Exposure-Response Analysis of the Sodium-Glucose Cotransporter-2 Inhibitors Dapagliflozin and Empagliflozin on Kidney Hemodynamics in Patients with Type 2 Diabetes.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve markers for renal and cardiovascular outcomes in patients with and without type 2 diabetes (T2D). To assess whether individual differences in plasma drug exposure can explain inter-individual response variation, we characterized the exposure-response relationship for two SGLT2 inhibitors on several clinical and kidney hemodynamic variables. Data were obtained from two studies, RED and RECOLAR, assessing the effects of once-daily 10 mg dapagliflozin or empagliflozin, respectively, on kidney hemodynamics in patients with T2D. Individual plasma exposure was estimated using non-compartmental analyses and exposure-response relationships were assessed using linear mixed-effects models. In 23 patients participating in RED, the dapagliflozin geometric mean apparent area under the concentration-time curve during one dosing interval at steady state (AUC0-tau,ss) was 1153.1 µg/L*h (coefficient of variation (CV) 81.8%) and associated, per doubling, with decreases in body weight (0.29 kg, p < 0.001), systolic blood pressure (0.80 mmHg, p = 0.002), measured glomerular filtration rate (mGFR) (0.83 mL/min, p = 0.03), and filtration fraction (0.09%, p = 0.04). In 20 patients participating in RECOLOR, the empagliflozin geometric mean AUC0-tau,ss was 2035.7 nmol/L*h (CV 48.4%) and associated, per doubling, with decreases in body weight (0.13 kg, p = 0.002), systolic blood pressure (0.65 mmHg, p = 0.045), and mGFR (0.78 mL/min, p = 0.002). To conclude, dapagliflozin and empagliflozin plasma exposure was highly variable between patients and associated with inter-individual variation in response variables.

SGLT2 Inhibition and Uric Acid Excretion in Patients with Type 2 Diabetes and Normal Kidney Function.

BACKGROUND AND OBJECTIVES: Sodium-glucose transporter 2 (SGLT2) inhibitor-induced uric acid lowering may contribute to kidney-protective effects of the drug class in people with type 2 diabetes. This study investigates mechanisms of plasma uric acid lowering by SGLT2 inhibitors in people with type 2 diabetes with a focus on urate transporter 1. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted an analysis of two randomized clinical trials. First, in the Renoprotective Effects of Dapagliflozin in Type 2 Diabetes study, 44 people with type 2 diabetes were randomized to dapagliflozin or gliclazide for 12 weeks. Plasma uric acid, fractional uric acid excretion, and hemodynamic kidney function were measured in the fasted state and during clamped euglycemia or hyperglycemia. Second, in the Uric Acid Excretion study, ten people with type 2 diabetes received 1 week of empagliflozin, urate transporter 1 blocker benzbromarone, or their combination in a crossover design, and effects on plasma uric acid, fractional uric acid excretion, and 24-hour uric acid excretion were measured. RESULTS: In the Renoprotective Effects of Dapagliflozin in Type 2 Diabetes study, compared with the fasted state (5.3±1.1 mg/dl), acute hyperinsulinemia and hyperglycemia significantly reduced plasma uric acid by 0.2±0.3 and 0.4±0.3 mg/dl (both P<0.001) while increasing fractional uric acid excretion (by 3.2%±3.1% and 8.9%±4.5%, respectively; both P<0.001). Dapagliflozin reduced plasma uric acid by 0.8±0.8 during fasting, 1.0±1.0 in hyperinsulinemic-euglycemic state, and 0.8±0.7 mg/dl during hyperglycemic conditions (P<0.001), respectively, whereas fractional uric acid excretion in 24-hour urine increased by 3.0%±2.1% (P<0.001) and 2.6%±4.5% during hyperinsulinemic-euglycemic conditions (P=0.003). Fractional uric acid excretion strongly correlated to fractional glucose excretion (r=0.35; P=0.02). In the Uric Acid Excretion study, empagliflozin and benzbromarone both significantly reduced plasma uric acid and increased fractional uric acid excretion. Effects of combination therapy did not differ from benzbromarone monotherapy. CONCLUSIONS: In conclusion, SGLT2 inhibitors induce uric acid excretion, which is strongly linked to urinary glucose excretion and is attenuated during concomitant pharmacologic blockade of urate transporter 1. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Renoprotective Effects of Dapagliflozin in Type 2 Diabetes (RED), NCT02682563; SGLT2 Inhibition: Uric Acid Excretion Study (UREX), NCT05210517.

