Urinary Glucose Excretion Research Articles

SGLT 2 Inhibitors: Mechanisms, Clinical Applications, and Future Directions

Due to the progressive and painful nature of type 2 diabetes (T2D), treatment may require periodic evaluation of patients, intensifying glucose-lowering therapy when glycaemic targets are not achieved and testing new methods. Among the newer classes of glucose-lowering drugs, sodium-glucose cotransporter 2 inhibitors (SGLT2is), which increase urinary glucose excretion to reduce hyperglycaemia, have made an impressive entry into the T2D treatment arsenal. Given their unique insulin-independent mode of action and favourable efficacy-adverse effect profiles, and their apparent benefits on cardiovascular-renal outcomes in intermediate-high-risk T2D patients, which have led to the updating of guidelines and product monographs, the role of this drug class in multidrug regimens is promising. However, despite much speculation based on pharmacokinetic and pharmacodynamic properties, physiological rationale and potential synergism, the glycaemic and pleiotropic effects of these agents when combined with other classes of glucose-lowering drugs remain largely under-researched. Therefore, this review discusses the mechanisms, clinical applications and future therapeutic role of SGLT2 inhibitors with a review of the literature.

Model-based meta-analysis of HbA1c reduction across SGLT2 inhibitors using dose adjusted by urinary glucose excretion

This study was aimed to evaluate whether the dose–response relationship of the sodium glucose co-transporter-2 inhibitors (SGLT2is) in patients with type 2 diabetes mellitus (T2DM)—canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, luseogliflozin, and tofogliflozin—can be explained in a unified manner based on their ability to promote urinary glucose excretion (UGE). Information on HbA1c reduction at various doses of each SGLT2i was collected from literatures on randomized controlled trials and was normalized based on the daily UGE data from phase I studies. After normalizing doses, the dose–response relationship of HbA1c reduction of most of SGLT2is was represented by a unified nonlinear mixed-effect model, with the estimated maximum HbA1c (%) reduction (Emax) of 0.796 points, whereas covariate analysis showed that canagliflozin had a 1.33-fold higher Emax than those of the other drugs. Other covariates included baseline HbA1c levels, body weight, disease duration, prior treatment, and renal function. Findings from this study would influence drug selection and adjustment in clinical practice. As with SGLT2is, in cases where the efficacy cannot be easily evaluated but an appropriate pharmacodynamic marker was assessed in early clinical trials, similar approaches for other drug classes can guide strategic and evidence-based dose selection in phase III trials.

Assessment of basic pharmacokinetic parameters of dapagliflozin in TTS formulations in male minipigs

Given the extended time over which diabetes treatment is administered, the transdermal delivery system is anticipated to be a more suitable option for older individuals who may experience difficulty swallowing. The continuous delivery of dapagliflozin and more stable plasma levels are anticipated to reduce the incidence of side effects and the frequency of dosing. The objectives of the study were to determine the safety and plasma pharmacokinetics of dapagliflozin in male minipigs following application of the ointment and skin patch. In the initial phase of the study, the potential for transdermal permeation of dapagliflozin from ointment and transdermal patch to blood plasma of 15 male Göttingen minipigs was investigated. In the subsequent phase, the efficacy of utilising patches of varying strengths and sizes was assessed. The LC/MS method was employed to quantify the concentration of the active substance. The transportation of the studied API to the general circulation and accumulation in tissues were confirmed. The maximum drug concentration (122.99 ng/mL) in plasma was observed on the fourth day of application. The highest calculated Cmax was 131.91 ng/mL with a mean AUC0-last of 6620.7 ng h/mL. Following transdermal administration, dapagliflozin is excreted in the urine. The trend between urinary dapagliflozin 3-O-glucuronide levels and urinary glucose excretion was also observed. The transdermal patch has been demonstrated to be an effective drug delivery system for dapagliflozin.

