Sodium-glucose Cotransporter Type Research Articles

New principles for the treatment of chronic heart failure: the phenomenon of sodium-glucose cotransporter type 2 inhibitors

Chronic heart failure (CHF) is one of the most important problems in clinical cardiology due to high morbidity, frequent hospitalizations and poor prognosis of patients. Quite unexpectedly, sodium-glucose cotransporter type 2 (SGLT2i) inhibitors dapagliflozin and empagliflozin, which were created for the treatment of diabetes mellitus, proved to be effective means of reducing the risk of an adverse outcome in patients with CHF, they were included in a new four-component therapy for CHF with a reduced left ventricular ejection fraction with a class of recommendations I and level of evidence A. The basis for changing the clinical guidelines for CHF was the results of large randomized trials of DAPA-HF and EMPEROR-Reduced. Despite the obvious clinical benefit of using SGLT2i in CHF, the mechanisms of the observed effects remain speculative and continue to be actively studied. In particular, the literature discusses the role of osmotic diuresis, lowering blood pressure and body weight, increasing erythropoietin production, influencing myocardial remodeling, modifying the energy metabolism of the heart, inhibiting the sodium-hydrogen exchanger, autophagy, and influencing leptin and adiponectin levels. SGLT2i has many of the qualities of an ideal agent for the treatment of CHF with reduced left ventricular ejection fraction, including a single dose without the need for titration, once daily administration, early positive effects on clinical outcomes and quality of life, a favorable safety and tolerability profile with a frequency of serious side effects not different from placebo. At the same time, the choice of medical tactics may be influenced by the features of the evidence base of SGLT2i, in particular, the reduction in cardiovascular mortality and death from any cause in a randomized trial of dapagliflozin.

Effect of SGLT2 inhibitors on the course of chronic heart failure in patients with type 2 diabetes mellitus

Diabetes mellitus (DM) is a group of metabolic diseases characterized by chronic hyperglycemia, which is the result of impaired insulin secretion, insulin action, or both. Chronic hyperglycemia in diabetes is accompanied by damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Diabetes mellitus plays a significant role in the formation and is one of the significant risk factors for the development of chronic heart failure (CHF) through its glucose toxic effect, the effect on hyperlipidemia and blood coagulation, impaired autonomic regulation of the heart and a number of other mechanisms. Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are a recently emerging class of antidiabetic drugs that act by inhibiting the reabsorption of glucose in the kidneys. Existing studies of the efficacy and safety of these drugs have shown that they have not only antidiabetic, but also a pronounced organoprotective, especially cardioprotective effect. Today it is believed that the main reason leading to this lies in a decrease in sodium reabsorption in the kidneys, a decrease in the content of intracellular calcium and sodium, and an increase in the concentration of calcium in mitochondria. The role of the ketogenic action of these drugs, their effect on oxidative stress and the processes of inflammation and fibrosis in the myocardium is also considered. The most common side effects of SGLT2 inhibitors include urinary tract and genital infections, euglycemic ketoacidosis. Other possible side effects include an increased risk of lower limb amputations, Fournier gangrene, breast cancer in women, bladder cancer in men, orthostatic hypotension and acute kidney injury, and an increased tendency to fracture. Most side effects can be avoided through adequate patient education and assessment of risk factors and contraindications before starting the use of drugs. Despite the clear need for more research on SGLT2 inhibitors, their widespread use will positively affect the health of the diabetic patient population.

