Beneficial Effect Of Sodium-glucose Co-transporter 2 Inhibitors Research Articles

A review of the latest real-world evidence studies in diabetic kidney disease: What have we learned about clinical practice and the clinical effectiveness of interventions?

Diabetic nephropathy, also known as diabetic kidney disease (DKD), remains a challenge in clinical practice as this is the major cause of kidney failure worldwide. Clinical trials do not answer all the questions raised in clinical practice and real-world evidence provides complementary insights from randomized controlled trials. Real-life longitudinal data highlight the need for improved screening and management of diabetic nephropathy in primary care. Adherence to the recommended guidelines for comprehensive care appears to be suboptimal in clinical practice in patients with DKD. Barriers to the initiation of sodium-glucose cotransporter-2 (SGLT2) inhibitors for patients with DKD persist in clinical practice, in particular for the elderly. Attainment of blood pressure targets often remains an issue. Initiation of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in routine clinical practice is associated with a reduced risk of albuminuria progression and a possible beneficial effect on kidney function. Real-world evidence confirms a beneficial effect of SGLT2 inhibitors on the decline of glomerular filtration, even in the absence of albuminuria, with a lower risk of acute kidney injury events compared to GLP-1RA use. In addition, SGLT2 inhibitors confer a lower risk of hyperkalaemia after initiation compared with dipeptidyl peptidase-4 inhibitors in patients with DKD. Data from a large population indicate that diuretic treatment increases the risk of a significant decline in glomerular filtration rate in the first few weeks of treatment after SGLT2 inhibitor initiation. The perspective for a global approach targeting multifaceted criteria for diabetic individuals with DKD is emerging based on real-world evidence but there is still a long way to go to achieve this goal.

Chronic Kidney Disease and SGLT2 Inhibitors

Sodium glucose cotransporter 2 (SGLT2) inhibitors were initially developed to enhance glycemic control in diabetic patients, but they have emerged as a promising treatment for individuals with chronic kidney disease (CKD) regardless of diabetic status. A collaborative meta-analysis of large-scale SGLT2 inhibitor trials has provided compelling evidence supporting recommendations for the use of these agents in CKD patients, regardless of their primary kidney disease diagnosis or whether they have diabetes. Notably, the kidney-protective benefits of SGLT2 inhibitors have been observed across various stages of CKD, including advanced stage 4 CKD, and across all levels of albuminuria. Given the robust evidence highlighting the benefits of SGLT2 inhibitors across a broad spectrum of CKD patients, these agents should be considered foundational therapy for CKD, in order to mitigate the progression to kidney failure and its associated complications. Although the beneficial effects of SGLT2 inhibitors may not be immediately apparent, they are expected to grow over time, potentially altering the prognosis for numerous CKD patients.

SGLT2 Inhibitors and Diabetes: Where Does It Come from and Where Does It Go?

Sodium glucose cotransporter 2 (SGLT2) inhibitors have emerged as powerful medications in the past decade. Numerous clinical trials have reported their cardio-renal protective effects and associated reductions in mortality. The beneficial effects of SGLT2 inhibitors in mediating heart failure and chronic kidney disease progression have been consistent across patients with and without diabetes regardless of ejection fraction. Therefore, SGLT2 inhibitors are not only antidiabetic drugs but also medications for heart failure and chronic kidney disease. However, adverse events such as genital infections and diabetic ketoacidosis should be considered. In this review, we explore the journey of SGLT2 inhibitors, often referred to as the “statins of the 21st century,” from their inception to the present day. We introduce the strengths and weaknesses of this medication and discuss unresolved issues that should be taken into considerations when prescribing SGLT2 inhibitors.

