From Diabetes Care to Heart Failure Management: A Potential Therapeutic Approach Combining SGLT2 Inhibitors and Plant Extracts

Abstract

Diabetes is a complex chronic disease, and among the affected patients, cardiovascular disease (CVD)is the most common cause of death. Consequently, the evidence for the cardiovascular benefit of glycaemic control may reduce long-term CVD rates. Over the years, multiple pharmacological approaches aimed at controlling blood glucose levels were unable to significantly reduce diabetes-related cardiovascular events. In this view, a therapeutic strategy combining SGLT2 inhibitors and plant extracts might represent a promising solution. Indeed, countering the main cardiometabolic risk factor using plant extracts could potentiate the cardioprotective action of SGLT2 inhibitors. This review highlights the main molecular mechanisms underlying these beneficial effects that could contribute to the better management of diabetic patients.

Keywords: SGLT2 inhibitors; cardiovascular risk; diabetes; inflammation; insulin resistance; lipid accumulation; nutraceutical supplementation; reactive oxygen species (ROS).

Figure 1

Metabolic alterations in diabetic patients. At the molecular level, insulin resistance causes an increase in both plasma glucose and serum insulin levels, which lead to a reduction in glucose transporter type 4 (GLUT4), and a decrease in glucose uptake. These events lead to a reduction in the glycolysis pathway and glucose oxidation caused by the downregulation of the pyruvate dehydrogenase complex (PDH). The hyperglycaemia is associated with the concomitant increase in hematic fatty acid concentration and the consequent upregulation of fatty acids uptake and oxidation due to the decreased levels of malonyl CoA and the consequent activation of carnitine palmitoyltransferase 1 (CPT1). CD36—cluster of differentiation 36; ACC—Acetyl-CoA carboxylase; MCD—Malonyl-CoA decarboxylase; CTP1—carnitine palmitoyltransferase 1; CTP2—carnitine palmitoyltransferase 2; MCP—mitochondrial pyruvate carrier; CT—carnitine translocase; PDH—pyruvate dehydrogenase complex; GLUT4—glucose transporter type 4.

Figure 2

Downregulation of NHE-1, modulation of intramyocardial Ca²⁺ and Na⁺ fluxes by SGLT-2 inhibitors. The sodium hydrogen exchanger-1 (NHE-1) is upregulated in heart failure (HF) and diabetes. SGLT2i have a key role in the inhibition of NHE-1, sodium-glucose co-transporter 1 (SGLT1), and Na⁺/Ca²⁺ exchanger (NCX), preserving the calcium and sodium homeostasis and attenuating the oxidative Ca²⁺/Calmodulin-dependent kinase IIδ (CaMKII) activity. The modulation of Ca²⁺ and Na⁺ fluxes lead to a reduction in reactive oxygen species (ROS) and prevention of the cytosolic increase in calcium because of the mitochondrial and sarcoplasmic release caused by mitochondrial Na⁺/Ca²⁺ exchanger (NCLX) and ryanodine receptor 2 S(RyR2).

Figure 3

Common cardioprotective effects of the plant extract supplementation and SGLT2 inhibitors. The SGLT2i and several phytocomplexes show a similar action to counteract the ROS production caused by hyperglycemia. In particular, they play a key role in the inhibition of the inflammasome, leading to a reduction in inflammation and fibrosis. The downregulation of LDL oxidation and PARP activation lead to the reduction in lipid peroxidation and endothelial dysfunction. PKC—Protein kinase C; OX-LDL—Oxidized Low-Density Lipoprotein; FFA—Free fatty acids; ROS—reactive oxygen species; TNF-α—Tumour Necrosis Factor α; IL-1β—Interleukin 1 beta; IL-6—Interleukin 6; VEGF—Vascular-Endothelial Growth Factor; ICAM-a—intracellular adhesion molecule a, TGF-β—Transforming Growth Factor Beta; PARP—Poly (ADP-ribose) polymerase; LDL—Low-Density Lipoprotein.