Direct Cardiac Mechanisms of the Sodium Glucose Co-Transporter 2 Inhibitor Class

Abstract

Background

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated significant cardiovascular benefits in clinical trial. While their role in reducing heart failure hospitalizations and cardiovascular mortality is well established, the precise mechanisms underlying their direct cardiac effects remain unclear. This literature review aims to synthesize current knowledge on the molecular and physiological pathways by which SGLT2 inhibitors may exert effects on cardiac tissue, independent of glycemic control.

Methods

A comprehensive review of peer-reviewed articles, randomized controlled trials, meta-analyses, and mechanistic studies published in PubMed and related databases was conducted. The search focused on studies examining the direct impact of SGLT2 inhibitors on cardiac function, remodeling, metabolism, and intracellular signaling pathways. Only studies evaluating the cardiac effects separate from their glucose-lowering action were included in the analysis.

Results

This review identified several key mechanisms by which SGLT2 inhibitors may benefit the heart directly, including reductions in oxidative stress, inflammation, and myocardial fibrosis. Emerging evidence suggests that these drugs modulate key pathways such as sodium-hydrogen exchange (NHE) inhibition, improvement of mitochondrial function, and promotion of ketone body utilization in cardiomyocytes.

Conclusions

SGLT2 inhibitors appear to confer direct cardioprotective effects. These include anti-inflammatory, anti-fibrotic, and energy efficiency improvements in the myocardium. The findings highlight new potential therapeutic mechanisms and provide a foundation for further research into the non-diabetic use of SGLT2 inhibitors in heart failure and other cardiac conditions. Understanding these direct effects could lead to optimized treatment strategies for patients with and without diabetes.

Introduction

Sodium-glucose cotransporter (SGLT)2 inhibitors induce glucosuria by reducing renal glucose reabsorption in the proximal tubule of the nephron. ¹ Initially developed to treat type 2 diabetes, large, randomized trials have demonstrated the cardioprotective value of SGLT2 inhibitors in both diabetes mellitus (DM) and heart failure (HF).^2–5 This generated interest in SGLT2 inhibitors as a potential treatment for HF, leading to studies such as DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), and EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction).^6–8 In all three trials, SGLT2 inhibitors reduced HF hospitalizations and cardiovascular deaths when compared to placebo, irrespective of the presence of DM or chronic kidney disease. ⁸

Several theories exist regarding the mechanism behind the cardiovascular benefits of SGLT2 inhibitors. The rapidity with which SGLT2 inhibitors impart cardiovascular protection suggests that mechanisms other than improved glycemic control are responsible, as glycemic reduction induced benefits alone would likely take years to have a measurable effect. ⁹ Other glycemic reducing agents, such as dipeptidyl peptidase 4 inhibitors, have not been demonstrated to lead to cardiovascular benefits despite similar induction of improved glycemic control. ¹⁰ Furthermore, the EMPA-REG OUTCOME trial found cardiovascular benefits of SGLT2 inhibitors to be observed independently of baseline hemoglobin A1c (HbA1c) and reductions seen in HbA1c throughout the trial. ²

These findings have generated interest in possible off target effects of SGLT2 inhibitors, specifically cardiomyocytes, a cell that lacks SGLT2. ¹¹ While prior reviews have provided valuable insights into the extra-renal effects of SGLT2 inhibitors, the continuous emergence of new literature necessitates periodic updates to ensure a current and comprehensive understanding. In this review we summarize the prevailing theories regarding off-target SGLT-2 mechanisms at the cellular level. Specifically, we focus on SGLT2 inhibitor induced ion homeostasis, oxidate stress, coronary metabolism and cardiac function Figure 1.

Figure 1.

File Designation.