Whole-body insulin clearance in people with type 2 diabetes and normal kidney function: Relationship with glomerular filtration rate, renal plasma flow, and insulin sensitivity.

OBJECTIVE: Kidney insulin clearance, proposed to be the main route of extra-hepatic insulin clearance, occurs in tubular cells following glomerular filtration and peritubular uptake, a process that may be impaired in people with type 2 diabetes (T2D) and/or impaired kidney function. Human studies that investigated kidney insulin clearance are limited by the invasive nature of the measurement. Instead, we evaluated relationships between whole-body insulin clearance, and gold-standard measured kidney function and insulin sensitivity in adults with T2D and normal kidney function. RESEARCH DESIGN AND METHODS: We determined insulin, inulin/iohexol and para-aminohippuric acid (PAH) clearances during a hyperinsulinemic-euglycemic clamp to measure whole-body insulin clearance and kidney function. Insulin sensitivity was expressed by glucose infusion rate (M value). Associations between whole-body insulin clearance, kidney function and insulin sensitivity were examined using univariable and multivariable linear regressions models. RESULTS: We investigated 44 predominantly male (77%) T2D adults aged 63 ± 7, with fat mass 34.5 ± 9 kg, lean body mass 63.0 ± 11.8 kg, and HbA1c 7.4 ± 0.6%. Average whole-body insulin clearance was 1188 ± 358 mL/min. Mean GFR was 110 ± 22 mL/min, mean ERPF 565 ± 141 mL/min, and M value averaged 3.9 ± 2.3 mg/min. Whole-body insulin clearance was positively correlated with lean body mass, ERPF and insulin sensitivity, but not with GFR. ERPF explained 6% of the variance when entered in a nested multivariable linear regression model op top of lean body mass (25%) and insulin sensitivity (15%). CONCLUSIONS: In adults with T2D and normal kidney function, whole-body insulin clearance was predicted best by lean body mass and insulin sensitivity, and to a lesser extent by ERPF. GFR was not associated with whole-body insulin clearance. In contrast to prior understanding, this suggests that in this population kidney insulin clearance may not play such a dominant role in whole-body insulin clearance.

Kidney hemodynamic profile and systemic vascular function in adults with type 2 diabetes: Analysis of three clinical trials.

AIMS: Glomerular hyperfiltration plays a key role in the pathophysiology of diabetic kidney disease (DKD). Mechanisms underlying this adverse hemodynamic profile are incompletely understood. We hypothesized that systemic vascular pathology, including endothelial dysfunction and arterial stiffness, relates to glomerular hyperfiltration indicated by filtration fraction (FF). METHODS: Baseline data of three trials of overweight adults with type 2 diabetes (TD2, n = 111) with relatively well preserved kidney function were analyzed. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and FF, were assessed with gold-standard clearance techniques. Systemic vascular resistance (SVR), an indicator of endothelial dysfunction, and pulse pressure (PP), a measure of arterial stiffness, were derived from continuous beat-to-beat monitoring. RESULTS: SVR related negatively to GFR (ß: -0.382, p < 0.001) and ERPF (ß: -0.475, p < 0.001), and positively to FF (ß:0.369, p < 0.001). Associations between SVR, ERPF and FF persisted after multivariable adjustments.. PP was negatively related to ERPF (ß: -0.252, p = 0.008), and positively to FF (ß: 0.257, p = 0.006), of which the latter remained significant in multivariable regression. CONCLUSION: Parameters of systemic vascular pathology, including endothelial dysfunction and arterial stiffness, relate to an adverse kidney hemodynamic profile characterized by glomerular hyperfiltration, which predisposes to the development of DKD.