Abstract 13109: Empagliflozin Reverses Oxidized LDL-Induced RECK Suppression, MMP Activation, and Human Aortic Smooth Muscle Cell Proliferation and Migration

Empagliflozin, an FDA-approved anti-hyperglycemic agent, is a potent and highly selective inhibitor of sodium glucose co-transporter-2 (SGLT-2) in renal proximal tubule epithelial cells. It blocks glucose reabsorption and promotes glucose excretion via urine. Intriguingly, several clinical trials have reported the pleiotropic beneficial effects of SGLT-2 inhibitors in cardiovascular diseases, including antioxidant and anti-inflammatory effects. Here we investigated whether empagliflozin reverses oxidatively modified LDL (OxLDL)-induced matrix metalloproteinase activation and smooth muscle cell (SMC) migration and proliferation. Quiesced human aortic SMCs (Lonza) were treated with empagliflozin (1 uM) followed by human medium OxLDL (40 ug/mL; Kalen Biomedical). OxLDL stimulated SMC migration (1.8-fold, P<0.05, n=4) and proliferation (1.5-fold, P<0.05, n=4), and empagliflozin attenuated both by 67% (P<0.05, n=4) and 61% (P<0.05, n=4), respectively. Increased migration and proliferation by OxLDL were accompanied by elevated MMP-2 (3.2-fold, P<0.05, n=5) and 9 (3.1-fold, P<0.05, n=5) activities, which were also suppressed by empagliflozin by 65% and 67%, respectively (both P<0.05, n=5). RECK (reversion inducing cysteine rich protein with Kazal motifs) is a membrane anchored MMP inhibitor, and we found that OxLDL dose-dependently downregulated RECK in SMCs (by 60%, P<0.05, n=3) via NF-kB-dependent miR-30b induction. Intriguingly, empagliflozin restored the OxLDL downregulation of RECK to 88% of the control (n=3), as it inhibited miR-30b induction (by 49%, P<0.05, n=5). Consistent with RECK-mediated effects of empagliflozin, adenoviral overexpression of RECK inhibited OxLDL-induced SMC migration (by 67%, P<0.05, n=5) and proliferation (by 50%, P<0.05, n=5). Together, these results suggest that the vasculoprotective effects of empagliflozin are at least in part mediated by restoring RECK, thereby attenuating SMC migration and proliferation under elevated oxidative stress condition. Our results also suggest therapeutic potential of empagliflozin or RECK overexpression in vascular proliferative diseases.

Left ventricular remodeling response to SGLT2 inhibitors in heart failure: an updated meta-analysis of randomized controlled studies

BackgroundRandomized controlled trials (RCTs) reported contrasting results about reverse left ventricular remodeling (LVR) after sodium-glucose co-transporter-2 inhibitors (SGLT2i) therapy in patients with heart failure (HF).Methods and resultsWe performed a metanalysis of RCTs of SGLT2i administration in HF outpatients published until June 2022 searching four electronic databases. The protocol has been published in PROSPERO. Primary LVR outcome was change in absolute LV end-diastolic (LVEDV) and end-systolic volume (LVESV) from baseline to study endpoint. Secondary outcomes included changes in LVEDV and LVESV indexed to body surface area, LV Mass index (LVMi), LV ejection fraction (LVEF), and N-terminal pro-B-type natriuretic peptide (NTproBNP). Mean differences (MDs) with 95% CIs were pooled. A total of 9 RCTs (1385 patients) were analyzed. All of them reported data on LVEF. Six trials reported data on LVESV and LVEDV (n = 951); LVMi was available in 640. SGLT2i treatment significantly reduced LVEDV [MD= -10.59 ml (-17.27; -3.91), P = 0.0019], LVESV [MD= -8.80 ml (-16.91; -0.694), P = 0.0334], and LVMI [MD= -5.34 gr/m2 (-9.76; -0.922), P = 0.0178], while LVEF significantly increased [MD = + 1.98% (0.67; 0.306), P = 0.0031]. By subgroup analysis, the beneficial effects of SGLT2i on LVEF did not differ by imaging method used, time to follow-up re-evaluation, or HF phenotype. Reduction in LV volumes tended to be greater in HF with reduced EF (HFrEF) than in those with preserved EF (HFpEF), while the opposite was observed for LVMi.ConclusionsTreatment with SGLT2i significantly reversed cardiac volumes, improving LV systolic function and LV mass, particularly in HFrEF patients.