Ion Homeostasis

Proposed Mechanism of Action

Recent studies have demonstrated that SGLT2 inhibitors block the activity of the cardiac Na⁺/H + exchanger (NHE-1).^12,13 Baartscheer et al. demonstrated that Empagliflozin (Empa) lowered cytosolic Na²⁺ while increasing mitochondrial Ca²⁺ through inhibition of NHE-1 in isolated rat and rabbit ventricular cardiomyocytes. ¹² Elevated Na⁺ concentration in the failing heart causes Ca²⁺ extrusion from the mitochondria. This in turn impairs Ca²⁺ stimulation of Krebs cycle dehydrogenases, preventing regeneration of NADH and NADPH. Thus, elevated Na²⁺ impairs ATP production and mitochondrial anti-oxidative defense. ¹⁴

Adenosine monophosphate kinase (AMPK) regulates NHE-1 expression. ¹⁵ Ye et al. demonstrated that SGLT2 inhibitor dapagliflozin (Dapa) increases AMPK phosphorylation, leading to anti-inflammatory effects in in vitro mouse cardiofibroblasts. ¹⁶ These anti-inflammatory effects are SGLT2-independent, as cardiofibroblasts do not express SGLT2. Moreover, Ye et al. could not replicate the protective effects of Dapa with phlorizin, a non-specific SGLT inhibitor. ¹⁶ AMPK inhibitor compound C prevented the anti-inflammatory effects of Dapa, further supporting Ye's theory that Dapa induces anti-inflammation in cardiofibroblasts via AMPK phosphorylation, subsequent down-regulation of NHE-1, and ultimately reduced cytoplasmic Na²⁺ in cardiomyocytes. ¹⁶

Cardiomyocytes

Studies have shown that SGLT2 inhibitors affect Na²⁺ and Ca²⁺ homeostasis in isolated cardiomyocytes. Uthman et al. revealed that healthy rabbit cardiomyocytes exposed to acute (< 10 min) or prolonged (3 h) Empa incubation lowered cytosolic Na²⁺ and Ca²⁺. ¹³ These effects were independent of the presence of glucose, suggesting they were not mediated by SGLT1 or SGLT2. ¹³ Similarly to the aforementioned study of Dapa by Ye et al., Uthman's work revealed that Empa's effects on Na²⁺ were attenuated in the presence of NHE-1 inhibitor cariporide, indicating Empa's impact on cytosolic Na²⁺ is through inhibition of NHE-1. ¹³ This mechanism of NHE-1 inhibition and subsequent reduced cytosolic Na²⁺ can be considered a class effect of SGLT2 inhibitors, in that Empa, Dapa, and canagliflozin (Cana) all have been shown to reduce cytosolic Na²⁺ in healthy murine cardiomyocytes.^13,17,18

The precise mechanism through which SGLT2 inhibitors alter NHE-1 activity remains elusive. Ye et al. found that Dapa significantly lowered NHE-1 mRNA levels but did not alter NHE-1 protein levels in the whole cell lysate. ¹⁶ This is suggestive of a Dapa-induced post-translation modification or translocation of NHE-1 for activation. Concurrently, Huang et al. demonstrated that lipopolysaccharide (LPS) increases NHE-1 activity via augmenting the association between NHE-1 and Heat-shock protein 70 (Hsp70) without changing total protein levels of NHE-1. ¹⁹ Ye et al. showed that Dapa attenuated NHE-1 association with Hsp70, an effect that was in turn block by AMPK inhibitor compound C, indicating AMPK activation plays a critical role in this process. ¹⁶ Additionally, a 2024 study by Chen et al. identified Empa as an inhibitor of RSK, a key regulator of NHE-1. ²⁰ This inhibition subsequently led to a reduction in NHE-1 activity. ²⁰ In summary, these findings highlight multiple mechanisms by which SGLT2i may indirectly inhibit NHE-1,ultimately resulting in lowered intra-cardiomyocyte Na²⁺_.

SGLT2i may additionally decrease cytosolic Na²⁺ by directly inhibiting NHE-1.^13,21 As stated, Studies have shown that the effects of SGLT2 inhibitors on ion homeostasis closely resemble those of cariporide, a known direct NHE-1 inhibitor.^13,22 Moreover, a 2021 study by Philippaert et al. demonstrated that SGLT2 inhibitors inhibit late voltage-gated sodium channels in a manner similar to tetrodotoxin, ranolazine, and lidocaine–each recognized as sodium channel inhibitors. ²³ Through in silico docking simulations using a 3D structural model of the human Nav1.5 sodium channel, Empa was shown to bind directly to Nav1.5 at a site shared with local anesthetics and ranolazine. ²³ Ultimately, both the indirect and direct mechanisms outlined above may contribute to the cardioprotective benefits observed in clinical studies.

