Increase In Urinary Glucose Excretion Research Articles

Acute over-additive natriuretic effects by a combination of finerenone and SGLT2 inhibition in rats with an activated renin-angiotensin-aldosterone system: a mechanistic basis for clinical outcomes?

Abstract Background Recent preclinical studies suggested an independent benefit of non-steroidal mineralocorticoid receptor (MR) antagonism by finerenone and SGLT2 inhibition in cardiorenal diseases, with a potential for combination therapy. Chronic low-dose combination of finerenone and empagliflozin in hypertensive rats revealed an early, sustained and over-additive reduction in proteinuria but the underlying mechanism(s) are not fully understood. Purpose To compare the acute glucosuric, natriuretic, kaliuretic and diuretic efficacy of individual dosages of finerenone and SGLT2 inhibitors (empagliflozin, canagliflozin or dapagliflozin) with the combined administration of both drug classes in conscious rats with an activated renin-angiotensin-aldosterone system (RAAS). Methods The RAAS was activated in male Wistar rats (body mass 250 to 500 g) by placing them on a low-salt diet containing 0.02% sodium chloride for 72 hours. In a series of three independent experiments, finerenone (1 mg/kg), SGLT2 inhibitor (3 mg/kg; either empagliflozin, canagliflozin or dapagliflozin) alone and the respective combinations were administered in 2-3 ml/kg of solvent (PEG400) by oral gavage and the animals (n=6-10 / group) were individually placed in metabolic cages on water ad libitum. The individual urine was collected for 24 hours and the concentration of glucose, sodium and potassium excreted in the urine was measured by a clinical-chemical analyzer system (ADVIA 2400). Results Administration of 1 mg/kg finerenone had no influence on urinary glucose, urinary volume and urinary potassium but caused an increase in urinary sodium excretion at least by trend. At a dose of 3 mg/kg, all SGLT2 inhibitors induced a strong increase in urinary glucose excretion but had no significant influence on urinary potassium and urinary sodium, while only dapagliflozin caused an increase in urinary volume at the tested dose. Administration of a combination of 1 mg/kg finerenone and 3 mg/kg SGLT2 inhibitor did not significantly modify urinary glucose and urinary potassium in comparison to the respective individual finerenone and SGLT2 inhibitor dosages and only the combination with empagliflozin increased urinary volume vs the respective monotherapies. Surprisingly, combination of finerenone with SGLT2 inhibition over-additively induced sodium excretion consistently in all three experiments (finerenone+empagliflozin: 171,4%; finerenone+canagliflozin: 139,6%; finerenone+dapagliflozin: 133,9%) in comparison to the calculated combination (set to 100%) of the respective individual finerenone and SGLT2 inhibitor groups. Conclusion Combination of MR antagonism by finerenone and SGLT2 inhibition revealed an acute over-additive natriuresis in a rat diuresis model. This might provide an additional mechanistic basis for near-term (e.g. hospitalization for heart failure) and long-term outcomes (e.g. blockade of the progression of kidney failure) in cardiorenal patient populations.

Empagliflozin reduces markers of acute kidney injury in patients with acute decompensated heart failure.

AimsIn this prospective, placebo‐controlled, double‐blind, exploratory study, we examined early and more delayed effects of empagliflozin treatment on haemodynamic parameters (primary endpoint: cardiac output) and kidney function including parameters of acute kidney injury (AKI) in patients with acute decompensated heart failure (HF).Methods and resultsPatients with acute decompensated HF with or without diabetes were randomized to empagliflozin 10 mg or placebo for 30 days. Haemodynamic, laboratory, and urinary parameters were assessed after 6 h, 1 day, 3 days, 7 days, and 30 days of treatment. Median time between hospital admission and randomization was 72 h. Baseline characteristics were not different in the empagliflozin (n = 10) and placebo (n = 9) groups. Empagliflozin led to a significant increase in urinary glucose excretion throughout the study (baseline: 37 ± 15 mg/24 h; Day 1: 14 565 ± 8663 mg/24 h; P = 0.001). Empagliflozin did not affect the primary endpoint of cardiac index or on systemic vascular resistance index at any time point. However, empagliflozin significantly reduced parameters of AKI (urinary TIMP‐2 and IGFBP7 by NephroCheck® as indicators of tubular kidney damage), which became significant after 3 days of treatment [placebo: 1.1 ± 1.1 (ng/mL)2/1000; empagliflozin: 0.3 ± 0.2 (ng/mL)2/1000; P = 0.02] and remained significant at the 7 day time point [placebo: 2.5 ± 3.8 (ng/mL)2/1000; empagliflozin: 0.3 ± 0.2 (ng/mL)2/1000; P = 0.003].ConclusionsIn this study, empagliflozin treatment did not affect haemodynamic parameters but significantly reduced markers of tubular injury in patients with acute decompensated HF.