Reno- and cardioprotective molecular mechanisms of SGLT2 inhibitors beyond glycemic control - from bedside to bench.

Large placebo-controlled clinical trials have shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) delay the deterioration of renal function and reduce cardiovascular events in a glucose-independent manner, thereby ultimately reducing mortality in patients with chronic kidney disease (CKD) and/or heart failure. These exiting clinical data stimulated preclinical studies aiming to understand the observed clinical effects. In animal models, it was shown that the beneficial effect of SGLT2i on the tubuloglomerular feedback (TGF) improves glomerular pressure and reduces tubular workload by improving renal haemodynamics, which appears to be dependent on salt intake. High salt intake might blunt the SGLT2i effects on the TGF. Beyond the salt-dependent effects of SGLT2i on renal haemodynamics, the beneficial effects of SGLT2i on CKD progression are at least partly mediated by targeting TGF-β1 and or STAT3 and or AMPK signaling pathways affecting macrophage differentiation and polarization as well as inhibiting the activation of inflammatory factors within macrophages. As macrophages are also important cells mediating atherosclerosis and myocardial remodeling after injury, the inhibitory effects of SGLT2i on macrophage differentiation and inflammatory responses may also play a role in stabilizing atherosclerotic plaques and ameliorating myocardial inflammation and fibrosis. Recent studies suggest that SGLT2i may also act directly on the Na+/H+ exchanger and Late-INa in cardiomyocytes thus reducing Na+ and Ca2+ overload-mediated myocardial damage, but studies in this area are limited. In addition, the renal-cardioprotective mechanisms of SGLT2i include systemic effects on the sympathetic nervous system, blood volume, salt excretion and energy metabolic patterns.

Obesity-associated cardiometabolic complications in polycystic ovary syndrome: The potential role of sodium-glucose cotransporter-2 inhibitors.

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is characterized by androgen excess, oligo/anovulation, and polycystic appearance of the ovaries. Women with PCOS have an increased prevalence of multiple cardiovascular risk factors such as insulin resistance, hypertension, renal injury, and obesity. Unfortunately, there is a lack of effective, evidence-based pharmacotherapeutics to target these cardiometabolic complications. Sodium-glucose cotransporter-2 (SGLT2) inhibitors provide cardiovascular protection in patients with and without type 2 diabetes mellitus. Although the exact mechanisms of how SGLT2 inhibitors confer cardiovascular protection remains unclear, numerous mechanistic hypotheses for this protection include modulation of the renin-angiotensin system and/or the sympathetic nervous system and improvement in mitochondrial function. Data from recent clinical trials and basic research show a potential role for SGLT2 inhibitors in treating obesity-associated cardiometabolic complications in PCOS. This narrative review discusses the mechanisms of the beneficial effect of SGLT2 inhibitors in cardiometabolic diseases in PCOS.

Administration of sodium-glucose cotransporter-2 inhibitors in IgA nephropathy; a new strategy in the management?

Some of the several effects of sodium-glucose cotransporter-2 inhibitors (SGLT-2i), including their metabolic, anti-inflammatory and hemodynamic properties, along with other kidney protective values, have directed clinicians to give these drugs in IgA-nephropathy (IgAN). According to recent studies regarding the beneficial effects of SGLT-2i on IgAN, it is clear that clinicians are changing their approach towards kidney transplantation when it comes to aggressive immunosuppression. This mini-review aims towards the evaluation of the protective efficacy of SGLT-2i in IgA-nephropathy.

Heterogeneity in cardiovascular death or hospitalization for heart failure benefits with flozins is linked to weight.