Role of SGLT2i on Oxidative Stress

Inflammation has been shown to be an independent risk factor for numerous cardiovascular conditions. ²⁴ Specifically, in the setting of heart failure (HF), inflammation plays an important pathophysiological role in both acute and chronic HF, predicting poor prognosis independently of ejection fraction. ²⁵ This process is mediated by an increase in pro-inflammatory cytokines (eg, interleukin (IL) 1, IL–6), reactive oxygen species (ROS), and a decrease in the availability of nitric oxide (NO). ²⁶ This leads to microvascular endothelial cell damage, with prolonged inflammation leading to infiltration of monocytes into the myocardium and further differentiation into proinflammatory macrophages (M1). ²⁷ Clinically, these effects lead to increased left ventricular stiffness and thus diastolic dysfunction.

Reducing inflammation is one of the proposed mechanisms for SGLT2i. SGLT2i have already been shown to reduce organ inflammation via reduction in the activity of nucleotide binding domain like receptor protein 3 (NLRP3) inflammasome. The normal function of NLRP3 is to induce a proinflammatory state via secretion of inflammatory cytokines. Previous research has shown that both Dapa and Empa reduce NLRP3 activity in cardiomyocytes, cardiac fibroblasts, and macrophages.^28–30 The purpose of this section is to review the cardioprotective role SGLT2i via attenuating the inflammatory response in cardiomyocytes, endothelial cells, and fibroblasts.

Proposed Mechanisms of Action

Before discussing the effects of SGLT2i on specific cell types, it is important to understand the proposed mechanisms behind these effects. Although the anti-inflammatory potential of SGLT2i is widely accepted, multiple signaling pathways have been implicated in carrying out these effects. It is difficult to determine the magnitude of effect for these pathways, but a discussion of two major hypotheses gaining increased support is warranted.

The first is the autophagy flux hypothesis, which suggests that SGLT2i simultaneously upregulate nutrient deprivation signaling and downregulate nutrient surplus signaling. ³¹ This is done by increased activity of the adenosine monophosphate–activated protein kinase (AMPK), sirtuin (SIRT), and peroxisome proliferator–activated receptor γ coactivator 1-α (PGC1-α) pathway and decreased activity of the mammalian target of rapamycin (mTOR) pathway. AMPK is a serine/threonine kinase that controls the levels of ATP (adenosine triphosphate) and AMP (adenosine monophosphate). Activation of AMPK reduces oxidative stress, mitochondrial dysfunction, proinflammatory pathways, fibrosis, and apoptosis and preserves ventricular function during cardiac stresses produced by ischemia, diabetes, pressure overload, or cardiotoxic agents. ³² mTOR is also a serine/threonine protein kinase that promotes cell growth and proliferation via production of ROS and activation of proinflammatory pathways. ³³ Over 60 studies in the last two years have supported this hypothesis across all the SGLT2i and in in vivo and vitro settings. ³¹ Blockade of the nutrient deprivation signaling pathways or ability to promote autophagy led to a loss of SGLT2i ability to reduce oxidative stress and decrease inflammation/fibrosis.^34,35

The second hypothesis regarding the inflammation lowering potential of SGLT2i is through inhibition of NHE1.^12,13 Multiple isoforms of NHE exist but the predominant isoform found in cardiomyocytes and neutrophils is NHE1.^36,37 Normal NHE1 function includes pH balance and regulation of cardiac function in ischemia-reperfusion injury. Further, due to its location on neutrophils, NHE1 plays a role in the regulation of inflammation. ³⁸ Compelling evidence exists that blockade of NHE1 causes cardioprotective effects and reduces neutrophil activation, chemokine production, and leukocyte endothelial cell interactions.^38,39 Recent literature has shown that inflammatory cytokines (eg, TNF-alpha) increased oxidative stress via activation of NHE1 and subsequent increase in intracellular sodium, suggesting a correlational role between increased sodium and ROS production. This demonstrates that Empa directly inhibits NHE1 in human endothelial cells and thus reduces intracellular sodium concentration and subsequent ROS production.^40,41

Although other mechanisms have been implicated, such as reduction in adhesion molecules needed for leukocyte activation and reduction in activation of angiotensin system, the two hypotheses above have gained increased attention over the last two years.^42,43 Understanding the mechanistic targets of SGLT2i is important as it can provide an improved understanding of disease pathophysiology and provide future therapeutic targets.