Kidney hemodynamic function in men and postmenopausal women with type 2 diabetes and preserved kidney function.

The progression of kidney disease may differ between sexes in type 2 diabetes (T2D), with previous studies reporting a slower decline in women. Glomerular hyperfiltration is a key factor driving the kidney function decline. The current study aimed to investigate the differences in kidney hemodynamic function between men and women with T2D. A cross-sectional analysis of pooled data from three studies compared kidney hemodynamic function between men and postmenopausal women with T2D without overt nephropathy. The outcome measures were glomerular filtration rate (GFR; inulin clearance), effective renal plasma flow (ERPF; p-aminohippurate clearance), filtration fraction (GFR/ERPF), and renal vascular resistance (RVR; mean arterial pressure/renal blood flow). Glomerular hydraulic pressure (PGLO) as well as afferent and efferent vascular resistance were estimated by Gomez formulae. Sex differences were assessed with linear regression models adjusted for systolic blood pressure, glucose, use of renin-angiotensin system blockers, and body mass index. In total, 101 men [age: 63 (58-68) yr, body mass index: 31.5 ± 3.9 kg/m2, GFR: 111 ± 18 mL/min, HbA1c: 7.4 ± 0.7%] and 27 women [age: 66 (62-69) yr, body mass index: 30.9 ± 4.5 kg/m2, GFR: 97 ± 11 mL/min, HbA1c: 7.1 ± 0.5%] were included. GFR was higher in men versus women [11.0 mL/min (95% confidence interval: 3.6, 18.4)]. Although statistically nonsignificant, PGLO trended higher in men [1.9 mmHg (95% confidence interval: -0.1, 4.0)], whereas RVR [-0.012 mmHg/L/min (95% confidence interval: -0.022, -0.002)] and afferent vascular resistance were lower [-361 dyn/s/cm5 (95% confidence interval: -801, 78)]. In conclusion, in adults without overt nephropathy, GFR was higher in men compared with women. PGLO also trended to be higher in men. Both findings are possibly related to afferent vasodilation and suggest greater prevalence of hyperfiltration. This could contribute to accelerated GFR loss over time in men with T2D.NEW & NOTEWORTHY In adults with type 2 diabetes, men had higher markers of hyperfiltration, which could potentially explain the accelerated progression of diabetic kidney disease in men compared with women.

SGLT2 inhibition versus sulfonylurea treatment effects on electrolyte and acid-base balance: secondary analysis of a clinical trial reaching glycemic equipoise: Tubular effects of SGLT2 inhibition in Type 2 diabetes.

Sodium-glucose transporter (SGLT)2 inhibitors increase plasma magnesium and plasma phosphate and may cause ketoacidosis, but the contribution of improved glycemic control to these observations as well as effects on other electrolytes and acid-base parameters remain unknown. Therefore, our objective was to compare the effects of SGLT2 inhibitors dapagliflozin and sulfonylurea gliclazide on plasma electrolytes, urinary electrolyte excretion, and acid-base balance in people with Type 2 diabetes (T2D). We assessed the effects of dapagliflozin and gliclazide treatment on plasma electrolytes and bicarbonate, 24-hour urinary pH and excretions of electrolytes, ammonium, citrate, and sulfate in 44 metformin-treated people with T2D and preserved kidney function. Compared with gliclazide, dapagliflozin increased plasma chloride by 1.4 mmol/l (95% CI 0.4-2.4), plasma magnesium by 0.03 mmol/l (95% CI 0.01-0.06), and plasma sulfate by 0.02 mmol/l (95% CI 0.01-0.04). Compared with baseline, dapagliflozin also significantly increased plasma phosphate, but the same trend was observed with gliclazide. From baseline to week 12, dapagliflozin increased the urinary excretion of citrate by 0.93 ± 1.72 mmol/day, acetoacetate by 48 µmol/day (IQR 17-138), and ß-hydroxybutyrate by 59 µmol/day (IQR 0-336), without disturbing acid-base balance. In conclusion, dapagliflozin increases plasma magnesium, chloride, and sulfate compared with gliclazide, while reaching similar glucose-lowering in people with T2D. Dapagliflozin also increases urinary ketone excretion without changing acid-base balance. Therefore, the increase in urinary citrate excretion by dapagliflozin may reflect an effect on cellular metabolism including the tricarboxylic acid cycle. This potentially contributes to kidney protection.

