Sodium-glucose co-transporter 2 (SGLT2) inhibitors are oral antidiabetic agents that have shown significant improvements in cardiovascular and renal outcomes among patients with heart failure (HF), regardless of diabetic status, establishing them as a cornerstone therapy. In addition to glycemic control and the osmotic diuretic effect, the inhibition of SGLT2 improves endothelial function and vasodilation, optimizing myocardial energy metabolism and preserving cardiac contractility. Moreover, SGLT2 inhibitors may exhibit anti-inflammatory properties and attenuate acute myocardial ischemia/reperfusion injury, thereby reducing cardiac infarct size, enhancing left ventricular function, and mitigating arrhythmias. These pleiotropic effects have demonstrated efficacy across various cardiovascular conditions, ranging from acute to chronic coronary syndromes and extending to arrhythmias, valvular heart disease, cardiomyopathies, cardio-oncology, and cerebrovascular disease. This review provides an overview of the current literature on the potential mechanisms underlying the effectiveness of SGLT2 inhibitors across a wide range of cardiovascular diseases beyond HF.

Sodium glucose cotransporter 2 inhibitors (SGLT2i) represent one of the four pillars of heart failure (HF) pharmacological therapy.

The study aims to clarify SGLT2i antiarrhythmic effect on patients with HF with reduced ejection fraction (HFrEF) in terms of atrial and ventricular arrhythmias (AAs and VAs) reduction.

HFrEF carriers of implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) followed by remote monitoring of Policlinico Umberto I of Rome for 1 year before and after SGLT2i therapy initiation were enrolled in the study. We compared the incidence of AAs and VAs as recorded at remote monitoring during 1 year preceding SGLT2i therapy initiation and after 1 year of SGLT2i therapy.

Among 198 enrolled patients, 135 patients had arrhythmic events before SGLT2i therapy prescription. There were 1353 arrhythmic events recorded in the year before SGLT2i therapy prescription, and 354 events were detected in the year after SGLT2i initiation, with a 73.8% reduction in events number after therapy initiation. After SGLT2i therapy initiation, the median number of total arrhythmic episodes significantly decreased from a median of 7 [3;12] to 1 [0;4] (P value < 0.001), AAs significantly decreased from a median of 4 [3;7] to 1 [0;3] episodes (P value < 0.001) and VAs were reduced from a median of 5.5 [3;10] to 0 [0;2] (P value < 0.001). When considering arrhythmia subtypes, larger reductions were recorded for atrial fibrillation (AF) episodes, reduced from 4 [3;8] to 0 [0;3], non-sustained ventricular tachycardia (NSVT) that decreased from 4 [2;8.75] to 0 [0;2] (P value < 0.001) and for sustained ventricular tachycardia (SVT) that were reduced from 3 [2;4] to 0 [0;1] (P value < 0.001).

In HFrEF carriers of ICD/CRT-D, the use of SGLT2i resulted in significant reduction of AA and VA events.

The effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on reducing cardiovascular events in different subgroups of diabetic patients are under investigation. The current systematic review and meta-analysis investigated the effects of SGLT2 inhibitors on preventing cardiovascular events and mortality and their adverse events in patients with active cancer and diabetes undergoing cardiotoxic cancer treatment.

We searched PubMed, Embase, Web of Science, and Scopus to find studies investigating the effects of SGLT2 inhibitors on patients with diabetes and confirmed cancer until 19 August 2024. Meta-analyses were conducted using the random-effects model to compare all-cause mortality, cancer-associated mortality, heart failure (HF) hospitalization, arrhythmia, and adverse event rates such as ketoacidosis, hypoglycemia, urinary tract infection, and sepsis between patients with or without SGLT2 inhibitors use. Risk ratios (RRs) with 95% confidence intervals (CI) were used to compare outcomes between SGLT2 inhibitors and non-SGLT2 inhibitors groups.

Eleven studies were included with 88,096 patients with confirmed cancer (49% male). Among the total population, 20,538 received SGLT2 inhibitors (age 61.68 ± 10.71), while 67,558 did not receive SGLT2 inhibitors (age 68.24 ± 9.48). The meta-analysis found that the patients who received SGLT2 inhibitors had a significantly lower mortality rate than those who did not receive SGLT2 inhibitors (RR 0.46, 95% CI 0.34 to 0.63, p-value < 0.0001). Similarly, the cancer-associated mortality rate was also lower (RR 0.29, 95% CI 0.27 to 0.30, p-value < 0.0001). Further analysis found that the SGLT2 inhibitor group had a lower rate of HF hospitalization, compared to controls (RR 0.44, 95% CI 0.27 to 0.70, p-value = 0.0007). Moreover, patients receiving SGLT2 inhibitors had a statistically lower rate of arrhythmia (RR 0.38, 95% CI 0.26 to 0.56, p-value < 0.0001). Finally, patients in the SGLT2 inhibitors group had a lower rate of adverse events (RR 0.51, 95% CI 0.42 to 0.62, p-value < 0.0001).

SGLT2 inhibitors are effective in reducing mortality (all-cause and cancer-associated), HF hospitalization, arrhythmia, and drug adverse events in patients with cancer. If confirmed in future studies, these agents could be a potentially ideal candidate to prevent cardiotoxicity of cancer therapies.

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and impaired metabolic efficiency. This study investigates the therapeutic potential of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin (EMPA) in ameliorating these pathological features in a mouse model carrying the myosin R403Q mutation.

Male mice harbouring the R403Q mutation were treated with EMPA for 16 weeks. Multi-nuclear magnetic resonance spectroscopy (31P, 13C, and 23Na MRS), echocardiography, transcriptomic, proteomic, and phosphoproteomic profiling were utilized to assess metabolic, structural, and functional changes.

Empagliflozin facilitated the coupling of glycolysis with glucose oxidation and normalized elevated intracellular sodium levels. Treatment resulted in a significant reduction in LVH and myocardial fibrosis as evidenced by echocardiography and histopathology. These structural improvements correlated with enhancements in mitochondrial adenosine triphosphate (ATP) synthesis, fatty acid oxidation, and branched-chain amino acid catabolism. Furthermore, EMPA improved left ventricular diastolic function and contractile reserve, underscored by improved ATP production and reduced energy cost of contraction. Notably, these benefits were linked to down-regulation of the mammalian target of rapamycin signalling pathway and normalization of myocardial substrate metabolic fluxes.

