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Hansjuergen Woerle - One of the best experts on this subject based on the ideXlab platform.
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Empagliflozin and kidney function decline in patients with type 2 diabetes a slope analysis from the empa reg outcome trial
Journal of The American Society of Nephrology, 2018Co-Authors: Christoph Wanner, Hansjuergen Woerle, Michaela Mattheus, Stefan Hantel, Bernard Zinman, Silvio E. Inzucchi, Hiddo J L Heerspink, Audrey Koitkaweber, Uli C BroedlAbstract:Background Empagliflozin slowed the progression of CKD in patients with type 2 diabetes and cardiovascular disease in the EMPA-REG OUTCOME Trial. In a prespecified statistical approach, we assessed treatment differences in kidney function by analyzing slopes of eGFR changes. Methods Participants ( n =7020) were randomized (1:1:1) to Empagliflozin 10 mg/d, Empagliflozin 25 mg/d, or placebo added to standard of care. We calculated eGFR slopes using random-intercept/random-coefficient models for prespecified study periods: treatment initiation (baseline to week 4), chronic maintenance treatment (week 4 to last value on treatment), and post-treatment (last value on treatment to follow-up). Results Compared with placebo, Empagliflozin was associated with uniform shifts in individual eGFR slopes across all periods. On treatment initiation, adjusted mean slope (eGFR change per week, ml/min per 1.73 m 2 ) decreased with Empagliflozin (−0.77; 95% confidence interval, −0.83 to −0.71; placebo: 0.01; 95% confidence interval, −0.08 to 0.10; P 2 per year) did not decline with Empagliflozin during chronic treatment (Empagliflozin: 0.23; 95% confidence interval, 0.05 to 0.40; placebo: −1.46; 95% confidence interval, −1.74 to −1.17; P 2 per week) increased and mean eGFR returned toward baseline level only in the Empagliflozin group (0.56; 95% confidence interval, 0.49 to 0.62; placebo −0.02; 95% confidence interval, −0.12 to 0.08; P Conclusions The hemodynamic effects of Empagliflozin, associated with reduction in intraglomerular pressure, may contribute to long-term preservation of kidney function.
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pooled analysis of phase iii trials indicate contrasting influences of renal function on blood pressure body weight and hba1c reductions with Empagliflozin
Kidney International, 2018Co-Authors: David Z.i. Cherney, Hansjuergen Woerle, Uli C Broedl, Egon Pfarr, Ilkka Tikkanen, Odd Erik Johansen, Mark E Cooper, Soren S LundAbstract:Sodium glucose cotransporter 2 (SGLT2) inhibitors reduce HbA1c, blood pressure, and weight in patients with type 2 diabetes. To investigate the effect of renal function on reductions in these parameters with the SGLT2 inhibitor Empagliflozin, we assessed subgroups by baseline estimated glomerular filtration rate (eGFR; Modification of Diet in Renal Disease) in pooled data from five 24-week trials of 2286 patients with type 2 diabetes randomized to Empagliflozin or placebo. Reductions in HbA1c with Empagliflozin versus placebo significantly diminished with decreasing baseline eGFR. Reductions in systolic blood pressure (SBP) with Empagliflozin were maintained in patients with lower eGFR. The mean placebo-corrected changes from baseline in systolic blood pressure at week 24 with Empagliflozin were -3.2 (95% confidence interval -4.9,-1.5) mmHg, -4.0 (-5.4, -2.6) mmHg, -5.5 (-7.6, -3.4) mmHg, and -6.6 (-11.4, -1.8) mmHg in patients with an eGFR of 90 or more, 60 to 89, 30 to 59, and under 30 ml/min/1.73m 2 , respectively. Similar trends were observed for diastolic blood pressure. Weight loss with Empagliflozin versus placebo tended to be attenuated in patients with a lower eGFR. Results were consistent in a 12-week ambulatory blood pressure monitoring trial in 823 patients with type 2 diabetes and hypertension. Thus, unlike HbA1c reductions, systolic blood pressure and weight reductions with Empagliflozin are generally preserved in patients with chronic kidney disease.
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Empagliflozin and Cerebrovascular Events in Patients With Type 2 Diabetes Mellitus at High Cardiovascular Risk.
