Glucose Cotransporter Research Articles

Sodium- glucose cotransporter inhibitors and the brain

Diabetes mellitus (DM) is associated with an increased risk of stroke and cognitive impairment. The problem of preventing cerebral disorders in diabetes has not been solved. The review presents current data on the place and role of sodium-glucose cotransporters (SGLTs) in the brain, whose receptors play an important role in ischemia-reperfusion injury of the brain and neurodegenerative changes. Modern studies on the cerebroprotective effects of hypoglycemic drugs – SGLT inhibitors – are presented and summarized.

Chitosan oligosaccharide improves intestinal function by promoting intestinal development, alleviating intestinal inflammatory response, and enhancing antioxidant capacity in broilers aged d 1 to 14

This study was conducted to investigate the effects of chitosan oligosaccharide (COS) supplementation on intestinal development and functions, inflammatory response, antioxidant capacity and the related signaling pathways in broilers aged d 1 to 14. A total of 240 one-day old male Arbor Acres broilers (40.47 ± 0.30 g) were randomly allotted to 4 groups, and each group consisted of 6 replicate pens with 10 broilers per replicate. Broilers fed a basal diet supplementation with COS at 0 (CON group), 200 (COS200 group), 400 (COS400 group), and 800 mg/kg (COS800 group) for 14 d, respectively. Broilers in the COS supplementation groups had no significant effects on growth performance. Compared to the CON group, dietary COS supplementation increased (P < 0.05) the relative weight of duodenum, jejunal lipase activity, duodenal and ileal villus surface area, and lower (P < 0.05) ileal amylase and alkaline phosphatase activity, and crypt depth. The expression level of duodenal glucose transporter 1 (GLUT1), Na+-glucose cotransporter 1 (SGLT1), peptide transporter 1 (PepT1), occludin, zonula occludens-1 (ZO-1), toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and interleukin-10 (IL-10), jejunal SGLT1, PepT1, occludin, tumor necrosis factor-α (TNF-α), and ileal SGLT1, PepT1, and fatty acid binding protein 1 (FABP1) was upregulated by COS. However, the expression level of duodenal FABP1 and TNF-α, jejunal GLUT1, ZO-1, TLR4, MyD88, nuclear factor kappa-B p65 (NF-κB p65), and IL-1β, and ileal GLUT1, NF-κB p65, and IL-1β was downregulated by COS. Furthermore, dietary COS supplementation increased duodenal catalase (CAT), glutathione peroxidase (GSH-Px), and total superoxide dismutase (T-SOD) activity, jejunal CAT and T-SOD activity, upregulated the expression level of duodenal nuclear factor-erythroid 2-related factor 2 (Nrf2), CAT, glutathione peroxidase 1 (GPX1), and copper and zinc superoxide dismutase (Cu/Zn SOD), jejunal CAT, and ileal Nrf2, CAT, and GPX1. These results suggested that COS could promote intestinal development and functions in broilers aged d 1 to 14, which might be mediated by alleviating intestinal inflammatory response and enhancing antioxidant capacity.

Fluid homeostatic action of dapagliflozin in patients with chronic kidney disease: the DAPA-BODY Trial.

Sodium glucose cotransporter 2 (SGLT2) inhibitors have both glucose-lowering and diuretic effects. We recently reported that the SGLT2 inhibitor dapagliflozin exerts short-term fluid homeostatic action in patients with chronic kidney disease (CKD). However, the long-term effects of SGLT2 inhibitors on body fluid status in patients with CKD remain unclear. This was a prospective, non-randomized, open-label study that included a dapagliflozin treatment group (n = 73) and a control group (n = 24) who were followed for 6 months. Body fluid volume was measured using a bioimpedance analysis device. The extracellular water-to-total body water ratio (ECW/TBW), a predictor of renal outcomes, was used as a parameter for body fluid status (fluid retention, 0.400 ≤ ECW/TBW). Six-month treatment with dapagliflozin significantly decreased ECW/TBW compared with the control group (-0.65% ± 2.03% vs. 0.97% ± 2.49%, p = 0.0018). Furthermore, dapagliflozin decreased the ECW/TBW in patients with baseline fluid retention, but not in patients without baseline fluid retention (-1.47% ± 1.93% vs. -0.01% ± 1.88%, p = 0.0017). Vasopressin surrogate marker copeptin levels were similar between the control and dapagliflozin groups at 6 months (32.3 ± 33.4 vs. 30.6 ± 30.1 pmol/L, p = 0.8227). However, dapagliflozin significantly increased the change in copeptin levels at 1 week (39.0% ± 41.6%, p = 0.0010), suggesting a compensatory increase in vasopressin secretion to prevent hypovolemia. Renin and aldosterone levels were similar between the control and dapagliflozin groups at 6 months, while epinephrine and norepinephrine (markers of sympathetic nervous system activity) were significantly lower in the dapagliflozin group than in the control group. In conclusion, the SGLT2 inhibitor dapagliflozin ameliorated fluid retention and maintained euvolemic fluid status in patients with CKD, suggesting that SGLT2 inhibitors exert sustained fluid homeostatic actions in patients with various fluid backgrounds. Clinical trial registration: https://www.umin.ac.jp/ctr/, identifier [UMIN000048568].