Empagliflozin significantly mitigates structural and metabolic dysfunctions in a mouse model of HCM, underscoring its potential as a therapeutic agent for managing this condition. These findings suggest broader applicability of SGLT2i in cardiovascular diseases, including those due to myocardial-specific mutations, warranting further clinical investigation.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder with a high prevalence and challenging treatment options. It significantly affects the function of various organs, including bones, and imposes substantial social and economic costs. Chronic hyperglycemia, insulin resistance, and abnormalities in glucolipid metabolism can lead to cellular damage within the body. Bone dysfunction represents a significant characteristic of diabetic osteoporosis (DOP). Recent studies confirm that cell death is a critical factor contributing to bone damage. Regulated cell death (RCD) is a highly controlled process that involves numerous proteins and specific signaling cascades. RCD processes, including apoptosis, autophagy, necroptosis, pyroptosis, ferroptosis, and cuproptosis, may be linked to the dysfunction of bone cells in T2DM. In this review, the cell death types of bone cell populations during the pathogenic process of DOP were explored, and the link between cellular RCD processes and the pathogenesis of DOP was further explored. In addition, the research progress on targeting RCD for DOP was summarized in this paper. This may provide a foundation for additional explorations and drug development, as well as new therapeutic concepts for the clinical management of DOP.

The co-occurrence of diabetes mellitus (DM) and atrial fibrillation (AF) poses growing health risks in the United States (U.S.), with diabetes patients having a 34 % higher risk of AF. This study examines trends in DM and AF related mortality among individuals aged ≥ 25 years in the U.S. from 1999 to 2020. Data from the CDC WONDER database were analyzed calculating age-adjusted mortality rates (AAMRs) per 100,000 and annual percent change (APC), stratified by age, sex, race/ethnicity, urbanization, and region. Between 1999 and 2020, 419,036 deaths were recorded among U.S. adults (≥25 years) with comorbid AF and DM. The AAMR rose from 4.83 in 1999 to 15.91 in 2020, with an APC increase of 15.01 from 2018 to 2020. Older adults (≥65) had higher AAMRs than younger adults (25-64). Men (11.23) had higher rates than women (7.16). NH American Indian/Alaskan Natives (9.54) and Whites (9.16) had the highest AAMRs, while NH Asian/Pacific Islanders (6.04) had the lowest. Non-metropolitan areas (10.32) exceeded metropolitan areas (8.53). The Western U.S. (9.87) had the highest regional AAMR. Rising DM and AF-related deaths highlight a growing burden, particularly in men, NH American Indian/Alaskan Natives and Whites, and rural populations, necessitating targeted interventions.

Atrial fibrillation (AF), the most prevalent arrhythmia, is associated with an increased risk of stroke, systemic embolism, and death.

This study aimed to investigate the secular trends in AF incidence rates (IRs) in different age, sex, and comorbidity subgroups in a Chinese population from 2000 to 2021.

This retrospective study used data from the National Health Insurance Research Database in Taiwan; determined AF cases by the International Classification of Diseases, Ninth Revision and Tenth Revision, Clinical Modification codes; and calculated and stratified the annual age-standardized IRs by age, sex, and comorbidity status.

The total number of AF cases increased from 24,450 in 2000 to 32,817 in 2021; the standardized IR (SIR) decreased from 170.62 to 112.38 per 100,000 person-years. Male patients demonstrated higher IRs than female patients across all age groups. The annual IRs substantially increased with age. IRs exhibited a declining trend, except in men aged 20-49 years and women aged 20-34 years. The trends of SIRs showed distinct patterns in patients with different comorbidity burdens. Individuals with lower comorbidity burden demonstrated lower SIRs and earlier declines in SIRs.

This study revealed complex secular trends of AF incidence in the past 21 years, with decreasing overall SIRs but increasing annual IRs in younger populations. The intricate interplay between AF incidence, age, and sex emphasizes the need for age- and sex-specific strategies in AF prevention and management. The observed relationship between comorbidity burden and AF incidence suggests differential effectiveness of cardiovascular risk management across patient subgroups.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) reportedly decreased the new-onset atrial arrhythmias in patients with type-2 diabetes (T2DM) or heart failure (HF). This study examined the impact of SGLT2is on catheter ablation for atrial fibrillation (AF) in HF patients without T2DM.

Persistent AF (PeAF) and HF (N-terminal prohormone of brain natriuretic peptide, NT-proBNP ≥400 pg/ml) patients without T2DM undergoing catheter ablation were prospectively enrolled (n = 102). SGLT2is were prescribed from ≥1 month prior to the procedure and were continued during the follow-up in 51 patients (SGLT2i[+]) but not prescribed in 51 patients (SGLT2i[-]). Left atrial pressure (LAP) was measured via the sheath placed in the LA before starting catheter ablation. The event-free rate of early and 1-year atrial-arrhythmia recurrence were compared between SGLT2i[+] and SGLT2i[-].

There was no significant difference in baseline characteristics between SGLT2i[+] and SGLT2i[-]. SGLT2i[+] significantly decreased average LAP compared to SGLT2i[-] (9.3 ± 4.8 mmHg vs. 12.1 ± 6.6 mmHg, p < 0.01); normalized LAP to systemic blood pressure also decreased in SGLT2i[+] (0.11 ± 0.05 vs. 0.15 ± 0.07, p < 0.01). The serum NT-proBNP levels at the enrollment were unchanged between the two groups but SGLT2i[+] had lower values on the day of catheter ablation (p = 0.06) and at 1 month after the procedure (p < 0.01) than SGLT2i[-]. SGLT2i[+] had significantly higher event-free rate of early (92 % vs. 60 %, p < 0.01) and 1-year (89 % vs. 75 %, p < 0.05) atrial-arrhythmia recurrence than SGLT2i[-].