Stroke, 2017Co-Authors: Bernard Zinman, Hansjuergen Woerle, Uli C Broedl, Michaela Mattheus, Sven Kohler, Christoph Wanner, Silvio E. Inzucchi, John M. Lachin, David Fitchett, Odd Erik JohansenAbstract:Background and Purpose— In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), Empagliflozin added to standard of care in patients with type 2 diabetes mellitus and high cardiovascular risk reduced the risk of 3-point major adverse cardiovascular events, driven by a reduction in cardiovascular mortality, with no significant difference between Empagliflozin and placebo in risk of myocardial infarction or stroke. In a modified intent-to-treat analysis, the hazard ratio for stroke was 1.18 (95% confidence interval, 0.89–1.56; P =0.26). We further investigated cerebrovascular events. Methods— Patients were randomized to Empagliflozin 10 mg, Empagliflozin 25 mg, or placebo; 7020 patients were treated. Median observation time was 3.1 years. Results— The numeric difference in stroke between Empagliflozin and placebo in the modified intent-to-treat analysis was primarily because of 18 patients in the Empagliflozin group with a first event >90 days after last intake of study drug (versus 3 on placebo). In a sensitivity analysis based on events during treatment or ≤90 days after last dose of drug, the hazard ratio for stroke with Empagliflozin versus placebo was 1.08 (95% confidence interval, 0.81–1.45; P =0.60). There were no differences in risk of recurrent, fatal, or disabling strokes, or transient ischemic attack, with Empagliflozin versus placebo. Patients with the largest increases in hematocrit or largest decreases in systolic blood pressure did not have an increased risk of stroke. Conclusions— In patients with type 2 diabetes mellitus and high cardiovascular risk, there was no significant difference in the risk of cerebrovascular events with Empagliflozin versus placebo. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01131676.
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Empagliflozin and cardiovascular outcomes in asian patients with type 2 diabetes and established cardiovascular disease results from empa reg outcome
Circulation, 2017Co-Authors: Kohei Kaku, Michaela Mattheus, Stefan Kaspers, Jisoo Lee, Jyothis T. George, Hansjuergen WoerleAbstract:Background In the EMPA-REG OUTCOME®trial, Empagliflozin added to standard of care reduced the risk of 3-point major adverse cardiovascular (CV) events (3-point MACE: composite of CV death, non-fatal myocardial infarction, or non-fatal stroke) by 14%, CV death by 38%, hospitalization for heart failure by 35%, and all-cause mortality by 32% in patients with type 2 diabetes (T2DM) and established CV disease. We investigated the effects of Empagliflozin in patients of Asian race.Methods and Results:Patients were randomized to receive Empagliflozin 10 mg, Empagliflozin 25 mg, or placebo. Of 7,020 patients treated, 1,517 (21.6%) were of Asian race. The reduction in 3-point MACE in Asian patients was consistent with the overall population: 3-point MACE occurred in 79/1,006 patients (7.9%) in the pooled Empagliflozin group vs. 58/511 patients (11.4%) in the placebo group (hazard ratio: 0.68 [95% confidence interval: 0.48-0.95], P-value for treatment by race interaction (Asian, White, Black/African-American): 0.0872). The effects of Empagliflozin on the components of MACE, all-cause mortality, and heart failure outcomes in Asian patients were consistent with the overall population (P-values for interaction by race >0.05). The adverse event profile of Empagliflozin in Asian patients was similar to the overall trial population. Conclusions Reductions in the risk of CV outcomes and mortality with Empagliflozin in Asian patients with T2DM and established CV disease were consistent with the overall trial population.
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Acute Pharmacodynamic Effects of Empagliflozin With and Without Diuretic Agents in Patients With Type 2 Diabetes Mellitus.