9210 Nephron specific ATP6AP2 knockout reduces renal fat accumulation in mice consuming high fat diet

Abstract Disclosure: S.A. Culver: None. J. Balugo: None. M. Jansen: None. T. Harris: None. H.M. Siragy: None. Diet induced obesity causes increased renal fat accumulation in both humans and mice which contributes to obesity related kidney injury. We have previously shown that mice with nephron specific ATP6AP2 knockout (KO) consuming high fat diet (HFD) are resistant to weight gain due to increased urinary excretion of glucose, albumin, and fatty acids. Magnetic resonance imaging (MRI) is a useful imaging modality for quantifying organ fat content in live animals though there are few reports of its use quantifying fat in murine kidney. We hypothesized that nephron specific ATP6AP2 knockout inhibits renal fat accumulation with HFD and that we would be able to detect this using MRI. Eight-week-old male wild type (WT) or inducible nephron specific ATP6AP2 KO mice underwent either induction with oral doxycycline or received sucrose water as controls before being placed on either normal diet (ND) (12% fat) or HFD (45% fat) for 3 months. Mice were then imaged using a 9.4 Tesla Bruker BioSpin MRI to determine both liver and kidney cortex fat content. The mean weight of WT HFD mice was 36.03 g compared to 29.03 g in WT ND controls. ND fed and HFD fed KO mice weighed 22.74 g and 23.03 g respectively. MRI showed significant 67% (p<0.05) increase in liver fat content in WT HFD compared to WT ND fed controls, confirming the ability of our MRI technique to detect expected differences in organ fat content. In renal cortex, MRI detected a 54% (p<0.05) increase in lipid content for WT HFD mice compared to WT ND controls. Nephron specific ATP6AP2 KO on HFD demonstrated reduced renal cortical lipid content by 36% (p<0.05) compared to WT HFD controls. These results indicate that ATP6AP2 KO is associated with reduced renal fat accumulation that is measurable with in vivo MRI. MRI therefore represents a valuable tool for studying renal sequelae of obesity in live murine models. Future investigation should examine whether ATP6AP2 KO prevents renal lipotoxicity and kidney injury in the setting of obesity. Presentation: 6/3/2024

Sodium-Glucose Cotransporter-2 Inhibitors In Heart Failure

Heart failure (HF) is a serious problem in a modern world, with increasing prevalence among ageing populations. The use of sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally intended to treat type 2 diabetes, has revolutionised the treatment of HF. In this review article, we present the latest evidence on the mechanism of action of SGLT2 inhibitors, also called flosins, in HF. The primary mechanism of action of flosins is to reduce glucose reabsorption from glomerular filtration in the proximal renal tubule with a concomitant reduction in sodium reabsorption, leading to urinary glucose excretion and osmotic diuresis. Based on experimental findings, several pleiotropic effects of SGLT2 inhibitors have been proposed. Mechanisms also include regulation of inflammatory and oxidative pathways along with improved endothelial function. Recent multicentre studies of SGLT2 inhibitors have shown that they reduce hospitalisations for heart failure after their use, regardless of type 2 diabetes and the degree of cardiac systolic dysfunction.

SGLT-2 Inhibitors: The Next-generation Treatment for Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) has become a worldwide concern in recent years, primarily in highly developed Western societies. T2DM causes systemic complications, such as atherosclerotic heart disease, ischemic stroke, peripheral artery disease, kidney failure, and diabetes-related maculopathy and retinopathy. The growing number of T2DM patients and the treatment of long-term T2DM-related complications pressurize and exhaust public healthcare systems. As a result, strategies for combating T2DM and developing novel drugs are critical global public health requirements. Aside from preventive measures, which are still the most effective way to prevent T2DM, novel and highly effective therapies are emerging. In the spotlight of next-generation T2DM treatment, sodium-glucose co-transporter 2 (SGLT-2) inhibitors are promoted as the most efficient perspective therapy. SGLT-2 inhibitors (SGLT2i) include phlorizin derivatives, such as canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. SGLT-2, along with SGLT-1, is a member of the SGLT family of proteins that play a role in glucose absorption via active transport mediated by Na+/K+ ATPase. SGLT-2 is only found in the kidney, specifically the proximal tubule, and is responsible for more than 90% glucose absorption. Inhibition of SGLT-2 reduces glucose absorption, and consequently increases urinary glucose excretion, decreasing blood glucose levels. Thus, the inhibition of SGLT-2 activity ultimately alleviates T2DM-related symptoms and prevents or delays systemic T2DM-associated chronic complications. This review aimed to provide a more detailed understanding of the effects of SGLT2i responsible for the acute improvement in blood glucose regulation, a prerequisite for T2DM-associated cardiovascular complications control.

