Sodium-glucose Transporter Type Research Articles

Nephroprotective and anticoagulant therapy in patients with atrial fibrillation and chronic kidney disease: real-world data

Aim. To assess the compliance of nephroprotective and anticoagulant therapy in patients with atrial fibrillation (AF) and chronic kidney disease (CKD) with modern clinical guidelines.Material and methods. The study included patients with CKD in combination with AF and in sinus rhythm. Clinical characteristics were retrospectively assessed, as were the use of renin-angiotensin system inhibitors (RASi), statins, sodium-glucose transporter type 2 inhibitors (SGLT-2i) and oral anticoagulants (OAC).Results. A total of 464 patients (aged 66-80 years) were divided retrospectively in two subgroups — with and without AF. AF was detected in 210 (45.3%) patients. Patients from the subgroup with AF were significantly older (75 vs 72 years, p=0.001), more often had type 2 diabetes mellitus (T2DM) (28.6% vs 20.5%, p=0.042), coronary artery disease (CAD) (40.5% vs 30.7%, p=0.028) and chronic heart failure (CHF). (57.6% vs 22.8%, p<0.001). Mean estimated glomerular filtration rate (eGFR) according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was lower (46 vs 51 ml/min/1.73 m2, p<0.001) in patients with AF compared with the group without AF. ACE inhibitors (ACEi) were prescribed in 127 cases (27.4%), angiotensin II receptor blockers (ARBs) — in 227 (49%), angiotensin receptor neprilysin inhibitor (ARNI) — 33 (7.1%), statins — 362 (78%), SGLT2i — 63 (13.6%), direct oral anticoagulants (DOACs) — 203 (43.8%) and warfarin — in 10 cases (2.2%). In those patients in whom SGLT2i was prescribed, eGFR according to the CKD-EPI equation was significantly lower (47 vs 49 ml/min/1.73 m2, p=0.043). In patients with T2DM, SGLT-2i-2 was prescribed in 33.9% of cases, in patients with chronic heart failure with reduced ejection fraction (CHFrEF) — in 68.4% of cases. In 196 patients with AF, DOACs were prescribed, in 10 cases — warfarin.Conclusion. Most patients with CKD receive nephroprotective therapy with RASi and statins according to current KDIGO guidelines. A significant proportion of patients with CHFrEF receive SGLT-2i, but only a third of patients with T2DM and CKD received SGLT-2i therapy.

Sodium glucose transporter 2 inhibitors: Will these drugs benefit non-diabetic veterinary patients with cardiac and kidney diseases?

Sodium glucose transporter type 2 (SGLT2) inhibitors have been introduced into human medicine where their beneficial effects go beyond the expected improvement in blood glucose control. These drugs appear to prevent progression of both cardiovascular and kidney diseases, not only in diabetic but also in non-diabetic human patients. As these drugs have received conditional approval for use in diabetic cats and are being used in other veterinary species, the intriguing question as to whether they will have similar cardioprotective and nephroprotective effects in dogs and cats is being asked. The primary mechanism(s) by which SGLT2 inhibitors are cardio- and nephroprotective remain to be fully characterized. This paper reviews these suggested mechanisms in the context of the pathophysiology of progressive cardiovascular and kidney diseases in dogs and cats with the goal of predicting which categories of non-diabetic veterinary patients these drugs might be of most benefit.

Advancements in diabetic kidney disease management: integrating innovative therapies and targeted drug development.

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease and affects approximately 40% of individuals with diabetes . Cases of DKD continue to rise globally as the prevalence of diabetes mellitus increases, with an estimated 415 million people living with diabetes in 2015 and a projected 642 million by 2040. DKD is associated with significant morbidity and mortality, representing 34% and 36% of all chronic kidney disease deaths in men and women, respectively. Common comorbidities including hypertension and ageing-related nephron loss further complicate disease diagnosis and progression. The progression of DKD involves several mechanisms including glomerular endothelial cell dysfunction, inflammation, and fibrosis. Targeting these mechanisms has formed the basis of several therapeutic agents. Renin-angiotensin-aldosterone system (RAAS) blockers, specifically angiotensin receptor blockers (ARBs), demonstrate significant reductions in macroalbuminuria. Sodium-glucose transporter type 2 (SGLT-2) inhibitors demonstrate kidney protection independent of diabetes control while also decreasing the incidence of cardiovascular events. Emerging agents including glucagon-like peptide 1 (GLP-1) agonists, anti-inflammatory agents like bardoxolone, and mineralocorticoid receptor antagonists show promise in mitigating DKD progression. Many novel therapies including monoclonal antibodies CSL346, lixudebart, and tozorakimab; mesenchymal stem/stromal cell infusion; and cannabinoid-1 receptor inverse agonism via INV-202 are currently in clinical trials and present opportunities for further drug development.