Comparisons of clinical outcomes between newly diagnosed early- and late-onset T2DM: a real-world study from the Shanghai Hospital Link Database.

The aim of this study was to compare the differences in incident population, comorbidities, and glucose-lowering drug prescriptions between newly diagnosed patients with early-onset type 2 diabetes mellitus (T2DM) and those with late-onset T2DM to provide real-world evidence for clinical practice. This study was based on the Shanghai Hospital Link Database (SHLD). Anonymized electronic medical record (EHR) data from 2013 to 2021 were included in this study. Newly diagnosed patients with T2DM were defined as those without related diagnostic records or glucose-lowering medicine prescriptions in the past 3 years. Early-onset T2DM was defined as patients who were aged 18-40 years old at the first visit for T2DM to represent those who were born after the 1980s. And late-onset T2DM was defined as those aged 65-80 years old to represent those who were born in a relatively undeveloped period. Descriptive statistical analyses were performed to describe their incidence number, glucose-lowering drug prescriptions, and comorbidities at the first visit to the hospital between two T2DM groups. There were a total of 35,457 newly diagnosed patients with early-onset T2DM and 149,108 newly diagnosed patients with late-onset T2DM included in this study. Patients with late-onset T2DM constituted the majority and their number increased by 2.5% on average by years, while the number of patients with early-onset T2DM remained stable each year. Compared with late-onset T2DM patients, more early-onset T2DM patients had dyslipidemia at the first visit to hospitals (9.5% vs 7.7%, P < 0.01) despite their significant age differences. Patients with early-onset T2DM were more likely to use metformin (74.8% vs 46.5, P < 0.01), dipeptidyl peptidase-4 inhibitors (DDP-4i) (16.7% vs 11.2%, P < 0.01), thiazolidinediones (TZD) (14.9% vs 8.4%, P < 0.01), sodium glucose cotransporter 2 inhibitors (SGLT2-i) (0.8% vs 0.3%, P < 0.01), and glucagon-like peptide 1 receptor agonists (GLP-1 RA) (3.7% vs 0.5%, P < 0.01) at their first visit to the hospital. Different characteristics were observed between patients with early-onset T2DM and those with late-onset T2DM. Compared with patients with late-onset T2DM, those with early-onset T2DM were more prone to dyslipidemia and had novel organ-protective drugs prescribed.

Effects of monosaccharides including rare sugars on proliferation of Entamoeba histolytica trophozoites in vitro.

Entamoeba histolytica is a parasitic protozoan with roles in pathogenicity of intestinal amoebiasis. E. histolytica trophozoites lack functional mitochondria and their energy production depends mostly on glycolysis. D-Glucose has a pivotal role in this process and trophozoites store this sugar as glycogen in glycogen granules. Rare sugars, which are defined as sugars present in nature in limited amounts, are of interest as natural low-calorie sweeteners for improving physical conditions of humans. One such rare sugar, D-allose, can be absorbed by a sodium-dependent glucose cotransporter as a substitute for D-glucose, and some rare sugars are known to inhibit growth of cancer cells, Caenorhabditis elegans and Tritrichomonas foetus. Based on these observations, we examined the effects of rare sugars on growth of E. histolytica trophozoites, together with those of D-galactose and D-fructose. The results indicate that treatment with D-allose or D-psicose (D-allulose) alone inhibits proliferation of E. histolytica trophozoites, but that these sugars enhance proliferation of trophozoites in the presence of D-glucose or D-galactose. The trophozoites could take up D-glucose and D-galactose, but not D-fructose, D-allose or D-psicose. Cell sizes of the trophozoites also differed depending on the culture medium.