Role of Sotagliflozin in Managing Heart Failure in Diabetes

A chronic illness that impairs heart function is heart failure. This malfunction can put strain on other organs and be especially dangerous for those who have long-term conditions like diabetes and high blood pressure. Patients with diabetes are more likely to develop heart failure. Sotagliflozin is an oral medication used to treat diabetes. A dual sodium drug called sotagliflozin shows promise in the treatment of heart failure. An essential new family of medications for the treatment of diabetes is the sodium-dependent glucose transporter 2 (SGLT2) inhibitors. The goal of developing SGLT2 inhibitors has been to achieve high SGLT2 protein selectivity compared to SGLT1 protein. Treating diabetes with a single drug that combines the inhibition of SGLT1 and SGLT2 would offer complementing insulin-independent strategies. Thus, sotagliflozin (LX4211) was created as a dual SGLT1 and SGLT2 inhibitor. Large postprandial glucose decrease, increase of glucagon-like peptide 1, and mild urine glucose excretion are the distinguishing clinical aspects of dual inhibitor of SGLT1 and SGLT2. These characteristics might have an impact on how sotagliflozin is used clinically to treat diabetes.

Nephron specific ATP6AP2 knockout increases urinary excretion of fatty acids and decreases renal cortical megalin expression

ATP6AP2 knockout in the renal nephron impairs receptor-mediated endocytosis, increasing urinary albumin and glucose excretion and impairing weight gain. Nonesterified fatty acids (NEFA) in urine are bound to albumin and reabsorbed in the proximal tubule through receptor-mediated endocytosis by the megalin–cubilin complex. We hypothesized that ATP6AP2 knockout increases urinary NEFA excretion through a reduction in megalin. Ten-week-old male C57BL/6 mice with nephron specific inducible ATP6AP2 knockout and noninduced controls were fed either normal diet (ND 12% fat) or high fat diet (HFD 45% fat) for 6 months. ATP6AP2 knockout significantly increased urine albumin:creatinine ratio in both ND and HFD fed mice while normalized urine NEFA concentration increased 489% and 259% in ND and HFD knockout mice compared to respective controls. Knockout decreased renal cortical megalin mRNA by 47% on ND and 49% on HFD while megalin protein expression decreased by 36% and 44% respectively. At the same time, markers of mTOR activity were increased while autophagy was impaired. Our results indicate that nephron specific ATP6AP2 knockout increases urinary NEFA excretion in the setting of impaired receptor-mediated endocytosis. Further investigation should determine whether ATP6AP2 contributes to obesity related ectopic lipid deposition in the proximal tubule.

Dark tea consumption is associated with a reduced risk of dysglycaemia and increased urinary glucose and sodium excretion in Chinese adults.

To examine the associations of tea consumption (both frequency and type) with (1) prediabetes and diabetes and (2) urinary glucose and sodium excretion in Chinese community-dwelling adults. In 1923 participants (457 with diabetes, 720 with prediabetes, and 746 with normoglycaemia), the frequency (occasional, frequent, daily, or nil) and type (green, black, dark, or other) of tea consumption were assessed using a standardized questionnaire. Morning spot urinary glucose and urine glucose-to-creatinine ratios (UGCRs) were assessed as markers of urinary glucose excretion. Tanaka's equation was used to estimate 24-h urinary sodium excretion. Logistic and multivariate linear regression analyses were performed. Compared with non-tea drinkers, the corresponding multivariable-adjusted odds ratios (ORs) for prediabetes and diabetes were 0.63 (95% confidence interval [CI] 0.48, 0.83) and 0.58 (95% CI 0.41, 0.82) in participants drinking tea daily. However, only drinking dark tea was associated with reduced ORs for prediabetes (0.49, 95% CI 0.36, 0.66) and diabetes (0.41, 95% CI 0.28, 0.62). Dark tea consumption was associated with increased morning spot urinary glucose (0.22 mmol/L, 95% CI 0.11, 0.34 mmol/L), UGCR (0.15 mmol/mmol, 95% CI 0.05, 0.25 mmol/L) and estimated 24-h urinary sodium (7.78 mEq/day, 95% CI 2.27, 13.28 mEq/day). Regular tea consumption, especially dark tea, is associated with a reduced risk of dysglycaemia and increased urinary glucose and sodium excretion in Chinese community-dwelling adults.