Withdrawn: SGLT2 inhibitor ipragliflozin poses a low risk of hypoglycaemia owing to its blood glucose-dependent urinary glucose excretion mechanism in mice.

Sodium-glucose cotransporter (SGLT) 2 inhibitors, which inhibit renal reabsorption of glucose and stimulate urinary glucose excretion, have been proposed as useful drugs for treating diabetes. This study examined the effects of the SGLT2 inhibitor ipragliflozin on blood glucose-dependent urinary glucose excretion in mice. To investigate the antihyperglycemic effects of ipragliflozin, several oral glucose tolerance tests (glucose load: 1-4 g/kg) were performed. Ipragliflozin significantly suppressed the increases in blood glucose levels concomitant with urinary glucose excretion. To investigate the risk of hypoglycemia, the effects of ipragliflozin were examined under fasting conditions in mice that prefasted for various time periods (0-24 h). Ipragliflozin significantly decreased blood glucose levels in mice that had prefasted for 0 or 6 h (non-hypoglycemic conditions), but not in mice that had prefasted for 12 h or more (hypoglycemic conditions). These ipragliflozin-induced hypoglycemic and urinary glucose excretion effects were well correlated with blood glucose levels. These results suggest that ipragliflozin-induced increases in urinary glucose excretion and accompanying hypoglycemic effects were caused by blood glucose-dependent mechanisms. Thus, ipragliflozin may be a useful antidiabetic agent that achieves ideal blood glucose control in diabetic patients with little risk of hypoglycemia.

Cardiovascular protection by combination of the selective nonsteroidal MR antagonist finerenone and the SGLT2 inhibitor empagliflozin in a preclinical model of hypertension-induced end-organ damage

Abstract Background The nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone and SGLT2 inhibitors have demonstrated clinical benefits in HFrEF and CKD patients with T2D. Cardiovascular protection with finerenone and the SGLT2 inhibitor empagliflozin in combination in hypertensive cardiorenal disease is unknown. Purpose To test the hypothesis that the combination of finerenone with empagliflozin provides cardiovascular protection in preclinical hypertension-induced end-organ damage. Methods Cardiovascular morbidity and mortality was studied in hypertensive L-NAME (20 mg/L) treated renin-transgenic (mRen2)27 rats. Rats (10–11 weeks old female, n=13–17/group) were treated once daily orally for up to 7 weeks with placebo, finerenone (1 and 3 mg/kg), empagliflozin (3 and 10 mg/kg), or a combination of the respective low doses. Blood pressure (week 1, 3 and 5), urinary (week 2 and 6) and plasma parameters (week 6 and at the end of the study) were determined during the course of the study, while cardiac histology and left ventricular gene expression analysis were performed after study end. Results Empagliflozin induced a strong and dose-dependent increase in urinary glucose excretion which was not influenced by finerenone co-administration in the combination arm. Treatment with 3 mg/kg finerenone and the low dose combination significantly decreased systolic blood pressure (SBP) after 3 and 5 weeks as well as plasma uric acid after 6 weeks. SBP was significantly more reduced in the combination arm vs. the individual monotherapies after 3 weeks. Plasma NT-proBNP was reduced by empagliflozin, finerenone and the combination with similar efficacy. There was a dose-dependent protection from cardiac vasculopathy, cardiac and vascular fibrosis with both agents while low dose combination therapy was more efficient than the respective monotherapy dosages on these cardiac histology parameters. Placebo-treated rats demonstrated a ca. 50% survival rate over the course of 7 weeks while low dose combination provided the most prominent survival benefit (93%). Conclusion Non-steroidal MR antagonism by finerenone and SGLT2 inhibition by empagliflozin confer cardiovascular protection in preclinical hypertensive-induced cardiorenal disease. Combination of these two modes of action at low dosages revealed efficacious reduction in blood pressure, cardiac lesions and mortality indicating a strong potential for combined clinical use in cardiorenal patient populations. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): BAYER AG

Potential mechanisms underlying cardiovascular protection by sodium glucose cotransporter 2 inhibitors (empagliflozin)

The presented literature review is devoted to the cardioprotective capabilities of a new class of antihyperglycemic drugs - sodium-glucose cotransporter 2 inhibitors (SGLT2), which improve glycemic control through an insulin-independent mechanism of action associated with an increase in urinary glucose excretion. The article presents the results of large-scale clinical trials on the use of SGLT2 inhibitors in patients with and without diabetes, and with cardiovascular diseases or multiple cardiovascular risk factors. A number of the most frequently discussed cardiac specific mechanisms mediated by the SGLT2 inhibitor affecting the Abstract state of the cardiovascular system are presented. Moreover, the article presents the results of a placebo-controlled clinical trial entitled “Empagliflozin reduces mortality in patients with type 2 diabetes at high cardiovascular risk” (EMPA-REG oUtcOmE) to analyze the cardioprotective capabilities of SGLT2 inhibitor empagliflozin in patients with type 2 diabetes and concomitant cardiovascular diseases. The article emphasizes the importance of further research to determine the degree of contribution of the above-mentioned mechanisms to the cardioprotective potential of SGLT2 inhibitors. PubMed database was used to identify relevant studies and systematic reviews.

