The incidence of myocardial infarction (MI) and sudden cardiac death (SCD) is significantly higher in individuals with Type 2 Diabetes Mellitus (T2DM) than in the general population. Strategies for the prevention of fatal arrhythmias are often insufficient, highlighting the need for additional non-invasive diagnostic tools. The T-wave heterogeneity (TWH) index measures variations in ventricular repolarization and has emerged as a promising predictor for severe ventricular arrhythmias. Although the EMPA-REG trial reported reduced cardiovascular mortality with empagliflozin, the underlying mechanisms remain unclear. This study investigates the potential of empagliflozin in mitigating cardiac electrical instability in patients with T2DM and coronary heart disease (CHD) by examining changes in TWH.

Participants were adult outpatients with T2DM and CHD who exhibited TWH > 80 µV at baseline. They received a 25 mg daily dose of empagliflozin and were evaluated clinically including electrocardiogram (ECG) measurements at baseline and after 4 weeks. TWH was computed from leads V4, V5, and V6 using a validated technique. The primary study outcome was a significant (p < 0.05) change in TWH following empagliflozin administration.

An initial review of 6,000 medical records pinpointed 800 patients for TWH evaluation. Of these, 412 exhibited TWH above 80 µV, with 97 completing clinical assessments and 90 meeting the criteria for high cardiovascular risk enrollment. Empagliflozin adherence exceeded 80%, resulting in notable reductions in blood pressure without affecting heart rate. Side effects were generally mild, with 13.3% experiencing Level 1 hypoglycemia, alongside infrequent urinary and genital infections. The treatment consistently reduced mean TWH from 116 to 103 µV (p = 0.01).

The EMPATHY-HEART trial preliminarily suggests that empagliflozin decreases heterogeneity in ventricular repolarization among patients with T2DM and CHD. This reduction in TWH may provide insight into the mechanism behind the decreased cardiovascular mortality observed in previous trials, potentially offering a therapeutic pathway to mitigate the risk of severe arrhythmias in this population.

NCT: 04117763.

Whether sodium-glucose cotransporter-2 inhibitors (SGLT2is) reduce ventricular arrhythmias and sudden cardiac death is controversial. Ventricular repolarization heterogeneity is associated with ventricular arrhythmias; however, the effect of SGLT2is on ventricular repolarization in patients with heart failure with reduced ejection fraction (HFrEF) has not been fully investigated. We prospectively evaluated 31 HFrEF patients in sinus rhythm who were newly started on dapagliflozin 10 mg/day. Changes in QT interval, corrected QT interval (QTc), QT dispersion (QTD), corrected QTD (QTcD), T peak to T end (TpTe), TpTe/QT ratio, and TpTe/QTc ratio were evaluated at 1-year follow-up. QT interval, QTc interval, QTD, QTcD, TpTe, and TpTe/QTc ratio decreased significantly at 1-year follow-up (427.6 ± 52.6 ms vs. 415.4 ± 35.1 ms; p = 0.047, 437.1 ± 37.3 ms vs. 425.6 ± 22.7 ms; p = 0.019, 54.1 ± 11.8 ms vs. 47.6 ± 14.7 ms; p = 0.003, 56.0 ± 11.2 ms vs. 49.4 ± 12.3 ms; p = 0.004, 98.0 ± 15.6 ms vs. 85.5 ± 20.9 ms; p = 0.018, and 0.225 ± 0.035 vs. 0.202 ± 0.051; p = 0.044, respectively). TpTe/QT ratio did not change significantly (0.231 ± 0.040 vs. 0.208 ± 0.054; p = 0.052). QT interval, QTD, and TpTe were significantly reduced 1 year after dapagliflozin treatment in patients with HFrEF. The beneficial effect of dapagliflozin on the heterogeneity of ventricular repolarization may contribute to the suppression of ventricular arrhythmias.Registry information https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000049428 . Registry number: UMIN000044902.