Periprocedural SGLT2i treatment decreased LAP and improved the outcomes of catheter ablation for PeAF in HF patients without T2DM.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have revolutionized the therapeutic scenario of heart failure, demonstrating favorable effects on mortality and quality of life. Previous studies have yielded conflicting data regarding the effects on ventricular arrhythmias.

A prospective observational study was conducted to investigate the anti-arrhythmic properties of SGLT2 inhibitors evaluating the intra-patient difference in major adverse arrhythmic cardiac events (MAACE) over a six-month period in patients with chronic heart failure who were undergoing continuous monitoring using a cardiac implantable electronic device.

From January 2022 to January 2023, 82 patients [median age 63 years (IQR 15), male 87 %] were enrolled in the study, with a median follow-up of 28 weeks (IQR 5). The rate of MAACE at baseline was 11 %, without relevant differences in the follow up in terms of major and minor arrhythmic events. In patients with an arrhythmic phenotype at baseline, a mild but non statistically significant reduction of MAACE (from 36 % to 28 %, p = 0.727) was observed and a significant decrease of non-sustained ventricular tachycardia (from 68 % to 32 %, p = 0.022).

Our findings suggest potential anti-arrhythmic properties of SGLT2 inhibitors, evident in patients with arrhythmic events before the initiation of the drug.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been associated with lower rates of cardiac arrhythmias in post hoc analyses. The real-world effect on cardiac arrhythmias is incompletely defined.

The purpose of this study was to determine the effects of SGLT2i on cardiac arrhythmias in a real-world, hospitalized population.

A retrospective cohort study was performed in South Australia, Australia. Patients (n = 882) with type 2 diabetes mellitus (T2DM) on oral diabetic therapy (33.6% females, median age 62.3 years) who received SGLT2i (for T2DM) were identified through public hospital admissions from 2011-2019. Patients were matched with 3282 contemporaneous controls with T2DM who did not receive SGLT2i. Baseline characteristics were adjusted using inverse probability treatment weighting. The primary outcome was incidence of atrial arrhythmias. Secondary outcomes included incidence of ventricular arrhythmias and cardiac arrest at 2 years.

All-cause mortality was higher in the SGLT2i group (hazard ratio [HR] 2.02, 95% confidence interval [CI] 1.55-2.63, P <.001) despite propensity matching, highlighting the greater unmeasured comorbidity burden of the SGLT2i-treated group. Despite this, SGLT2i treatment was associated with fewer atrial arrhythmias (HR 0.17, 95% CI 0.07-0.41, P <.001) at 2 years. The relationship between SGLT2i use and ventricular arrhythmias (HR 0.25, 95% CI 0.06-1.03, P = .055) and cardiac arrest (HR 0.82, 95% CI 0.20-3.45, P = .796) did not reach statistical significance.

In this real-world, comorbid inpatient cohort, SGLT2i treatment was associated with a lower incidence of atrial arrhythmias. Prospective randomized trials evaluating SGLT2i as specific atrial fibrillation pharmacotherapy are underway.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have shown promising results in reducing hospitalizations from heart failure (HF) and cardiovascular mortality. However, their effect on arrhythmia and sudden cardiac death (SCD) is not well established.

The authors sought to evaluate the association between SGLT2i and the risk of arrhythmias and SCD in patients with type 2 diabetes mellitus, HF, or chronic kidney disease.

We performed a systematic literature search on PubMed, EMBASE, and Scopus for relevant randomized controlled trials from inception until February 10, 2023. ORs and 95% CIs were pooled using a random effect model.

A total of 38 randomized controlled trials with 88,704 patients (48,435 in the SGLT2i group and 40,269 in the control group) were included in the study. The mean age of patients among SGLT2i and control groups was 56.8 and 56.7 years, respectively. The mean follow-up duration was 1.6 years. Pooled analysis of primary and secondary outcomes showed that SGLT2i significantly reduced the risk of incident atrial arrhythmia (OR: 0.85 [95% CI: 0.75-0.98], P = 0.02), SCD (OR: 0.72 [95% CI: 0.55-0.94], P = 0.02) compared with placebo. However, the risk of ventricular arrhythmia (OR: 1.03 [95% CI: 0.84-1.26], P = 0.77) and cardiac arrest (OR: 0.94 [95% CI: 0.72-1.23] P = 0.67) was comparable between both groups of patients.

SGLT2i therapy was associated with an overall lower risk of atrial arrythmia and SCD in patients with type 2 diabetes mellitus and/or HF or chronic kidney disease. However, SGLT2i therapy was not associated with a lower risk of ventricular arrhythmia.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to lower the risk of re-hospitalization and cardiovascular mortality among heart failure (HF) patients. Nevertheless, the impact of these agents on ventricular arrhythmias (VAs) has not been thoroughly investigated. To assess the beneficial impact of SGLT2 inhibitors on VAs in patients at various stages of HF, a systematic review and meta-analysis of randomized controlled trials involving SGLT2 inhibitors in this patient population was performed.

A comprehensive search of the PubMed, Embase, Ovid, ProQuest, Scopus, and Cochrane databases was performed for clinical trials published up to November 21, 2024. The primary outcomes of interest were incidences of VAs and sudden cardiac death (SCD) between the groups receiving SGLT2 inhibitors and the control drugs. For the outcomes observed in the populations of the included trials and in specific subgroups, hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled and meta-analysed across the analyses.

A total of 23 randomized trials (22 placebo-controlled trials and 1 active-controlled trial) involving 74,380 patients (37,372 receiving SGLT2 inhibitors and 37,008 in the control group) were included. The analysed SGLT2 inhibitors included canagliflozin, dapagliflozin, empagliflozin, bexagliflozin, sotagliflozin, and ertugliflozin. The participants were non-advanced HF patients, including at-risk for HF, pre-HF, and symptomatic HF, with follow-up duration ranging from 12 to 296 weeks. Compared with the control, treatment with SGLT2 inhibitors was associated with significantly reduced risk of VAs (risk ratio (RR) 0.85, 95% confidence interval (CI) 0.74-0.98; P = 0.02) and SCD (RR 0.79, 95% CI 0.64-0.98; P = 0.03). Subgroup analyses indicated that longer follow-up (≥ 1 year) taking SGLT2 inhibitors can still reduce the risk of VAs (RR 0.79, 95% CI 0.65-0.96; P = 0.02) and SCD (RR 0.80, 95% CI 0.65-0.99; P = 0.04).