Innovations and applications of ketone body monitoring in diabetes care.

Ketone bodies, comprising β-hydroxybutyric acid (BHB), acetoacetate (AcAc), and acetone, play a vital role as essential energy substrates. In individuals with diabetes, ketone bodies can be elevated under various conditions, including diabetic ketoacidosis, use of sodium-glucose transporter type 2 (SGLT2) inhibitors, and extreme carbohydrate restriction. There are three methods for measuring ketone bodies. Urine ketone analysis (AcAc) is a standard clinical test, whereas blood ketone testing (BHB+AcAc) is valuable in identifying or resolving diabetic ketoacidosis. Recently, technology for measuring breath acetone has been introduced, which provides an easy means of monitoring ketogenic diets in obese individuals. The basic breath alcohol detector also reacts with breath acetone. Therefore, it is important for professional drivers taking SGLT2 inhibitors to be cautious as workplace breath alcohol detectors may show false-positive results. Conversely, if a positive result is obtained, a detailed examination of ketosis is necessary. This review provides an overview of ketone body measurements in individuals with diabetes.

#993 The molecular effects of SGLT2i (Empagliflozin) on α-Klotho and Nephrin/Podocin proteins in type II diabetic mice model

Abstract Background and Aims Type 2 diabetes mellitus (T2DM), especially hyperglycemia, is associated with increased glucose cell toxicity and oxidative stress that can lead to irreversible damage in the kidney such as diabetic nephropathy (DN). DN is one of the most common microvascular complications of diabetes and is the leading cause of end-stage renal disease (ESRD) and replacement therapy. Several works in the setting of early experimental diabetic nephropathy using the recent anti-diabetic drugs such as sodium-glucose transporter type 2 inhibitors in the prevention, development or amelioration of renal injury. The exact mechanisms, by which these drugs ameliorate glomerular injury from hyperglycemia, had not been clarified well. Klotho and Podocin-Nephrin proteins are an important proteins involved in the tubule-glomerular injury. The Klotho is a circulating anti-ageing hormone with anti-oxidative and anti-inflammatory properties with vascular protective effects in animal studies. Podocin & Nephrin are important component of the glomerular foot-process membrane, the slit-diaphragm. Recently, several experimental reports showed decreased α-Klotho, Nephrin and Podocin expression in different models of diabetic nephropathy. Method We used BTBR mouse strain with the ob/ob leptin-deficiency mutation, which develops T2DM with hyperglycemia and DN; C57/BL mice were the control (CON). EMPA was administrated to T2DM mice (T2DM+EMPA) via drinking water for 12 weeks. Blood parameters were measured repeatedly, and at sacrifice, mice kidneys were harvested for histological and biochemical analyses. We evaluated renal glomerular structure of Nephrin, Podocin and α-Klotho proteins expression. Results EMPA treatment reduced T2DM blood glucose vs C57 group (P < 0:01), and increase urine glucose in EMPA+DM group (P < 0:001) EMPA vs. C57BL/6 and DM). Histological analyses in kidney sections, revealed decreased α-Klotho expression in glomeruli of DM mice vs Control mice (15.95 ± 0.64 vs 36 ± 2.42, (P < 0:01), and restored back in DM+ EMPA mice vs control mice (27.64 ± 0.94 vs 15.95 ± 0.64, P < 0:01). Podocin expression in glomeruli: control mice 31.3 ± 3.7 VS DM mice 21.26 ± 1.22 and DM + EMPA mice 28.22 ± 0.50 VS DM mice 21.26 ± 1.22 Conclusion Hyperglycemia (DM type II) reduces Podocin-Nephrin and α-Klotho proteins expression in the glomeruli kidney and upregulated by EMPA treatment. SGLT2i (EMPA) treatment in DM patients can significantly reduce progression of DN and onset of ESRD probably through its effect on α-Klotho/Podocin-Nephrin proteins.