Effects of dapagliflozin and gliclazide on the cardiorenal axis in people with type 2 diabetes.

OBJECTIVES: There is a bidirectional relationship between cardiovascular and renal disease. The drug-class of SGLT2 inhibitors improves outcomes at both ends of this so called cardiorenal axis. We assessed the effects of SGLT2 inhibition and sulfonylurea treatment on systemic hemodynamic function and investigated whether SGLT2 inhibitor-induced changes in systemic hemodynamics correlate with changes in renal hemodynamics. METHODS: Forty-four people with type 2 diabetes were randomized to 12 weeks of dapagliflozin 10 mg/day or gliclazide 30 mg/day treatment. Systemic hemodynamic function, autonomic nervous system activity, and vascular stiffness were measured noninvasively, whereas renal hemodynamics, glomerular filtration rate (GFR) and effective renal plasma flow, were assessed with gold-standard urinary clearances of inulin or iohexol and para-aminohippuric acid, respectively. Correlation analyses were performed to assess relationships between dapagliflozin-induced changes in cardiovascular and renal variables. RESULTS: Dapagliflozin reduced stroke volume by 4%, cardiac output by 5%, vascular stiffness by 11%, and mean arterial pressure by 5% from baseline, without increasing heart rate or sympathetic activity, while simultaneously lowering glomerular filtration rate by 8%. Despite similar improvements in glycemic control by dapagliflozin and gliclazide (-0.5 ±â€Š0.5 versus-0.7 ±â€Š0.5%; P = 0.12), gliclazide did not affect any of these measurements. There was no clear association between the dapagliflozin-induced changes in cardiovascular and renal physiology. CONCLUSION: Dapagliflozin seemingly influences systemic and renal hemodynamics independently and beyond glucose lowering in people with type 2 diabetes.This clinical trial was registered at https://clinicalTrials.gov (ID: NCT02682563).

The effect of dapagliflozin on apolipoprotein B and glucose fluxes in patients with type 2 diabetes and well-controlled plasma LDL cholesterol.

AIM: To dissect the effects of the sodium-glucose linked transporter 2 inhibitor dapagliflozin on lipid metabolism and assess whether these effects could potentially offset cardiovascular benefit with this drug-class. MATERIALS AND METHODS: We assessed the effect of dapagliflozin on lipid metabolism in 11 adults with uncomplicated type 2 diabetes. After 4 weeks of statin wash-out and 4 weeks of rosuvastatin 10 mg treatment, participants were treated with dapagliflozin 10 mg once-daily for 5 weeks. Before and after dapagliflozin, plasma lipids were measured and very low-density lipoprotein (VLDL)-1 and VLDL-2 apolipoprotein (Apo)B fluxes were assessed using (5.5.5-2 H3 )-leucine tracer infusion. In addition, hepatic and peripheral insulin sensitivity as well as insulin-mediated inhibition of peripheral lipolysis were measured during a two-step hyperinsulinemic-euglycaemic clamp using (6,6-2 H2 )-glucose and (1,1,2,3,3-2 H5 )-glycerol tracers. RESULTS: Rosuvastatin decreased all plasma lipids significantly: total cholesterol from 4.5 (3.2-6.2) to 3.1 (2.5-3.8) mmol/L, LDL cholesterol from 2.6 (1.7-3.4) to 1.5 (1.1-2.2) mmol/L, HDL cholesterol from 1.34 (0.80-2.02) to 1.19 (0.74-1.89) mmol/L and triglycerides from 0.92 (0.31-3.91) to 0.79 (0.32-2.10) mmol/L. The addition of dapaglifozin to rosuvastatin did not raise either LDL cholesterol or total cholesterol, and only increased HDL cholesterol by 0.08 (-0.03-0.13) mmol/L (P = 0.03). In line with this, dapagliflozin did not affect VLDL-1 or VLDL-2 ApoB fluxes. Fasting endogenous glucose production tended to increase by 0.9 (-3.4-3.1) µmol kg-1 min-1 (P = 0.06), but no effect on hepatic and peripheral insulin sensitivity or on peripheral lipolysis was observed. CONCLUSIONS: Dapagliflozin has no effect on plasma LDL-cholesterol levels or VLDL-apoB fluxes in the context of optimal lipid-lowering treatment, which will thus not limit cardiovascular benefit when lipids are adequately controlled.