Effect of sodium-glucose cotransporter type 2 inhibitors on non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease is one of the most common liver diseases, morphologically representing a whole spectrum of pathological conditions, from steatosis and steatohepatitis to fibrosis, the clinical outcomes of which can be liver cirrhosis and hepatocellular carcinoma. The frequency of adverse outcomes in the course of non-alcoholic fatty liver disease significantly increases against the background of type 2 diabetes mellitus, which is probably due to the pathogenetic synergy of non-alcoholic fatty liver disease and type 2 diabetes mellitus associated with metabolic syndrome. The commonality of pathogenetic links, as a result, suggests the unidirectionality of therapeutic approaches. In this connection, a search was made for studies and meta-analyses in large electronic databases (MEDLINE, Scopus, UpToDate, CyberLeninka) in order to study modern methods of pharmacotherapy for non-alcoholic fatty liver disease and type 2 diabetes mellitus. The results of a number of experimental and clinical studies evaluating the effect of hypoglycemic drugs of the group of sodium-glucose cotransporter type 2 inhibitors on non-alcoholic fatty liver disease demonstrate a wide range of intrahepatic effects that affect the manifestations of liver steatosis and fibrosis through the regulation of oxidative stress, endoplasmic reticulum stress, effects on intrahepatic inflammation, autophagy and apoptosis, as well as indirectly affecting hepatic metabolism, by reducing body weight. In addition, today gliflozins are rushing to occupy a completely new therapeutic niche, demonstrating anticarcinogenic effects in experimental studies. Thus, the pleiotropic effect of inhibitors of the sodium-glucose cotransporter type 2 suggests a potential hepatoprotective effect in the treatment of non-alcoholic fatty liver disease and its outcomes.

Sodium glucose co-transporter 2 inhibition prevents muscle energy metabolism changes in infarcted rats

Abstract Introduction Skeletal muscle energy metabolism is commonly altered in heart failure patients, with a metabolic shift from oxidative to glycolytic muscle fiber. These changes contribute to reduced functional capacity. Sodium glucose co-transporter type 2 (SGLT2) inhibitors improve cardiovascular outcomes in both diabetic and non-diabetic patients, as well as those with and without heart failure. However, the effects of SGLT2 inhibitors on skeletal muscle during heart failure have not been established. The aim of this study was to assess the metabolic effect of empagliflozin (EMPA) on skeletal muscle of rats with myocardial infarction (MI)-induced heart failure. Methods One week after MI induction or simulated surgery, male Wistar rats were divided into four groups: Sham (n=10), Sham+Empa (n=12), MI (n=10), and MI+Empa (n=09). EMPA was added to rat chow (5 mg/kg/day). Rats were supplied with ad libitum water and chow for 12 weeks. Infarct size was measured by histological analysis. Metabolic enzyme activity in the soleus muscle was assessed by spectrophotometry. Statistical analysis: ANOVA and Tukey, and Student's t tests. Results Only rats with infarction size greater than 35% of total left ventricle area were included in this study. Infarction size did not differ between infarcted groups (MI 41.8±4.2; MI+Empa 40.7±5.7 of total left ventricle area). In the MI soleus muscle, metabolic enzyme activity of glucose-6-phosphate-dehydrogenase, citrate synthase and beta-hydroxy-acyl-dehydrogenase was higher than the Sham group. These changes were not observed in the MI+Empa group. MI+Empa had lower hexokinase, phosfructokinase, and pyruvate kinase activity (glycolytic metabolism enzymes), and lower citrate synthase and glucose-6-phosphate-dehydrogenase activity than MI. Conclusion Chronic treatment with SGLT2 inhibitor empagliflozin prevents metabolic abnormalities in skeletal muscle in infarcted rats. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): CAPES, CNPq, FAPESP

Outcomes of sodium-glucose co-transporter type 2 inhibitors use in elderly patients with heart failure with reduced ejection fraction