Tetrazoles and Related Heterocycles as Promising Synthetic Antidiabetic Agents.

Tetrazole heterocycle is a promising scaffold in drug design, and it is incorporated into active pharmaceutical ingredients of medications of various actions: hypotensives, diuretics, antihistamines, antibiotics, analgesics, and others. This heterocyclic system is metabolically stable and easily participates in various intermolecular interactions with different biological targets through hydrogen bonding, conjugation, or van der Waals forces. In the present review, a systematic analysis of the activity of tetrazole derivatives against type 2 diabetes mellitus (T2DM) has been performed. As it was shown, the tetrazolyl moiety is a key fragment of many antidiabetic agents with different activities, including the following: peroxisome proliferator-activated receptors (PPARs) agonists, protein tyrosine phosphatase 1B (PTP1B) inhibitors, aldose reductase (AR) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists, G protein-coupled receptor (GPCRs) agonists, glycogen phosphorylases (GP) Inhibitors, α-glycosidase (AG) Inhibitors, sodium glucose co-transporter (SGLT) inhibitors, fructose-1,6-bisphosphatase (FBPase) inhibitors, IkB kinase ε (IKKε) and TANK binding kinase 1 (TBK1) inhibitors, and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In many cases, the tetrazole-containing leader compounds markedly exceed the activity of medications already known and used in T2DM therapy, and some of them are undergoing clinical trials. In addition, tetrazole derivatives are very often used to act on diabetes-related targets or to treat post-diabetic disorders.

Association of Continued Use of SGLT2 Inhibitors From the Ambulatory to Inpatient Setting With Hospital Outcomes in Patients With Diabetes: A Nationwide Cohort Study.

Limited data are available on the continuation of outpatient sodium glucose cotransporter 2 inhibitors (SGLT2is) during hospitalization. The objective was to evaluate associations of SGLT2i continuation in the inpatient setting with hospital outcomes. This nationwide cohort study used Veterans Affairs health care system data of acute care hospitalizations between 1 April 2013 and 31 August 2021. A total of 36,505 admissions of patients with diabetes with an outpatient prescription for an SGLT2i prior to hospitalization were included. The exposure was defined as SGLT2i continuation during hospitalization. Admissions where SGLT2i was continued were compared with admissions where it was discontinued. The primary outcome was in-hospital mortality. Secondary outcomes were acute kidney injury (AKI) and length of stay (LOS). Negative binomial propensity score-weighted and zero-truncated analyses were used to compare outcomes and adjusted for multiple covariates, including demographics and comorbidities. Mean (SE) age was 67.2 (0.1) and 67.5 (0.1) years (P = 0.03), 97.0% and 96.6% were male (P = 0.1), 71.3% and 72.1% were White, and 20.8% and 20.5% were Black (P = 0.52) for the SGLT2i continued and discontinued groups, respectively. After adjustment for covariates (age, sex, race, BMI, Elixhauser comorbidity index, procedures/surgeries, and insulin use), the SGLT2i continued group had a 45% lower mortality rate (incidence rate ratio [IRR] 0.55, 95% CI 0.42-0.73, P < 0.01), no difference in AKI (IRR 0.96, 95% CI 0.90-1.02, P = 0.17), and decreased LOS (4.7 vs. 4.9 days) (IRR 0.95, 95% CI 0.93-0.98, P < 0.01) versus the SGLT2i discontinued group. Similar associations were observed across multiple sensitivity analyses. Continued SGLT2i during hospitalization among patients with diabetes was associated with lower mortality, no increased AKI, and shorter LOS.

Abstract #1608339: Sodium–Glucose Co-transporter 2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists, Efficacy and Safety in Diabetic Kidney Transplant Recipients

Abstract #1608339: Sodium–Glucose Co-transporter 2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists, Efficacy and Safety in Diabetic Kidney Transplant Recipients

Ligand-Based and Structure-Based Virtual Screening of New Sodium Glucose Cotransporter Type 2 Inhibitors.