SGLT2 inhibitors have beneficial effects on lowering risks of VAs and SCD in patients with type 2 diabetes, cardiovascular diseases, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), and heart failure with mildly reduced ejection fraction (HFmrEF), with longer follow-up duration reinforcing these findings. However, future prospective trials are needed to verify the effects of SGLT2 inhibitors on VAs and SCD.

PROSPERO (CRD42024601914).

Background: In recent years, sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated significant cardiovascular and renal benefits in patients with heart failure (HF), in addition to their established antidiabetic effects. However, their role in arrhythmia prevention remains unclear. This study aimed to assess the effect of SGLT2 inhibitors on the incidence of supraventricular tachycardia (SVT) and ventricular tachycardia (VT) in patients with HF with reduced ejection fraction (HFrEF) during an extended follow-up period. Methods: This retrospective cohort study was conducted between January 2019 and November 2024 at the Ulm University Heart Center. All patients exhibited severely reduced left ventricular function and underwent primary prophylactic implantable cardioverter-defibrillator (ICD) implantation. Half of the cohort initiated SGLT2 inhibitor therapy alongside optimal medical HF treatment (the SGLT2 group). Patients were followed for approximately three years (846.2 ± 520.0 days) and the incidence of SVT and VT was analyzed using intracardiac Holter records of the ICD. Results: The study population consisted of 78 patients with a mean age of 66.6 ± 12.9 years. Over the follow-up period, a significant prolongation in the time to first occurrence of SVT was observed in the SGLT2 group (Log-Rank p = 0.03), suggesting a potential protective effect of SGLT2 inhibitors. However, regarding VT, additional SGLT2 inhibitor therapy did not show an additional benefit to optimal medical HF treatment. Conclusions: This study suggests that SGLT2 inhibitors may play a beneficial role in reducing the incidence of SVT in patients with HFrEF. These results highlight the importance of further investigating the antiarrhythmic potential of SGLT2 inhibitors through large-scale, prospective studies to better understand their clinical implications and mechanisms of action.

Implantable cardioverter-defibrillators (ICDs) are recommended to reduce the risk of sudden cardiac death (SCD) in patients with heart failure with reduced ejection fraction (HFrEF). The landmark studies leading to the current guideline recommendations preceded the 4 pillars of guideline-directed medical therapies (GDMTs). Therefore, some have questioned the role of ICDs for primary prevention in current clinical practice. In this paper, the authors provide an overview of the current ICD recommendations, including the instrumental clinical trials, the risk of SCD as observed in clinical trials vs real-world scenarios, disparities in ICD use among different patient populations, the impact of contemporary GDMT on outcomes, and ongoing and future trials and methodologies to help identify patients who are at an increased risk of SCD and who may benefit from an ICD. The authors also propose a pragmatic guidance for clinicians when they engage in the shared decision-making discussions for primary ICD implantation.

Diabetes mellitus (DM) and atrial Fibrillation (AF) are among the most common health issues. They are responsible for the highest rates of morbidity and mortality. The importance of sodium glucose cotransporter-2 inhibitors (SGLT-2is) in treating DM has increased significantly in recent years. In our article, we aimed to evaluate the effect of SGLT-2i on the clinical outcomes of AF patients with DM.

Our study is a retrospective, observational study. The patients with AF and DM were divided into two groups: those using SGLT-2i or not using SGLT-2i, and 3-year follow-up results were examined. The endpoints of the study were defined as all-cause death, the development of myocardial infarction (MI), major bleeding requiring hospitalization, and an ischemic cerebrovascular event (CVE). Differences between groups according to SGLT-2i use were analyzed.

The study included 485 patients, 205 (42.3%) of whom were male and had an average age of 70.7 ± 9.7 years. A total of 138 of 485 patients (28.5%) received SGLT-2i. All-cause mortality was lower in the group receiving SGLT-2i (p < 0.001). Similarly, a significant reduction in major bleeding events was observed among those who received SGLT-2i treatment (p = 0.009). The incidence of CVEs was lower among SGLT-2i recipients, but the difference was not statistically significant (p = 0.066). SGLT2i usage did not mitigate the risk of MI development (p = 0.317).

In our study, SGLT-2i treatment was associated with a significant reduction in all-cause mortality and major bleeding in diabetic AF patients. Our study provides evidence of the clinical benefit of SGLT-2i in AF patients.

In the acute phase of acute coronary syndrome (ACS), ventricular tachycardia (VT) and/or ventricular fibrillation (VF) leading to resuscitation are not considered to be associated with increased long-term sudden cardiac death (SCD) because the cause-acute ischaemia-is believed to be reversible. The aim of this study is to investigate whether ventricular arrhythmias (VAs) leading to sudden cardiac arrest during ACS are associated with the risk of incident SCD in patients with a normal or mildly impaired left ventricular ejection fraction (LVEF).

This study is based on a retrospective analysis of all 8062 consecutive ACS patients undergoing coronary angiography with the baseline LVEF ≥40% between 2007 and 2018 (follow-up until 31 December 2021). The primary outcome was SCD-equivalent life-threatening VAs (LTVAs) composed of true SCDs and SCDs aborted by successful resuscitation or appropriate implantable cardiac device (ICD) therapy. The risk of sudden LTVA was estimated with a multivariate subdistribution hazard model using other deaths as competing events. Two-hundred thirteen (n = 211, 2.6%) patients suffered acute phase VF/VT leading to resuscitation and survived to discharge, and most occurred before angiography (80.6%, n = 170) and were VF (92.9%, n = 196). During a median follow-up of 7.6 years, 3.9% (n = 316) of all the patients had LTVA (10.0% in the VF/VT group vs. 3.8% in other patients). Ventricular fibrillation/VTs during ACS are associated with an increased risk for future SCD (hazard ratio 3.07; 95% confidence interval 1.94-4.85, P < 0.001). Most LTVAs occurred in patients without ICDs.

