The Cardioprotective and Anticancer Effects of SGLT2 Inhibitors: JACC: CardioOncology State-of-the-Art Review

Abstract

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally approved for type 2 diabetes mellitus, have demonstrated efficacy in reducing cardiovascular events, particularly heart failure, in patients with and without diabetes. An intriguing research area involves exploring the potential application of SGLT2 inhibitors in cardio-oncology, aiming to mitigate the cardiovascular adverse events associated with anticancer treatments. These inhibitors present a unique dual nature, offering both cardioprotective effects and anticancer properties, conferring a double benefit for cardio-oncology patients. In this review, the authors first examine the established cardioprotective effects of SGLT2 inhibitors in heart failure and subsequently explore the existing body of evidence, including both preclinical and clinical studies, that supports the use of SGLT2 inhibitors in the context of cardio-oncology. The authors further discuss the mechanisms through which SGLT2 inhibitors protect against cardiovascular toxicity secondary to cancer treatment. Finally, they explore the potential anticancer effects of SGLT2 inhibitors along with their proposed mechanisms.

Keywords: SGLT2 inhibitors; anthracyclines; cancer; cardio-oncology; cardiotoxicity.

Graphical abstract

Central Illustration

The Role of SGLT2 Inhibitors in Cardio-Oncology This illustration summarizes both the cardioprotective and the anticancer mechanisms of sodium-glucose cotransporter-2 (SGLT2) inhibitors. AMPK = adenosine monophosphate–activated protein kinase; ER = endoplasmic reticulum; PI3K = phosphoinositide 3-kinase.

Figure 1

Cardioprotective Mechanisms of SGLT2 Inhibitors Against Cancer Treatment–Induced Cardiotoxicity Sodium-glucose cotransporter-2 (SGLT2) inhibitors protect against cardiovascular toxicity induced by anticancer drugs via multiple mechanisms. They enhance energy metabolism by increasing the activation of nutrient deprivation pathways (adenosine monophosphate-activated protein kinase [AMPK] and sirtuin [SIRT] 1, SIRT3, and SIRT6) while inhibiting the nutrient surplus pathways (AKT/mammalian target of rapamycin [mTOR]), resulting in enhanced autophagy and increased mitochondrial biogenesis (peroxisome proliferator–activated receptor-γ coactivator-1α [PGC-1α]). Additionally, SGLT2 inhibitors mitigate oxidative and endoplasmic reticulum (ER) stress, block inflammatory pathways, inhibit ferroptosis, and enhance ketogenesis. Created using BioRender.com. ATF-4 = activating transcription factor 4; CHOP = C/EBP homologous protein; eIF-2α = eukaryotic initiation factor 2α; Ho-1 = heme oxygenase 1; MDA = malondialdehyde; MMP = matrix metalloproteinase; NLRP-3 = nod-like receptor pyrin domain containing 3; NF-κB = nuclear factor κB; NOX-1 = NADPH oxidase 1; NOX-2 = NADPH oxidase 2; Nrf-2 = nuclear factor erythroid 2–related factor 2; NQO1 = NAD(P)H quinone dehydrogenase 1; PERK = protein kinase R-like endoplasmic reticulum kinase; ROS = reactive oxygen species; SOD = superoxide dismutase; TNF = tumor necrosis factor.

Figure 2

Mechanisms of the Anticancer Effects of SGLT2i SGLT2 inhibitors (SGLT2i) inhibit glucose uptake by inhibiting SGLTs (SGLT-1 and SGLT-2) and glucose transporters (GLUTs). SGLT2 inhibitors, especially canagliflozin, inhibit mitochondrial complex I–supported cellular respiration, reducing adenosine triphosphate production and activating AMPK. Activated AMPK inhibits acetyl–coenzyme A carboxylase (ACC), suppressing fatty acid synthesis. It also down-regulates forkhead box A1 (FOXA1) and sonic hedgehog signaling molecule (Shh) and inhibits mTOR and p70S6K, thereby suppressing protein synthesis. Inhibited mTOR results in the down-regulation of hypoxia-inducible factor-1α (HIF-1α). SGLT2 inhibitors inhibit the phosphoinositide 3-kinase (PI3K)/AKT pathway. SGLT2 inhibitors inhibit the Hippo signaling pathway by down-regulating the heterogeneous nuclear ribonucleoprotein K (hnRNPK)/YES-associated protein 1 (YAP1) axis. Additionally, SGLT2 inhibitors inhibit epidermal growth factor receptor (EGFR) kinase and angiogenesis activators. Created using BioRender.com. ANG = angiogenin; FA = fatty acid; IL8 = interleukin 8; TIMP1 = tissue inhibitor of metalloproteinase 1; other abbreviations as in Figure 1.