SGLT2 inhibitor ipragliflozin exerts antihyperglycemic effects via the blood glucose-dependent increase in urinary glucose excretion in type 2 diabetic mice

This study investigated the antihyperglycemic effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin via the blood glucose-dependent increase in urinary glucose excretion in KK/Ay type 2 diabetic mice. In oral glucose tolerance tests (glucose load: 1, 2, or 4 g/kg) in 24-h-fasted mice, blood glucose levels increased in a glucose-loading dose-dependent manner. Oral administration of ipragliflozin (1 mg/kg) significantly inhibited the increase in blood glucose concomitant with urinary glucose excretion. To investigate the effects of ipragliflozin under low blood glucose conditions, blood glucose level and urinary glucose excretion were examined under fasting conditions in diabetic mice that had prefasted for 0, 6, 12, 18, or 24 h. Ipragliflozin significantly lowered blood glucose levels in mice that had prefasted for 0, 6, or 12 h, but not 18 h or more. Blood glucose level was well correlated with ipragliflozin-induced antihyperglycemic and urinary glucose excretion effects, suggesting that these effects occur in a blood glucose-dependent manner. Thus, in a hyperglycemic state, ipragliflozin exerts a potent antihyperglycemic effect and marked increases in urinary glucose excretion; however, in a non-hyperglycemic or hypoglycemic state, the hypoglycemic effect is weak. Ipragliflozin may therefore be a useful antidiabetic agent for normalizing daily blood glucose fluctuations in type 2 diabetes.

Effects of empagliflozin on erythropoiesis in patients with type 2 diabetes: Data from a randomized, placebo-controlled study.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to significantly reduce hospitalization for heart failure (HHF) and cardiovascular (CV) mortality in various CV outcome trials in patients with and without type 2 diabetes mellitus (T2D). SGLT2 inhibition further increased haemoglobin and haematocrit levels by an as yet unknown mechanism, and this increase has been shown to be an independent predictor of the CV benefit of these agents, for example, in the EMPA-REG OUTCOME trial. The present analysis of the EMPA haemodynamic study examined the early and delayed effects of empagliflozin treatment on haemoglobin and haematocrit levels, in addition to measures of erythropoiesis and iron metabolism, to better understand the underlying mechanisms. In this prospective, placebo-controlled, double-blind, randomized, two-arm parallel, interventional and exploratory study, 44 patients with T2D were randomized into two groups and received empagliflozin 10 mg or placebo for a period of 3months in addition to their concomitant medication. Blood and urine was collected at baseline, on Day 1, on Day 3 and after 3months of treatment to investigate effects on haematological variables, erythropoietin concentrations and indices of iron stores. Baseline characteristics were comparable in the empagliflozin (n=20) and placebo (n=22) group. Empagliflozin led to a significant increase in urinary glucose excretion (baseline: 7.3 ± 22.7g/24h; Day 1: 48.4 ± 34.7g/24h; P < 0.001) as well as urinary volume (baseline: 1740 ± 601mL/24h; Day 1: 2112 ± 837 mL/24h; P=0.011) already after 1day and throughout the 3-month study period, while haematocrit and haemoglobin were only increased after 3months of treatment (haematocrit: baseline: 40.6% ± 4.6%; Month 3: 42.2% ± 4.8%, P < 0.001; haemoglobin: baseline: 136 ± 19g/L; Month 3: 142 ± 25g/L; P=0.008). In addition, after 3months, empagliflozin further increased red blood cell count (P < 0.001) and transferrin concentrations (P=0.063) and there was a trend toward increased erythropoietin levels (P=0.117), while ferritin (P=0.017), total iron (P=0.053) and transferrin saturation levels (P=0.030) decreased. Interestingly, the increase in urinary glucose excretion significantly correlated with the induction of erythropoietin in empagliflozin-treated patients at the 3-month timepoint (Spearman rho 0.64; P=0.008). Empagliflozin increased haemoglobin concentrations and haematocrit with a delayed time kinetic, which was most likely attributable to increased erythropoiesis with augmented iron utilization and not haemoconcentration. This might be attributable to reduced tubular glucose reabsorption in response to SGLT2 inhibition, possibly resulting in diminished cellular stress as a mechanism for increased renal erythropoietin secretion.