Diabetes mellitus is a metabolic disease that causes multiple complications and common comorbidities, which decreases the quality of life for people affected by the disease. Sodium glucose cotransporter type 2 (SGLT2) reabsorbs 90% of glucose in the kidneys; therefore, it is an attractive drug target for controlling blood glucose levels. The aim of this work was to obtain new potential SGLT2 inhibitors. A ligand-based virtual screening (LBVS) from the ZINC15, PubChem and ChemSpider databases using the maximum common substructure (MCS) scaffold was performed. A total of 341 compounds were obtained and analyzed by molecular docking on the active site of SGLT2. Subsequently, 15 compounds were selected for molecular dynamics (MD) simulation analysis. The compounds derived from spiroketal Sa1, Sa4, and Sa9 (≤ 3.5 Å) in complex with the receptor SGLT2 showed good stability during 120 ns of MD. These compounds are proposed as potential SGLT2 inhibitors.

Service evaluation of the implementation of SGLT-2 Inhibitor checklist on information communicated and documented to patients and transfer of care-records

Abstract Introduction Sodium Glucose Co-Transporter 2 (SGLT-2) Inhibitors’ therapeutic role has evolved1 as recent clinical trials showed they have beneficial effects across all stages of the cardio-renal metabolic spectrum2. There are different indications and specialities responsible for the initiation of these medications, so communication from health professionals to patients and documentation of this on transfer of care records is paramount3. It is important all health-care professionals ensure their clinical knowledge is current and updated to be able to communicate accurate and correct information to patients on their medications. A SGLT-2 Inhibitor counselling checklist was developed and approved for implementation in The Trust to promote awareness of new clinical guidelines and support the counselling provided to patients. The checklist included recommendations of the information to communicate and document on patient care records. Aim The aim was to assess the impact of the SGLT-2 Inhibitor counselling checklist on the information provided to patients and to identify if the indication and speciality responsible were recorded on transfer of patient care records for patients newly prescribed SGLT-2 inhibitors. Methods Ethical approval was not required for this quantitative research service evaluation. A data collection tool designed in Excel Microsoft 365 was used to collect data. Data was collected manually by the lead author retrospectively (pre-implementation of the checklist) from 1st January – 30th March 2022, and prospectively (post-implementation) from 1st July – 30th September 2022 from discharge prescriptions detailing newly prescribed SGLT-2 Inhibitors related to patients from four selected wards (A- D). Descriptive statistical analysis was carried out to compare the pre and post implementation data. Results Over the 6 month study period, a total of 110 patients were newly prescribed a SGLT-2 Inhibitor (63 pre- implementation and 47 post implementation). There was increased information communicated to patients in the post implementation group when compared to the pre implementation group. The percentage of patients provided with medicine information books and ‘protect my kidney’ cards increased from 25% to 70% and the proportion that received counselling increased from 27% to 70%. The indication and speciality involved with initiation and prescribing of SGLT-2 Inhibitors was well communicated and documented from 3% unknown in the pre group compared to 0% in the post implementation group. Discussion/Conclusion Despite this study being limited to a short collection period and a small sample size, the data collected demonstrates that the SGLT-2 inhibitor counselling checklist can increase the information communicated to patients and improve information included on transfer of care records, which is paramount between healthcare professionals to ensure a seamless transfer of care3. A key implication is the need to ensure use of counselling checklists as part of the discharge process.

Investigating the Cardiovascular Benefits of Dapagliflozin: Vasodilatory Effect on Isolated Rat Coronary Arteries

Dapagliflozin, a sodium–glucose co-transporter 2 (SGLT2) inhibitor, is an antidiabetic medication that reduces blood glucose. Although it is well known that dapagliflozin has additional benefits beyond glycemic control, such as reducing blood pressure and lowering the risk of cardiovascular events, no sufficient research data are available on the direct effect of dapagliflozin on cardiovascular function. Thus, in this study, we investigated the direct vascular effect of dapagliflozin on isolated rat coronary arteries. The left descending coronary arteries of 13-week-old male Sprague Dawley rats were cut into segments 2–3 mm long and mounted in a multi-wire myography system to measure isometric tension. Dapagliflozin effectively reduced blood vessel constriction induced by U-46619 (500 nM) in coronary arteries regardless of the endothelium. Treatment with an eNOS inhibitor (L-NNA, 100 μM), sGC inhibitor (ODQ, 5 μM), or COX inhibitor (indomethacin, 3 μM) did not affect the vasodilation induced by dapagliflozin. The application of a Ca2+-activated K+ channel (KCa) blocker (TEA, 2 mM), voltage-dependent K+ channel (KV) blocker (4-AP, 2 mM), ATP-sensitive K+ channel blocker (KATP) glibenclamide (3 μM), and inward-rectifier K+ channel (KIR) blocker (BaCl2, 30 μM) did not affect the dapagliflozin-induced vasodilation either. The treatment with dapagliflozin decreased contractile responses induced by the addition of Ca2+, which suggested that the extracellular Ca2+ influx was inhibited by dapagliflozin. Treatment with dapagliflozin decreased the phosphorylation level of the 20 kDa myosin light chain (MLC20) in vascular smooth muscle cells. In the present study, we found that dapagliflozin has a significant vasodilatory effect on rat coronary arteries. Our findings suggest a novel pharmacologic approach for the treatment of cardiovascular diseases in diabetic patients through the modulation of Ca2+ homeostasis via dapagliflozin administration.