Abstract Background Heart failure is a highly prevalent condition, especially in patients over 75 years. In recent years, new therapeutic lines have emerged for the management of heart failure with reduced ejection fraction (HFrEF), most notably sodium-glucose co-transporter type 2 inhibitors (iSGLT2). However, there are currently low evidence of the benefit in this subgroup. Methods A retrospective study was conducted from January 2016 to December 2020 in our hospital. All patients aged ≥75 years, diagnosed with HFrEF (defined by left ventricular ejection fraction <40%), and current guidelines recommendations for iSGLT2 were included. Clinical, electrocardiographic and echocardiographic data were collected. Results A total of 616 patients were included, with a mean age at the inclusion of 83.3 years (standard deviation, SD, ± 5); 65.6% of the patients included were male. 81.2% were hypertensive, 35.4% were diabetic. 46.2% had chronic kidney disease (defined as glomerular filtrate <60mL/min/1.73 m2). Chronic lung disease was present in 14.8% of the patients, 16.2% had a history of cerebrovascular events and 12.7% suffered from peripheral vascular disease. The most frequent cause of HFrEF was ischemic, with 53.9%. A total of 86.8% presented a NYHA I-II; in 60.3% of the subjects, the rhythm at inclusion was sinus rhythm. The percentage of patients with BB was 76.9%, with ACEI / ARB 69.8%, 14.3% with ARNI and with anti-aldosterone agents 40.4%. The percentage of patients with SGLT2i was only 4.2%. The median follow-up was 34.5 months, during which 50.4% of the population died and 62.5% had a cardiovascular event (death or hospitalization for heart failure). A survival analysis using Cox regression showed that SGLT2i in this subgroup of patients was a protective factor against mortality (HR 0.124; 95% CI 0.031–0.497) and cardiovascular events (HR 0.428; 95% CI 0.221–0.830) Conclusion Despite current recommendations in the guidelines, there is marked underuse in elderly patients of SGLT2i. This could be related to greater intolerance or contraindication, but also to a lesser application of the clinical evidence in this population group. However, the use of SGLT2i has been shown as a significant factor associated with improved survival and comorbidity rate in our study population. Funding Acknowledgement Type of funding sources: None.

A Systematic Review and Meta-Analysis on the Efficacy and Safety of Combination Therapy with Sodium-Glucose Cotransporter Type 2 Inhibitor (SGLT2i) and Dipeptidase-4 Inhibitor (DPP4i) in Treatment of Type 2 Diabetes

Background: The management and treatment of type 2 diabetes (T2D) remain difficult and complex, despite the wide range of pharmacotherapies available for glycemic control. As a result, researchers continue to look for new therapeutic molecules with modes of action that might fill in the gaps left by currently existing medications.The aim of this study was to assess the efficacy and safety of sodium-glucose cotransporter type2 inhibitor (SGLT2i) and dipeptidyl peptidase-4 inhibitor (DPP4i) in combination for treatment and management of type 2 diabetes (T2D). Methods: EMBASE, MEDLINE, PUBMED and Cochrane Central Register of Controlled Trials were subjected to literature search. RCTs comparing SGLT2i plus DPP4i (SGLT2i/DPP4i) to DPP4iplacebo or SGLT2iplacebo were eligible if they were published in English and compared SGLT2i plus DPP4i (SGLT2i/DPP4i) to DPP4iplacebo or SGLT2iplacebo. The change in HbA1c from baseline was the primary endpoint. Results: The study comprised of eight RCTs comparing SGLT2i/DPP4i and DPP4ionly, five RCTs comparing SGLT2i/DPP4i and SGLT2ionly, and three RCTs involving both comparisons. The combination of both inhibitors resulted in a greater average HbA1c reduction [WMD: 0.62 percent] than DPP4i alone, which resulted in a much lesser reduction (WMD: -0.35 percent) than SGLT2i alone. Furthermore, only SGLT2i/DPP4i vs. DPP4i revealed notable differences in body weight loss from baseline, but not SGLT2i.The risk of hypoglycemia was modest and consistent across treatment groups. Any reduction by SGLT2i/DPP4i in relation to DPP4i was proportionate to baseline HbA1c levels when patients were stratified based on baseline HbA1c levels. However, despite of baseline HbA1c, HbA1c reductions with combination were minor when compared to SGLT2i alone. Conclusion: Combination of these two inhibitors is found to be safe and effective. A significant extra glucose-lowering impact is observed when SGLT2i is used with or added to DPP4i, but not the other way around. The extra hypoglycemic effects of SGLT2i in combination with DPP4i were assessed by baseline HbA1c. Keywords: Efficacy, safety, DPP4i, SGLT2i, Treatment, Type 2 Diabetes