Cardiomyocytes

Numerous in vivo mice studies have induced ROS production in cardiomyocytes using a variety of methods including high fat diets, hyperglycemia, and ischemic injury.^44,45 In each of these settings, treatment with SGLT2i leads to a reduction in ROS. The major limitation to these in vivo studies is that large differences in plasma glucose levels existed between the treatment and control group, such that it is difficult to attribute the findings directly to the use of SGLT2i itself. To address this, in vitro and ex vivo studies were conducted in environments without significant differences in plasma glucose. Again, SGLT2i was found to decrease ROS production. Specifically, treatment with Empa reduced oxidative stress in cardiomyocytes isolated from high-fat treated mice, ⁴⁶ in murine cardiomyocytes subject to ischemic injury, ⁴⁷ and in skinned fibers from ventricular biopsies of HFpEF patients. ⁴⁸

A 2024 study by Chen et al. demonstrated that Empa acts as a direct inhibitor of NHE-1, reducing intracellular sodium and calcium overload in cardiomyocytes. ⁴⁹ This inhibition of NHE-1 led to decreased mitochondrial ROS production and preserved NO bioavailability, which improved cardiac and endothelial function. In a heart failure murine model, the study also showed that cardiac ROS levels, measured by 4-hydroxynonenal (4-HNE), were elevated in the disease state but significantly reduced by SGLT2i treatment. Similarly, NHE-1 inhibition alone produced a comparable reduction in ROS, and no additive effect was observed when SGLT2i were combined with NHE-1 inhibition in vivo. ⁴⁹ These findings suggest that the antioxidative effects of SGLT2i are mediated through NHE-1 inhibition, rather than SGLT2 inhibition. Importantly, these effects occurred independently of glucose levels or SGLT2 expression, highlighting an off-target mechanism of Empa that contributes to its cardioprotective effects. These results underscore the central role of NHE-1 in oxidative stress regulation

Endothelial Cells

Endothelial cells play an important vasoregulatory role through the release of relaxing and vasoconstricting substances. ⁵⁰ The vasodilatory effect of the endothelium is mediated by the synthesis and release of NO. In both preserved and reduced HF, endothelial dysfunction is mediated by increased production of ROS, which in turn causes inactivation of NO. Loss of endothelium vasodilatory control can cause repeated episodes of ischemia/reperfusion and lead to stunned myocardium with systolic dysfunction and increased diastolic stiffness with diastolic dysfunction. ⁵¹ Endothelial dysfunction is associated with worse prognosis and higher rates of cardiovascular events, emphasizing the importance of therapeutic interventions aimed at mitigating effects.

SGLT2i serves as one of these therapeutic interventions. Through the mechanisms described above and others, the net effect of SGLT2i on endothelial cells is improved vasodilation through restoration of NO production, enhanced endothelial cell viability, and reduction in oxidative stress and inflammation. ⁵² SGLT2i also prevents the contraction of vascular smooth muscle cells and block the proliferation and migration of these cells. ⁵³ Although not a direct effect on endothelial cells, modulating vascular smooth muscle helps to maintain overall vessel integrity. In conclusion, restoration of NO synthesis and production restores endothelial cell hemostasis.

Cardiac Fibroblasts

Cardiac fibrosis is characterized by transformation of fibroblasts into myofibroblasts and deposition of extracellular matrix proteins within the myocardium. This leads to impaired ventricular compliance and thus development of HF. ⁵⁴ Experimental research suggests that SGLT2 receptors in the heart promote cardiac fibrosis, suggesting a potential role for SGLT2i to attenuate this response. ⁵⁵ Indeed, SGLT2i have been shown to mediate multiple steps in cardiac fibrosis. Dapa shows antifibrotic effects via increasing activation of M2 macrophages and inhibiting myofibroblast activation. ⁵⁶ In contrast to M1 macrophages, M2 macrophages resolve inflammation and assist with tissue healing. Similarly, Empa decreased the expression of key pro-fibrotic markers that increase extracellular protein deposition. ⁵⁷ Interestingly, the same results were not seen with canagliflozin in experimental studies. ⁵⁸ Regardless, SGLT2i does show a favorable effect on cardiac fibroblast.