Cardiovascular outcome trials with sodium-glucose cotransporter 2 inhibitors (SGLT-2is) have documented a positive impact on micro- and macrovascular complications of type 2 diabetes (T2D). Most analyses suggest that these benefits are independent of achieving metabolic control. This meta-regression analysis was undertaken to explore the relationship between metabolic components positively influenced by SGLT-2is and a reduction in cardiovascular death (CV death) or hospitalization due to heart failure (hHF). A database search was conducted using the Cochrane Library to identify relevant studies. Analysis was conducted using CMA and RStudio (2022.07.1) software. The hazard ratios of the individual studies were used to compute the random effects model mean effect size for CV death or hHF, and the prediction interval was used to identify the uncertainty in the summary treatment effect. Heterogeneity was quantified using Q statistics. A pooled population of 46969 patients from five studies was included for analysis. The Cochrane risk of bias tool was used to assess the quality of the studies. There was a significant 23% reduction in CV deaths or hHFs in the SGLT-2i arm compared with the placebo arm [hazard ratio (HR): 0.77, 95% confidence interval (CI) 0.70-0.85]. However, the prediction interval (0.57-1.05) and the Q statistics [8.06>degrees of freedom (df) of 4] were indicative of uncertainty in the true effect or heterogeneity. Nearly 50% of the variance of the observed effects were related to the true effects (I2 =50%). Among the moderators selected, a significant correlation of the outcomes was found with the weight variable (P<0.01). Weight differential could explain the entire variance in true effect size (R2 =1.00) ruling out any sampling error. The results of this meta-regression analysis suggest that the beneficial effects of SGLT-2is in reducing CV deaths and hHFs are related to the weight variable.

Addressing Cardiovascular Disparities in Racial/Ethnic Populations: The Blood Pressure-Lowering Effects of SGLT2 Inhibitors.

The racial/ethnic disparities in cardiometabolic risk factors and cardiovascular diseases (CVD) are prominent in non-Hispanic Black adults and other United States (U.S.) sub-populations, with evidence of differential access and quality of health care. High blood pressure (BP) is the most potent and prevalent risk factor for adverse cardiovascular (CV) outcomes across all populations globally, but especially in the non-Hispanic Black adults in the U.S. The use of sodium-glucose cotransporter-2 inhibitors (SGLT2is) demonstrate favorable effects in patients with and without type 2 diabetes (T2DM) in CVD especially for heart failure (HF), as the contemporary clinical practice recommendations and standards of care advocate. The beneficial effects of SGLT2is have been most profoundly documented with HF, including reduced (HFrEF) or preserved ejection fraction (HFpEF), and chronic kidney disease (CKD) with T2DM. Given that hypertension (HTN), CVD, HF, and CKD are significantly greater in certain racial/ethnic populations, the potential impact of SGLT2is will be more significant on the excess cardiometabolic and renal disease, especially in the Black patients. Moreover, there is a need for increased diverse representation in clinical trials. Inclusion of larger members of various racial/ethnic populations may assure that new and emerging data accurately reflect the diversity of the U.S. population. This review highlights potential benefits of SGLT2is, as noted in the most recent literature, and their BP-lowering impact on potentially reducing CV disparities, especially in Black adults. Furthermore, this commentary emphasizes the need to increase diversity in clinical trials to reduce the disparity gaps.

Sodium-glucose co-transporter 2 inhibitors for the treatment of cardio-renal syndrome.

The 2021 guidelines of the European Society of Cardiology on the diagnosis and therapy of heart failure (HF) introduced relevant changes in the pharmacological treatment of chronic HF. Among these, certainly the most significant was the introduction in the therapeutic flow-chart (with the highest recommendation level) of the sodium glucose co-transporter 2 (SGLT2) inhibitors. In fact, SGLT2 inhibitors are responsible for major paradigm shifts in the care of patients with or at high risk for HF, progression of chronic kidney disease, or both. SGLT2 inhibition demonstrated to improve cardiovascular outcomes in patients with HF over a wide range of ejection fractions, regardless of diabetic status, and have a strong nephroprotective effect. There are several important interactions between heart disease and kidneys disease. Indeed, acute or chronic dysfunction of the heart or kidneys can induce acute or chronic dysfunction in the other organ. The term 'cardiorenal syndrome' has been applied to these interactions. Since kidneys dysfunction in the setting of HF has a strong prognostic relevance, drugs that can slow down the decline of renal function are of utmost importance. Here, we discuss about the beneficial effects of SGLT2 inhibitors on the kidneys function in patients with HF and how these effects can improve both renal and cardiovascular outcomes.