Glucocorticoid-induced acute diuresis in rats in relation to the reduced renal expression of sodium-dependent cotransporter genes

Although several studies have shown that glucocorticoids exert diuretic effects in animals and humans, the underlying mechanism responsible for the acute diuretic effect remains obscure. Here we examined the mechanism in terms of gene-expression. We observed that glucocorticoids, including dexamethasone (Dex) and prednisolone (PSL), acutely induced diuresis in rats in a dose-dependent manner. Free water clearance values were negative after Dex or PSL treatment, similar to those observed after treatment with osmotic diuretics (furosemide and acetazolamide). Dex significantly increased the urinary excretion of sodium, potassium, chloride, glucose, and inorganic phosphorus. Renal microarray analysis revealed that Dex significantly altered the renal expression of genes related to transmembrane transport activity. The mRNA levels of sodium/phosphate (NaPi-2a/Slc34a1, NaPi-2b/Slc34a2, and NaPi-2c/Slc34a3) and sodium/glucose cotransporters (Sglt2/Slc5a2) were significantly reduced in the Dex-treated kidney, being negatively correlated with the urinary excretion of their corresponding solutes. Dex did not affect renal expression of the natriuretic peptide receptor 1 (Npr1) gene, or the expression, localization, and phosphorylation of aquaporin-2 (AQP2), a water channel protein. These findings suggest that the acute diuretic effects of glucocorticoids might be mediated by reduced expression of sodium-dependent cotransporter genes.

Aerobic training increases renal antioxidant defence and reduces angiotensin II levels, mitigating the high mortality in SHR-STZ model

Objectve The purpose of the research was to investigate the effects of aerobic training on renal function, oxidative stress, intrarenal renin–angiotensin system, and mortality of hypertensive and diabetic (SHR-STZ) rats. Materials and Methods Blood pressure, creatinine, urea levels, urinary glucose, urine volume, and protein excretion were reduced in trained SHR-STZ rats. Results Aerobic training not only attenuated oxidative stress but also elevated the activity of antioxidant enzymes in the kid′ney of SHR-STZ rats. Training increased intrarenal levels of angiotensin-converting enzymes (ACE and ACE2) as well as the neprilysin (NEP) activity, along with decreased intrarenal angiotensin II (Ang II) levels. Aerobic training significantly improved the survival of STZ-SHR rats. Conclusion The protective role of aerobic training was associated with improvements in the renal antioxidative capacity, reduced urinary protein excretion along with reduced intrarenal Ang II and increased NEP activity. These findings might reflect a better survival under the combined pathological conditions, hypertension, and diabetes.

Sodium-glucose transport protein 2 inhibitor use in the management of insulin dysregulation in ponies and horses.

