Sodium-dependent glucose transporter 2 inhibitors improve heart function in patients with type 2 diabetes and heart failure

Abstract

This article discusses the study by Grubić Rotkvić et al on the mechanisms of action of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) and heart failure (HF). T2DM and HF are highly comorbid, with a significantly increased prevalence of HF in patients with T2DM. SGLT2i exhibit potential in reducing hospitalization rates for HF and cardiovascular mortality through multiple mechanisms, including improving blood glucose control, promoting urinary sodium excretion, reducing sympathetic nervous system activity, lowering both preload and afterload on the heart, alleviating inflammation and oxidative stress, enhancing endothelial function, improving myocardial energy metabolism, and stabilizing cardiac ion homeostasis. Further research and clinical practice will help optimize the use of SGLT2i in HF patients.

Key Words: Sodium-glucose cotransporter 2 inhibitors; Type 2 diabetes mellitus; Heart failure; Diabetic cardiomyopathy; Cardiovascular disease

Core Tip: Sodium-glucose cotransporter 2 inhibitor exert significant effects in patients with type 2 diabetes and heart failure (HF) through multiple mechanisms, including improving blood glucose control, promoting osmotic diuresis, reducing inflammation and oxidative stress, optimizing myocardial energy metabolism, regulating myocardial ion homeostasis, enhancing endothelial function, reducing sympathetic nervous system activity, and alleviating ventricular remodeling. These effects collectively improve cardiac function and prognosis, thereby reducing hospitalization rates and cardiovascular mortality in patients with various types of HF.

TO THE EDITOR

The number of patients with heart failure (HF) remains alarmingly high, with approximately 64 million individuals affected worldwide, and this number continues to rise[1]. Among patients hospitalized for HF, whether with HF with preserved ejection fraction (HFpEF), HF with mid-range ejection fraction (HFmrEF), or HF with reduced ejection fraction (HFrEF), the 5-year mortality rate is as high as 75%[2]. Diabetes is strongly associated with the development of HF, with the prevalence of HF in diabetic patients being 2 to 5 times higher than in the general population[3,4].

The development of HF in patients with type 2 diabetes mellitus (T2DM) is the result of multiple contributing factors. In addition to the direct and indirect damage caused by hyperglycemia, other comorbid metabolic diseases, such as obesity, also contribute to myocardial injury[5]. Diabetic cardiomyopathy (DCM) refers to myocardial disease in diabetic patients that cannot be explained by hypertension, coronary artery disease, valvular heart disease, or other cardiac conditions[6]. DCM is characterized by pathological changes including interstitial fibrosis in myocardial tissue, thickening of the capillary basement membrane, intimal thickening, and proliferation of subendothelial fibroblasts[7], along with DNA fragmentation and apoptosis of myocardial cells[8]. Existing research indicates that pathophysiological processes such as metabolic dysregulation of myocardial cells, impaired calcium ion regulation, mitochondrial dysfunction, oxidative stress, poor microcirculatory perfusion, and excessive activation of neurohumoral factors play significant roles in the development and progression of HF in diabetic patients[9-11].

SGLT2I REDUCE CARDIOVASCULAR MORTALITY IN HF PATIENTS

As the evidence supporting the use of sodium-glucose cotransporter 2 inhibitor (SGLT2i) in HF continues to accumulate, the recommendations for their use in authoritative guidelines have progressively strengthened. First, the EMPA-REG OUTCOME trial[12], CANVAS trial[13], DECLARE–TIMI 58 trial[14], and VERTIS-CV trial[15] all demonstrated that SGLT2i have advantages in improving cardiovascular mortality, all-cause mortality, and HF hospitalization rates in patients with T2DM. Second, the DAPA-HF trial[16] and EMPEROR-Reduced trial[17], which focused on patients with HFrEF, found that SGLT2i treatment reduced the risk of HF worsening and cardiovascular death, regardless of the presence of T2DM. Moreover, the DELIVER trial[18] and EMPEROR-Preserved trial[19] extended the applicability of SGLT2i to patients with HFmrEF and HFpEF. Meanwhile, the SOLOIST-WHF trial[20] and EMPULSE trial[21] expanded the benefits of SGLT2i to patients with T2DM who were hospitalized due to worsening HF. Additionally, while reducing cardiovascular risk in T2DM patients, SGLT2i also lower the risk of kidney failure. For example, the DECLARE–TIMI 58 trial[14] showed that, regardless of baseline estimated glomerular filtration rate or urine albumin-to-creatinine ratio, SGLT2i reduced the risk of kidney-specific endpoints in T2DM patients. The DAPA-CKD trial[22] demonstrated that SGLT2i significantly reduced the risk of heart-kidney events in patients with chronic kidney disease (CKD), with consistent benefits observed regardless of T2DM status. Based on these findings, the 2022 AHA/ACC/HFSA HF management guidelines recommend SGLT2i as a Class I, Level A recommendation for symptomatic HFrEF patients, regardless of T2DM status, to reduce HF hospitalization and cardiovascular mortality[23]. Furthermore, the 2023 ESC HF guidelines recommend the use of SGLT2i in patients with HFmrEF and HFpEF to reduce the risk of HF hospitalization or cardiovascular death, also as a Class I, Level A recommendation[24].

