injury, 11,12 and this too represents a target for SGLT2is.…”