Metabolism and Energetics

The Healthy Heart

Typically, healthy myocardial cells use ATP produced through mitochondrial oxidation of free fatty acids (FFAs) as their main energy source, as FFAs are the most energy-dense substrate available to the heart. Under normal circumstances, the heart also exhibits metabolic flexibility enabling it to utilize multiple different substrates such as glucose, ketone bodies, lactate, and branched-chain amino acids depending on workload and substrate availability.^59–61 Almost all ATP generated by the healthy cardiomyocyte is through mitochondrial oxidation (95%) with just 5% coming from glycolysis.^62,63 Oxygen is required for mitochondrial oxidation, but not for glycolysis. Due to the heart's high metabolic requirement and inability to store the required nutrients, it depends on a continuous supply of blood to bring in oxygen and other nutrients for energy production. ⁶⁴

The Failing Heart

It has been theorized that the failing heart reverts to a fetal metabolic state in advanced heart failure with reduced ejection fraction (HFrEF), decreasing mitochondrial oxidation and exhibiting metabolic rigidity. This may manifest as a decrease in utilization of FFAs and increases in utilization of glucose as a fuel source.^64–66 Although fatty acids are the most energy-dense substrate, they are also the least oxygen efficient, requiring more oxygen per ATP produced. In addition, glycolytic intermediates from glycolysis are preferentially shuttled through other glycolytic pathways such as the hexosamine biosynthetic pathway and the pentose phosphate pathways rather than through the TCA cycle and mitochondrial oxidation. ⁵⁹ This results in less ATP produced per 2-carbon moiety, while utilizing less oxygen. This deficit has contributed to the metabolic switch theory as a possible mechanism underlying the “energy-starved” myocardium.^59,61,67 This phenomenon is seen across the phenotypic spectrum of heart failure from HFrEF to HFpEF. ⁶⁸

Ketone metabolism also undergoes an alteration in heart failure. Even in the absence of diabetes, serum ketone levels in heart failure patients are elevated.^65,69,70 This may be due to increased lipolysis and ketogenesis as a result of activation of the sympathetic nervous system that is seen in chronic heart failure. ⁶⁵ Ketone body uptake into myocardial cells is directly proportional to its plasma concentration and transit time through the cardiac vasculature, so the increased plasma concentration of ketones and the longer transit time with decreased cardiac output leads to increased ketone body uptake and utilization.^66,71 This metabolic change has been proposed to be adaptive and is the basis of the energetic hypothesis.^71–73

The Energetic Hypothesis

SGLT2i may improve cardiovascular outcomes through enhanced myocardial metabolism and energetics. SGLT2i use, through its glycosuric effect, lowers serum glucose which catalyzes the shift in metabolism to a starvation state.^68,74–76 A decrease in the insulin/glucagon ratio catalyzes the shift toward increased lipolysis and subsequently ketone production by the liver. It is well documented that with SGLT2i use, serum ketones are significantly increased.^77,78 Per carbon, ketones produce more ATP and at a lower oxygen cost than FFAs. ⁵⁴ Thus the theory was formed that SGLT2i alters the metabolic milieu of the myocardium forcing the diseased heart to utilize a more energy-efficient substrate, ketones.

However, recent studies have found conflicting evidence. Preclinical studies in mice showed that SGLT2i increases rates of ketone body oxidation and resulted in 30% more ATP produced without changing rates of glucose or fatty acid oxidation. The cardiac efficiency, defined as the amount of work done per oxygen molecule used, did not change.^73,79 However other preclinical animal models have shown SGLT2i can cause the heart to utilize ketones as an alternative energy source.^59,80 Santos-Gallegos et al. showed in their metabolomics study of a porcine model of ischemic cardiomyopathy that Empa increased the utilization of ketones, FFAs, and BCAAs as fuel while decreasing glucose utilization. In addition, the Empa-treated pig hearts showed increased ATP content and improved efficiency.^59,80