Hydrogen sulfide ameliorates senescence in vascular endothelial cells through ameliorating inflammation and activating PPARδ/SGLT2/STAT3 signaling pathway.

Mounting evidence demonstrates that hydrogen sulfide (H 2S) promotes anti-inflammatory molecules and inhibits pro-inflammatory cytokines in endothelial cells (ECs). This study aims to investigate the favorable action of H 2S on endothelial function in senescence by inhibiting the production of inflammatory molecules. Senescent ECs exhibit a reduction in H 2S, endothelial nitric oxide synthase (eNOS) and peroxisome proliferator-activated receptor δ (PPARδ), coupled with increased inflammatory molecules, sodium glucose transporter type 2 (SGLT2) and phosphorylation of STAT3, which could be reversed by the administration of a slow but sustained release agent of H 2S, GYY4137. Decreased production of eNOS and upregulated p-STAT3 and SGLT2 levels in senescent ECs are reversed by replenishment of the SGLT2 inhibitor EMPA and the PPARδ agonist GW501516. The PPARδ antagonist GSK0660 attenuates eNOS expression and increases the production of p-STAT3 and SGLT2. However, supplementation with GYY4137 has no beneficial effect on GSK0660-treated ECs. GYY4137, GW501516 and EMPA preserve endothelial-dependent relaxation (EDR) in D-gal-treated aortae, while GSK0660 destroys aortic relaxation even with GYY4137 supplementation. In summary, senescent ECs manifest aggravated the expressions of the inflammatory molecules SGLT2 and p-STAT3 and decreased the productions of PPARδ, eNOS and CSE. H 2S ameliorates endothelial dysfunction through the anti-inflammatory effect of the PPARδ/SGLT2/p-STAT3 signaling pathway in senescent ECs and may be a potential therapeutic target for anti-ageing treatment.

Right Ventricular Dysfunction and Exercise Impairment in Patients with Heart Failure, Insulin Resistance, and Diabetes Mellitus: Insights from the T.O.S.CA. Registry (Cardiovascular Diabetology 2022).

Insulin resistance (IR) and type 2 diabetes mellitus (T2D) are known to affect the progression of chronic heart failure (CHF), but little evidence exists about the impact of IR and T2D on right ventricular dysfunction and exercise tolerance. Insights from the T.O.S.C.A. Registry: Echocardiographic hallmarks and cardiopulmonary exercise test (CPET) results were evaluated at baseline and after an average time of 36 months. T2D patients exhibited a greater intraventricular septum (IVS) thickness (11 ± 2 mm, 10 ± 2 mm, 10 ± 2 mm, in T2D, IR, and EU, respectively; p<.05) and LV wall thickness (0.34 ± 0.1, 0.32 ± 0.1, and 0.32 ± 0.1, in T2D, IR, and EU, respectively; p<.05). Moreover, T2D patients exhibited worse LV filling dynamics with larger left atrial volume index compared to IR and EU. Right ventricle dysfunction, expressed as a lower TAPSE/PASP ratio, was found in T2D [0.52(0.32-0.72)] than in EU and IR [0.60(0.30-0.90); p<.05]. T2D patients showed a significantly lower VO2 max peak when compared to IR and EU patients (15.8 ± 3.8 vs. 16.5 ± 4.3 vs. 18.4 ± 4.3 ml/Kg/min; p<.003), with an inverse relationship between the HOMAIR classes and VO2 max. Right ventricle structure and function deteriorated more rapidly in T2D, as suggested by more relevant deterioration in TAPSE/PASP ratio (-10% in EU patients, -14% in IR patients, -21% in T2D; p<.05). The study findings suggest that the right ventricle structure, function, and cardiopulmonary performance deteriorate with IR and, more evidently, due to chronic exposure to hyperglycemia in T2D. Impaired exercise tolerance, poor cardiorespiratory fitness, diastolic dysfunction, and left atrial enlargement predispose patients to poor quality of life, suboptimal adherence to physical activity, and an overall increase in the risk of all-cause and cardiovascular mortality. In addition, chronic hyperglycemia accelerates the progression of these alterations, especially in patients with poor glycemic control over time. Highly selective and even more non-selective sodium glucose transporter type 2 inhibitors and glucagon-like peptide 1 receptor agonists should be considered as the first-line therapy for improving CV outcomes in T2D and CHF. Further studies are needed to understand the role of these molecules in treating pre-clinical conditions, such as IR and metabolic syndrome.