Empagliflozin suppresses urinary mitochondrial DNA copy numbers and interleukin-1β in type 2 diabetes patients

Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular and renal outcomes in type 2 diabetes mellitus (T2DM) patients. However, the mechanisms by which SGLT2 inhibitors improve the clinical outcomes remain elusive. We evaluated whether empagliflozin, an SGLT2 inhibitor, ameliorates mitochondrial dysfunction and inflammatory milieu of the kidneys in T2DM patients. We prospectively measured copy numbers of urinary and serum mitochondrial DNA (mtDNA) nicotinamide adenine dinucleotide dehydrogenase subunit-1 (mtND-1) and cytochrome-c oxidase 3 (mtCOX-3) and urinary interleukin-1β (IL-1β) in healthy volunteers (n = 22), in SGLT2 inhibitor-naïve T2DM patients (n = 21) at baseline, and in T2DM patients after 3 months of treatment with empagliflozin (10 mg, n = 17 or 25 mg, n = 4). Both urinary mtDNA copy numbers and IL-1β levels were higher in the T2DM group than in healthy volunteers. Baseline copy numbers of serum mtCOX-3 in the T2DM group were lower than those in healthy volunteers. Empagliflozin induced marked reduction in both urinary and serum mtND-1 and mtCOX-3 copy numbers, as well as in urinary IL-1β. Empagliflozin could attenuate mitochondrial damage and inhibit inflammatory response in T2DM patients. This would explain the beneficial effects of SGLT2 inhibitors on cardiovascular and renal outcomes.

Physicians' Considerations and Practice Recommendations Regarding the Use of Sodium-Glucose Cotransporter-2 Inhibitors.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), although initially developed as glucose-lowering drugs, provide significant beneficial effects on cardiorenal outcomes, including heart failure, regardless of type 2 diabetes status. Integration of SGLT-2is into clinical practice requires practical guidance for physicians about their use. To overcome physicians’ clinical inertia for SGLT-2i use, including addressing safety, potentially a barrier to their use, a roundtable discussion with physicians from three specialties (cardiology, endocrinology, and nephrology) was conducted. This review summarizes the physicians’ clinical experience and recommendations about SGLT-2i use across different patient populations, taking into consideration the beneficial effects of SGLT-2is and their safety. The key aspects discussed regarding SGLT-2i safety include acute effects on kidney function (estimated glomerular filtration rate acute dip upon SGLT-2i initiation and acute kidney injury), volume depletion, diabetic ketoacidosis, genitourinary infections, hyperkalemia, and hypoglycemia. To mitigate any potential risks related to SGLT-2i safety, physicians can make minor adjustments to an individual patient’s treatment plan, while retaining the SGLT-2i cardiorenal benefits for effective disease management. Recognition by physicians that the benefits of SGLT-2i use on clinical outcomes outweigh the risks will result in the integration of SGLT-2is into clinical practice and lead to improved patient care and outcomes.