Ингибиторы НГЛТ-2 при хронической болезни почек: современное состояние проблемы

All patients with chronic kidney disease (CKD) require treatment to reduce the risk of cardiovascular events and to prevent progression of renal failure. ACE inhibitors and angiotensin receptor blockers are widely used for cardio- and nephroprotection in patients with CKD. Sodium glucose cotransporter type 2 (SGLT-2) inhibitors show significant prospects for reducing morbidity and mortality in this population. SGLT-2 inhibitors have been developed for treatment of patients with type 2 diabetes mellitus. However, evidence from multiple randomized clinical trials suggested that these drugs have cardio- and nephroprotective effects in patients with and without diabetes. Despite a wealth of data, SGLT-2 inhibitors remain underused by nephrologists or cardiologists. This is not surprising since new therapies traditionally take decades from research to clinical implementation due to many barriers, including lack of knowledge, concern about drug side effects, lack of decision support, cost, and clinical inertia. The review article presents data from scientific studies on the renoprotective effect of SGLT-2 inhibitors and the mechanisms of this activity in CKD patients.

Еvaluation the functional reserve of the kidneys in patients with chronic heart failure who have had the COVID-19 infection

THE AIM: to evaluate the functional reserve of the kidneys (FRK), and the effectiveness of empagliflozin (EMPA), a selective reversible inhibitor of sodium-glucose cotransporter type 2 (SGLT 2), in patients with chronic heart failure who have had COVID-19 infection. PATIENTS AND METHODS: To assess the state of renal function in patients with coronary heart disease (CHF), the most accessible and convenient method for determining FRK using 0.45 % saline was chosen. The study involved 110 patients with CHF developed as a result of coronary artery disease and hypertension. The first group consisted of 40 patientswith CHF who have had COVID-19 infection (16 (40 %) men and 24 (60 %) women, mean age 63.2 ± 1.2 years). They received EMPA in addition to standard therapy. The second group consisted of 40 patients with CHF who have also had COVID-19 (24 (60 %) men and 16 (40 %) women, mean age 64.1 ± 1.2 years). They received only standard therapy (ACE inhibitors or ARB,beta-blockers, AMCR). The control group consisted of 30 CHF patients who haven’t had COVID-19 infection (16 (53.33 %) men and 14 (46.67 %) women, mean age 61.8 ± 1.2 years). They received only standard therapy. RESULTS. In patients of the first group (standard treatment+ EMPA) the FRK was 2.9 ± 0.2 % before and 8.1 ± 0.2 % after the treatment, which indicates a significant increase (p<0.001). The creatinine level before the treatment and exercise was 147.7±2.7 μmol/l, and after the exercise, it decreased to 144.7±2.5 μmol/l. After the standard therapy, a decrease in its index by 102.5±1.4 μmol/l and 99.7 ± 1.3 μmol/l, respectively, was established. The glomerular filtration rate before treatment and exercise was 56.8 ± 1.5 ml/min, and after exercise, it increased to 54.3 ± 1.6 ml/min. After the treatment, these values were 60.3 ± 2.01 ml/min and 62.7±2.08 ml/min, respectively. In patients of the second group (standard treatment), FRK was 4.4 ± 0.1 % before and 3.0 ± 0.2 % after treatment. CONCLUSION: Thus, in patients of the first group, who received EMPA along with standard CHF treatment, an increase in FRK by 2.8 times was found (p < 0.01). In the group of patients with CHF who did not receive an inhibitor of sodium-glucose transporter type 2 EMPA in combination with standard therapy, a decrease in FRK by 1.3 times was found (p > 0.05). While in the control group, FRK increased by 1.1 times (p > 0.05). Thus, the results show that in the first group, the FRK index was 2.9 %, which indicates the absence of a reserve, while after complex therapy in combination with EMPA, this increased to 8.1 %, which indicates the presence of a reserve. However, in the second group, the decrease in these indicators from 4.4 % to 3.3 %, respectively, suggests the absence of FRK. In the control group, this figure increased from 6.7 % before treatment to 7.1 % after.This indicates a decrease in FRK in this group of patients. Thus, the decrease in the FRK in patients of the first group compared with the control indicates an adverse effect of COVID-19 on the kidneys. It is confirmed in numerous studies, which makes us think about its long-term effect not only in the acute period of infection but also after the clinical convalescence.