Syzygium zeylanicum (L.) DC. polyphenols exhibit anti-diabetic activity by modulation of ACC1, SGLT1, and GLP-1 genes and restoration of gut microbiota in overfeeding and high glucose exposure-induced diabetic zebrafish

Syzygium zeylanicum (L.) DC. (SZL) has long been used as a traditional remedy for diabetes, but its underlying mechanisms of action remain unknown. This study aimed to investigate the antidiabetic activity of SZL polyphenols (SZL_EAF) via anti-hyperglycemic effect, regulation of gene expression related to lipid metabolism, glucose uptake and glucose utilization, and the gut microbiome modulation in diabetic zebrafish models. The results revealed that SZL_EAF exhibited a significant anti-hyperglycemic effect after five days of treatment. It also effectively regulated the expression of genes such as Acetyl-CoA carboxylase 1 (ACC1), Sodium–glucose cotransporters (SGLT1), and Glucagon-like peptide-1 (GLP-1) in diabetic zebrafish models. Additionally, SZL_EAF exhibited anti-pathogenic properties, promoted probiotics under hyperglycemic conditions, and restored the gut microbiome of diabetic zebrafish to normal levels. Overall, our finding indicated that SZL_EAF alleviates diabetes by reducing the blood glucose level, regulating the expression of diabetes-related genes, and restoring the gut microbiota.

Polypill Therapy for Cardiovascular Disease Prevention and Combination Medication Therapy for Hypertension Management

Although various guidelines for cardiovascular disease prevention have been established, the optimal drug therapy is often not implemented due to poor medication adherence and the clinical inertia of healthcare practitioners. Polypill strategies are one solution to this problem. Previous studies have established the usefulness of polypills, i.e., combination tablets including three or more medications, for the prevention of cardiovascular disease. For this purpose, the polypills generally contain an antiplatelet medication, an antihypertensive medication, and a statin. For the specific management of hypertension, combination therapy including more than two classes of antihypertensive medications is recommended by most international guidelines. Combination tablets including two classes of antihypertensive medications, such as renin-angiotensin system (RAS) inhibitors (angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin receptor blockers [ARBs]) and Ca-channel blockers or thiazide diuretics, have been reported to be useful for cardiovascular disease prevention and lowering blood pressure (BP) levels. The use of RAS inhibitors is recommended for a wide range of complications, including diabetes, chronic heart failure, and chronic kidney disease. The combination of an RAS inhibitor and diuretic or Ca-channel blocker is thus recommended for the management of hypertension. Finally, we expect that novel medications such as angiotensin receptor neprilysin inhibitors (ARNIs) and sodium glucose cotransporter 2 inhibitors (SGLT2i), which have a more diverse range of effects in hypertension, heart failure, or diabetes, may be a solution to the problem of polypharmacy. Evidence is accumulating on the benefits of polypill strategies in cardiovascular disease prevention. Combination tablets are also effective for the treatment of hypertension.

Effectiveness and safety of sodium-glucose cotransporter 2 inhibitors in Asian populations.

Effectiveness and safety of sodium-glucose cotransporter 2 inhibitors in Asian populations.

Sodium glucose co-transporter 2 inhibitors and quality of life in patients with heart failure: a comprehensive systematic review and meta-analysis of randomized controlled trials.