Clinical Therapeutics, 2016Co-Authors: Tim Heise, Hansjuergen Woerle, Sreeraj Macha, Michaela Mattheus, Soren S Lund, Jens Jordan, Christoph Wanner, Martina Heer, Uli C BroedlAbstract:Abstract Purpose The goal of this study was to investigate the pharmacodynamic effects of co-administration of Empagliflozin, a sodium glucose cotransporter 2 inhibitor, with diuretic agents. Methods In a randomized, open-label cross-over study, 22 patients with type 2 diabetes mellitus received Empagliflozin 25 mg for 5 days and either hydrochlorothiazide 25 mg for 4 days followed by hydrochlorothiazide 25 mg plus Empagliflozin 25 mg for 5 days, or torasemide 5 mg for 4 days followed by torasemide 5 mg plus Empagliflozin 25 mg for 5 days; 20 completed treatment. Food, fluid, and sodium intake were standardized for 3 days before and during treatment. Findings At baseline, the median age of the treated patients was 56 years (range, 40–65 years), body mass index was 26.8 kg/m 2 (range, 20.1–34.4 kg/m 2 ), fasting plasma glucose was 8.6 mmol/L (range, 6.0–12.9 mmol/L), and glycosylated hemoglobin level was 7.6% (range, 7%–10%). Empagliflozin significantly increased 24-hour urinary glucose excretion and reduced fasting serum glucose levels. These effects were maintained after co-administration with either diuretic. Urinary sodium excretion did not significantly change with Empagliflozin or diuretic administration alone, but seemed to increase compared with either diuretic alone when Empagliflozin was co-administered with either diuretic. Plasma renin and serum aldosterone levels were unaltered with Empagliflozin or torasemide alone, but tended to increase with hydrochlorothiazide alone, and tended to increase when Empagliflozin was co-administered with a diuretic compared with either diuretic alone. Urinary volume did not increase with Empagliflozin or diuretics alone, but increased when Empagliflozin was co-administered with either diuretic. Implications Empagliflozin alone for 5 days increased urinary glucose excretion but did not seem to have a relevant impact on urine volume or electrolytes. When Empagliflozin was co-administered with a diuretic agent, urinary glucose excretion remained increased, and the renin-angiotensin system was activated. Clinicaltrials.gov identifier: NCT01276288.
Uli C Broedl - One of the best experts on this subject based on the ideXlab platform.
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Empagliflozin and kidney function decline in patients with type 2 diabetes a slope analysis from the empa reg outcome trial
Journal of The American Society of Nephrology, 2018Co-Authors: Christoph Wanner, Hansjuergen Woerle, Michaela Mattheus, Stefan Hantel, Bernard Zinman, Silvio E. Inzucchi, Hiddo J L Heerspink, Audrey Koitkaweber, Uli C BroedlAbstract:Background Empagliflozin slowed the progression of CKD in patients with type 2 diabetes and cardiovascular disease in the EMPA-REG OUTCOME Trial. In a prespecified statistical approach, we assessed treatment differences in kidney function by analyzing slopes of eGFR changes. Methods Participants ( n =7020) were randomized (1:1:1) to Empagliflozin 10 mg/d, Empagliflozin 25 mg/d, or placebo added to standard of care. We calculated eGFR slopes using random-intercept/random-coefficient models for prespecified study periods: treatment initiation (baseline to week 4), chronic maintenance treatment (week 4 to last value on treatment), and post-treatment (last value on treatment to follow-up). Results Compared with placebo, Empagliflozin was associated with uniform shifts in individual eGFR slopes across all periods. On treatment initiation, adjusted mean slope (eGFR change per week, ml/min per 1.73 m 2 ) decreased with Empagliflozin (−0.77; 95% confidence interval, −0.83 to −0.71; placebo: 0.01; 95% confidence interval, −0.08 to 0.10; P 2 per year) did not decline with Empagliflozin during chronic treatment (Empagliflozin: 0.23; 95% confidence interval, 0.05 to 0.40; placebo: −1.46; 95% confidence interval, −1.74 to −1.17; P 2 per week) increased and mean eGFR returned toward baseline level only in the Empagliflozin group (0.56; 95% confidence interval, 0.49 to 0.62; placebo −0.02; 95% confidence interval, −0.12 to 0.08; P Conclusions The hemodynamic effects of Empagliflozin, associated with reduction in intraglomerular pressure, may contribute to long-term preservation of kidney function.