Effects of Finerenone Combined with Empagliflozin in a Model of Hypertension-Induced End-Organ Damage

Introduction: The nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone and sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated clinical benefits in CKD patients with type 2 diabetes. Clinical data analyzing the potential value of a combination therapy are currently limited. We therefore investigated cardiorenal protection of respective mono- and combination therapy in a preclinical model of hypertension-induced end-organ damage. Methods: Cardiovascular (CV) morbidity and mortality were studied in hypertensive, N(ω)-nitro-L-arginine methyl ester-treated, renin-transgenic (mRen2)27 rats. Rats (10- to 11-week-old females, n = 13–17/group) were treated once daily orally for up to 7 weeks with placebo, finerenone (1 and 3 mg/kg), empagliflozin (3 and 10 mg/kg), or a combination of the respective low doses. Key outcome parameters included mortality, proteinuria, plasma creatinine and uric acid, blood pressure, and cardiac and renal histology. Results: Placebo-treated rats demonstrated a 50% survival rate over the course of 7 weeks. Drug treatment resulted in variable degrees of survival benefit, most prominently in the low-dose combination group with a survival benefit of 93%. Monotherapies of finerenone or empagliflozin dose-dependently reduced proteinuria, while low-dose combination revealed an early, sustained, and over-additive reduction in proteinuria. Empagliflozin induced a strong and dose-dependent increase in urinary glucose excretion which was not influenced by finerenone coadministration in the combination arm. Low-dose combination but not respective low-dose monotherapies significantly reduced plasma creatinine and plasma uric acid after 6 weeks. Treatment with finerenone and the low-dose combination significantly decreased systolic blood pressure after 5 weeks. There was a dose-dependent protection from cardiac and kidney fibrosis and vasculopathy with both agents, while low-dose combination therapy was more efficient than the respective monotherapy dosages on most cardiorenal histology parameters. Discussion/Conclusions: Nonsteroidal MR antagonism by finerenone and SGLT2 inhibition by empagliflozin confer CV protection in preclinical hypertension-induced cardiorenal disease. Combination of these 2 independent modes of action at low dosages revealed efficacious reduction in important functional parameters such as proteinuria and blood pressure, plasma markers including creatinine and uric acid, cardiac and renal lesions as determined by histopathology, and mortality indicating a strong potential for combined clinical use in cardiorenal patient populations.

Do sodium-glucose co-transporter-2 inhibitors increase plasma glucagon by direct actions on the alpha cell? And does the increase matter for the associated increase in endogenous glucose production?

Sodium-glucose co-transporter-2 inhibitors (SGLT2is) lower blood glucose and are used for treatment of type 2 diabetes. However, SGLT2is have been associated with increases in endogenous glucose production (EGP) by mechanisms that have been proposed to result from SGLT2i-mediated increases in circulating glucagon concentrations, but the relative importance of this effect is debated, and mechanisms possibly coupling SGLT2is to increased plasma glucagon are unclear. A direct effect on alpha-cell activity has been proposed, but data on alpha-cell SGLT2 expression are inconsistent, and studies investigating the direct effects of SGLT2 inhibition on glucagon secretion are conflicting. By contrast, alpha-cell sodium-glucose co-transporter-1 (SGLT1) expression has been found more consistently and appears to be more prominent, pointing to an underappreciated role for this transporter. Nevertheless, the selectivity of most SGLT2is does not support interference with SGLT1 during therapy. Paracrine effects mediated by secretion of glucagonotropic/static molecules from beta and/or delta cells have also been suggested to be involved in SGLT2i-induced increase in plasma glucagon, but studies are few and arrive at different conclusions. It is also possible that the effect on glucagon is secondary to drug-induced increases in urinary glucose excretion and lowering of blood glucose, as shown in experiments with glucose clamping where SGLT2i-associated increases in plasma glucagon are prevented. However, regardless of the mechanisms involved, the current balance of evidence does not support that SGLT2 plays a crucial role for alpha-cell physiology or that SGLT2i-induced glucagon secretion is important for the associated increased EGP, particularly because the increase in EGP occurs before any rise in plasma glucagon.