Preclinical studies can only provide so much information, however. DEFINE-HF was the first large-scale randomized clinical study to examine the metabolic changes seen with SGLT2i use and its link to improved energetics. ⁷⁸ It showed that SGLT2i treatment led to increased ketone and fatty acid oxidation metabolites in circulating plasma, suggesting a reversal in the mitochondrial dysfunction seen in heart failure. However, a static view of the plasma metabolome may not provide a completely accurate assessment of the cardiac tissue level metabolism. Still, whether SGLT2i-induced ketogenesis acts as an alternative fuel source or an additional fuel source, it seems likely that increased mitochondrial ketone oxidation provides the failing heart with the necessary ATP to ameliorate the relative energy deficit.

Most recently, the landmark EMPA-VISION trial was the first randomized clinical trial to specifically examine the energetic hypothesis of SGLT2i's benefit in heart failure. ⁸¹ It found that the phosphocreatine to ATP ratio, which noninvasively measures the balance of energy consumption to energy supply in the heart and serves as a proxy for cardiac energy status, was not different between treatment and placebo groups. ⁸¹ This result throws a wrench into the energetics hypothesis. Although the study population was mainly nonischemic, nondiabetics, there is still a possibility that SGLT2i could behave differently in ischemic cardiomyopathy patients with diabetes. It is important to note that ketones are increased in diabetic patients compared to nondiabetics which could lend itself to a greater energetic effect, although no clinical differences were seen in the original SGLT2i heart failure trials between the two subgroups. ⁸² Also, ischemic cardiomyopathy may also behave differently from nonischemic cardiomyopathy given the relatively hypoxic environment, but again no difference in outcomes was seen between ischemic and nonischemic cardiomyopathy in the original SGLT2i heart failure trials. ⁸³ More research is needed in these specific subgroups of heart failure patients to determine whether SGLT2i exerts heterogeneous effects across heart failure etiologies and patient comorbidities. Alternatively, ketones may exert their protective effect through a different mechanism entirely such as by decreasing inflammation or promoting autophagy. ⁸⁴

Oxygen Delivery

SGLT2i may also optimize cardiac energetics by increasing oxygen delivery to the heart through a moderate increase in hematocrit levels. Initially, through the diuretic effect of SGLT2i, plasma volume decreases which leads to mild hemoconcentration. Although the increased urine volume seen immediately after initiation returns to baseline levels after 1 week, this can’t explain the rise in hematocrit which continues for 2 months and remains persistently elevated during the duration of treatment.^68,85 To explain this, erythropoietin (EPO) levels increase with SGLT2i treatment and plateau at around 1 month. The mechanism of this rise in EPO is not entirely understood, but there is increased production of EPO by the kidneys. ⁸⁶ Interestingly, typical biomarkers of iron deficiency are worsened with SGLT2 inhibition, but as Packer explains, this is a red herring and the true state of iron homeostasis is improved through the decrease in inflammation-induced functional iron deficiency.^86,87 This is also reflected in the similar levels of serum iron between treatment and placebo groups in DAPA-HF. ⁸⁷ Overall, improvement in iron homeostasis and increased hematocrit levels improves oxygen delivery to the failing myocardium and may help ameliorate the energy deficit.

Conclusion

In conclusion, the emerging understanding of sodium-glucose cotransporter 2 (SGLT2) inhibitors highlights their multifaceted role in managing heart failure beyond their initial use in diabetes. The evidence reviewed underscores the significant direct cardiac benefits these agents provide, which are critical for optimizing heart failure treatment. SGLT2 inhibitors enhance cardiac ion homeostasis by inhibiting the Na+/H + exchanger, thereby reducing intracellular sodium and mitigating the detrimental effects associated with elevated cytosolic sodium. Additionally, they exhibit notable anti-inflammatory and antioxidative properties, which contribute to reduced myocardial stress and improved cardiac function. By influencing cardiac metabolism, particularly through enhanced ketone utilization, these drugs address the metabolic inefficiencies inherent in heart failure. While the precise mechanisms of action remain under investigation, the consistent findings across various studies reinforce the therapeutic value of SGLT2 inhibitors in heart failure management. Future research should continue to explore these pathways, particularly in isolated cardiomyocytes, to further refine and enhance the therapeutic strategies for heart failure.