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pooled analysis of phase iii trials indicate contrasting influences of renal function on blood pressure body weight and hba1c reductions with Empagliflozin
Kidney International, 2018Co-Authors: David Z.i. Cherney, Hansjuergen Woerle, Uli C Broedl, Egon Pfarr, Ilkka Tikkanen, Odd Erik Johansen, Mark E Cooper, Soren S LundAbstract:Sodium glucose cotransporter 2 (SGLT2) inhibitors reduce HbA1c, blood pressure, and weight in patients with type 2 diabetes. To investigate the effect of renal function on reductions in these parameters with the SGLT2 inhibitor Empagliflozin, we assessed subgroups by baseline estimated glomerular filtration rate (eGFR; Modification of Diet in Renal Disease) in pooled data from five 24-week trials of 2286 patients with type 2 diabetes randomized to Empagliflozin or placebo. Reductions in HbA1c with Empagliflozin versus placebo significantly diminished with decreasing baseline eGFR. Reductions in systolic blood pressure (SBP) with Empagliflozin were maintained in patients with lower eGFR. The mean placebo-corrected changes from baseline in systolic blood pressure at week 24 with Empagliflozin were -3.2 (95% confidence interval -4.9,-1.5) mmHg, -4.0 (-5.4, -2.6) mmHg, -5.5 (-7.6, -3.4) mmHg, and -6.6 (-11.4, -1.8) mmHg in patients with an eGFR of 90 or more, 60 to 89, 30 to 59, and under 30 ml/min/1.73m 2 , respectively. Similar trends were observed for diastolic blood pressure. Weight loss with Empagliflozin versus placebo tended to be attenuated in patients with a lower eGFR. Results were consistent in a 12-week ambulatory blood pressure monitoring trial in 823 patients with type 2 diabetes and hypertension. Thus, unlike HbA1c reductions, systolic blood pressure and weight reductions with Empagliflozin are generally preserved in patients with chronic kidney disease.
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Empagliflozin and Cerebrovascular Events in Patients With Type 2 Diabetes Mellitus at High Cardiovascular Risk.
Stroke, 2017Co-Authors: Bernard Zinman, Hansjuergen Woerle, Uli C Broedl, Michaela Mattheus, Sven Kohler, Christoph Wanner, Silvio E. Inzucchi, John M. Lachin, David Fitchett, Odd Erik JohansenAbstract:Background and Purpose— In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), Empagliflozin added to standard of care in patients with type 2 diabetes mellitus and high cardiovascular risk reduced the risk of 3-point major adverse cardiovascular events, driven by a reduction in cardiovascular mortality, with no significant difference between Empagliflozin and placebo in risk of myocardial infarction or stroke. In a modified intent-to-treat analysis, the hazard ratio for stroke was 1.18 (95% confidence interval, 0.89–1.56; P =0.26). We further investigated cerebrovascular events. Methods— Patients were randomized to Empagliflozin 10 mg, Empagliflozin 25 mg, or placebo; 7020 patients were treated. Median observation time was 3.1 years. Results— The numeric difference in stroke between Empagliflozin and placebo in the modified intent-to-treat analysis was primarily because of 18 patients in the Empagliflozin group with a first event >90 days after last intake of study drug (versus 3 on placebo). In a sensitivity analysis based on events during treatment or ≤90 days after last dose of drug, the hazard ratio for stroke with Empagliflozin versus placebo was 1.08 (95% confidence interval, 0.81–1.45; P =0.60). There were no differences in risk of recurrent, fatal, or disabling strokes, or transient ischemic attack, with Empagliflozin versus placebo. Patients with the largest increases in hematocrit or largest decreases in systolic blood pressure did not have an increased risk of stroke. Conclusions— In patients with type 2 diabetes mellitus and high cardiovascular risk, there was no significant difference in the risk of cerebrovascular events with Empagliflozin versus placebo. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01131676.
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Acute Pharmacodynamic Effects of Empagliflozin With and Without Diuretic Agents in Patients With Type 2 Diabetes Mellitus.