The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve hard renal outcomes in type 2 diabetes. This is possibly explained by the fact that SGLT2i normalize the measured glomerular filtration rate (mGFR) by increasing renal vascular resistance, as was shown in young people with type 1 diabetes and glomerular hyperfiltration. Therefore, we compared the renal hemodynamic effects of dapagliflozin with gliclazide in type 2 diabetes. The mGFR and effective renal plasma flow were assessed using inulin and para-aminohippurate clearances in the fasted state, during clamped euglycemia (5 mmol/L) and during clamped hyperglycemia (15 mmol/L). Filtration fraction and renal vascular resistance were calculated. Additionally, factors known to modulate renal hemodynamics were measured. In 44 people with type 2 diabetes on metformin monotherapy (Hemoglobin A1c 7.4%, mGFR 113 mL/min), dapagliflozin versus gliclazide reduced mGFR by 5, 10, and 12 mL/min in the consecutive phases while both agents similarly improved Hemoglobin A1c (-0.48% vs -0.65%). Dapagliflozin also reduced filtration fraction without increasing renal vascular resistance, and increased urinary adenosine and prostaglandin concentrations. Gliclazide did not consistently alter renal hemodynamic parameters. Thus, beyond glucose control, SGLT2i reduce mGFR and filtration fraction in type 2 diabetes. The fact that renal vascular resistance was not increased by dapagliflozin suggests that this is due to post-glomerular vasodilation rather than pre-glomerular vasoconstriction.

Insulin Sensitivity and Renal Hemodynamic Function in Metformin-Treated Adults With Type 2 Diabetes and Preserved Renal Function.

OBJECTIVE: Impaired insulin sensitivity is associated with hyperfiltration (i.e., elevated glomerular filtration rate [GFR]) in adolescents with type 2 diabetes (T2D) and adults with prediabetes. Yet, these relationships are based on studies that relied on estimated GFR (eGFR), estimates of insulin sensitivity, or both. We aimed to verify the relationship between insulin sensitivity and renal hemodynamic function by gold standard methods in adults with T2D. RESEARCH DESIGN AND METHODS: Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp (M value) (glucose infusion rate in mg/kglean/min) and renal hemodynamic function by urinary inulin (GFR) and para-aminohippuric acid (effective renal plasma flow [ERPF]) clearances in participants with T2D without overt kidney disease. Filtration fraction (FF) (GFR/ERPF) was calculated. Relationships between insulin sensitivity and renal hemodynamic parameters were examined by multivariable linear regression. Renal hemodynamic parameters were examined across tertiles of M values. RESULTS: We tested 44 adults with T2D, of whom 77% were male, with mean ± SD age 63 ± 7 years, BMI 31.2 ± 4.0 kg/m2, and HbA1c 7.4 ± 0.6%. Average GFR was 110 ± 26 mL/min, with an FF of 22.1 ± 2.8% and median 24-h urinary albumin excretion of 11.3 mg (interquartile range 5.8-17.0). Average M value was 5.6 ± 2.9 mg/kglean/min. Insulin sensitivity inversely correlated with GFR (r = -0.44, P < 0.01) and FF (r = -0.40, P < 0.01), and these associations remained significant after multivariable adjustments for age, sex, renin-angiotensin system inhibitor use, and HbA1c. In addition, GFR, FF, and urinary albumin excretion were highest in the participants in the lowest M value tertile. CONCLUSIONS: For the first time, we demonstrate that impaired insulin sensitivity is associated with intrarenal hemodynamic dysfunction by gold standard techniques in adults with T2D treated with metformin monotherapy.