RF16 | PSUN335 Clinical Effects of Sodium Glucose Transporter Type 2 Inhibitors in Patients with Severe Insulin Resistance

Abstract Background Severe insulin resistance syndromes including lipodystrophy and pathogenic variants in the insulin receptor (INSR) lead to diabetes that is challenging to control. Oral antidiabetic agents have been used to control hyperglycemia, however the efficacy of these treatments has not been studied systematically. This study explores safety and efficacy of sodium glucose cotransporter 2 inhibitors (SGLT2i) in these patients. Methods This was a retrospective chart-review assessing safety (N=31) and efficacy (N=18) of SGLT2i use in patients with clinically or genetically confirmed diagnosis of lipodystrophy or INSR pathogenic variants at our institute. Efficacy outcomes included HbA1c, insulin dose, C-peptide, fasting insulin and 24-hour urine glucose at 12 months and throughout follow-up from 2 to 24 months. Glycemic parameters were analyzed as change from baseline (prior to SGLT2i) adjusted for baseline values after 12 months of SGLT2i and across all timepoints using linear mixed models with post-hoc Dunnett-adjusted comparison of each time point compared to baseline. For HbA1c, additional models were conducted including change in insulin dose as a covariate. Results HbA1c did not significantly change after 1 year of SGLT2i (baseline 9.5±2.5 [80.3±27.7]; 12 months 8.8±2.3% [72.6±25.3 mmol/mol]; p=0.093), or across all time points (p=0.11). However, most patients (83%) were taking insulin, and SGLT2i treatment led to 35% reduction in total daily dose of insulin after 12 months (baseline 186 [100,1010]; 12 months 120 [75,260] units/day; p=0.07) and across all visits (p=0.035), which may have mitigated the reduction in HbA1c. Reduction in HbA1c was significant after adjustment for changes in insulin dose over time (p=0.0498). No significant change was noted in C-peptide, however fasting insulin decreased after 12 months (p=0.021) and across all visits (p=0.005). Urinary glucose excretion increased greater than 5-fold after 12 months of SGLT2i, to over 80 grams per day after 1 year (p=0.04). Adverse effects occurring in &amp;gt;1 subject included hypoglycemia, fungal infections, and extremity pain. Conclusions SGLT2i reduced insulin dose, insulinemia, and insulin dose-adjusted HbA1c in patients with severe insulin resistance, with a similar safety profile compared to type 2 diabetes. SGLT2i use may lead to overall better glycemic control and should be considered as part of the treatment armamentarium for these rare forms of diabetes, but larger trials are needed to confirm these findings. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 12:36 p.m. - 12:41 p.m.

PSUN249 Starvation Ketoacidosis as the Presenting Finding of Glycogen Storage Disorder Type III