Ventricular fibrillation/VT in ACS is associated with a remarkably high long-term risk for SCD in patients with an LVEF ≥40%.

Diabetes mellitus (DM) is characterized by chronic hyperglycemia, and despite intensive glycemic control, the risk of heart failure in patients with diabetes remains high. Diabetes-induced heart failure (DHF) presents a unique metabolic challenge, driven by significant alterations in cardiac substrate metabolism, including increased reliance on fatty acid oxidation, reduced glucose utilization, and impaired mitochondrial function. These metabolic alterations lead to oxidative stress, lipotoxicity, and energy deficits, contributing to the progression of heart failure. Emerging research has identified novel mechanisms involved in the metabolic remodeling of diabetic hearts, such as autophagy dysregulation, epigenetic modifications, polyamine regulation, and branched-chain amino acid (BCAA) metabolism. These processes exacerbate mitochondrial dysfunction and metabolic inflexibility, further impairing cardiac function. Therapeutic interventions targeting these pathways-such as enhancing glucose oxidation, modulating fatty acid metabolism, and optimizing ketone body utilization-show promise in restoring metabolic homeostasis and improving cardiac outcomes. This review explores the key molecular mechanisms driving metabolic remodeling in diabetic hearts, highlights advanced methodologies, and presents the latest therapeutic strategies for mitigating the progression of DHF. Understanding these emerging pathways offers new opportunities to develop targeted therapies that address the root metabolic causes of heart failure in diabetes.

Sodium-glucose transporter 2 (SGLT2) inhibitors such as empagliflozin are one of the main treatments for type 2 diabetes mellitus (DM2) and heart failure (HF). They have also demonstrated anti-arrhythmic effects in some preclinical and clinical studies. The purpose of this study was to assess the effects of empagliflozin on ventricular arrhythmias in HF patients with an implantable cardioverter-defibrillator (ICD). In a prospective double-blinded, randomized controlled trial of Iran County, Mashhad (72 patients 1:1), we compared the frequency and proportion of ventricular arrhythmias and ICD therapies during the 24 weeks to the prior 24 weeks. Results revealed that empagliflozin significantly reduced the frequency and proportion of ventricular tachycardia (VT)/fibrillation (VF) episodes (P = 0.019 and 0.039, respectively). Moreover, it tended to reduce the frequency and proportion of ICD therapies, including anti-tachycardia pacing (ATP) and shock. Subgroup analysis of patients with or without any antiarrhythmic drugs (digoxin, mexiletine, amiodarone, or sotalol) revealed that only patients who were previously on the antiarrhythmic drugs benefit from empagliflozin antiarrhythmic effects. In conclusion, empagliflozin exhibits anti-arrhythmic effects in HF patients with an ICD. Larger and long-term clinical studies are still needed to investigate and confirm all positive effects of SGLT2 inhibitors in this regard. Trial registration number: IRCT20120520009801N7 (Approval date: June 11, 2022).

Cardiovascular autonomic neuropathy (CAN) is an under-recognised yet highly prevalent microvascular complication of diabetes. CAN affects approximately 20% of people with diabetes, with recent studies highlighting the presence of CAN in prediabetes (impaired glucose tolerance and/or impaired fasting glucose), indicating early involvement of the autonomic nervous system. Understanding of the pathophysiology of CAN continues to evolve, with emerging evidence supporting a potential link between lipid metabolites, mitochondrial dysfunction and genetics. Recent advancements, such as streamlining CAN detection through wearable devices and monitoring of heart rate variability, present simplified and cost-effective approaches for early CAN detection. Further research on the optimal use of the extensive data provided by such devices is required. Despite the lack of specific pharmacological interventions targeting the underlying pathophysiology of autonomic neuropathy, several studies have suggested a favourable impact of newer glucose-lowering agents, such as sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, where there is a wealth of clinical trial data on the prevention of cardiovascular events. This review delves into recent developments in the area of CAN, with emphasis on practical guidance to recognise and manage this underdiagnosed condition, which significantly increases the risk of cardiovascular events and mortality in diabetes.

This study is aimed at evaluating the effect of empagliflozin in preventing atrial fibrillation after coronary artery bypass grafting (CABG). Eighty-two patients who fulfilled the inclusion criteria were allocated to the empagliflozin group (n = 43) or placebo group (n = 39). In two groups, patients received empagliflozin or placebo tablets 3 days before surgery and on the first three postoperative days (for 6 days) in addition to the standard regimen during hospitalization. During the first 3 days after surgery, types of arrhythmias after cardiac surgery, including supraventricular arrhythmias, especially postoperative atrial fibrillation (POAF), ventricular arrhythmias, and heart blocks, were assessed by electrocardiogram monitoring. C-reactive protein (CRP) levels were evaluated pre-operatively and postoperative on the third day. The incidence of POAF in the treatment group was lower compared to the control group; however, this reduction was statistically non-significant (p = 0.09). The frequency of ventricular tachycardia was reduced significantly in the treatment group versus patients in the control (p = 0.02). Also, a significant reduction in the frequency of premature ventricular contractions (PVCs) was seen in the treatment group in comparison with the control group (p = 0.001). After the intervention, CRP levels were significantly less in the empagliflozin group compared to the control group in the third postoperative day (p = 0.04). The prophylactic use of empagliflozin effectively reduced the incidence of ventricular arrhythmia in patients undergoing CABG surgery.

Specific cancer treatments can lead to cancer therapy-related cardiac dysfunction (CTRCD). Sodium glucose cotransporter-2 inhibitors (SGLT2is) can potentially prevent these cardiotoxic effects.

This study sought to determine whether SGLT2i use is associated with a lower incidence of CTRCD in patients with type 2 diabetes mellitus (T2DM) and cancer, exposed to potentially cardiotoxic antineoplastic agents, and without a prior documented history of cardiomyopathy or heart failure.

We conducted a retrospective analysis of patients aged ≥18 years within the TriNetX database with T2DM, cancer, exposure to cardiotoxic therapies, and no prior documented history of cardiomyopathy or heart failure. Patients were categorized by SGLT2i use. After propensity score matching, outcomes were compared over 12 months using Cox proportional HRs. Subgroup analyses focusing on different cancer therapy classes were performed.