Refractory Arterial Hypertension: Features of Neurohormonal and Water-salt Imbalanceand Approaches to Antihypertensive Drug Therapy

Refractory arterial hypertension is characterized by a lack of control of target blood pressure, despite the prolonged use >5 antihypertensive drugs with different mechanisms of action, including longacting diuretic chlorthalidone and the mineralcorticoid receptor antagonists (spironolactone or eplerenone). The review presents the results of clinical studies devoted the elucidating peculiarities of the neurohormonal status and water-salt balance in such patients and developing new approaches to antihypertensive drug therapy based on them. According to these studies, individuals with refractory hypertension differ from patients with resistant hypertension with the higher of sympathetic nervous system activity and the absence of an increased of intrathoracic fluid volume, which indirectly indicates a significant decrease in the intravascular fluid volume. In this regard, the review focuses on the data obtained in assessing the clinical efficacy of sympatholytics clonidine and reserpine in patients with resistant and refractory hypertension, as well as renal sodium-glucose co-transporter type 2 inhibitors, which suppress the sympathetic nervous system activity and can be used to overcome refractory hypertension in patients with type 2 diabetes.

Review of the efficacy and safety of SGLT2 inhibitors in heart failure patients with low left ventricular ejection fraction without diabetes mellitus

Heart failure (HF) with low left ventricular ejection fraction (LVEF) is a disease with an unfavorable prognosis, for the treatment of which there is a need to search for drugs that improve patients’ quality of life. Such a group of drugs is inhibitors of sodium-glucose cotransporter type 2 (iSGLT-2). Purpose of the study: to assess the efficacy and safety of the new class of antihyperglycemic drugs — iSGLT-2.

Is there any robust evidence showing that SGLT2 inhibitor use predisposes to acute kidney injury?

A novel class of oral glucose lowering drugs, sodium-glucose co-transporter type 2 inhibitors (SGLT2is), has shown additional beneficial effects on body weight, serum uric acid levels, blood pressure, and cardiac and renal function. Conflicting data have been published regarding the potential risk of acute kidney injury (AKI) when using SGLT2is. Aim of this manuscript was to review the current literature on this issue. SGLT2isinduce a mild acute decline in estimated glomerular filtration rate, attributed to the effect of proximal tubular natriuresis on tubuloglomerular feedback through increased macula densa sodium delivery, leading to afferent arteriole vasoconstriction and reduced intraglomerular pressure. This functional effect with a subsequent rise in serum creatinine fulfills the creatinine-basedcriteria for AKI,as defined in clinical practice and trial settings. Other proposed potential mechanisms as tohow SGLT2islead to AKI include osmotic diuresis leading to volume depletion, increased urinary uric acid levels, intratubular oxidative stress, local inflammation and tubular injury. Despite the warning published by the US Food and Drug Administration in 2016 about a potential risk of AKI and the report of some clinical cases of AKI after treatment with SGLT2is, large observational real-life retrospective studies, randomized controlled trials and propensity-matched analyses of data from clinical practice unambiguously demonstrate that SGLT2is are safe for the kidney and do not predispose to AKI. In conclusion, while we can probably stop worrying about AKI risk when using SGLT2is, the question whether these agents should be withheld in the presence of clinical situations at high risk for AKIremains unaddressed.

Opinión sobre la guía ESC 2021 sobre insuficiencia cardiaca. Una encuesta a 387 médicos