Abstract A 30-year woman with a history of heart transplantation and a history of post-transplant diabetes mellitus presents with severe euglycemic ketoacidosis. Initial concern was for diabetes related ketoacidosis given history of diabetes however blood glucose was within goal range in the absence of pregnancy and use of sodium glucose transporter type 2 inhibitor use. Initial laboratory evaluation showed a serum glucose of 177 mg/dL, a serum beta hydroxybutyrate of greater than 12.66 mmol/L, serum lactate of 0.6 mmol/L, with a calculated anion gap of greater than 30 mmol/L. C-peptide levels were repeatedly normal and appropriate for blood glucose level ranging between 2.8 ng/mL and 7.5 ng/mL ruling out insulin deficiency as causative. It was discovered that the patient had intentionally fasted for greater than 18 hours and thus had not used the premixed insulin regimen prescribed. Metabolic disturbance corrected with a dextrose and insulin infusion. Evaluation for inborn error of metabolism showed: acylcarnitine panel returned normal making an inborn error of fatty acid metabolism unlikely. The mitochondrial DNA mutation panel was negative for point mutations or deletions. Further testing for urinary organic acids did not reveal elevation of 3-hydroxybutyric acid suggesting SCOT enzyme levels were sufficient in our patient. Review of pathology records for heart transplantation completed for idiopathic cardiomyopathy 20 years prior to this presentation showed high levels of glycogen deposition prompting evaluation for glycogen storage disorders. Results revealed a heterozygous abnormality at exon 9 of the AGL gene; AGL gene c.1139A&amp;gt;G (p.Glu380Gly). This is not a reported pathologic mutation, and given the heterozygosity of the mutation in this autosomal recessive condition, it is felt that either environmental factors or the presence of other unrecognized genetic mutations allowed for the phenotypic expression of GSDIII with euglycemic starvation ketoacidosis. The patient was treated with dietary counseling regarding ketone suppression with basal insulin during periods of fasting and preference to avoid periods of prolonged fasting with frequent carbohydrate-containing meals. Conclusion This case represents a novel, potentially pathologic defect in the AGL gene. This finding should prompt further investigations into genetic variabilities that may lead to this phenotypic expression. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

The Role of the Non-Steroidal Mineralocorticoid Antagonist Finerenone in Cardiorenal Management.

Finerenone is a novel, non-steroidal mineralocorticoid receptor antagonist (MRAs) that has been investigated for the management of cardiorenal conditions. This article provides an overview of recent evidence of benefits on cardiovascular (CV) outcomes. The recently published phase III FIDELIO-DKD and FIGARO-DKD, alone and pooled, in patients with CKD and diabetes demonstrate that finerenone reduces the composite of CV death, non-fatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure (HF) with hospitalization for HF being the primary driver of this composite. Finerenone is indicated to reduce renal and CV outcomes in patients with CKD and diabetes. Future investigations of this agent include patients with non-diabetic CKD, HF with preserved ejection fraction, and with the use of sodium-glucose transporter type 2 inhibitors.

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&lt;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 &lt; 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 &gt; 0.05). While in the control group, FRK increased by 1.1 times (p &gt; 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.

Clinical Effects of Sodium-Glucose Transporter Type 2 Inhibitors in Patients With Partial Lipodystrophy

ObjectiveSevere insulin resistance syndromes, such as lipodystrophy, lead to diabetes, which is challenging to control. This study explored the safety and efficacy of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in a series of 12 patients with severe insulin resistance due to partial lipodystrophy. MethodsA retrospective chart review of the safety (N = 22) and efficacy (N = 12) of SGLT2is in patients with partial lipodystrophy was conducted at our institution. The efficacy outcomes included hemoglobin A1C level, insulin dose, fasting plasma glucose level, C-peptide level, lipid profile, 24-hour urinary glucose excretion, estimated glomerular filtration rate, and blood pressure before and after 12 months of SGLT2i treatment. ResultsThe hemoglobin A1C level decreased after SGLT2i treatment (at baseline: 9.2% ± 2.0% [77.0 ± 21.9 mmol/mol]; after 12 months: 8.4% ± 1.8% [68.0 ± 19.7 mmol/mol]; P = .028). Significant reductions were also noted in systolic (P = .011) and diastolic blood pressure (P = .013). There was a trend toward a decreased C-peptide level (P = .071). The fasting plasma glucose level, lipid level, and estimated glomerular filtration rate remained unchanged. The adverse effects included extremity pain, hypoglycemia, diabetic ketoacidosis (in a patient who was nonadherent to insulin), pancreatitis (in a patient with prior pancreatitis), and fungal infections. ConclusionSGLT2is reduced the hemoglobin A1C level in patients with partial lipodystrophy, with a similar safety profile compared with that in patients with type 2 diabetes. After individual consideration of the risks and benefits of SGLT2is, these may be considered a part of the treatment armamentarium for these rare forms of diabetes, but larger trials are needed to confirm these findings.