The primary pharmacological action of sodium-glucose co-transporter 2 (SGLT2) inhibitors is to inhibit the reabsorption of glucose and sodium ions from the proximal tubules of the kidney and to promote urinary glucose excretion. Notably, several clinical trials have recently demonstrated potent protective effects of SGLT2 inhibitors in patients with heart failure (HF) or chronic kidney disease (CKD), regardless of the presence or absence of diabetes. However, the impact of SGLT2 inhibitors on sudden cardiac death (SCD) or fatal ventricular arrhythmias (VAs), the pathophysiology of which is partly similar to that of HF and CKD, remains undetermined. The cardiorenal protective effects of SGLT2 inhibitors have been reported to include hemodynamic improvement, reverse remodeling of the failing heart, amelioration of sympathetic hyperactivity, correction of anemia and impaired iron metabolism, antioxidative effects, correction of serum electrolyte abnormalities, and antifibrotic effects, which may lead to prevent SCD and/or VAs. Recently, as possible direct cardiac effects of SGLT2 inhibitors, not only inhibition of Na⁺/H⁺ exchanger (NHE) activity, but also suppression of late Na⁺ current have been focused on. In addition to the indirect cardioprotective mechanisms of SGLT2 inhibitors, suppression of aberrantly increased late Na⁺ current may contribute to preventing SCD and/or VAs via restoration of the prolonged repolarization phase in the failing heart. This review summarizes the results of previous clinical trials of SGLT2 inhibitors for prevention of SCD, their impact on the indices of electrocardiogram, and the possible molecular mechanisms of their anti-arrhythmic effects.

Empagliflozin treatment is significantly associated with lower risk of cardiovascular events in patients with diabetes mellitus (DM) independent of its antihyperglycemic effect. However, little is known regarding the impact of empagliflozin on electrocardiography (ECG) parameters. This study aimed to investigate whether empagliflozin has favourable effect on frontal plane QRS-T (fQRST) angle, which is an ECG sign of ventricular repolarization heterogeneity, in patients with type 2 DM.

We prospectively enrolled 111 patients with known diagnosis of type 2 DM who newly prescribed empagliflozin on top of their standard anti-diabetic therapy. Patients were divided into two groups according to presence or absence of cardiovascular disease (CVD) at baseline and followed-up for 6 months. The impact of empagliflozin treatment on fQRST angle was investigated and patient groups were compared regarding the pre- and post-treatment fQRST angle.

Among 111 patients, 32 (28.8%) had CVD and 79 (71.2%) had no CVD. Empagliflozin treatment lead a significant decrease in the mean fQRST angle throughout the study period and mean fQRST angle was significantly lower at 3- and 6-month follow-up visits compared to baseline values (62° ± 17.4° vs. 57.2° ± 14.8° vs. 50.5° ± 13.6°, p < 0.001 for all dual comparisons). However, despite similar antihyperglycemic effect with empagliflozin treatment in patients with and without CVD, the significant decrease in the mean fQRST angle was observed only in patients with CVD and no significant decrease was observed in the mean fQRST angle in patients without CVD.

Empagliflozin leads a significant narrowing in the fQRST angle in type 2 DM patients with known CVD.

The beneficial cardiorenal outcomes of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) have been substantiated by multiple clinical trials, resulting in increased interest in the multifarious pathways by which their mechanisms act. The principal effect of SGLT2i (-flozin drugs) can be appreciated in their ability to block the SGLT2 protein within the kidneys, inhibiting glucose reabsorption, and causing an associated osmotic diuresis. This ameliorates plasma glucose elevations and the negative cardiorenal sequelae associated with the latter. These include aberrant mitochondrial metabolism and oxidative stress burden, endothelial cell dysfunction, pernicious neurohormonal activation, and the development of inimical hemodynamics. Positive outcomes within these domains have been validated with SGLT2i administration. However, by modulating the sodium-glucose cotransporter in the proximal tubule (PT), SGLT2i consequently promotes sodium-phosphate cotransporter activity with phosphate retention. Phosphatemia, even at physiologic levels, poses a risk in cardiovascular disease burden, more so in patients with type 2 diabetes mellitus (T2DM). There also exists an association between phosphatemia and renal impairment, the latter hampering cardiovascular function through an array of physiologic roles, such as fluid regulation, hormonal tone, and neuromodulation. Moreover, increased phosphate flux is associated with an associated increase in fibroblast growth factor 23 levels, also detrimental to homeostatic cardiometabolic function. A contemporary commentary concerning this notion unifying cardiovascular outcome trial data with the translational biology of phosphate is scant within the literature. Given the apparent beneficial outcomes associated with SGLT2i administration notwithstanding negative effects of phosphatemia, we discuss in this review the effects of phosphate on the cardiometabolic status in patients with T2DM and cardiorenal disease, as well as the mechanisms by which SGLT2i counteract or overcome them to achieve their net effects. Content drawn to develop this conversation begins with proceedings in the basic sciences and works towards clinical trial data.

