Empagliflozin protects against atherosclerosis progression by modulating lipid profiles and sympathetic activity

Abstract

Background Several large clinical trials have confirmed the cardioprotective role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes. However, whether empagliflozin, as an SGLT2i, could alleviate atherosclerosis progression in non-diabetic states remain unknown. Methods ApoE-/- mice were fed a Western diet for 12 weeks to induce atherosclerosis. On the 7th week, a group of mice were treated with drinking water containing empagliflozin (10 mg/kg/day), while another group was given normal water. At the 12th week, the whole aortas of each group were harvested. Oil Red O, HE and Movat staining were performed for atherosclerotic lesion area and size. Mouse serum lipid profiles (total cholesterol [TC], triglyceride [TG], low-density lipoprotein-c [LDL], and high-density lipoprotein-c [HDL]), systemic inflammation levels (IL-1β, IL-6 and IL-10), renin-angiotensin-aldosterone system (RAAS) components and sympathetic activity (norepinephrine and neuropeptide Y) indicators were measured by ELISA. Results Empagliflozin reduced the atherosclerotic lesion burden (-8.6 %, P = 0.004) at aortic root in ApoE-/- mice. In addition, empagliflozin decreased body weight (-3.27 g, P = 0.002), lipid profiles (TC: [-15.3 mmol/L, P = 0.011]; TG: [-2.4 mmol/L, P < 0.001]; LDL: [-2.9 mmol/L, P = 0.010]), RAAS (renin [-9.3 ng/L, P = 0.047]; aldosterone [-16.7 ng/L, P < 0.001]) and sympathetic activity (norepinephrine [-8.9 ng/L, P = 0.019]; neuropeptide Y [-8.8 ng/L, P = 0.002]). However, the anti-inflammatory effect of empagliflozin was not significantly evident. Conclusions The early atherosclerotic lesion size was less visible in empagliflozin-treated mice. Empagliflozin could decrease lipid profiles and sympathetic activity in atherosclerosis.

The Role of SGLT2 Inhibitors in Atherosclerosis: A Narrative Mini-Review

“…Oxidative stress was also reversed by empagliflozin in porcine endothelial cells, through inhibition of nitric oxide formation (Park et al, 2021). Additionally, the administration of empagliflozin in normoglycemic mice reduced renin, aldosterone, norepinephrine, and neuropeptide Y (Liu et al, 2021).…”

“…Several underlying mechanisms can explain the role of SLGT2-is in the pathogenesis of atherosclerosis (Figure 1; Table 1). SGLT2-is may prevent the development of atheroma by adjusting dyslipidemia, restoring normal endothelial function, reducing oxidative stress, decreasing inflammation, and inhibiting monocyte-macrophage-foam cell evolution (Terasaki et al, 2015;Leng et al, 2016;Han et al, 2017;Al-Sharea et al, 2018;Dimitriadis et al, 2019;Ganbaatar et al, 2020;Lee et al, 2020;Liu et al, 2021;Park et al, 2021). Furthermore, SGLT2-is may prevent the progression of atherosclerosis by reducing plaque size and burden, altering plaque composition, and improving plaque stability (Terasaki et al, 2015;Leng et al, 2016;Al-Sharea et al, 2018;Lee et al, 2020).…”

“…Excess cholesterol substrates can increase the susceptibility of arterial walls to atherosclerosis. Several studies in animals and humans have shown that SGLT2-is reduce serum total cholesterol and triglyceride levels (Calapkulu et al, 2019;Ganbaatar et al, 2020;Liu et al, 2021). In patients with diabetes, dapagliflozin reduced the potent atherogenic particles of low-density lipoprotein (LDL) (Hayashi et al, 2017), while canagliflozin increased highdensity lipoprotein (HDL) levels (Kamijo et al, 2019).…”

“…In patients with diabetes, dapagliflozin reduced the potent atherogenic particles of low-density lipoprotein (LDL) (Hayashi et al, 2017), while canagliflozin increased highdensity lipoprotein (HDL) levels (Kamijo et al, 2019). In normoglycemic mice models, empagliflozin reduced LDL, but no changes in HDL levels were observed (Liu et al, 2021).…”

“…SGLT2-is can affect inflammatory cytokines that promote activation and migration of monocytes into the tunica intima in both diabetic and normoglycemic models (Leng et al, 2016;Han et al, 2017;Dimitriadis et al, 2019;Ganbaatar et al, 2020;Lee et al, 2020;Liu et al, 2021). Empagliflozin reduced monocyte chemoattractant protein (MCP)-1, interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α in both normoglycemic and diabetic mice (Han et al, 2017;Dimitriadis et al, 2019;Ganbaatar et al, 2020;Liu et al, 2021). Dapagliflozin reduced IL-1β, IL-18, and NLRP3 inflammasome activation in diabetic mice (Leng et al, 2016).…”