Sodium glucose co-transporter 2 inhibitors (SGLT2i) are one of the cornerstones of heart failure (HF) therapy. While benefits in terms of HF hospitalizations and death are well established, their impact on quality-of-life (QoL) has not been systematically investigated. This systematic review and meta-analysis aims to evaluate the impact of SGLT2i treatment on QoL in patients with HF, by analysing data from randomized clinical trials (RCTs). We identified a total of 23 RCTs that investigated the role of SGLT2i on quality of life in patients with HF, irrespective of their left ventricular ejection fraction (LVEF). RCTs that used Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS) to assess QoL and had a minimum follow-up of 3 months were included. The difference in mean change of the KCCQ-OSS between the SGLT2i group and the standard of care (SOC) group at 3 and 6 months from baseline was considered as the outcome measure. Fourteen RCTs (21737 patients) were included in the analysis. A significant improvement in KCCQ-OSS over time (p<0.001) was observed in both patients receiving SOC and those receiving SGLT2i in addition. The pooled estimate showed a significant improvement of 1.94 points [95% confidence interval (CI), 1.41-2.46] in KCCQ-OSS mean change at 3 months and of 2.18 points (95% CI, 1.13-3.24) at 6 months from baseline, with SGLT2i compared to SOC alone, irrespective of LVEF. A greater improvement in KCCQ-OSS was observed among patients with a recent episode of worsening HF compared to those with chronic stable HF. Among patients with HF, irrespective of their LVEF and clinical status, the addition of SGLT2i to SOC demonstrated a significant improvement in quality of life as early as at 3-month follow-up.

Time to completely eradicate diabetic nephropathy

Abstract Diabetes mellitus (DM) is the most important cause of end-stage renal disease, blindness, autonomic neuropathy, and heart failure. These complications endanger life expectancy, quality of life, and health costs in patients suffering from DM. These complications start to develop, especially in type 2 DM (T2DM), before the onset of this disease. Accumulating evidence proves that complications of diabetes are due to hyperglycemia that develops many years before the patients fulfill the diagnostic criteria of T2DM. Pathologic changes of diabetic kidney disease (DKD) in these patients have already developed by the time of onset of frank DM but are still clinically silent. These facts can explain the failure of the different sodium–glucose cotransporter 2 inhibitors (SGLT2Is) to completely prevent renal events even in diabetic patients with apparently normal kidneys. Many studies have used different SGLT2Is in patients devoid of diabetes without the fear of hypoglycemia. Available evidence pushes toward the use of SGLT2Is as early as the onset of prediabetes. This approach would eradicate not only DKD but also other known complications. The use of these agents by the onset of T1DM might be also justifiable. The early use of SGLT2Is as early as the onset of prediabetes might abort the development of DKD completely. This review provides insights for prospective studies that would make this hope a reality.

Glycogen storage disease type Ib: modern understanding of the pathogenesis of neutropenia and prospects for its treatment with empagliflozin

Glycogen storage disease type Ib (GSD Ib) — is a disease from the group of hereditary metabolic diseases caused by insufficiency of the glucose-6-phosphate transporter (G6PT, SLC37A4), which leads to a violation of both glycogenolysis and gluconeogenesis and, as a consequence, to excessive accumulation of glycogen and fat in the liver, kidneys and intestinal mucosa. The main clinical manifestations and laboratory data include growth retardation, hepatomegaly, hypoglycemia, lactic acidosis, hyperuricemia and hyperlipidemia. Complications of this disease are hepatocellular adenoma with a possible risk of malignancy, nephropathy and osteoporosis. A specific sign of GSD Ib is neutropenia with impaired neutrophil function, which creates prerequisites for recurrent infections and the development of inflammatory bowel disease. Until the present, enzyme replacement therapy of GSD Ib has not been developed, therefore, the main methods of treatment are a specialized diet with the addition of raw corn starch (for relief of hypoglycemia) and the use of granulocyte colony stimulating factor (for relief of neutropenia). However, the recent establishment of the role of 1,5-anhydroglucitol in the pathogenesis of neutrophil dysfunction in GSD Ib has led to a reprofiling of indications for the use of empagliflozin, a type 2 renal sodium—glucose cotransporter inhibitor (SGLT2). In the modern literature, it is reported about a minor, but very successful experience of its use in patients with GSD Ib (outside the framework of official indications for use) and a beneficial effect on neutrophil dysfunction and its clinical consequences. Oddly enough, this hypoglycemic drug improved not only metabolic, but also glycemic control in patients with GSD Ib, despite the fact that the pathology is based on chronic hypoglycemia. More and more evidence points to the role of empagliflozin in the regulation of cellular homeostasis (for example, fatty acid metabolism, glucose, cholesterol, apoptosis and cell proliferation, in particular in the liver) by influencing the activity of sirtuin 1 (SIRT1), AMP-activated protein kinase (AMPK) and signal molecules such as -serine/threonine protein kinase (Akt) and a mechanical target of rapamycin (mTOR), which leads to an improvement in the structure and function of mitochondria, stimulation of autophagy, reducing oxidative stress and suppressing inflammation. Modulation of these pathways shifts oxidative metabolism from carbohydrates to lipids and leads to a key decrease in insulin levels, resistance to it, glucose and lipotoxicity. This review presents current data on the pathogenesis of neutropenia and the possibility of using empagliflozin for its relief in patients with GSD Ib.