The study included 8,675 propensity-matched patients in each cohort (mean age = ∼65 years, 42% females, 71% White, ∼19% gastrointestinal malignancy, and ∼25% anthracyclines). Patients prescribed SGLT2is had a lower risk of developing CTRCD (HR: 0.76: 95% CI: 0.69-0.84). SGLT2is also reduced heart failure exacerbations (HR: 0.81; 95% CI: 0.72-0.90), all-cause mortality (HR: 0.67; 95% CI: 0.61-0.74), and all-cause hospitalizations/emergency department visits (HR: 0.93; 95% CI: 0.89-0.97). Subgroup analyses also demonstrated reduced CTRCD risk across various classes of cancer therapies in patients prescribed SGLT2is.

SGLT2i administration was associated with a significantly decreased risk of developing CTRCD in patients with T2DM and cancer.

Diabetes mellitus (DM) confers an increased risk of sudden cardiac death (SCD) independent of its associated cardiovascular comorbidities. DM induces adverse structural, electrophysiologic, and autonomic cardiac remodeling that can increase one's risk of ventricular arrhythmias and SCD. Although glycemic control and prevention of microvascular and macrovascular complications are cornerstones in the management of DM, they are not adequate for the prevention of SCD. In this narrative review, we describe the contribution of DM to the pathophysiologic mechanism of SCD beyond its role in atherosclerotic cardiovascular disease and heart failure. On the basis of this pathophysiologic framework, we outline potential preventive and therapeutic strategies to mitigate the risk of SCD in this population of high-risk patients.

Atrial fibrillation and heart failure with preserved ejection fraction (HFpEF) are frequent concomitant diseases sharing several pathophysiological mechanisms leading to structural remodelling of both atria and ventricles. We present a case of an HFpEF patient with rapid atrial fibrillation who remained symptomatic even after successful cardioversion, initiation of antiarrhythmic therapy, and treatment of comorbidities. Due to asymmetric septal hypertrophy, the stress test was performed to exclude outflow tract obstruction and revealed a low basal heart rate with significant chronotropic insufficiency. In addition to SGLT2 initiation, the beta-blocker dose was reduced, and amiodarone was discontinued. This therapy modification led to a marked improvement in exercise capacity, significant reduction of palpitations, reduction of NT-proBNP, and signs of a decreased left ventricular filling pressure with reverse remodelling of LA. This case shows the importance of both individual tailoring of medical therapy and chronotropic insufficiency in HFpEF patients.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have beneficial pleiotropic effects, contributing to improved cardiovascular and renal outcomes for patients with and without diabetes. The impact of SGLT2is on arrhythmic burden remains largely unexplored through randomized trials.

In this multicenter, double-blind, randomized, placebo-controlled trial, we investigated the effects of ertugliflozin on arrhythmic burden among patients with heart failure with an ejection fraction less than 50%. All patients had an implantable cardioverter-defibrillator (ICD) with or without a cardiac resynchronization therapy device (CRT-D) and were randomized (1:1) to receive either ertugliflozin 5 mg once daily or placebo. The primary end point was the number of incident sustained (>30 seconds) ventricular tachycardia or ventricular fibrillation events from baseline to week 52. Secondary end points included the total number of non-sustained ventricular tachycardias, appropriate ICD therapies, changes in N-terminal pro-brain-type natriuretic peptide (NTproBNP) levels, and the number of heart failure hospitalizations.

Randomization was prematurely terminated, after class IA guideline recommendations were published for SGLT2is in patients with heart failure regardless of the ejection fraction. The final analysis included 46 patients (11% of the originally planned sample size). The yearly rate of the primary end point was 3.5 (95% confidence interval [CI] 2.8 to 4.4) with ertugliflozin compared with 13.3 with placebo (95% CI 11.8 to 14.8; rate ratio 0.16, 95% CI 0.04 to 0.61; P<0.001). There were no apparent differences in appropriate ICD therapies, hospitalizations, NTproBNP levels, or predefined adverse and serious adverse events.

Ertugliflozin reduced sustained ventricular tachycardia or ventricular fibrillation events in adults with heart failure and an ICD compared with placebo; however, our trial ended early and thus results should be interpreted with caution. (Funded by Investigator-initiated Studies Program of Merck Sharp & Dohme Corp and Pfizer; EudraCT number, 2020-002581-14; ClinicalTrials.gov number NCT04600921.).

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) can ameliorate arrhythmias; however, the mechanisms underlying their antiarrhythmic effect remain unclear. Therefore, we aimed to test the hypothesis that the SGLT2i empagliflozin (EMPA) ameliorates ventricular arrhythmias caused by myocardial infarction (MI) by inhibiting sympathetic remodeling.

Male nondiabetic Sprague-Dawley rats were divided into Sham ( n  = 10), MI ( n  = 13), low-EMPA (10 mg/kg/day; n  = 13), and high-EMPA (30 mg/kg/day; n  = 13) groups. Except for the Sham group, MI models were established by ligation of the left anterior descending coronary artery. After 4 weeks, the hearts were removed. Echocardiography, electrical stimulation, hematoxylin-eosin staining and Masson's staining, Western blotting, immunohistochemistry (IHC), and ELISA were performed.

Except for left ventricular posterior wall thickness (LVPWT), EMPA treatment significantly ameliorated the left ventricular anterior wall thickness (LVAWT), interventricular septum thickness (IVST), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), and left ventricular ejection fraction (LVEF) in MI rats; there was no statistical difference between the low-EMPA and high-EMPA groups. The threshold for ventricular fibrillation induction and myocardial fibrosis was significantly ameliorated in EMPA-treated rats, and there was no statistical difference between the high-EMPA and low-EMPA groups. EMPA decreased the expression of nerve growth factor (NGF), tyrosine kinase receptor A (TrkA), tyrosine hydroxylase, and growth-associated protein 43 (GAP43) in the left ventricular infarction margin myocardium of MI rats, especially in the high-EMPA group, with a statistically significant difference between the high-EMPA and low-EMPA groups. High-EMPA significantly decreased noradrenaline (NE) levels in the blood of MI rats; however, there was no statistical difference between the low-EMPA and MI groups.