MECHANISMS OF SGLT2IS BENEFITS ON CARDIAC FUNCTION

The mechanisms by which SGLT2i improve cardiac function are complex and involve multiple pathophysiological processes. These effects are primarily achieved through various pathways, including reducing water and sodium retention, alleviating inflammation and oxidative stress, and improving myocardial energy metabolism (Figure 1; Table 1).

Figure 1 Mechanism diagram of sodium-glucose cotransporter 2 inhibitor on different tissues and organs. NEFA: Nonesterified fatty acids; NHE: Na+/H+ exchanger; CaMK2: Calcium/calmodulin-dependent protein kinase 2; SGLT2i: Sodium-glucose cotransporter 2 inhibitor.

Table 1 The beneficial effects of sodium-glucose cotransporter 2 inhibitor on type 2 diabetes mellitus with heart failure.

Beneficial factors of SGLT2i with ability to improve T2DM with HF
1 Reducing inflammation
2 Inhibiting oxidative stress
3 Attenuating myocardial fibrosis and apoptosis
4 Improving myocardial energetics
5 Improving myocardial fatty acid and glucose metabolism
6 Improving mitochondrial function
7 Normalizing intracellular Ca2+ handling in cardiomyocytes
8 Inhibiting the sympathetic nervous system
9 Improving adverse cardiac remodeling
10 Reducing hyperglycemic toxicity
11 Osmotic diuretics
12 Lowering blood pressure

SGLT2i: Sodium-glucose cotransporter 2 inhibitor; T2DM: Type 2 diabetes mellitus; HF: Heart failure.

Diuretic and antihypertensive effects of SGLT2i

SGLT2is produce an osmotic diuretic effect by inhibiting sodium reabsorption in the renal proximal tubules, promoting urinary sodium excretion. This helps improve water and sodium retention, reduce blood pressure, and decrease both the preload and afterload on the heart, thereby benefiting HF patients[25]. In a study by Grubić Rotkvić et al[26], a significant and meaningful antihypertensive effect was observed in patients with initially high systolic blood pressure (> 131 mmHg) and diastolic blood pressure (> 80 mmHg). In the subgroup with an initial systolic blood pressure ≤ 131 mmHg, an increase in systolic blood pressure was noted. Similar to this study, the EMPA-REG OUTCOME trial found that empagliflozin clearly lowered both systolic and diastolic blood pressure[27]. The DAPA-HF trial found that although HFrEF patients with systolic blood pressure < 110 mmHg may have poorer prognosis due to lower cardiac output and compromised hemodynamics, these patients tolerated dapagliflozin well, with an increase in systolic blood pressure, while patients with higher initial blood pressure showed a reduction in systolic blood pressure[28]. Furthermore, the EMPA-REG METSU trial found that while empagliflozin lowered systolic blood pressure, it did not cause an increase in heart rate[29]. Given these findings, SGLT2 inhibitors are not only effective antihypertensive agents but may also work synergistically with other antihypertensive medications to further enhance blood pressure-lowering effects.

SGLT2i improve inflammation and oxidative stress

In a study by Grubić Rotkvić et al[26], it was observed that SGLT2is can reduce the expression of circulating inflammatory markers, such as myeloperoxidase and high-sensitivity C-reactive protein, thereby lowering levels of inflammation and oxidative stress, which benefits cardiovascular health. The potential mechanisms underlying the anti-inflammatory effects of SGLT2is are multifaceted. First, SGLT2is improve glycemic control by promoting urinary glucose excretion[30], reducing hyperglycemic toxicity[31], and preventing systemic metabolic abnormalities. Second, SGLT2is can reduce body weight[32,33] and improve insulin sensitivity[31]. Additionally, SGLT2is promote uric acid excretion by SGLT2 in the kidneys, which increases urinary glucose excretion while simultaneously promoting uric acid excretion. SGLT2is also reduce uric acid synthesis by acting on different pathways of uric acid metabolism, lowering intracellular hypoxanthine levels and inhibiting purine synthesis, which helps prevent and improve hyperuricemia[34-36]. However, it remains unclear how long the serum uric acid-lowering effect of SGLT2is lasts, and whether there are ethnic or gender differences in this effect.

Basic research has found that SGLT2is exert beneficial effects on cardiac cells through various mechanisms, such as reducing oxidative stress and inflammation. The specific pathophysiological mechanisms include inhibiting fibrosis, improving mitochondrial function, regulating ion transport, suppressing endoplasmic reticulum stress, modulating apoptosis and autophagy, alleviating cellular hypertrophy, and possessing anti-inflammatory and antioxidant properties, all of which contribute to improved cardiac function[37]. Overall, SGLT2is alleviate oxidative stress and inflammation in HF through multiple molecular pathways. However, these effects are unlikely to be mediated by cardiac SGLT2, as SGLT2 is not expressed in the heart[38-40].