Short term effect of sodium glucose cotransporter 2 inhibitors and sacubitril/valsartan on comprehensive geriatric assessment and oxidative stress in elderly with chronic heart failure (from MAGIC-HF)

Abstract Background Sodium Glucose Cotransporter 2 inhibitors (SGLT2i) and Sacubitril/Valsartan (Sac/Val) have improved clinical prognosis in patients affected by heart failure (HF) with reduced ejection fraction (HFrEF). Cognitive impairment, depression, and poor physical functional performance are a very common comorbidity in patients with HF and result in a worse prognosis. Purpose The aim of this study was to evaluate the potential effects of SGLT2i on functional, humoral, and cognitive aspects, assessed by performing a comprehensive geriatric assessment (CGA), and on oxidative stress and platelets activation biomarkers, in a cohort of HFrEF elderly, and any differences between men and women. Methods We enrolled 91 HFrEF patients (63 men and 28 women, mean age 73.7±4.7 years) in the "MAgna GraecIa evaluation of Comorbidities in patients with Heart Failure STUDY (MAGIC-HF STUDY). Men and women differed for use of glucagon-like-peptide 1 receptor agonists, antiplatelet drugs, and circulating levels of NADPH Oxidase 2 (Nox-2). SGLT2i therapy was introduced in patients already treated with Sac/Val for at least 12 months who were taking an average dose of 273.6±102.0 mg/die. Results After 3 months follow-up, we observed a significant improvement in cognitive, humoral and functional parameters of CGA, NTpro-BNP levels and echocardiographic parameters. Changes (Δ) in Montreal Cognitive Assessment (MoCA) (p=0.015) and Cardiac Index (CI) which were greater in men (p&amp;lt;0.0001) and Geriatric Depression Scale (GDS) which were greater in women (p=0.029). In the whole population, multivariate analysis shows that Δ of CI, Homeostatic model assessment (HOMA), Sp-Selectina, Nox-2 and 8-Isoprostane contributed for 19.7% (p&amp;lt;0.0001), 9.4% (p=0.001), 6.4% (p=0.002), 3.8% (p=0.013) and 2.9% (p=0.024) to Mini mental state examination (MMSE) variability, respectively, and the whole model accounted for a 42.2% of MMSE variation; moreover Δ of HOMA, Sp-Selectina and highly sensitive c-reactive protein (hs-CRP) contributed for 21.6% (p&amp;lt;0.0001), 5.7% (p=0.002) and 4.0% (p=0.014) to MoCA variability, respectively, and the whole model accounted for a 33.3% of MoCA variation. In addition, Δ of Sp-Selectina, Nox-2, CI and HOMA globally contributed for 37.5% of GDS variation (p&amp;lt;0.05); and Δ of HOMA and Sp-Selectina contributed for 30.9% of Short performance physical battery variation (p&amp;lt;0.0001). Conclusions This represents the first real-world study carried out in an elderly population suffering from chronic HFrEF with several comorbidities, in which the addition of SGLT2i, in patients already treated with the best medical therapy including Sac/Val, after three months induced important improvements in clinical, humoral, hemodynamic, functional outcomes and cognitive performance. This study shows that echocardiographic and cognitive improvements are greater in men than in women, instead metabolic and humoral improvements are greater in women.