Laminitis is a common and painful condition of the equine foot and approximately 90% of cases are associated with insulin dysregulation (ID) that is a central feature of the common endocrine disorder equine metabolic syndrome (EMS) and occurs in a subset of animals with pituitary pars intermedia dysfunction. Additional features of EMS include obesity, altered circulating concentrations of adipokines (particularly adiponectin and leptin) and hypertriglyceridaemia. Obesity, ID, hypoadiponectinaemia, hyperleptinaemia and an altered plasma lipid profile are also features of human metabolic syndrome (HMS) alongside hyperglycaemia. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel class of oral hypoglycaemic agents used in combination with lifestyle changes in the management of HMS. SGLT2 receptors are responsible for 90% of the renal glucose reabsorption that occurs in the proximal convoluted tubule. Thus, these drugs increase urinary glucose excretion by suppressing glucose reabsorption from the glomerular filtrate resulting in urinary calorie loss with consequent weight loss and improvements in ID, hyperglycemia, hypoadiponectinaemia and hyperleptinaemia. There are no licenced veterinary drugs available for treating ID and preventing insulin-associated laminitis in horses. Thus, the use of SGLT2i for the control of equine hyperinsulinaemia with the goal of improving recovery from associated active laminitis or preventing future laminitis has recently been advocated. There are a small number of published studies reporting the use of the SGLT2i canagliflozin, ertugliflozin and velagliflozin to aid the management of equine ID. However, the doses used are largely extrapolated from human studies with limited consideration of species-specific variations. In addition, there is limited evaluation of the fundamental differences between ID in horses and humans, particularly the fact that most horses with ID remain hyperinsulinaemic but normoglycaemic such that increased urinary loss of glucose may not explain the beneficial effects of these drugs. Further study of the potential deleterious effects of treatment-associated hypertriglyceridaemia is required together with the effect of SGLT2i therapy on circulating concentrations of adipokines in horses.

A novel heterozygous likely pathogenic SLC5A2 variant in a diabetic patient with glucosuria and aminoaciduria.

Familial renal glucosuria (FRG) is a rare renal tubular disorder characterized by increased urinary glucose excretion despite normoglycemia. It is most commonly caused by pathogenic variants in the solute carrier family V member 2 (SLC5A2) gene. This gene encodes the sodium-glucose cotransporter 2, crucial for glucose reabsorption. We report the case of a 44-year-old male referred to the endocrinology outpatient clinic for unexplained glucosuria despite well-controlled diabetes mellitus with metformin and gliclazide therapy. His main complaints were nocturia and an unintentional 5 kg weight loss in 1 year. A 24-h urinary collection revealed overt glucosuria (23.3 g/1.73 m2/24 h), generalized aminoaciduria, and increased uric acid excretion (fractional excretion: 6.4%). Whole-exome sequencing revealed a novel heterozygous c.469-1G>A likely pathogenic variant in the SLC5A2 gene. Specific analysis of the maturity-onset diabetes of the young type (MODY) gene panel showed no pathogenic variants in the hepatocyte nuclear factor-1A (HNF-1A; MODY3) nor in other MODY-associated genes. We assume that the association of glucosuria, aminoaciduria, and increased uric acid excretion can be explained by the combination of diabetes and the likely pathogenic SLC5A2 variant in this patient. In conclusion, we describe a well-controlled diabetic patient with FRG, associated with a novel heterozygous c.469-1G>A likely pathogenic variant in the SLC5A2 gene. The diagnosis of a renal tubular disorder should be considered in patients with unexplained glucosuria and diabetes mellitus, especially if the latter is well controlled. FRG usually presents with glucosuria but may be associated with generalized aminoaciduria and hyperuricosuria. Genetic analysis should be considered in patients with young-onset diabetes and glucosuria, particularly with a positive family history.

Research progress on the effects of sodium-glucose linked transporter 2 inhibitors on multiple metabolic disorders in metabolic syndrome.

Metabolic syndrome is a complex group of metabolic disorders with an increasing global incidence rate, posing a serious threat to human health. Sodium-glucose linked transporter 2 (SGLT2) inhibitors are a new type of oral hypoglycemic drug. SGLT2 inhibitors not only lower blood glucose level in a non-insulin-dependent manner by inhibiting glucose reabsorption by renal proximal convoluted tubular epithelial cell to promote urinary glucose excretion, but also by improving islet β cell function, reducing inflammatory responses, and inhibiting oxidative stress. In addition, SGLT2 inhibitors can reduce body weight through osmotic diuresis and increase fat metabolism; reduce blood pressure by inhibiting excessive activation of sympathetic nervous system and by improving vascular function. They can also improve blood lipids by increasing degradation of triacylglycerol; reduce blood uric acid by promoting uric acid excretion in kidney and intestine, and by reducing uric acid synthesis. This article reviews the effects and mechanisms of SGLT2 inhibitors on multiple metabolic disorders in metabolic syndrome and explores their potential application in metabolic syndrome treatment.