Empagliflozin does not change cardiac index nor systemic vascular resistance but rapidly improves left ventricular filling pressure in patients with type 2 diabetes: a randomized controlled study

BackgroundIn the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial) treatment with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin significantly reduced heart failure hospitalization (HHF) in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease. The early separation of the HHF event curves within the first 3 months of the trial suggest that immediate hemodynamic effects may play a role. However, hitherto no data exist on early effects of SGLT2 inhibitors on hemodynamic parameters and cardiac function. Thus, this study examined early and delayed effects of empagliflozin treatment on hemodynamic parameters including systemic vascular resistance index, cardiac index, and stroke volume index, as well as echocardiographic measures of cardiac function.MethodsIn this placebo-controlled, randomized, double blind, exploratory study patients with T2D were randomized to empagliflozin 10 mg or placebo for a period of 3 months. Hemodynamic and echocardiographic parameters were assessed after 1 day, 3 days and 3 months of treatment.ResultsBaseline characteristics were not different in the empagliflozin (n = 22) and placebo (n = 20) group. Empagliflozin led to a significant increase in urinary glucose excretion (baseline: 7.3 ± 22.7 g/24 h; day 1: 48.4 ± 34.7 g/24 h; p < 0.001) as well as urinary volume (1740 ± 601 mL/24 h to 2112 ± 837 mL/24 h; p = 0.011) already after one day compared to placebo. Treatment with empagliflozin had no effect on the primary endpoint of systemic vascular resistance index, nor on cardiac index, stroke volume index or pulse rate at any time point. In addition, echocardiography showed no difference in left ventricular systolic function as assessed by left ventricular ejections fraction and strain analysis. However, empagliflozin significantly improved left ventricular filling pressure as assessed by a reduction of early mitral inflow velocity relative to early diastolic left ventricular relaxation (E/eʹ) which became significant at day 1 of treatment (baseline: 9.2 ± 2.6; day 1: 8.5 ± 2.2; p = 0.005) and remained apparent throughout the study. This was primarily attributable to reduced early mitral inflow velocity E (baseline: 0.8 ± 0.2 m/s; day 1: 0.73 ± 0.2 m/sec; p = 0.003).ConclusionsEmpagliflozin treatment of patients with T2D has no significant effect on hemodynamic parameters after 1 or 3 days, nor after 3 months, but leads to rapid and sustained significant improvement of diastolic function.Trial registration EudraCT Number: 2016-000172-19; date of registration: 2017-02-20 (clinicaltrialregister.eu)

Tubular effects of sodium–glucose cotransporter 2 inhibitors: intended and unintended consequences

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antihyperglycemic drugs that act by inhibiting renal sodium-glucose cotransport. Here we present new insights into 'off target', or indirect, effects of SGLT2 inhibitors. SGLT2 inhibition causes an acute increase in urinary glucose excretion. In addition to lowering blood glucose, there are several other effects that contribute to the overall beneficial renal and cardiovascular effects. Reabsorption of about 66% of sodium is accomplished in the proximal tubule and dependent on the sodium-hydrogen exchanger isoform 3 (NHE3). SGLT2 colocalizes with NHE3, and high glucose levels reduce NHE3 activity. The proximal tubule is also responsible for the majority of phosphate (Pi) reabsorption. SGLT2 inhibition is associated with increases in plasma Pi, fibroblast growth factor 23 and parathyroid hormone levels in nondiabetics and type 2 diabetes mellitus. Studies in humans identified a urate-lowering effect by SGLT2 inhibition which is possibly mediated by urate transporter 1 (URAT1) and/or glucose transporter member 9 in the proximal tubule. Of note, magnesium levels were also found to increase under SGLT2 inhibition, an effect that was preserved in nondiabetic patients with hypomagnesemia. Cardiorenal effects of SGLT2 inhibition might involve, in addition to direct effects on glucose homeostasis, effects on NHE3, phosphate, urate, and magnesium homeostasis.

SGLT2 inhibitors for genetic and acquired insulin resistance: Considerations for clinical use.

Administration of an sodium-glucose cotransporter2 inhibitor to individuals with insulin resistance reduces the level of glucose disposal necessary to maintain glycemia as a result of the induced increase in urinary glucose excretion. The amount of insulin required for a certain level of glucose disposal, on which the evaluation of insulin resistance is usually based, might thus decrease even without amelioration of insulin resistance.

138-LB: First-in-Human Study of YG1699, an SGLT1 and SGLT2 Dual Transporter Inhibitor

YG1699 is an orally-delivered, small molecule drug candidate that inhibits both the sodium glucose transporter 1 (SGLT1, IC50 = 16.6 nM) and the sodium glucose transorter 2 (SGLT2, IC50 = 1.49 nM). In the preclinical studies, YG1699 could suppress plasma glucose increases following acute glucose challenges in rat oral glucose tolerance tests, and decrease plasma glucose levels in db/db mice in a dose dependent manner. YG1699 can suppress intestinal glucose absorbance and increase both urine and fecal glucose excretion. In addition, YG1699 could significantly increase plasma GLP-1 and PYY levels in animal models. In this upcoming conference, we would like to report our first-in-human clinical trial for YG1699. This clinical study was conducted in USA (Identifier: NCT03953092) with 64 healthy volunteers participated in this single ascending dose (SAD) and multiple ascending dose (MAD) as well as food effect studies. In this Phase 1 clinical trial, YG1699 was well tolerated at all dose levels and produced a dose-dependent increase in urinary glucose excretion in both SAD and MAD studies. YG1699 also demonstrated a very good pharmacokinetic profile with linear, and dose-dependent exposure. The data also show that YG1699 has adequate half-life that can support once daily dosing in Phase II clinical trials. Adverse events were low and generally mild and no SAEs were observed. Disclosure C. Li: None. T. Li: None. F. Lee: None. R.H. Xu: None. H. Wang: Board Member; Self; Youngene Therapeutics. Stock/Shareholder; Self; Youngene Therapeutics.