PCSK9, like other novel non-statin drugs were primarily developed to help patients achieve low-density lipoprotein cholesterol targets, especially in patients with dyslipidemia not achieving lipid goals with statins due to poor tolerance or inadequate response. PCSK9 inhibitors, in addition to modulating lipid metabolism, improve mortality outcomes in cardiovascular disease. These benefits are markedly pronounced in patients with type 2 diabetes mellitus. However, these benefits do not come without associated risk. Multiple trials, studies, and case reports have attempted to explain observed outcomes with PCSK9 expression and administration of PCSK9 inhibitors from multiple perspectives, such as their effects on insulin sensitivity and glucose tolerance, changes in renal physiology, thyroid physiology, vascular tone, intestinal regulation of lipids, and improved cardiovascular function. These agents represent an opportunity for physicians to exercise prudence by using appropriate clinical judgement when managing comorbidities in the hyperglycemic patient, a concept that extends to other novel non-statin drugs.

Recent clinical trials involving the systemic effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) have revealed beneficial outcomes pertaining to the microvascular sequelae of type 2 diabetes mellitus (T2DM) such as nephropathy, as well as macrovascular effects such as major adverse cardiovascular effects (MACE). Such findings have spurred the elevation of these agents to level A-tiers of recommendation within clinical guidelines addressing the management of complicated T2DM. While the mechanisms of SGLTi (-flozin drugs) are still being elucidated, a paucity of data exists within the literature appraising the role of neuromodulation and associated mechanisms in the aforementioned outcome studies. Given the role of the nervous system in orchestrating the pathologic processes that hamper cardio-renal status, insight into this topic offers an expanded perspective on T2DM. In this review we investigate the mechanisms by which SGLTi improve cardio-renal function in T2DM patients with emphases on neural tone and nervous system physiology.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a class of drugs that promote urinary glucose excretion in the treatment of diabetes, have provoked large interest of scientific and professional community due to their positive and, somehow, unexpected results in the three major cardiovascular outcome trials (EMPA-REG OUTCOME trial with empagliflozin, CANVAS Program with canagliflozin, and DECLARE-TIMI 58 with dapagliflozin). In fact, along with the reduction of major adverse cardiovascular events, SGLT2 inhibitors reduced significantly hospitalization for heart failure regardless of existing atherosclerotic cardiovascular disease or a history of heart failure. The latter have reminded us of the frequent but neglected entity of diabetic cardiomyopathy which is currently poorly understood despite its great clinical importance. Physiological mechanisms responsible for the benefits of SGLT2 inhibitors are complex and multifactorial and still not well defined. Interestingly, the time frame of their effect excludes a glucose- and antiatherosclerotic-mediated effect. It would be of great importance to better understand SGLT2 inhibitor mechanisms of action since they could have a potential to be used in early stages of diabetes as cardioprotective agents. There are widely available biomarkers as well as echocardiography that are used in everyday clinical practice and could elucidate physiological mechanisms in the heart protection with SGLT2 inhibitors treatment but studies are still lacking. The purpose of this minireview is to summarize the latest concepts about SGLT2 inhibitors and its benefits regarding diabetic cardiomyopathy especially on its early stage development and to discuss controversies and potential future developments in the field.

Three major cardiovascular outcome trials (CVOTs) with a new class of antidiabetic drugs - sodium-glucose cotransporter 2 (SGLT2) inhibitors (EMPA-REG OUTCOME trial with empagliflozin, CANVAS Program with canagliflozin, DECLARE-TIMI 58 with dapagliflozin) unexpectedly showed that cardiovascular outcomes could be improved possibly due to a reduction in heart failure risk, which seems to be the most sensitive outcome of SGLT2 inhibition. No other CVOT to date has shown any significant benefit on heart failure events. Even more impressive findings came recently from the DAPA-HF trial in patients with confirmed and well-treated heart failure: Dapagliflozin was shown to reduce heart failure risk for patients with heart failure with reduced ejection fraction regardless of diabetes status. Nevertheless, despite their possible wide clinical implications, there is much doubt about the mechanisms of action and a lot of questions to unravel, especially now when their benefits translated to non-diabetic patients, rising doubts about the validity of some current mechanistic assumptions.The time frame of their cardiovascular benefits excludes glucose-lowering and antiatherosclerotic-mediated effects and multiple other mechanisms, direct cardiac as well as systemic, are suggested to explain their early cardiorenal benefits. These are: Anti-inflammatory, antifibrotic, antioxidative, antiapoptotic properties, then renoprotective and hemodynamic effects, attenuation of glucotoxicity, reduction of uric acid levels and epicardial adipose tissue, modification of neurohumoral system and cardiac fuel energetics, sodium-hydrogen exchange inhibition. The most logic explanation seems that SGLT2 inhibitors timely target various mechanisms underpinning heart failure pathogenesis. All the proposed mechanisms of their action could interfere with evolution of heart failure and are discussed separately within the main text.