The gender gap in prescription pattern of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes

Abstract Background The major benefit of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes mellitus (T2DM) on cardiovascular outcome has been undoubtably proven in several landmark trials and different populations. In consideration of emerging evidence that there are clinically relevant gender-related differences in the course of T2DM and subsequent cardiovascular outcomes, it is unknown if SGLT2i therapy is gender independent utilized in clinical practice. In this regard, real-world data are needed to determine whether there is a gender gap in SGLT2i prescription and if this influences long-term outcome. Methods Patients with T2DM admitted to a tertiary academic center between 01/2014 and 04/2020 were identified through a search of electronic health records. Data on antidiabetic therapy was acquired at discharge, and were screened for SGLT2i prescription. Subsequently, the entire cohort was prospectively followed. Results In total, 812 patients (median age 70 years, 29.7% female) were included in the present analysis. Only 17.3% of the study population received an SGLT2i. In direct comparison between sexes, females show lower rates of SGLT2i prescription (11,2% vs. 19,8%, p=0.003), despite comparable patient characteristics. Furthermore, males show a significantly higher probability of SGLT2i prescription, illustrated as an adjusted odds ratio of 2.59 (CI 95% 1.29–5.19; p=0.008). During a median follow-up time of 2.3 years, a total of 142 patients died due to cardiovascular causes – corresponding to 103 (18.0%) male and 39 (16.2%) female participants. Females who did not receive a SGLT2i showed higher rates of chronic kidney disease (CKD, 25.2% vs. 7.4%, p=0.039) and greater levels of proBNP (2092 pg/ml (IQR: 738–5279) vs. 825 pg/ml (IQR: 298–2479), p=0.011) as compared to non-SGLT2i females. Conclusion Despite clear evidence on the beneficial effect of SGLT2i, the present data suggest a gender-gap in SGLT2i prescription and thus missed potential in female patients. The most common reason for not prescribing a SGLT2i in females was the presence of CKD. However, SGLT2i (i.e. Empagliflozin) are approved to use in individuals with a glomerular filtration rate (GFR) as low as ≥20ml/min, and therefore more awareness has to be raised, that SGLT2i are feasible to prescribe in such vulnerable patients with present cardiovascular comorbidities, to achieve a benefit as shown in several landmark trials. Additionally, more attention is needed to address this gender-gap and ensure that both sexes receive equal attention, in terms of state of the art T2DM therapy to reduce mortality and morbidity. Funding Acknowledgement Type of funding sources: None.

Re-examining the widespread policy of stopping sodium-glucose cotransporter-2 inhibitors during acute illness: A perspective based on the updated evidence.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are now seen as an integral part of therapy in type 2 diabetes to control not only blood glucose but to improve cardiovascular and kidney outcomes. Diabetic ketoacidosis (DKA) is an uncommon but serious complication of type 2 diabetes, which has a high case fatality rate. The absolute risk of DKA in large, prospective randomized clinical trials in people with type 2 diabetes using SGLT2 inhibitors has been low, although the relative risk is higher in those assigned to SGLT2 inhibitors compared with placebo. In those without diabetes but prescribed SGLT2 inhibitors for heart failure or chronic kidney disease, the risk of DKA is similar to placebo. Over the course of the COVID-19 pandemic, cases of DKA have also been reported in cases of COVID-19 hospitalizations. Consensus guidelines have recommended that SGLT2 inhibitors should be avoided in cases of serious illness and suggest they are not recommended for routine in-hospital use. However, recent data suggest potential beneficial effects of SGLT2 inhibitors in the setting of acute illness with COVID-19 with no increase in adverse events and low rates of DKA, which were non-severe. Given the low rates of DKA in cardiovascular outcome trials and in hospitalized patients with type 2 diabetes, the potential for SGLT2 inhibitors not being re-initiated following discharge and their cardiovascular and kidney benefits, we believe the practice of routine 'sick day' guidance should be re-examined based on current evidence with a call for further research in this area. Furthermore, high-quality trials of initiation of SGLT2 inhibitors in people admitted to hospital with cardiovascular disease or kidney disease, and trials of continuation of SGLT2 inhibitors in people, with careful monitoring of DKA should be conducted. These should be further supplemented with large observational studies.

SGLT2 Inhibition in Type 1 Diabetes with Diabetic Kidney Disease: Potential Cardiorenal Benefits Can Outweigh Preventable Risk of Diabetic Ketoacidosis.