Sodium Glucose Cotransporter-2 Inhibitors: Spotlight on Favorable Effects on Clinical Outcomes beyond Diabetes.

Sodium glucose transporter type 2 (SGLT2) molecules are found in proximal tubules of the kidney, and perhaps in the brain or intestine, but rarely in any other tissue. However, their inhibitors, intended to improve diabetes compensation, have many more beneficial effects. They improve kidney and cardiovascular outcomes and decrease mortality. These benefits are not limited to diabetics but were also found in non-diabetic individuals. The pathophysiological pathways underlying the treatment success have been investigated in both clinical and experimental studies. There have been numerous excellent reviews, but these were mostly restricted to limited aspects of the knowledge. The aim of this review is to summarize the known experimental and clinical evidence of SGLT2 inhibitors’ effects on individual organs (kidney, heart, liver, etc.), as well as the systemic changes that lead to an improvement in clinical outcomes.

Inhibitors of the sodium-glucose transporter type 2 and new possibilities for managing vascular age in patients with type 2 diabetes mellitus

The article discusses the pathophysiological mechanisms of the development of vascular aging as a combination of the influence on the body of genetic, environmental, regulatory, metabolic and other factors causing biochemical, enzymatic and cellular changes in the arterial vascular bed. The concept of “early vascular aging” and “healthy vascular aging” is defined depending on the ratio of the biological and chronological age of the vessels. The role of diabetes mellitus in increasing vascular stiffness, early vascular aging, as well as the progression of atherosclerotic cardiovascular diseases and their complications is considered in detail. Approaches to multifactorial management of vascular age in patients with type 2 diabetes (lifestyle modification with strategy of aggressive treatment of modifiers of atherosclerosis, rejection of bad habits, adherence to dietary recommendations and the use of modern organo- and vasoprotective antidiabetic drugs) are revealed. The mechanism of realization of vasoprotective effects of inhibitors of sodium-glucose transporter-2 (iNGLT-2) is described in detail. The results of completed large random ized trials EMPA-REG Outcome and EMPA-REG BP of the most studied representative of the IGLT-2 group, empagliflozin, are presented. It has been shown that due to their glucose and natriuretic effects, the ability to reduce body weight and blood pressure, improve myocardial metabolism and bioenergetics, decrease the activity of the sympathetic nervous system, as well as positive effects on vascular stiffness, NGLT-2 inhibitors are the drugs of choice in patients with type 2 diabetes mellitus (T2DM) and cardiovascular diseases. This makes it possible to widely use this group of drugs for managing the vascular age of patients and represents a new opportunity in the prevention of vascular aging in T2DM.

Mechanisms of SGLT2 (Sodium-Glucose Transporter Type 2) Inhibition-Induced Relaxation in Arteries From Human Visceral Adipose Tissue.

As novel drug treatments for diabetes have shown favorable cardiovascular effects, interest has mounted with regard to their possible vascular actions, particularly in relation to visceral adipose tissue perfusion and remodeling in obesity. The present study tested the vasorelaxing effect of the SGLT2 (sodium-glucose transporter type 2) inhibitor canagliflozin in arteries from visceral adipose tissue of either nonobese or obese humans and investigated the underlying mechanisms. Also, the vasorelaxing effect of canagliflozin and the GLP-1 (glucagon-like peptide 1) agonist liraglutide were compared in arteries from obese patients. To these purposes, small arteries (116-734 μm) isolated from visceral adipose tissue were studied ex vivo in a wire myograph. Canagliflozin elicited a higher concentration-dependent vasorelaxation in arterioles from obese than nonobese individuals (P=0.02). The vasorelaxing response to canagliflozin was not modified (P=0.93) by inhibition of nitric oxide synthase (L-NAME) or prostacyclin (indomethacin), or by H2O2 scavenging (catalase); also, canagliflozin-induced relaxation was similar (P=0.23) in endothelium-intact or -denuded arteries precontracted with high potassium concentration, thereby excluding an involvement of endothelium-derived hyperpolarizing factors. The vasorelaxing response to canagliflozin was similar to that elicited by the Na+/H+ exchanger 1 inhibitor BIX (P=0.67), but greater than that to the Na+/Ca++ exchanger inhibitor SEA 0400 (P=0.001), hinting a role of Na+/H+ exchanger inhibition in canagliflozin-induced relaxation. In arterioles from obese patients, the vasorelaxing response to canagliflozin was greater than that to liraglutide (P=0.004). These findings demonstrate that canagliflozin induces endothelium-independent vasorelaxation in arterioles from human visceral adipose tissue, thereby suggesting that SGLT2 inhibition might favorably impact the processes linking visceral adipose burden to vascular disease in obesity.