SGLT2i improve myocardial energy metabolism

In HF, myocardial energy metabolism is impaired, with a decline in glucose utilization and an increase in non-esterified fatty acid (NEFA) oxidation. This leads to elevated reactive oxygen species (ROS) generation in cardiomyocytes, exacerbating oxidative stress and lipid peroxidation damage. These changes contribute to mitochondrial dysfunction, cell necrosis or apoptosis, ventricular remodeling, and ultimately, cardiac dysfunction.

Beta-hydroxybutyrate is considered a "super fuel" that can substitute glucose and NEFAs as an energy source for the myocardium. SGLT2 inhibitors can increase fatty acid oxidation and ketone body production, reducing the toxic effects of hyperglycemia on cardiomyocytes, enhancing myocardial utilization of ketone bodies, and thereby improving myocardial energy metabolism[41]. The increase in beta-hydroxybutyrate can also elevate Adenosine Triphosphate levels within cardiomyocytes, improve mitochondrial function, and reduce ROS generation[42].

SGLT2 inhibitors regulate myocardial ion homeostasis

SGLT2is can improve myocardial contraction and active relaxation by regulating myocardial ion homeostasis. In HF patients, the upregulation of Na+-H+ exchanger (NHE) activity leads to increased cytoplasmic Na+ concentration, calcium (Ca²⁺) overload, and reduced mitochondrial Ca²⁺ concentration. This not only accelerates the progression of HF but also increases the risk of sudden cardiac death in patients with arrhythmias. Studies have shown that SGLT2is reduce cytoplasmic Na+ and Ca²⁺ concentrations by inhibiting NHE, while increasing mitochondrial Ca²⁺ levels[43]. The increase in mitochondrial Ca²⁺ concentration is crucial for myocardial cell excitability, contraction, and mitochondrial antioxidant capacity. Additionally, SGLT2is can inhibit calcium/calmodulin-dependent protein kinase 2 (CaMK2), a key regulator. Overexpression and activation of CaMK2 are markers of HF, leading to reduced calcium concentration in the sarcoplasmic reticulum, which triggers cardiac contractile dysfunction and arrhythmias[44,45].

SGLT2is improve ventricular remodeling and left ventricular function

In this study, Grubić Rotkvić et al[26] observed that after SGLT2i treatment, left ventricular longitudinal strain (GLS) showed beneficial improvements compared to pre-treatment levels, as previously reported[46,47], indicating that SGLT2is improved left ventricular function. GLS, which assesses left ventricular myocardial function, can detect early subtle abnormalities and helps predict outcomes in various cardiac conditions. For HF patients, GLS can be used to predict subclinical left ventricular dysfunction or to better identify the severity or prognosis of the disease, outperforming traditional echocardiographic parameters[47].

A key potential mechanism of SGLT2is in HF management lies in their ability to improve adverse cardiac remodeling. SGLT2is enhance cardiac autonomic function in patients with T2DM[48], reduce levels of tyrosine hydroxylase and norepinephrine in the heart and kidneys[49], thereby inhibiting the sympathetic nervous system and improving adverse cardiac remodeling. Preclinical studies have also shown that empagliflozin can reduce cardiomyocyte apoptosis, decrease fibroblast activation, and attenuate extracellular matrix remodeling, thus exerting antifibrotic effects[50].

CHALLENGES AND PROSPECTS OF SGLT2IS IN CLINICAL APPLICATION

As SGLT2is become increasingly popular, clinicians need to be aware of certain rare side effects and further investigate their underlying causes and mechanisms. For instance, in patients who have recently started SGLT2i treatment, it is important to promptly identify the cause and suspend the use of the drug during an acute pancreatitis episode[51]. Additionally, some experts recommend temporarily withholding SGLT2i in patients with advanced CKD within 24 hours before or after receiving high-dose contrast agents or undergoing selective coronary interventions[52]. Furthermore, theoretically, SGLT2i may increase the risk of dehydration, orthostatic hypotension, or falls due to osmotic diuresis and reduced blood volume, which could lead to a higher risk of fractures[53]. It is also important to note that SGLT2i can potentially lead to diabetic ketoacidosis, which requires healthcare providers to consider whether to pause treatment in patients undergoing any acute events, including surgery[54].

Finally, we are pleased to see a series of recent studies investigating the use of SGLT2is in patients with acute myocardial infarction. These studies have shown a reduction in NT-proBNP levels and improvements in some echocardiographic parameters in the short term. However, whether this will significantly improve patient prognosis and quality of life still requires validation through future clinical trials.

CONCLUSION

In summary, SGLT2is have emerged as a standout treatment for patients with T2DM and HF, significantly reducing cardiovascular mortality and hospitalization rates in HF patients. They benefit various types of HF patients, whether acute or chronic, and regardless of ejection fraction status, whether preserved or reduced. Furthermore, SGLT2is exert cardioprotective effects through multiple mechanisms, such as controlling blood glucose, inducing osmotic diuresis, lowering blood pressure, improving inflammation and oxidative stress, optimizing myocardial energy metabolism, regulating myocardial ion homeostasis, and improving ventricular remodeling, all of which contribute to enhanced heart function and prognosis. Although there are still some challenges in their clinical application, such as rare adverse effects and usage restrictions, these issues are expected to be better addressed with further research and the accumulation of clinical experience.