The aim of this review is to summarize existing research investigating the use of sodium glucose cotransporter-2 (SGLT2) inhibitors in patients with type 1 diabetes mellitus (T1DM) while highlighting potential strategies to mitigate the risk of diabetic ketoacidosis (DKA). SGLT2 inhibitors have been studied in patients with T1DM in phase 3 clinical trials such as the inTandem, DEPICT, and EASE trials, which demonstrated consistent reductions in HbA1c. Secondary analyses of these trials have also reported potential kidney protective effects that are independent of improved glycemic control. However, trials in patients with type 2 diabetes mellitus (T2DM) have found an increased risk of DKA with SGLT2 inhibitors, a serious concern in patients with T1DM. SGLT2 inhibitors provide cardiovascular benefits and kidney protection in patients with T2DM and are a promising therapeutic option for patients with T1DM due to overlapping pathophysiological mechanisms. However, SGLT2 inhibitors increase the risk of DKA, and there is currently a lack of research investigating the beneficial effects of SGLT2 inhibitors in patients with T1DM. Preventative measure for DKA would have to be implemented and the risks would need to be carefully balanced with the benefits offered by SGLT2 inhibitors. Additional research will also be required to determine the kidney protective effects of SGLT2 inhibitors in patients with T1DM and diabetic kidney disease and to quantify the risk of DKA after the implementation of preventative measures, proper patient education, and ketone monitoring.

Dapagliflozin, sildenafil and their combination in monocrotaline-induced pulmonary arterial hypertension

BackgroundDapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), can reduce cardiovascular events and mortality in patients with heart failure. A number of mechanisms have been proposed to explain the beneficial effects of SGLT2 inhibitors. The purpose of this study was to determine whether dapagliflozin can improve pulmonary vascular remodelling and the efficacy of dapagliflozin as an add-on therapy to sildenafil in rats with pulmonary arterial hypertension (PAH).MethodsA monocrotaline (MCT)-induced PAH rat model was used in our study. MCT-injected rats were randomly divided into four groups and treated for 3 weeks with daily per os treatment with vehicle, dapagliflozin (1 mg/kg/day), sildenafil (25 mg/kg/day), or a combination of dapagliflozin (1 mg/kg/day) and sildenafil (25 mg/kg/day). Haemodynamic measurements, histological analysis, enzyme-linked immunosorbent assay and western blotting analysis were employed to detect the changes in PAH rats after treatments.ResultsDapagliflozin significantly attenuated MCT-induced increases in right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) in PAH rats. Dapagliflozin effectively decreased the thickening of pulmonary artery media and decreased the muscularization of pulmonary arterioles in PAH rats. Moreover, dapagliflozin attenuated nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation in lung tissues and the levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18) in plasma. However, dapagliflozin as an add-on therapy to sildenafil in rats with PAH did not show a more pronounced beneficial effect on right ventricular systolic pressure and pulmonary vascular remodelling in MCT rats than sildenafil alone.ConclusionsDapagliflozin reduces right ventricular systolic pressure and pulmonary vascular remodelling in a rat model of PAH. However, combination therapy with dapagliflozin and sildenafil was not more effective than monotherapy with sildenafil in PAH rats.

Attenuation of Adverse Postinfarction Left Ventricular Remodeling with Empagliflozin Enhances Mitochondria-Linked Cellular Energetics and Mitochondrial Biogenesis.