EMPA ameliorated the occurrence of ventricular arrhythmias in MI rats, which may be related to a reduction in sympathetic activity, inhibition of the NGF/TrkA pathway, inhibition of sympathetic remodeling, and improvement in cardiac function and cardiac structural remodeling.

Cardiac magnetic resonance imaging (CMR)-defined ventricular scar and anatomic conduction channels (CMR-CCs) offer promise in delineating ventricular tachycardia substrate. No studies have validated channels with coregistered histology, nor have they ascertained the histological characteristics of deceleration zones (DZs) within these channels. We aimed to validate CMR scar and CMR-CCs with whole-heart histology and electroanatomic mapping in a postinfarction model.

Five sheep underwent anteroseptal infarction. CMR (116±20 days post infarct) was postprocessed using ADAS-3D, varying pixel intensity thresholds (5545, 6040, 6535, and 7030). DZs were identified by electroanatomic mapping (129±12 days post infarct). Explanted hearts were sectioned and stained with Picrosirius red, and whole-heart histopathologic shells were generated. Scar topography as well as percentage fibrosis, adiposity, and remaining viable myocardium within 3 mm histological biopsies and within CMR-CCs were determined.

Using the standard 6040 thresholding, CMR had 83.8% accuracy for identifying histological scar in the endocardium (κ, 0.666) and 61.4% in the epicardium (κ, 0.276). Thirty-seven CMR-CCs were identified by varying thresholding; 23 (62%) were unique. DZs colocalized to 19 of 23 (83%) CMR-CCs. Twenty (87%) CMR-CCs were histologically confirmed. Within-channel histological fibrosis did not differ by the presence of DZs (P=0.242). Within-channel histological adiposity was significantly higher at sites with versus without DZs (24.1% versus 8.3%; P<0.001).

Postprocessed CMR-derived scars and channels were validated by histology and electroanatomic mapping. Regions of CMR-CCs at sites of DZs had higher adiposity but similar fibrosis than regions without DZs, suggesting that lipomatous metaplasia may contribute to arrhythmogenicity of postinfarction scar.

The role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in managing cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM) is evolving. This meta-analysis seeks to explore the influence of SGLT2i on the recurrence of atrial fibrillation (AF) following catheter ablation (CA) in individuals with T2DM qualitatively and quantitatively.

A comprehensive literature search was conducted in electronic databases. Studies meeting predefined criteria were included. Individual patient data (IPD) were used from reconstructed time-to-event data to estimate hazard ratios (HRs) and 95% confidence intervals for AF recurrence. IPD meta-analysis was followed by a direct meta-analysis to assess the risk of AF recurrence.

A total of five studies [one randomized controlled trial (RCT) and four cohort studies] were included in this study, and five studies were included in the qualitative analysis, while four studies comprising 1043 patients with T2DM were included in the quantitative analysis. The pooled Kaplan-Meier curve based on reconstructed data showed a significantly lower risk of AF recurrence in the SGLT2i group compared with all antidiabetic drugs (log-rank P = 0.00011) and dipeptidyl-peptidase IV inhibitors (DPP4i) (log-rank P = 0.01). Cox regression analysis showed consistent results. Direct meta-analysis showed that SGLT2i, compared with all antidiabetic medications (HR 0.57, 95% CI [0.44, 0.73], I2) and DPP4i (HR 0.41, 95% CI [0.24, 0.70], I2), was associated with a lower risk of AF recurrence.

SGLT2i are associated with a reduced risk of AF recurrence after CA in patients with T2DM. These results suggest that SGLT2i is promising in improving clinical outcomes for this population.

Gliflozins are recommended as first-line treatment in patients with heart failure and/or cardiovascular comorbidities and are demonstrated to reduce atrial fibrillation (AF) occurrence. However, it is not well known which gliflozin yields the larger cardioprotection in terms of AF occurrence reduction. Hence, we aimed to compare data regarding AF recurrence associated with different gliflozins.

An accurate search of online scientific libraries (from inception to June 1, 2023) was performed. Fifty-nine studies were included in the meta-analysis involving 108 026 patients, of whom 60 097 received gliflozins and 47 929 received placebo.

Gliflozins provided a statistically significant reduction of AF occurrence relative to standard of care therapy in the overall population (relative risks [RR]: 0.8880, 95% CI: [0.8059; 0.9784], p = .0164) and in patients with diabetes and cardiorenal diseases (RR: 0.8352, 95% CI: [0.7219; 0.9663], p = .0155). Dapagliflozin significantly decreased AF occurrence as compared to placebo (0.7259 [0.6337; 0.8316], p < .0001) in the overall population, in patients with diabetes (RR: 0.2482, 95% CI: [0.0682; 0.9033], p = .0345), with diabetes associated with cardiorenal diseases (RR: 0.7192, 95% CI: [0.5679; 0.9110], p = .0063) and in the subanalysis including studies with follow-up ≥1 year (RR: 0.7792, 95% CI: [0.6508; 0.9330], p = .0066). No significant differences in terms of AF protection were found among different gliflozins.

Dapagliflozin use was associated with significant reduction in AF risk as compared to placebo in overall population and patients with diabetes, whereas the use of other gliflozins did not significantly reduce AF occurrence.

Atrial fibrillation (AF) is a common arrhythmic complication in cancer patients and can be exacerbated by traditional cytotoxic and targeted anticancer therapies. Increased incidence of AF in cancer patients is independent of confounding factors, including preexisting myocardial arrhythmogenic substrates, type of cancer, or cancer stage. Mechanistically, AF is characterized by fast unsynchronized atrial contractions with rapid ventricular response, which impairs ventricular filling and results in various symptoms such as fatigue, chest pain, and shortness of breath. Due to increased blood stasis, a consequence of both cancer and AF, concern for stroke increases in this patient population. To compound matters, cardiotoxic anticancer therapies themselves promote AF; thereby exacerbating AF morbidity and mortality in cancer patients. In this review, we examine the relationship between AF, cancer, and cardiotoxic anticancer therapies with a focus on the shared molecular and electrophysiological mechanisms linking these disease processes. We also explore the potential role of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in the management of anticancer-therapy-induced AF.