The osteoblast: Linking glucocorticoid-induced osteoporosis and hyperglycaemia? A post-hoc analysis of a randomised clinical trial.

HYPOTHESIS: Glucocorticoids (GCs) induce osteoporosis predominantly by inhibiting osteoblast activity. We hypothesised that osteoblastic factors could also be linked to GC-induced adverse metabolic effects. METHODS: We performed a post-hoc analysis of a randomised, placebo-controlled, double blind, dose-response intervention study involving 32 healthy males (age: 22 ±â€¯3 years; BMI 22.4 ±â€¯1.7 kg/m2) who were allocated to prednisolone (PRED) 7.5 mg once daily (n = 12), PRED 30 mg once daily (n = 12), or placebo (n = 8) for two weeks using block randomisation. Mean outcomes measures included osteocalcin, N-terminal propeptide of type 1 procollagen (P1NP) and their relation to glucose and lipid metabolism, measured by stable isotopes, before and at 2 weeks of treatment, in the fasted state and during a two-step hyperinsulinaemic clamp. RESULTS: Osteocalcin and P1NP concentrations were dose-dependently decreased by PRED treatment (p < 0.001 both). PRED dosages dose-dependently reduced sensitivity of the liver and skeletal muscle for insulin (p < 0.001 both) and impaired suppression of lipolysis mediated by insulin (p < 0.01). In multivariate analyses, GC-induced changes in osteocalcin concentrations related to reduces hepatic insulin sensitivity (ß = -0.315; p = 0.044). In addition, GC-induced changes in P1NP were negatively related to changes in insulin-mediated suppression of hepatic glucose production (r = -0.582; p = 0.001), and were positively related to insulin-stimulated glucose uptake (r = 0.638; p < 0.001). Finally, changes in PN1P were negatively related to changes in fasting hypertriglyceridemia (r = -0.499; p = 0.004) and insulin-induced suppression of lipolysis rates (r = -0.494; p = 0.006). CONCLUSION: GC treatment alters osteoblastic function which is associated with several adverse metabolic effects of GC treatment. Future causal studies are needed to assess the specific mediator(s) by which the osteoblast alters intermediary metabolism. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN83991850.

SGLT2 Inhibition in the Diabetic Kidney-From Mechanisms to Clinical Outcome.

Diabetic kidney disease not only has become the leading cause for ESRD worldwide but also, highly contributes to increased cardiovascular morbidity and mortality in type 2 diabetes. Despite increased efforts to optimize renal and cardiovascular risk factors, like hyperglycemia, hypertension, obesity, and dyslipidemia, they are often insufficiently controlled in clinical practice. Although current drug interventions mostly target a single risk factor, more substantial improvements of renal and cardiovascular outcomes can be expected when multiple factors are improved simultaneously. Sodium-glucose cotransporter type 2 in the renal proximal tubule reabsorbs approximately 90% of filtered glucose. In type 2 diabetes, the maladaptive upregulation of sodium-glucose cotransporter type 2 contributes to the maintenance of hyperglycemia. Inhibiting these transporters has been shown to effectively improve glycemic control through inducing glycosuria and is generally well tolerated, although patients experience more genital infections. In addition, sodium-glucose cotransporter type 2 inhibitors favorably affect body weight, BP, serum uric acid, and glomerular hyperfiltration. Interestingly, in the recently reported first cardiovascular safety trial with a sodium-glucose cotransporter type 2 inhibitor, empagliflozin improved both renal and cardiovascular outcomes in patients with type 2 diabetes and established cardiovascular disease. Because the benefits were seen rapidly after initiation of therapy and other glucose-lowering agents, with the exception of liraglutide and semaglutide, have not been able to improve cardiovascular outcome, these observations are most likely explained by effects beyond glucose lowering. In this mini review, we present the drug class of sodium-glucose cotransporter type 2 inhibitors, elaborate on currently available renal and cardiovascular outcome data, and discuss how the effects of these agents on renal physiology may explain the data.