Highlights in heart failure.

Heart failure (HF) remains a major cause of mortality, morbidity, and poor quality of life. It is an area of active research. This article is aimed to give an update on recent advances in all aspects of this syndrome. Major changes occurred in drug treatment of HF with reduced ejection fraction (HFrEF). Sacubitril/valsartan is indicated as a substitute to ACEi/ARBs after PARADIGM‐HF (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.73 to 0.87 for sacubitril/valsartan vs. enalapril for the primary endpoint and Wei, Lin and Weissfeld HR 0.79, 95% CI 0.71–0.89 for recurrent events). Its initiation was then shown as safe and potentially useful in recent studies in patients hospitalized for acute HF. More recently, dapagliflozin and prevention of adverse‐outcomes in DAPA‐HF trial showed the beneficial effects of the sodium–glucose transporter type 2 inhibitor dapaglifozin vs. placebo, added to optimal standard therapy [HR, 0.74; 95% CI, 0.65 to 0.85;0.74; 95% CI, 0.65 to 0.85 for the primary endpoint]. Trials with other SGLT 2 inhibitors and in other patients, such as those with HF with preserved ejection fraction (HFpEF) or with recent decompensation, are ongoing. Multiple studies showed the unfavourable prognostic significance of abnormalities in serum potassium levels. Potassium lowering agents may allow initiation and titration of mineralocorticoid antagonists in a larger proportion of patients. Meta‐analyses suggest better outcomes with ferric carboxymaltose in patients with iron deficiency. Drugs effective in HFrEF may be useful also in HF with mid‐range ejection fraction. Better diagnosis and phenotype characterization seem warranted in HF with preserved ejection fraction. These and other burning aspects of HF research are summarized and reviewed in this article.

Liraglutide vs. lixisenatide in obese type 2 diabetes mellitus patients: What effect should we expect in routine clinical practice?

AimLiraglutide and lixisenatide improved glycemic control, weight and cardiovascular risk factors (CVRF) in type 2 diabetes mellitus (T2DM) patients. Our objective was to analyze clinical efficacy and safety differences in routine clinical practice. MethodsA 24-week prospective observational study to compare the effect of liraglutide versus lixisenatide in obese T2DM patients in routine clinical practice. The main objective was to analyze between-group glycosylated hemoglobin (HbA1c) differences at the end of the study. Secondary objectives included differences in body weight, other CVRF, changes in medication, side effects, satisfaction and safety. ResultsA total of 100 patients (50 liraglutide, 50 lixisenatide) were included. Both groups experienced a decrease in HbA1c values (liraglutide, −1.4%, CI 95% −2, −0.8, P < 0.001 vs. lixisenatide, −0.8%, 95% CI −1.2, −0.5, P < 0.001). No differences were found in final HbA1c values between both groups (liraglutide 7.3 ± 0.9% vs. lixisenatide 7.2 ± 1.5%, P = 0.7). We did not detect between groups differences in anthropometric variables or CVRF at the study end. A lower proportion of patients received treatment with a maximum dose of liraglutide compared with lixisenatide (27% vs. 95%, P < 0.001). In contrast, a greater percentage of patients in the lixisenatide group than in liraglutide group (29% vs. 9%, P = 0.026) intensified treatment by the addition of sodium-glucose transporter type 2 inhibitors. Adverse events were less frequently reported in liraglutide treated patients compared with lixisentatide (80% vs. 96%, P = 0.014). No serious adverse events were detected. ConclusionsThese results confirm the efficacy and safety of liraglutide and lixisenatide in routine clinical practice. Moreover, a different therapeutic effect between liraglutide and lixisenatide was detected.