Introduction and objectivesOur aim was to assess the degree of acceptance of the European clinical practice guidelines (CPG) on heart failure (HF) among Spanish physicians. MethodsCross-sectional study conducted via a Google form, distributed by a group of HF experts from the Community of Madrid between November 2021 and February 2022, among specialists and residents of Cardiology, Internal Medicine and Primary Care from Spain. ResultsA total of 387 doctors participated (mean age 39.5±10.3 years, 45% women), from 128 centers (60% from the Community of Madrid and 40% from other regions). The most represented specialty was Cardiology (76%), followed by Internal Medicine (20%), and Primary Care (4%); 37% of them were HF physicians. On a scale of 1 to 10, participants scored the CPG with a mean of 7.7±1.3 points. The best valued aspect was the positioning of the quadruple therapy at the same level (192, 50%), and the majority considered necessary to develop specific protocols for its implementation (353, 91%). Management (adjustment of diuretics, monitoring, antidiabetics, etc.) of sodium-glucose co-transporter type 2 inhibitors (SGLT2i) in patients with HF and reduced left ventricular ejection fraction (LVEF) was positive among the participants, but a relatively low use in other scenarios was observed. ConclusionsAlthough the new CPG on HF have been well received, the need to develop clinical protocols to facilitate its implementation is detected. SGLT2i are managed on an outpatient basis in patients with HF and reduced LVEF, but there are clinical scenarios (hospitalization and preserved LVEF) where their use can be increased.

Repurposing of Empagliflozin as a Possible Treatment for Neutropenia and Inflammatory Bowel Disease in Glycogen Storage Disease Type Ib: A Case Report

Glycogen storage disease type Ib (GSD-Ib) is an autosomal-recessive inborn error of carbohydrate metabolism, where severe fasting hypoglycemia is associated (among other manifestations) with neutropenia and neutrophil dysfunction (predisposing to recurrent, potentially life-threatening infections) and inflammatory bowel disease (IBD). Granulocyte colony-stimulating factors (G-CSFs) are commonly used for its treatment. Although they have improved the prognosis of the disease, these medicines have also led to concerns about complications associated with their use (namely splenomegaly and hematopoietic malignancies), not to mention their increased cost. Recently, a novel new treatment for neutropenia associated with this disease was discovered. It was found that sodium-glucose cotransporter type 2 (SGLT-2) inhibitors, usually used for the treatment of diabetes mellitus, can ameliorate both neutropenia and IBD-related symptoms and improve the quality of life in patients suffering from these diseases. They do it by inhibiting the renal reabsorption of 1,5-anhydroglucitol, a dietary analog of glucose, whose accumulation due to the specific enzyme deficiency leads to toxic effects on granulocytes. Herein we report the treatment of an adult patient suffering from GSD-Ib with empagliflozin, an SGLT-2 inhibitor.

Revisiting diuretic choice in chronic kidney disease.

Existing guidelines offer little direction about the use of thiazide and loop diuretics in patients with chronic kidney disease (CKD). This review summarizes recent studies impacting indications and safety considerations for these agents in patients with CKD. Chlorthalidone reduces blood pressure compared to placebo in patients with advanced CKD, challenging the belief that thiazide diuretics lose efficacy at lower glomerular filtration rates (GFR). Existing studies show no clear impact of thiazide or loop diuretic use on kidney or cardiovascular outcomes in patients with CKD. Sodium-glucose co-transporter type 2 (SGLT2) inhibitors have diuretic effects, but concomitant use of a diuretic does not diminish the preventive benefits of these agents against acute kidney injury (AKI). Despite theoretical concerns, thiazide diuretics likely do not worsen circulating vasopressin levels or cyst progression in polycystic kidney disease and may be useful for alleviating polyuria from tolvaptan. Diuretics cause multiple adverse effects, including electrolyte abnormalities, hemodynamic-mediated decrease in estimated GFR, and AKI. Recent evidence supports expanded indications for diuretics in patients with kidney disease, including chlorthalidone for hypertension in advanced CKD. Monitoring electrolytes and estimated GFR is critical to ensure patient safety when prescribing these agents for patients with CKD.

Sodium-glucose Cotransporter Type 2 Inhibitors: A New Insight into the Molecular Mechanisms of Diabetic Nephropathy.