Sodium–glucose cotransporter 2 (SGLT2) inhibitors such as empagliflozin are known to reduce the risk of hospitalizations related to heart failure irrespective of diabetic state. Meanwhile, adverse cardiac remodeling remains the leading cause of heart failure and death in the USA. Thus, understanding the mechanisms that are responsible for the beneficial effects of SGLT2 inhibitors is of the utmost relevance and importance. Our previous work illustrated a connection between adverse cardiac remodeling and the regulation of mitochondrial turnover and cellular energetics using a short-acting glucagon-like peptide-1 receptor agonist (GLP1Ra). Here, we sought to determine if the mechanism of the SGLT2 inhibitor empagliflozin (EMPA) in ameliorating adverse remodeling was similar and/or to identify what differences exist, if any. To this end, we administered permanent coronary artery ligation to induce adverse remodeling in wild-type and Parkin knockout mice and examined the progression of adverse cardiac remodeling with or without EMPA treatment over time. Like GLP1Ra, we found that EMPA affords a robust attenuation of PCAL-induced adverse remodeling. Interestingly, unlike the GLP1Ra, EMPA does not require Parkin to improve/maintain mitochondria-related cellular energetics and afford its benefits against developing adverse remodeling. These findings suggests that further investigation of EMPA is warranted as a potential path for developing therapy against adverse cardiac remodeling for patients that may have Parkin and/or mitophagy-related deficiencies.

Enhanced Expression and Function of Renal SGLT2 (Sodium-Glucose Cotransporter 2) in Heart Failure: Role of Renal Nerves.

Recent clinical studies demonstrate that SGLT2 (sodium-glucose cotransporter 2) inhibitors ameliorate heart failure (HF). The present study was conducted to assess the expression and function of renal SGLT2 and the influence of enhanced renal sympathetic tone in HF. Four weeks after coronary artery ligation surgery to induce HF, surgical bilateral renal denervation (RDN) was performed in rats. Four groups of rats (Sham-operated control [Sham], Sham+RDN, HF and HF+RDN; n=6/group) were used. Immunohistochemistry and Western blot analysis were performed to evaluate the renal SGLT2 expression. One week after RDN (5 weeks after induction of HF), intravenous injection of SGLT2 inhibitor dapagliflozin were performed to assess renal excretory responses. In vitro, human embryonic kidney cells were used to investigate the fractionation of SGLT2 after norepinephrine treatment. In rats with HF, (1) SGLT2 expression in the proximal tubule of the kidney was increased; (2) the response of increases in urine flow, sodium excretion, and glucose excretion to dapagliflozin were greater; and (3) RDN attenuated renal SGLT2 expression and normalized renal functional responses to dapagliflozin. In vitro, norepinephrine promoted translocation of SGLT2 to the cell membrane. These results indicate that the enhanced tonic renal sympathetic nerve activation in HF increases the expression and functional activity of renal SGLT2. Potentiated trafficking of SGLT2 to cell surface in renal proximal tubules mediated by norepinephrine may contribute to this functional activation of SGLT2 in HF. These findings provide critical insight into the underlying mechanisms for the beneficial effects of SGLT2 inhibitors on HF reported in the clinical studies.

Effects of Sodium-Glucose Co-Transporter 2 Inhibitors on Vascular Cell Function and Arterial Remodeling

Cardiovascular disease is the leading cause of morbidity and mortality in diabetes. Recent clinical studies indicate that sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in patients with diabetes. The mechanism underlying the beneficial effect of SGLT2 inhibitors is not completely clear but may involve direct actions on vascular cells. SGLT2 inhibitors increase the bioavailability of endothelium-derived nitric oxide and thereby restore endothelium-dependent vasodilation in diabetes. In addition, SGLT2 inhibitors favorably regulate the proliferation, migration, differentiation, survival, and senescence of endothelial cells (ECs). Moreover, they exert potent antioxidant and anti-inflammatory effects in ECs. SGLT2 inhibitors also inhibit the contraction of vascular smooth muscle cells and block the proliferation and migration of these cells. Furthermore, studies demonstrate that SGLT2 inhibitors prevent postangioplasty restenosis, maladaptive remodeling of the vasculature in pulmonary arterial hypertension, the formation of abdominal aortic aneurysms, and the acceleration of arterial stiffness in diabetes. However, the role of SGLT2 in mediating the vascular actions of these drugs remains to be established as important off-target effects of SGLT2 inhibitors have been identified. Future studies distinguishing drug- versus class-specific effects may optimize the selection of specific SGLT2 inhibitors in patients with distinct cardiovascular pathologies.