Clinical Therapeutics, 2016Co-Authors: Tim Heise, Hansjuergen Woerle, Sreeraj Macha, Michaela Mattheus, Soren S Lund, Jens Jordan, Christoph Wanner, Martina Heer, Uli C BroedlAbstract:Abstract Purpose The goal of this study was to investigate the pharmacodynamic effects of co-administration of Empagliflozin, a sodium glucose cotransporter 2 inhibitor, with diuretic agents. Methods In a randomized, open-label cross-over study, 22 patients with type 2 diabetes mellitus received Empagliflozin 25 mg for 5 days and either hydrochlorothiazide 25 mg for 4 days followed by hydrochlorothiazide 25 mg plus Empagliflozin 25 mg for 5 days, or torasemide 5 mg for 4 days followed by torasemide 5 mg plus Empagliflozin 25 mg for 5 days; 20 completed treatment. Food, fluid, and sodium intake were standardized for 3 days before and during treatment. Findings At baseline, the median age of the treated patients was 56 years (range, 40–65 years), body mass index was 26.8 kg/m 2 (range, 20.1–34.4 kg/m 2 ), fasting plasma glucose was 8.6 mmol/L (range, 6.0–12.9 mmol/L), and glycosylated hemoglobin level was 7.6% (range, 7%–10%). Empagliflozin significantly increased 24-hour urinary glucose excretion and reduced fasting serum glucose levels. These effects were maintained after co-administration with either diuretic. Urinary sodium excretion did not significantly change with Empagliflozin or diuretic administration alone, but seemed to increase compared with either diuretic alone when Empagliflozin was co-administered with either diuretic. Plasma renin and serum aldosterone levels were unaltered with Empagliflozin or torasemide alone, but tended to increase with hydrochlorothiazide alone, and tended to increase when Empagliflozin was co-administered with a diuretic compared with either diuretic alone. Urinary volume did not increase with Empagliflozin or diuretics alone, but increased when Empagliflozin was co-administered with either diuretic. Implications Empagliflozin alone for 5 days increased urinary glucose excretion but did not seem to have a relevant impact on urine volume or electrolytes. When Empagliflozin was co-administered with a diuretic agent, urinary glucose excretion remained increased, and the renin-angiotensin system was activated. Clinicaltrials.gov identifier: NCT01276288.
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Initial Combination of Empagliflozin and Metformin in Patients With Type 2 Diabetes.
Diabetes Care, 2016Co-Authors: Samy Hadjadj, Hansjuergen Woerle, Julio Rosenstock, Thomas Meinicke, Uli C BroedlAbstract:OBJECTIVE This study compared the efficacy and safety of initial combinations of Empagliflozin + metformin with Empagliflozin and metformin monotherapy in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS The study randomized 1,364 drug-naive patients (HbA1c >7.5 to ≤12% [>58 to ≤108 mmol/mol]) for 24 weeks to Empagliflozin 12.5 mg b.i.d. + metformin 1,000 mg b.i.d., Empagliflozin 12.5 mg b.i.d. + metformin 500 mg b.i.d., Empagliflozin 5 mg b.i.d + metformin 1,000 mg b.i.d., Empagliflozin 5 mg b.i.d. + metformin 500 mg b.i.d., Empagliflozin 25 mg q.d., Empagliflozin 10 mg q.d., metformin 1,000 mg b.i.d., or metformin 500 mg b.i.d. The primary end point was change from baseline in HbA1c at week 24. RESULTS At week 24, reductions in HbA1c (mean baseline 8.6–8.9% [70–73 mmol/mol]) were −1.9 to −2.1% with Empagliflozin + metformin twice-daily regimens, −1.4% with both Empagliflozin once-daily regimens, and −1.2 to −1.8% with metformin twice-daily regimens. Reductions in HbA1c were significantly greater with Empagliflozin + metformin twice-daily regimens than with Empagliflozin once-daily regimens (P CONCLUSIONS Initial combinations of Empagliflozin + metformin for 24 weeks significantly reduced HbA1c versus Empagliflozin once daily and metformin twice daily, without increased hypoglycemia, reduced weight versus metformin twice daily, and were well tolerated.
Michael Mark - One of the best experts on this subject based on the ideXlab platform.
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Empagliflozin via switching metabolism toward lipid utilization moderately increases ldl cholesterol levels through reduced ldl catabolism
Diabetes, 2016Co-Authors: Francois Briand, Michael Mark, Eric Mayoux, Emmanuel Brousseau, Noemie Burr, Isabelle Urbain, Clement Costard, Thierry SulpiceAbstract:In clinical trials, a small increase in LDL cholesterol has been reported with sodium-glucose cotransporter 2 (SGLT2) inhibitors. The mechanisms by which the SGLT2 inhibitor Empagliflozin increases LDL cholesterol levels were investigated in hamsters with diet-induced dyslipidemia. Compared with vehicle, Empagliflozin 30 mg/kg/day for 2 weeks significantly reduced fasting blood glucose by 18%, with significant increase in fasting plasma LDL cholesterol, free fatty acids, and total ketone bodies by 25, 49, and 116%, respectively. In fasting conditions, glycogen hepatic levels were further reduced by 84% with Empagliflozin, while 3-hydroxy-3-methylglutaryl-CoA reductase activity and total cholesterol hepatic levels were 31 and 10% higher, respectively (both P < 0.05 vs. vehicle). A significant 20% reduction in hepatic LDL receptor protein expression was also observed with Empagliflozin. Importantly, none of these parameters were changed by Empagliflozin in fed conditions. Empagliflozin significantly reduced the catabolism of (3)H-cholesteryl oleate-labeled LDL injected intravenously by 20%, indicating that Empagliflozin raises LDL levels through reduced catabolism. Unexpectedly, Empagliflozin also reduced intestinal cholesterol absorption in vivo, which led to a significant increase in LDL- and macrophage-derived cholesterol fecal excretion (both P < 0.05 vs. vehicle). These data suggest that Empagliflozin, by switching energy metabolism from carbohydrate to lipid utilization, moderately increases ketone production and LDL cholesterol levels. Interestingly, Empagliflozin also reduces intestinal cholesterol absorption, which in turn promotes LDL- and macrophage-derived cholesterol fecal excretion.