Empagliflozin in Heart Failure: Diuretic and Cardiorenal Effects.

Sodium-glucose cotransporter-2 inhibitors improve heart failure-related outcomes. The mechanisms underlying these benefits are not well understood, but diuretic properties may contribute. Traditional diuretics such as furosemide induce substantial neurohormonal activation, contributing to the limited improvement in intravascular volume often seen with these agents. However, the proximal tubular site of action of the sodium-glucose cotransporter-2 inhibitors may help circumvent these limitations. Twenty patients with type 2 diabetes mellitus and chronic, stable heart failure completed a randomized, placebo-controlled crossover study of empagliflozin 10 mg daily versus placebo. Patients underwent an intensive 6-hour biospecimen collection and cardiorenal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with the above protocol repeated. Oral empagliflozin was rapidly absorbed as evidenced by a 27-fold increase in urinary glucose excretion by 3 hours (P<0.0001). Fractional excretion of sodium increased significantly with empagliflozin monotherapy versus placebo (fractional excretion of sodium, 1.2±0.7% versus 0.7±0.4%; P=0.001), and there was a synergistic effect in combination with bumetanide (fractional excretion of sodium, 5.8±2.5% versus 3.9±1.9%; P=0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (-208 mL [interquartile range, -536 to 153 mL] versus -14 mL [interquartile range, -282 to 335 mL]; P=0.035) and plasma volume (-138 mL, interquartile range, -379 to 154±453 mL; P=0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation because the change in norepinephrine was superior (P=0.02) and all other neurohormones were similar (P<0.34) during the empagliflozin versus placebo period. Furthermore, there was no evidence of potassium wasting (P=0.20) or renal dysfunction (P>0.11 for all biomarkers), whereas both serum magnesium (P<0.001) and uric acid levels (P=0.008) improved. Empagliflozin causes significant natriuresis, particularly when combined with loop diuretics, resulting in an improvement in blood volume. However, off-target electrolyte wasting, renal dysfunction, and neurohormonal activation were not observed. This favorable diuretic profile may offer significant advantage in the management of volume status in patients with heart failure and may represent a mechanism contributing to the superior long-term heart failure outcomes observed with these agents. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03027960.

Increase in Endogenous Glucose Production With SGLT2 Inhibition Is Unchanged by Renal Denervation and Correlates Strongly With the Increase in Urinary Glucose Excretion.

Sodium-glucose cotransporter 2 (SGLT2) inhibition causes an increase in endogenous glucose production (EGP). However, the mechanisms are unclear. We studied the effect of SGLT2 inhibitors on EGP in subjects with type 2 diabetes (T2D) and without diabetes (non-DM) in kidney transplant recipients with renal denervation. Fourteen subjects who received a renal transplant (six with T2D [A1C 7.2 ± 0.1%] and eight non-DM [A1C 5.6 ± 0.1%) underwent measurement of EGP with [3-3H]glucose infusion following dapagliflozin (DAPA) 10 mg or placebo. Plasma glucose, insulin, C-peptide, glucagon, and titrated glucose-specific activity were measured. Following placebo in T2D, fasting plasma glucose (FPG) (143 ± 14 to 124 ± 10 mg/dL; P = 0.02) and fasting plasma insulin (12 ± 2 to 10 ± 1.1 μU/mL; P < 0.05) decreased; plasma glucagon was unchanged, and EGP declined. After DAPA in T2D, FPG (143 ± 15 to 112 ± 9 mg/dL; P = 0.01) and fasting plasma insulin (14 ± 3 to 11 ± 2 μU/mL; P = 0.02) decreased, and plasma glucagon increased (all P < 0.05 vs. placebo). EGP was unchanged from baseline (2.21 ± 0.19 vs. 1.96 ± 0.14 mg/kg/min) in T2D (P < 0.001 vs. placebo). In non-DM following DAPA, FPG and fasting plasma insulin decreased, and plasma glucagon was unchanged. EGP was unchanged from baseline (1.85 ± 0.10 to 1.78 ± 0.10 mg/kg/min) after DAPA, whereas EGP declined significantly with placebo. When the increase in EGP production following DAPA versus placebo was plotted against the difference in urinary glucose excretion (UGE) for all patients, a strong correlation (r = 0.824; P < 0.001) was observed. Renal denervation in patients who received a kidney transplant failed to block the DAPA-mediated stimulation of EGP in both individuals with T2D and non-DM subjects. The DAPA-stimulated rise in EGP is strongly related to the increase in UGE, blunting the decline in FPG.