Structural biology workflow for the expression and characterization of functional human sodium glucose transporter type 1 in Pichia pastoris

Heterologous expression of human membrane proteins is a challenge in structural biology towards drug discovery. Here we report a complete expression and purification process of a functional human sodium/D-glucose co-transporter 1 (hSGLT1) in Pichia pastoris as representative example of a useful strategy for any human membrane protein. hSGLT1 gene was cloned in two different plasmids to develop parallel strategies: one which includes green fluorescent protein fusion for screening optimal conditions, and another for large scale protein production for structural biology and biophysics studies. Our strategy yields at least 1 mg of monodisperse purified recombinant hSGLT1 per liter of culture, which can be characterized by circular dichroism and infrared spectroscopy as an alpha-helical fold protein. This purified hSGLT1 transports co-substrates (Na+ and glucose) and it is inhibited by phlorizin in electrophysiological experiments performed in planar lipid membranes.

Activation of c-Jun N-terminal kinase and p38 after cerebral ischemia upregulates cerebral sodium-glucose transporter type 1

Cerebral ischemic stress increases cerebral sodium-glucose transporter type 1 (SGLT-1). However, the mechanism by which cerebral ischemia leads to the up-regulation of SGLT-1 remains unclear. In peripheral tissue, the activation of mitogen-activated protein kinases (MAPKs) increases SGLT-1. MAPK pathways [c-Jun N-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated protein kinase (ERK)] are activated by cerebral ischemic stress. Therefore, we confirmed the involvement of MAPKs in the up-regulation of cerebral SGLT-1 after cerebral ischemia. Male ddY mice were subjected to middle cerebral artery occlusion (MCAO). Protein expression was assessed by western blotting. Mice received an intracerebroventricular (i.c.v.) injection of SP600125 (JNK inhibitor), SB203580 (p38 inhibitor), and PD98059 (MEK inhibitor) immediately after reperfusion. The infarction and behavioral abnormalities were assessed on days 1 and 3 after MCAO. The MAPK inhibitors suppressed the activation of JNK, p38, and ERK 3 h after MCAO. SP600125 and SB203580 administration ameliorated cerebral ischemic neuronal damage, whereas PD98059 administration exacerbated cerebral ischemic neuronal damage. SP600125 and SB203580 significantly suppressed the increase in SGLT-1 12 h after MCAO. PD98059 had no effect on SGLT-1 expression after MCAO. Our results indicate that the activation of JNK and p38 participate in the up-regulation of cerebral SGLT-1 after MCAO.

Dapagliflozin attenuates human vascular endothelial cell activation and induces vasorelaxation: A potential mechanism for inhibition of atherogenesis.

Sodium glucose transporter type 2 inhibitors may reduce cardiovascular events in type 2 diabetes. Our study aimed to determine the effect of the sodium glucose transporter type 2 inhibitor dapagliflozin on endothelial cell activation, vasoreactivity and atherogenesis using in vitro and in vivo models and identify associated molecular mechanisms. In vitro studies utilised human vascular endothelial cells stimulated with tumour necrosis factor α or hyperglycaemic conditions. In vivo studies were performed in C57Bl/6J mice to evaluate direct vasorelaxation responses evoked by acute dapagliflozin administration and acute vaso-protective effects of dapagliflozin on hyperglycaemia-induced endothelial dysfunction. Adult and aged Apolipoprotein E-deficient mice maintained on a high-fat diet were used to investigate endothelial-dependent vascular reactivity and atherogenesis. Dapagliflozin treatment (1.0 mg/kg/day) was administered for 4 weeks. In vitro studies demonstrated dapagliflozin-mediated attenuation of tumour necrosis factor α- and hyperglycaemia-induced increases in intercellular adhesion molecule-1, vascular cell adhesion molecule-1, plasminogen activator inhibitor type 1 and NFκB expression. Acute dapagliflozin administration dose-dependently induced endothelium-independent vasorelaxation. Chronic dapagliflozin treatment improved endothelial function and significantly reduced in vivo vascular adhesion molecule and phospho-IκB expression together with macrophage vessel wall infiltration. These observations identify a potential role for dapagliflozin in the attenuation of atherogenesis and identify anti-inflammatory molecular mechanisms associated with these effects.