Myocardial infarction (MI) is a life-threatening cardiovascular disease that, on average, results in 8.5 million deaths worldwide each year. Timely revascularization of occluded vessels is a critical method of myocardial salvage. However, reperfusion paradoxically leads to the worsening of myocardial damage known as myocardial ischaemia/reperfusion injury (MI/RI). Therefore, reducing the size of myocardial infarction after reperfusion is critical and remains an important therapeutic goal. The susceptibility of the myocardium to MI/RI may be increased by diabetes. Currently, some traditional antidiabetic agents such as metformin reduce MI/RI by decreasing inflammation, inhibiting oxidative stress, and improving vascular endothelial function. This appears to be a new direction for the treatment of MI/RI. Recent cardiovascular outcome trials have shown that several oral antidiabetic agents, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP-4is), and sodium-glucose-linked transporter-2 inhibitors (SGLT-2is), not only have good antidiabetic effects but also have a protective effect on myocardial protection. This article aims to discuss the mechanisms and effects of oral antidiabetic agents, including GLP-1RAs, DPP-4is, and SGLT-2is, on MI/RI to facilitate their clinical application.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have a direct cardiac effect that is likely to be independent of its glucose lowering renal effect. Previous research has shown that SGLT2-is mitigate heart failure and prevent arrhythmic cardiac death. Our objective is to determine whether SGLT-2is reduce atrial fibrillation (AF) in comparison to other second-to third-line antidiabetic drugs in type 2 diabetes.

We conducted a population-based, new-user active comparator cohort study using data from the UK Clinical Practice Research Datalink. We identified a cohort of patients initiating a new antidiabetic drug class between January 2013 and September 2020. This cohort included patients initiating their first ever non-insulin antidiabetic drug, as well as those who switched to or added-on an antidiabetic drug class not previously used in their treatment history. Individuals with a diagnosis of AF or atrial flutter at any time before cohort entry were excluded. Cox regression analysis with time-dependent covariates was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of AF comparing SGLT-2-is with other second-line to third-line antidiabetic drugs. Stratified analyses were performed according to sex, diabetes duration (<5 or ≥ 5 years), body mass index (BMI), HbA1c, and presence of heart failure.The cohort comprised 142 447 patients. SGLT-2is were associated with a statistically significant reduced hazard of AF compared to other second-line to third-line antidiabetic drugs (adjusted HR: 0.77 [95% CI: 0.68-0.88]). This reduced risk was present in both sexes but was more prominently among women (adjusted HRwomen: 0.60 [95% CI: 0.45-0.79]; HRmen: 0.85 [95% CI: 0.73-0.98]; P-value interaction: 0.012). There was no evidence for effect modification when stratifying on duration of diabetes, BMI, HbA1c, or presence of heart failure.

SGLT-2is were associated with a reduced risk of AF in patients with type 2 diabetes compared to other second-line to third-line antidiabetic drugs. This reduced risk occurs in both sexes but more prominently among women.

Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) were initially recommended as oral anti-diabetic drugs to treat type 2 diabetes (T2D), by inhibiting SGLT2 in proximal tubule and reduce renal reabsorption of sodium and glucose. While many clinical trials demonstrated the tremendous potential of SGLT2i for cardiovascular diseases. 2022 AHA/ACC/HFSA guideline first emphasized that SGLT2i were the only drug class that can cover the entire management of heart failure (HF) from prevention to treatment. Subsequently, the antiarrhythmic properties of SGLT2i have also attracted attention. Although there are currently no prospective studies specifically on the anti-arrhythmic effects of SGLT2i. We provide clues from clinical and fundamental researches to identify its antiarrhythmic effects, reviewing the evidences and mechanism for the SGLT2i antiarrhythmic effects and establishing a novel paradigm involving intracellular sodium, metabolism and autophagy to investigate the potential mechanisms of SGLT2i in mitigating arrhythmias.

In this paper, we concentrate on updating the clinical research on sodium-glucose cotransporter inhibitors (SGLTis) for patients with type 2 diabetes who have heart failure with a preserved injection fraction, acute heart failure, atrial fibrillation, primary prevention of atherosclerotic cardiovascular disease/cardiovascular disease, and acute myocardial infarction. We searched the data of randomized controlled trials and meta-analyses of SGLTis in patients with diabetes from PubMed between January 1, 2020 and April 6, 2024 for our review. According to our review, certain SGLTis (empagliflozin, dapagliflozin, canagliflozin, and tofogliflozin), but not sodium-glucose cotransporter 1 inhibitor (SGLT1i), exhibit relatively superior clinical safety and effectiveness for treating the abovementioned diseases. Proper utilization of SGLTis in these patients can foster clinical improvement and offer an alternative medication option. However, clinical trials involving SGLTis for certain diseases have relatively small sample sizes, brief intervention durations, and conclusions based on weak evidence, necessitating additional data. These findings are significant and valuable for providing a more comprehensive reference and new possibilities for the clinical utilization and scientific exploration of SGLTis.

The role of proximal tubules (PTs), a major component of the renal tubular structure in the renal cortex, has been examined extensively. Along with its physiological role in the reabsorption of various molecules, including electrolytes, amino acids and monosaccharides, transcellular transport of different hormones and regulation of homeostasis, pathological events affecting PTs may underlie multiple disease states. PT hypertrophy or a hyperfunctioning state, despite being a compensatory mechanism at first in response to various stimuli or alterations at tubular transport proteins, have been shown to be critical pathophysiological events leading to multiple disorders, including diabetes mellitus, obesity, metabolic syndrome and congestive heart failure. Moreover, pharmacotherapeutic agents have primarily targeted PTs, including sodium-glucose cotransporter 2, urate transporters and carbonic anhydrase enzymes. In this narrative review, we focus on the physiological role of PTs in healthy states and the current understanding of the PT pathologies leading to disease states and potential therapeutic targets.