Exposure-response relationships for the sodium-glucose co-transporter-2 inhibitor dapagliflozin with regard to renal risk markers.

AimsTo quantitate the consistency of an individual's plasma exposure to dapagliflozin upon re‐exposure, and to investigate whether the individual's systemic exposure to dapagliflozin explains inter‐individual variation in response to dapagliflozin with regard to multiple renal risk markers.MethodsData were used from a crossover randomized clinical trial that assessed the albuminuria‐lowering effect of dapagliflozin in 33 people with type 2 diabetes and elevated albuminuria. Fifteen participants were exposed twice to dapagliflozin. Trough plasma concentrations of dapagliflozin were measured for each participant at steady state. Dapagliflozin plasma concentrations were measured by liquid chromatography tandem mass spectrometry, and pharmacokinetic characteristics were simulated based on a population pharmacokinetic model. Linear mixed‐effects models were used to quantify the exposure–response relationships.ResultsThe median plasma concentration after first and second exposure to dapagliflozin was 5.3 ng/mL vs 4.6 ng/mL, respectively (P = 0.78). Lin's concordance correlation coefficient between occasions was 0.73 (P < 0.0021). Every 100 ng.h/mL increment in area under the dapagliflozin plasma concentration curve was associated with a decrease in log‐transformed urinary albumin:creatinine ratio (β = −5.9, P < 0.01), body weight (β = −0.3, P < 0.01) and estimated glomerular filtration rate (β = −0.7, P = 0.01) and an increase in urinary glucose excretion (β = 17.0, P < 0.001).ConclusionAn individual's exposure to dapagliflozin is consistent upon re‐exposure and correlates with pharmacodynamic response in renal risk markers.

Pharmacokinetics and pharmacodynamics of rongliflozin, a novel selective inhibitor of sodium-glucose co-transporter-2, in people with type 2 diabetes mellitus.

To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of rongliflozin in a cohort of healthy Chinese people and people with type 2 diabetes mellitus (T2DM). We examined the effects of a single ascending dose (SAD) of rongliflozin (10-200 mg) in combination with food (20 mg) in 50 healthy people, and a multiple ascending dose (MAD) of rongliflozin (10-50 mg once daily for 12 days) in 36 people with T2DM. No serious adverse events (AEs) or discontinuations as a result of AEs (related to rongliflozin) occurred in either study. In healthy participants and those with T2DM, rongliflozin was rapidly absorbed, with a time to maximum plasma concentration of 0.63 to 1.75 hours. Systemic exposure (maximum observed serum concentration and area under the curve) to rongliflozin and its inactive major metabolites (T1444, T1454 and T1830) increased in proportion to dose. In the SAD and MAD studies, there was a dose-related increase in urinary glucose excretion (UGE) ranging from 10 to 50 mg rongliflozin. This increase in UGE was associated with dose-related decreases in serum glucose values in people with T2DM in the MAD group. In the SAD group, UGE plateaued at 50 to 200 mg. Rongliflozin was well tolerated in all participants. The PK and PD measurements obtained for rongliflozin demonstrate a dose-response relationship when the drug is administered at doses ranging from 10 to 50 mg in healthy people and in people with T2DM.

162-LB: Pharmacokinetics, Pharmacodynamics, and Tolerability of Single- and Multiple-Dose of Janagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, in Chinese Patients with Type 2 Diabetes Mellitus