Analytical Method Development and Optimization on High Performance Liquid Chromatography for Related Substances Test of Gliclazide Drug as Active Pharmaceutical Ingredient

Diabetes mellitus, particularly Type 2 Diabetes Mellitus (T2DM), presents a significant global health challenge, necessitating continuous advancements in therapeutic strategies. Gliclazide, an oral selective inhibitor of sodium glucose co-transporter-2 (SGLT2), has emerged as a promising agent for managing T2DM by facilitating urinary glucose excretion and reducing plasma glucose levels. However, ensuring the quality and efficacy of pharmaceutical formulations remains crucial for regulatory approval and clinical effectiveness. In this study, we present the development of an improved stability-indicating Reverse Phase-High Performance Liquid Chromatography (RP-HPLC) method for the precise quantification of Gliclazide. The novel analytical method employs 0.1% Potassium Phosphate in water 0.1% Potassium Phosphate in methanol (MeOH) as the mobile phase, demonstrating enhanced sensitivity, cost-effectiveness, and reduced reliance on organic chemicals. Through rigorous validation following International Conference on Harmonisation (ICH) guidelines, the developed method exhibited superior performance in terms of retention times compared to existing methodologies. The proposed analytical approach holds promise for routine analysis of Gliclazide in both bulk and tablet formulations, offering a valuable tool for pharmaceutical quality control and clinical research in the management of T2DM.

#1299 The SGLT2 inhibitor canagliflozin, but not dapagliflozin or empagliflozin, ameliorates vascular calcification in a mouse model of nephrocalcinosis

Abstract Background and Aims Vascular calcification, defined as the abnormal deposition of minerals in blood vessels, is a major cardiovascular risk factor in patients with kidney failure. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, commonly known as gliflozins, are a class of pharmaceutical compounds that have revolutionised the therapeutic management of type 2 diabetes. These drugs target the SGLT2 transporter, increasing glucose elimination through the urine, effectively lowering hyperglycaemia. In addition to their effect on blood sugar control, SGLT2 inhibitors have recently gained attention for potential cardiovascular benefits in patients with type 2 diabetes, chronic kidney disease (CKD) or established cardiovascular disease. Initially thought to be secondary to the promotion of urinary sodium and glucose excretion and weight loss, recent studies have also reported direct effects of gliflozins on the vascular compartment. Given the significant impact of vascular calcification on cardiovascular health in patients with kidney failure, the aim of this study was to investigate whether the three different SGLT2 inhibitors (canagliflozin, empagliflozin and dapagliflozin) could reduce the development of vascular calcification. Method Western blotting was used to investigate SGLT2 expression in mouse and human vascular smooth muscle cells (VSMC) and vascular explants. Human and mouse aortic VSMC and mouse aorta and human epigastric and iliac artery segments were treated with calcification medium supplemented with 1 or 5 µM of gliflozins. A nephrocalcinosis mouse model consisting of 2 weeks of high phosphorus diet (2%) in female DBA/2 mice was used in in vivo experiments. The animals were treated daily with the different gliflozins (3 mg/kg/j) by oral gavage. Calcium deposits were quantified using a quantitative colorimetric assay and alizarin red staining, blood and urine glucose levels were measured using a quantitative colorimetric assay and glomerular filtration rate (GFR) was measured using sinistrin-FITC excretion. Results We observed that SGLT2 is expressed in mouse and human vessels and vascular smooth muscle cells (VSMC). Treatment with canagliflozin, but not dapagliflozin or empagliflozin, reduced calcification in vitro, in human and mouse VSMC and ex vivo, in mouse aorta and human epigastric and iliac artery segments. The high phosphorus diet in mice led to nephrocalcinosis associated with impaired renal function as well as vascular calcification development in the aorta. In this model, although all 3 gliflozins showed efficacy in increasing urinary glucose excretion, blood glucose levels were not affected by gliflozins and renal function was not improved. However, canagliflozin, but not dapagliflozin or empagliflozin, significantly reduced vascular calcification in this nephrocalcinosis mouse model. Conclusion Our study demonstrated that canagliflozin reduces vascular calcification development, highlighting its potential as a therapeutic strategy. This protective effect was found to be drug-dependent and not class-dependent, as the other two SGLT2 inhibitors, dapagliflozin and empagliflozin, showed no significant effect on vascular calcification. Further studies are needed to understand the mechanisms and pathways involved and to determine whether the differential effect of the gliflozins is due to an off-target action of canagliflozin on other SGLT transporters.