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the sodium glucose cotransporter type 2 inhibitor Empagliflozin preserves β cell mass and restores glucose homeostasis in the male zucker diabetic fatty rat
Journal of Pharmacology and Experimental Therapeutics, 2014Co-Authors: Henrik H Hansen, Thomas Klein, Michael Mark, Jacob Jelsing, Carl Frederik Hansen, Gitte Hansen, Niels Vrang, Eric MayouxAbstract:Type 2 diabetes is characterized by impaired β-cell function associated with progressive reduction of insulin secretion and β-cell mass. Evidently, there is an unmet need for treatments with greater sustainability in β-cell protection and anti-diabetic efficacy. Through an insulin and β-cell independent mechanism, Empagliflozin, a specific sodium glucose co-transporter type-2 (SGLT-2) inhibitor, may potentially provide longer efficacy. This study compared the anti-diabetic durability of Empagliflozin treatment (10 mg/kg, p.o.) against glibenclamide (3 mg/kg, p.o.) and liraglutide (0.2 mg/kg, s.c.) on deficient glucose homeostasis and β-cell function in Zucker diabetic Fatty (ZDF) rats. Empagliflozin and liraglutide led to marked improvements in fed glucose and HbA1c levels, as well as impeding a progressive decline in insulin levels. In contrast, glibenclamide was ineffective. Whereas the effects of liraglutide were less pronounced at week 8 of treatment compared to week 4, those of Empagliflozin remained stable throughout the study period. Similarly, Empagliflozin improved glucose tolerance and preserved insulin secretion after both 4 and 8 weeks of treatment. These effects were reflected by a less reduction in β-cell mass with Empagliflozin or liraglutide at week 4, while only Empagliflozin showed β-cell sparing effects at week 8. While this study cannot be used to dissociate the absolute anti-diabetic efficacy among those different mechanisms of action, the study demonstrates that Empagliflozin exerts a more sustained improvement of glucose homeostasis and β-cell protection ZDF rats. In comparison to other type 2 diabetic treatments, SGLT-2 inhibitors may through insulin-independent pathways thus enhance durability of β-cell protection and anti-diabetic efficacy.
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Empagliflozin a novel potent and selective sglt 2 inhibitor improves glycaemic control alone and in combination with insulin in streptozotocin induced diabetic rats a model of type 1 diabetes mellitus
Diabetes Obesity and Metabolism, 2012Co-Authors: Gerd Luippold, Michael Mark, Thomas Klein, Rolf GremplerAbstract:Aim: Sodium glucose cotransporter-2 (SGLT-2) is key to reabsorption of glucose in the kidney. SGLT-2 inhibitors are in clinical development for treatment of type 2 diabetes mellitus (T2DM). The mechanism may be of value also in the treatment of type 1 diabetes mellitus (T1DM). This study investigated effects of the SGLT-2 inhibitor, Empagliflozin, alone and in combination with insulin, on glucose homeostasis in an animal model of T1DM. Methods: Sprague–Dawley rats were administered a single intraperitoneal injection of streptozotocin (STZ; 60 mg/kg). Acutely, STZ rats received two doses of insulin glargine with or without Empagliflozin, and blood glucose was measured. In a subchronic study, STZ rats received Empagliflozin alone, one or two insulin-releasing implants or a combination of one implant and Empagliflozin over 28 days; blood glucose and HbA1c were measured. Results: In the acute setting, Empagliflozin in combination with 1.5 IU insulin induced a similar glucose-lowering effect as 6 IU insulin. Both interventions were more efficacious than monotherapy with 1.5 IU insulin. In the subchronic study, 12-h blood glucose profile on day 28 in the combination group was lower than with one implant, and similar to two implants. Plasma HbA1c was improved in the combination group and in animals with two implants. Conclusions: Empagliflozin reduced blood glucose levels in a T1DM animal model. Empagliflozin combined with low-dose insulin showed comparable glucose-lowering efficacy to treatment with high-dose insulin. Our data suggest that Empagliflozin is an efficacious adjunctive-to-insulin therapy with the clinical potential for the treatment of T1DM.