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a class of drugs that were primarily developed for the treatment of type 2 diabetes mellitus. However, these agents have shown to provide additional beneficial effects. We will discuss three main topics regarding the use of SGLT2 inhibitors: noncardiovascular effects, cardiovascular benefits, and novel clinical indications. Multiple clinical trials and preliminary studies across varying disciplines have shown that these agents exhibit cardiorenal-protective benefits, retinoprotective benefits, and may aid in weight loss without causing marked hypoglycemia. Therefore, these agents represent an avenue in clinical practice to manage comorbid conditions in the hyperglycemic patient. Because of their multifaceted effects and robust action, SGLT2 inhibitors represent therapy options for providers that not only provide beneficial clinical results but also reduce total patient drug burden.

Increased heterogeneity in ventricular repolarization is a risk factor of sudden cardiac death, but its natural history is unclear. Here we examined whether insulin resistance is associated with longitudinal change in ventricular repolarization heterogeneity in apparently healthy subjects.

The study subjects were participants in health checkups in cohort 1 and cohort 2, which were followed up for 6 years and 5 years, respectively. Subjects with diabetes, cardiovascular disease, or renal disease at baseline were excluded from the analyses. As indices of insulin resistance, the homeostasis model assessment of insulin resistance (HOMA-IR) and triglyceride to HDL-cholesterol ratio (TG/HDL-C) were used in cohort 1 and cohort 2, respectively. Heterogeneity in ventricular repolarization was assessed by heart rate-corrected Tpeak-Tend interval in V5 (cTpTe), QT interval, and QT dispersion. In regression analyses, parameters with a skewed distribution were normalized by logarithmic transformation or by Box-Cox transformation.

In longitudinal analyses, Box-Cox-transformed cTpTe at the end of follow-up was weakly correlated with log HOMA-IR at baseline in cohort 1 (n = 153, r = - 0.207, 95% CI - 0.354 to - 0.050, p = 0.010) and with log TG/HDL-C at baseline in cohort 2 (n = 738, r = - 0.098, 95% CI - 0.169 to - 0.026, p = 0.008). Multiple regression analysis showed that indices of insulin resistance, but not glycosylated hemoglobin (HbA1c) or plasma glucose, at baseline were significant explanatory variables for cTpTe at the end of follow-up. Neither QT interval nor QT dispersion was correlated with metabolic parameters.

Insulin resistance may be involved in the longitudinal increase of ventricular repolarization heterogeneity in apparently healthy subjects.

Although the positive effects of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on hospitalization for heart failure in type 2 diabetes (T2D) seem definite, some doubt exists about their effects on atherosclerotic cardiovascular disease (ASCVD). This study aims to shed light on this debatable issue.

An electronic database search (Cochrane Library, PubMed and Embase) was performed using two groups of terms ["sodium glucose cotransporter2 inhibitor", "dapagliflozin", "canagliflozin", "empagliflozin", "ertugliflozin"] AND ["major adverse cardiac events", "MACE", "cardiovascular death or hospitalization for heart failure", non-fatal myocardial infarction", "non-fatal stroke", "cardiovascular death", "hospitalization for heart failure"] and the cardiovascular outcome trials (CVOT) and pre-approval studies in phase 3 of all the SGLT2i analysed using comprehensive meta-analysis (CMA) software, version 3, Biostat Inc., Englewood, NJ, USA.