#2595 Evolution of hemoglobin and serum uric acid levels after SGLT2i initiation in patients with and without diabetic nephropathy

Abstract Background and Aims Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are glucose-lowering drugs that inhibit glucose reabsorption in the proximal tubule, enhancing urinary glucose excretion. SGLT2i exhibit significant cardio- and renoprotective effects due to their capacity to increase diuresis and weight loss and reduce intraglomerular and blood pressure. Moreover, recent studies have described the potential of SGLT2i to improve additional cardiovascular risk factors, such as anemia or hyperuricemia. In this study, we aimed to describe the evolution of hemoglobin (Hb) and serum uric acid (SUA) levels in CKD patients with and without diabetic nephropathy before and after the initiation of SGLT2i therapy. Method CKD patients with and without diabetic nephropathy that were followed in the outpatient clinic of a tertiary referral academic hospital during January 2020 to September 2023 and that started SGLT2i therapy during that period were randomly recruited in the study. Patient characteristics, CKD staging, and levels of Hb and SUA before and after SGLT2i initiation were compared between groups. Hb and SUA levels were averaged considering all available laboratory controls during the last 12 months before treatment initiation and any available controls after treatment start. Results Demographic and clinical characteristics of enrolled patients are summarized in Fig. 1. Subjects with diabetic nephropathy were significantly older, more commonly hypertensive, presented worse kidney function, had received SGLT2i for a lengthier time and had lower hemoglobin values. We observed no change in hemoglobin levels after the initiation of SGLT2i in our sample, independently of diabetic nephropathy status or CKD stage (Fig. 2A, C). In contrast, SUA levels decreased significantly both in patients with and without diabetic nephropathy (Fig. 2B). This effect was observed across all the spectrum of CKD in our sample (Fig. 2D). Conclusion In our sample, SGLT2i initiation was associated with a significant decrease in SUA levels, both in patients with and without diabetic nephropathy and independently of CKD stage, which may help to explain its cardio- and nephroprotective effects. No change in Hb levels was observed, possibly due to a low prevalence of anaemia in our sample.

Evaluation of Drug-Drug Interaction Between Henagliflozin and Hydrochlorothiazide in Healthy Chinese Volunteers.

Henagliflozin is an original, selective sodium-glucose cotransporter 2 (SGLT2) inhibitor. Hydrochlorothiazide (HCTZ) is a common anti-hypertensive drug. This study aimed to evaluate the potential interaction between henagliflozin and HCTZ. This was a single-arm, open-label, multi-dose, three-period study that was conducted in healthy Chinese volunteers. Twelve subjects were treated in three periods, period 1: 25 mg HCTZ for four days, period 2: 10 mg henagliflozin for four days and period 3: 25 mg HCTZ + 10 mg henagliflozin for four days. Blood samples and urine samples were collected before and up to 24 hours after drug administrations on day 4, day 10 and day 14. The plasma concentrations of henagliflozin and HCTZ were analyzed using LC-MS/MS. The urine samples were collected for pharmacodynamic glucose and electrolyte analyses. Tolerability was also evaluated. The 90% CI of the ratio of geometric means (combination: monotherapy) for AUCτ,ss of henagliflozin and HCTZ was within the bioequivalence interval of 0.80-1.25. For henagliflozin, co-administration increased Css, max by 24.32% and the 90% CI of the GMR was (108.34%, 142.65%), and the 24-hour urine volume and glucose excretion decreased by 0.43% and 19.6%, respectively. For HCTZ, co-administration decreased Css, max by 19.41% and the 90% CI of the GMR was (71.60%, 90.72%), and the 24-hour urine volume and urinary calcium, potassium, phosphorus, chloride, and sodium excretion decreased by 11.7%, 20.8%, 11.8%, 11.9%, 22.0% and 15.5%, respectively. All subjects (12/12) reported adverse events (AEs), but the majority of theses AEs were mild and no serious AEs were reported. Although Css,max was affected by the combination of henagliflozin and HCTZ, there was no clinically meaningful safety interaction between them. Given these results, coadministration of HCTZ should not require any adaptation of henagliflozin dosing. ClinicalTrials.gov NCT06083116.