Feasibility, efficacy and safety of early and rapid initiation of evidence-based treatment for patients with HFrEF- a real world experience of the "four drugs in four weeks" strategy

Abstract Background Evidence-based treatment for heart failure with reduced ejection fraction (HFrEF) is associated with improved outcomes for patients. However, there is uncertainty as to how treatment with these foundational drugs should best be implemented. Objectives To evaluate whether early and rapid initiation of medications for patients with HFrEF using a 4 x 4 approach (4 pillars of HFrEF therapy in 4 weeks) is feasible, safe, and effective. Methods We recruited consecutive patients from April to July 2021 with a new diagnosis of HFrEF who were either assessed at our urgent HF clinic or had a recent HF hospitalisation. All patients had regular reviews (every 1-2 weeks, combination of telephone and face-to-face) at our hospital-based HF clinic by a HF consultant or senior HF specialist nurse for initiation and up-titration of guideline-recommended therapy including angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor neprilysin inhibitor (ARNI), beta blockers (BB), mineralocorticoid receptor antagonist (MRA) and sodium glucose co-transporter inhibitor (SGLT2i). Results Of 100 patients approached, 19 patients were considered unsuitable for the 4x4 pathway (79% due to severe frailty or significant comorbidities). 81 patients were enrolled (61% male, median (IQR) age: 73 (67-82) years, median (IQR) NT-proBNP: 3764 (1597-7487) ng/L); 39 (48%) patients achieved "4 drugs at 4 weeks". Of the 42 patients who did not, 33 (79%) had contraindication to one or more of the drug classes at the outset, including renal impairment (28%), bradycardia (18%) and hyperkalaemia (15%). Patients who did not achieve "4 drugs at 4 weeks" were older, more symptomatic, and had higher NTproBNP and worse renal function. During a median follow up of 554 days, 6 (7%) patients died and 31 (38%) experienced the combined outcome of all-cause death / hospitalisation. Patients who did not achieve "4 drugs at 4 weeks", compared to those who did, had a 2.5 fold increased risk of the combined outcome (Figure 1). They were also less likely to be up-titrated to targeted doses of HF medications (Figure 2). There was noticeable improvement in NTproBNP with no significant change in renal function or systolic BP in both groups. Compared to those who did not achieve "4 drugs at 4 weeks", those who did showed larger improvement in LVEF (8% vs 2%) at 6 months. 5 patients (6%) experienced significant side effects during medication up-titration: 4 had symptomatic hypotension and 1 had hyperkalaemia. Conclusion The 4x4 strategy is clinically feasible and safe when implemented in selected patients with HFrEF and may be associated with improved outcomes. Our results support larger studies to further investigate the generalisability and effectiveness of the 4x4 strategy.

The effect of SGLT2 inhibitor on clinical outcomes in patients with type 2 diabetes and atrial fibrillation

Abstract Background Atrial fibrillation (AF) is the most common arrhythmia and represents a significant public health burden with an increased risk of stroke, heart failure (HF) and mortality. Sodium glucose cotransporter 2 (SGLT2) inhibitors improve clinical outcomes in several populations including type 2 diabetes, chronic renal insufficiency, and HF. However, limited data exist on their effects on AF. Purpose We investigated impact of SGLT2 inhibitor on clinical outcomes compared to dipeptidyl peptidase 4 (DPP4) inhibitor among patients with type 2 diabetes and AF. Methods We conducted a retrospective cohort study using the National Health Insurance Service database. A total of 4,771 patients with type 2 diabetes and AF who were newly prescribed SGLT2 inhibitors or DPP4 inhibitors from Jan 2014 to Dec 2019 were selected and matched in a 1:2 ratio by propensity score with 38 confounding variables. We assessed the relationship of SGLT2 inhibitor with clinical outcomes including mortality, stroke, myocardial infarction (MI) and hospitalization for HF compared with DPP4 inhibitor using Cox regression model. Results Over the follow-up, 181 patients (3.7%) died, 121 patients (2.5%) were hospitalized for HF, 95 patients (2.0%) experienced MI, and 293 patients (6.1%) had stroke. Compared to DPP4 inhibitor, SGLT2 inhibitor was associated with lower risk of mortality (HR 0.61; 95% CI 0.39-0.94; P=0.025), but not of MI (HR 1.22 [95% CI 0.71-2.08]; P=0.46) or stroke (HR 1.0 [95% CI 0.75-1.33]; P=0.98). While the incidence of hospitalizations for HF tended to be lower in the SGLT2 inhibitor group, it did not reach a statistical significant level (HR 0.63 [95% CI 0.39-1.02]; P=0.06). Conclusion In a nationwide cohort of patients with type 2 diabetes and AF, SGLT2 inhibitor was associated with a lower risk of mortality compared to DPP4 inhibitor.