Objectives: Janagliflozin (JGZ) is a novel sodium-glucose cotransporter 2 (SGLT2) inhibitor in development for the treatment of type 2 diabetes mellitus (T2DM). This study assessed the pharmacokinetics, pharmacodynamics, and tolerability of JGZ in Chinese patients with T2DM. Methods: In this double-blind, parallel-controlled study, 36 patients with inadequately controlled T2DM were randomized into JGZ 25 mg, JGZ 50 mg, dapagliflozin 10 mg, or placebo cohort in a 1:1:1:1 ratio. Patients were treated with a single dose on Day 1, and then once daily from Day 4 to Day 17. Results: JGZ was readily absorbed with Cmax observed at 2.00 hours (median). The half-life was estimated to be 21.2-23.3 hours at steady state. Plasma JGZ exposure increased in a dose-proportional manner and the accumulation rates were relatively low in Cmax (1.46-1.49) and AUC0-24 (1.67-1.81). Mean (SD) changes from baseline in 24 hour urinary glucose excretion (UGE) were 72.8 (26.2), 78.7 (17.3), 85.8 (25.2), and 2.20 (7.22) g after single dose, and were 92.4 (25.4), 94.2 (29.1), 87.6 (32.2), and 6.26 (24.3) g after multiple doses with JGZ 25 mg, JGZ 50 mg, dapagliflozin 10 mg, and placebo, respectively. Mean (SD) changes from baseline in fasting plasma glucose on Day 17 were 2.18 (1.62), 2.66 (2.01), 2.79 (1.44), and 1.70 (2.04) mmol/L for the four groups, respectively. Mean (SD) changes from baseline in A1C on Day 18 were 0.45% (0.29%), 0.33% (0.57%), 0.62% (0.35%), and 0.07% (0.80%) for the four groups, respectively. Adverse events were mostly mild or moderate with no hypoglycemia episode, serious adverse event, or discontinuation due to adverse event. Conclusions: JGZ exhibited favorable pharmacokinetics profiles in Chinese patients with T2DM and was well tolerated. JGZ treatments resulted in increase in UGE and improvement in glycemic control. JGZ 25 mg and 50 mg are recommended for further clinical studies. Disclosure Y. Ding: None. Funding XuanZhu Pharma Co., Ltd.

Effects of the SGLT2 inhibitor ipragliflozin on various diabetic symptoms and progression of overt nephropathy in type 2 diabetic mice.

Diabetic nephropathy is the leading cause of end-stage renal disease and is associated with high-cardiovascular risk and significant morbidity and mortality. The recent development of sodium-glucose cotransporter (SGLT) 2 inhibitors offers a new antidiabetic therapy via enhanced glucose excretion; however, the beneficial effect of these drugs on the development of type 2 diabetic overt nephropathy is still largely unclear. We examined the therapeutic effects of the SGLT2 inhibitor ipragliflozin on various diabetic symptoms and the progression of nephropathy in uninephrectomized type 2 diabetic mice, which exhibit not only typical diabetic symptoms, such as impaired insulin secretion, glucose intolerance, hyperglycemia, and obesity, but also overt nephropathy with decline in renal function. Diabetes was induced by intraperitoneal administration of nicotinamide (1000mg/kg) and streptozotocin (150mg/kg) to uninephrectomized high-fat diet-fed mice. Ipragliflozin (0.1-3mg/kg) was orally administered to diabetic mice once daily for 4weeks. Repeated administration of ipragliflozin improved diabetic symptoms, such as hyperglycemia and insulin resistance, via an increase in urinary glucose excretion. In addition, ipragliflozin attenuated albuminuria/proteinuria and the decline in renal function, and improved renal injury, including glomerulosclerosis and interstitial fibrosis. Our results demonstrate that ipragliflozin improves various diabetic symptoms and delays development of diabetic nephropathy. Therefore, SGLT2 inhibitors could constitute a novel therapeutic target for the treatment of type 2 diabetes with overt nephropathy.

Antidiabetic and antiobesity effects of SGLT2 inhibitor ipragliflozin in type 2 diabetic mice fed sugar solution

Obesity due to excessive calorie intake is a known aggravating factor contributing to the development and progression of type 2 diabetes. Recently, excessive intake of sugar-sweetened beverages has presented challenges in stemming the tide of obesity. Here, we investigated the possible effects of sugar solution intake on the antidiabetic effects of sodium-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin in type 2 diabetic mice that were fed ordinary drinking water, water + glucose solution, or water + sucrose solution. Under all feeding conditions, all mice exhibited type 2 diabetic symptoms, including hyperglycemia, hyperinsulinemia, and obesity; ipragliflozin subsequently improved these symptoms through increases in urinary glucose excretion. Effective dose of and response to ipragliflozin for diabetes improvement did not significantly differ by feeding condition. Further, under all feeding conditions, ipragliflozin administration resulted in significantly increased intake of both water and sugar solutions in association with increased urine volume resulting from increased urinary glucose excretion. In sugar solution-fed diabetic mice, ipragliflozin administration tended to slightly increase the proportion of sugar solution intake in total drinking volume, although not significantly so. In addition, ipragliflozin significantly decreased calorie balance, as calculated using calorie intake from food and sugar solution and calorie excretion via urinary glucose excretion. Our observation that the antidiabetic and antiobesity effects of the SGLT2 inhibitor ipragliflozin were not greatly affected by sugar solution intake in type 2 diabetic mice suggests that, in a clinical setting, ipragliflozin will remain an effective treatment for type 2 diabetic patients with excessive intake of carbohydrates.