Analysis of the CVOT revealed that the hazard ratio of the pooled effect size for MACE was statistically significant (HR 0.89, 95% CI 0.83-0.96, P = 0.002). There was a significant reduction in non-fatal myocardial infarction (MI) (HR 0.87, 95% CI 0.78-0.97, P = 0.01), but no improvement was seen for non-fatal stroke (HR 1.01, 95% CI 0.89-1.16, P = 0.83). The pooled analysis of this end point showed statistically significant reduction of the composite of CV death or hospitalization for heart failure (hHF) (HR 0.76, 95% CI 0.67-0.87, P < 0.001) and hHF (HR 0.69, 95% CI 0.61-0.79, P < 0.001), but not for CV death alone (HR 0.82, 95% CI 0.64-1.05, P = 0.11). The meta-analysis of the events in the pooled analysis of the phase 3 trials reveals that the hazard ratio for MACE was statistically nonsignificant (HR 0.83, 95% CI 0.66-1.03, P = 0.10). There was a 34% statistically significant reduction in MI (95% CI 0.48-0.91, P = 0.01), a 36% statistically significant reduction in CV death (95% CI 0.41-0.97, P = 0.04) and a 64% statistically significant reduction in hHF (95% CI 0.18-0.69, P < 0.01). In contrast, there was a 17% statistically nonsignificant increased risk of stroke (95% CI 0.80-1.70, P = 0.40).

The predominant impact of SGLT-2i is on "hHF or CV mortality" composite driven predominantly by reduction in hHF and not atherosclerotic CV disease.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors showed significant effects in patients with diabetes or metabolic syndrome (MetS) with high cardiovascular risk. Although the increased intracellular Zn²⁺ level ([Zn²⁺]_i), oxidative stress, and altered cardiac matrix metalloproteinases (MMPs) in diabetic cardiomyopathy can intersect with different signaling pathways, the exact mechanisms are not known yet. Since either MMPs or SGLT2 have important roles in cardiac-fibrosis under hyperglycemia, we aimed to examine the role of SGLT2 inhibitor dapagliflozin (DAP) on cardiac Zn²⁺-transporters responsible for [Zn²⁺]_i-regulation, comparison to insulin (INS), together with MMP levels and systemic oxidative stress status in MetS-rats. High-carbohydrated diet-induced MetS-rats received DAP or INS for 2 weeks. DAP but not INS in MetS-rats significantly decreased high blood-glucose levels, while both treatments exerted benefits on increased total oxidative status and decreased total antioxidant status in MetS-rat plasma as well as in heart tissue. Protein levels of Zn²⁺-transporters, responsible for Zn²⁺-influx into cytosol, ZIP7 and ZIP14 were increased with significant decrease in ZIP8 of MetS-rat cardiomyoctes, while Zn²⁺-transporters, responsible for cytosolic Zn²⁺-efflux, ZnT7 was decreased with no change in ZnT8. Both treatments induced significant beneficial effects on altered ZIP14, ZIP8, and ZnT7 levels. Furthermore, both treatments exerted benefits on depressed gelatin-zymography and protein expression levels of MMP-2 and MMP-9 in MetS-rat ventricular cardiomyocytes. The direct effect of DAP on heart was also confirmed with measurements of left ventricular developed pressure. Overall, we showed that DAP has important antioxidant-like cardio-protective effects in MetS-rats, similar to INS-effect, affecting Zn²⁺-regulation via Zn²⁺-transporters, MMPs, and oxidative stress. Therefore one can suggest that SGLT2 inhibitors can be new therapeutic agents for cardio-protection not only in hyperglycemia but also in failing heart.

Diabetes mellitus currently affects over 350 million patients worldwide and is associated with many deaths from cardiovascular complications. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are a novel class of antidiabetic drugs with cardiovascular benefits beyond other antidiabetic drugs. In the EMPA-REG OUTCOME trial, empagliflozin significantly decreases the mortality rate from cardiovascular causes [38% relative risk reduction (RRR)], the mortality rate from all-causes (32% RRR) and the rate of heart failure hospitalization (35% RRR) in diabetic patients with established cardiovascular diseases. The possible mechanisms of SGLT-2 inhibitors are proposed to be systemic effects by hemodynamic and metabolic actions. However, the direct mechanisms are not fully understood. In this review, reports concerning the effects of SGLT-2 inhibitors in models of diabetic cardiomyopathy, heart failure and myocardial ischemia from in vitro, in vivo as well as clinical reports are comprehensively summarized and discussed. By current evidences, it may be concluded that the direct effects of SGLT-2 inhibitors are potentially mediated through their ability to reduce cardiac inflammation, oxidative stress, apoptosis, mitochondrial dysfunction and ionic dyshomeostasis.