Diabetic nephropathy is one of the chronic microvascular complications of diabetes and is a leading cause of end-stage renal disease. Fortunately, clinical trials have demonstrated that sodium-glucose cotransporter type 2 inhibitors could decrease proteinuria and improve renal endpoints and are promising agents for the treatment of diabetic nephropathy. The renoprotective effects of sodium-glucose cotransporter type 2 inhibitors cannot be simply attributed to their advantages in aspects of metabolic benefits, such as glycemic control, lowering blood pressure, and control of serum uric acid, or improving hemodynamics associated with decreased glomerular filtration pressure. Some preclinical evidence suggests that sodium-glucose cotransporter type 2 inhibitors exert their renoprotective effects by multiple mechanisms, including attenuation of oxidative and endoplasmic reticulum stresses, anti-fibrosis and anti-inflammation, protection of podocytes, suppression of megalin function, improvement of renal hypoxia, restored mitochondrial dysfunction and autophagy, as well as inhibition of sodium-hydrogen exchanger 3. In the present study, the detailed molecular mechanisms of sodium-glucose cotransporter type 2 inhibitors with the actions of diabetic nephropathy were reviewed, with the purpose of providing the basis for drug selection for the treatment of diabetic nephropathy.

Prevention of Cardiorenal Complications with Sodium-Glucose Cotransporter Type 2 Inhibitors: A Narrative Review.

Heart failure (HF) and chronic kidney disease (CKD) are the most frequent first cardiorenal conditions in patients with type 2 diabetes (T2D), which can be exacerbated by other comorbidities, such as hypertension, dyslipidemia, and obesity. To improve their clinical outcomes, patients with T2D need to achieve and maintain glycemic targets, as well as prevent cardiorenal disease onset and progression. Several clinical trials evaluating the sodium–glucose cotransporter type 2 inhibitors (SGLT2i) dapagliflozin, empagliflozin, canagliflozin, and ertugliflozin have shown consistent risk reduction in major adverse cardiovascular events and/or hospitalization for HF, together with lower risk of kidney disease progression. The benefits associated with SGLT2i in T2D are distinct from other antihyperglycemic drugs since they have been proposed to exert pleiotropic metabolic and direct effects on the kidney and the heart. In this review, we summarize and discuss the evidence regarding the mechanisms of action, the efficacy and safety profiles, and the clinical guidelines on the use of the therapeutic class of SGLT2i, highlighting their role in cardiorenal prevention beyond glycemic control.

Review of SGLT2i for the Treatment of Renal Complications: Experience in Patients with and Without T2D

The management of type 2 diabetes (T2D) involves decreasing plasma glucose levels and reducing cardiovascular and microvascular complications. Diabetic kidney disease (DKD), defined as presence of albuminuria, impaired glomerular filtration, or both, is an insidious microvascular complication of diabetes that generates a substantial personal and clinical burden. The progressive reduction in renal function and increased albuminuria results in an increase of cardiovascular events. Thus, patients with DKD require exhaustive control of the associated cardiovascular risk factors. People with diabetes and renal impairment have fewer options of antidiabetic drugs because of contraindications, adverse effects, or altered pharmacokinetics. Sodium–glucose cotransporter type 2 inhibitors (SGLT2i) reduce blood glucose concentrations by blocking the uptake of sodium and glucose in the proximal tubule and promoting glycosuria, and these agents now have an important role in the management of T2D. The results of several cardiovascular outcomes trials suggested that SGLT2i are associated with improvements in renal endpoints in addition to their reduction in cardiovascular events and mortality, which represents a major advance in the care of this population. The dedicated kidney outcomes trials have confirmed the renoprotective action of SGLT2i across different glomerular filtration and albuminuria values, even in patients with non-diabetic chronic kidney disease. Notably, this improvement in kidney function may indirectly benefit cardiac function through multifaceted interorgan cross talk, which can break the cardiorenal vicious circle linked to T2D. In this article, we briefly review the different mechanisms of action that may explain the renal beneficial effects of SGLT2i and disclose the results of the key renal outcome trials and the subsequent update of related clinical guidelines.

Cell-Target-Specific Anti-Inflammatory Effect of Empagliflozin: In Vitro Evidence in Human Cardiomyocytes.