Sex Differences in Ammoniagenesis in Obese, Diabetic, ZSF1 Rats

Diabetic ketoacidosis develops when insulin is insuffcient to clear blood sugar into cells for energy, then the liver breaks down fat for fuel with production of ketoacids. Lower pH activates proximal tubule PEPCK expression to replenish bicarbonate and excrete acid via NHE3 as ammonia, known as, “ammoniagenesis.” Baseline female (F) rodents exhibit greater ammoniagenesis and less NHE3 activity than males (M). We examined ammoniagenesis in male (M) and female (F) ZSF1 rats, a model of obesity and diabetic kidney disease. ZSF1 rats are born lean (L) or obese (O). OM display hyperglycemia and glucosuria at 10 wk, not yet evident in OF at 18 wk. We tested three hypotheses in ZSF1 rats (n=4-6/group): 1) ammoniagenesis rate is greater in OM and OF than LM and LF, 2) LF exhibit a higher rate of ammoniagenesis than OF, and 3) the blood glucose lowering SGLT2 inhibitor empagliflozin (SGLT2i) reduces ammoniagenesis in OM. Ammoniagenesis was measured as ammonia/24 hr/tibia length because OM and OF weigh 50% more than LM and LF. Abundance of PEPCK and NHE3 was assessed by semiquantitative immunoblots. Titratable acidity (TA) was measured as classically defined. In OM, ammoniagenesis was 6X greater (P< 0.0001), and TA elevated (P=0.0003) versus LM. Ammoniagenesis was not different in OF vs LF (P=0.99). Ammoniagenesis was only 2X greater in OM vs OF (P=0.001) indicative of higher baseline ammoniagenesis in F vs M. PEPCK abundance was 2.8X greater in both OM and OF vs LM and LF (P< 0.001), and NHE3 abundance was lower by 35 and 20%, respectively, in OM and OF vs LM and LF (P< 0.003). Oral SGLT2i treatment (10 mg/d, n=5-6/group, 6 wks starting at 20 wk old) vs vehicle lowered plasma glucose 35%, doubled urine glucose excretion, but did not significantly alter ammoniagenesis, PEPCK or NHE3 abundance (but tended to reduce urine TA). These findings demonstrate that at 16 weeks, OM exhibit highly elevated ammoniagenesis and TA along with hyperglycemia. In contrast, OF do not exhibit hyperglycemia nor elevated ammoniagenesis, illustrating a resistance to diabetic ketoacidosis at 16 wk, despite obesity, higher TA (P= 0.003), higher PEPCK and lower NHE3. In 20 wk old OM ZSF1, SGLT2i treatment does not reverse ammoniagenesis despite lowering plasma glucose for 6 weeks. R01 DK083785, R25DK113659, NIH Step Up U24 DK115255,. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

An Overview of Dapagliflozin

Type 2 diabetes, a chronic, progressive condition, causes hyperglycemia in the heart, liver, skeletal muscle, and adipose tissue. The latest forecasts show 592 million diabetics globally by 2035, up from 382 million in 2013. A new line of medicines blocks the kidney-based transporter protein sodium glucose co- transporter-2 (SGLT2) independently of insulin, complementing insulin treatment. Dapagliflozin (Forxiga) is a new EU-approved type 2 diabetes medication. This insulin-dependent process boosts urine glucose excretion. By specifically and potentially inhibiting SGLT2, dapagliflozin decreases blood glucose without insulin. Dapagliflozin had no clinically meaningful pharmacokinetic interactions with metformin, pioglitazone, sitagliptin, or glimepiride in healthy volunteers. The principal findings of clinical trials employing dapagliflozin to treat type 2 diabetes showed that the prescribed dosage (10 mg/day) was beneficial. Dapagliflozin works best with type 2 diabetes and cardiovascular disease or risk factors.