The antidiabetic sodium–glucose cotransporter type 2 inhibitor (SGLT2i) empagliflozin efficiently reduces heart failure (HF) hospitalization and cardiovascular death in type 2 diabetes (T2D). Empagliflozin-cardioprotection likely includes anti-inflammatory effects, regardless glucose lowering, but the underlying mechanisms remain unclear. Inflammation is a primary event in diabetic cardiomyopathy (DCM) and HF development. The interferon (IFN)γ-induced 10-kDa protein (IP-10/CXCL10), a T helper 1 (Th1)-type chemokine, promotes cardiac inflammation, fibrosis, and diseases, including DCM, ideally representing a therapeutic target. This preliminary study aims to explore whether empagliflozin directly affects Th1-challenged human cardiomyocytes, in terms of CXCL10 targeting. To this purpose, empagliflozin dose–response curves were performed in cultured human cardiomyocytes maintained within a Th1-dominant inflammatory microenvironment (IFNγ/TNFα), and CXCL10 release with the intracellular IFNγ-dependent signaling pathway (Stat-1) was investigated. To verify possible drug–cell-target specificity, the same assays were run in human skeletal muscle cells. Empagliflozin dose dependently inhibited CXCL10 secretion (IC50 = 76,14 × 10-9 M) in association with Stat-1 pathway impairment only in Th1-induced human cardiomyocytes, suggesting drug-selective cell-type-targeting. As CXCL10 plays multifaceted functions in cardiac remodeling toward HF and currently there is no effective method to prevent it, these preliminary data might be hypothesis generating to open new scenarios in the translational approach to SGLT2i-dependent cardioprotection.

C23 HOW TO IMPROVE ADHERENCE TO ESC HF GUIDELINES THE PONTE (PDTA FOR INTEGRATED FOLLOW–UP TERRITORY HOSPITAL OF THE PATIENT WITH CARDIAC HEART FAILURE) PROJECT

Abstract Background A careful and integrated follow up after hospitalization for heart failure (HF) may represent a feasible strategy to optimize the adherence to ESC guidelines and reduce the occurrence of adverse events (mortality, re–hospitalizations). Methods A strict integration between hospital and local health district proximity office cardiologist through an integrated clinical data sharing software has been implemented in Apulia region, Italy, in order to optimize the management of the HF patient after an hospitalization: the PONTE (PDTA FOR INTEGRATED FOLLOW–UP TERRITORY HOSPITAL OF THE PATIENT WITH CARDIAC HEART FAILURE) (bridge) project. As until December 2021, 1200 patients with HF have been enrolled in the project, both with reduced (HFrEF) and preserved ejection fraction (HFpEF). Adherence to ESC HF guidelines in HFrEF patients before vs after December 2020 was compared. Results In the HFrEF population (56%) the mean age was 63 years, 38% were hypertensive, 15% diabetic, 40% had ischemic heart disease, 42% were previously treated with coronary angioplasty, 56% had an ICD/CRT, 22% had atrial fibrillation. Mean NYHA class was 2.2, mean LVEF 30%, mean NT–proBNP values 4027 pg/mL, mean serum creatinine 1 mg/dL, 91% were taking beta–blockers (BB), 86% mineral corticoid receptor antagonists (MRA), 98% ACE–inhibitors/angiotensin–receptor–antagonists/neprilysin and angiotensin receptor antagonists (ACE/ARB/ARNI), and 13% ARNI. Compared to patients enrolled before 2020, ARNI prescription increased in 2021 (60% vs 13%, p < 0.001); in 30% ARNI were prescribed in hospital before discharge. Furthermore, in 10% of the population (most diabetics), sodium glucose cotransporter type 2 inhibitors (SGLT2i) have been prescribed as indicated by the latest ESC 2021 guidelines. Conclusions The implementation the PONTE project shows an improved adherence to ESC HF guidelines.

Empagliflozyna w niewydolności serca — przewodnik klinicysty

Empagliflozin belongs to the new class of drugs for the treatment of heart failure, sodium-glucose co-transporter type 2 inhibitors. Results of the EMPEROR-Reduced, EMPEROR-Preserved and EMPULSE trials confirmed the clinical benefits of empagliflozin over the whole spectrum of symptomatic heart failure. The present article provides clinicians with practical guidance regarding empagliflozin therapy in HF.