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long term treatment with Empagliflozin a novel potent and selective sglt 2 inhibitor improves glycaemic control and features of metabolic syndrome in diabetic rats
Diabetes Obesity and Metabolism, 2012Co-Authors: Leo Thomas, Rolf Grempler, Matthias Eckhardt, Frank Himmelsbach, Achim Sauer, Thomas Klein, Peter Eickelmann, Michael MarkAbstract:Empagliflozin is a potent, selective sodium glucose co-transporter-2 inhibitor that is in development for the treatment of type 2 diabetes. This series of studies was conducted to assess the in vivo pharmacological effects of single or multiple doses of Empagliflozin in Zucker diabetic fatty rats. Single doses of Empagliflozin resulted in dose-dependent increases in urinary glucose excretion and reductions in blood glucose levels. After multiple doses (5 weeks), fasting blood glucose levels were reduced by 26 and 39% with 1 and 3 mg/kg Empagliflozin, respectively, relative to vehicle. After 5 weeks, HbA1c levels were reduced (from a baseline of 7.9%) by 0.3 and 1.1% with 1 and 3 mg/kg Empagliflozin, respectively, versus an increase of 1.1% with vehicle. Hyperinsulinaemic-euglycaemic clamp indicated improved insulin sensitivity with Empagliflozin after multiple doses versus vehicle. These findings support the development of Empagliflozin for the treatment of type 2 diabetes.
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Empagliflozin a novel selective sodium glucose cotransporter 2 sglt 2 inhibitor characterisation and comparison with other sglt 2 inhibitors
Diabetes Obesity and Metabolism, 2012Co-Authors: Rolf Grempler, Leo Thomas, Matthias Eckhardt, Frank Himmelsbach, Achim Sauer, Thomas Klein, Michael Mark, D E Sharp, Remko Bakker, Peter EickelmannAbstract:Aims: Empagliflozin is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor in clinical development for the treatment of type 2 diabetes mellitus. This study assessed pharmacological properties of Empagliflozin in vitro and pharmacokinetic properties in vivo and compared its potency and selectivity with other SGLT-2 inhibitors. Methods: [14C]-alpha-methyl glucopyranoside (AMG) uptake experiments were performed with stable cell lines over-expressing human (h) SGLT-1, 2 and 4. Two new cell lines over-expressing hSGLT-5 and hSGLT-6 were established and [14C]-mannose and [14C]-myo-inositol uptake assays developed. Binding kinetics were analysed using a radioligand binding assay with [3H]-labelled Empagliflozin and HEK293-hSGLT-2 cell membranes. Acute in vivo assessment of pharmacokinetics was performed with normoglycaemic beagle dogs and Zucker diabetic fatty (ZDF) rats. Results: Empagliflozin has an IC50 of 3.1 nM for hSGLT-2. Its binding to SGLT-2 is competitive with glucose (half-life approximately 1 h). Compared with other SGLT-2 inhibitors, Empagliflozin has a high degree of selectivity over SGLT-1, 4, 5 and 6. Species differences in SGLT-1 selectivity were identified. Empagliflozin pharmacokinetics in ZDF rats were characterised by moderate total plasma clearance (CL) and bioavailability (BA), while in beagle dogs CL was low and BA was high. Conclusions: Empagliflozin is a potent and competitive SGLT-2 inhibitor with an excellent selectivity profile and the highest selectivity window of the tested SGLT-2 inhibitors over hSGLT-1. Empagliflozin represents an innovative therapeutic approach to treat diabetes.
Eric Mayoux - One of the best experts on this subject based on the ideXlab platform.
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The Favorable Effect of Empagliflozin on Erectile Function in an Experimental Model of Type 2 Diabetes
The Journal of Sexual Medicine, 2018Co-Authors: Rana Assaly, Eric Mayoux, Diane Gorny, Sandrine Compagnie, Jacques Bernabé, Laurent Alexandre, François Giuliano, Delphine Behr-rousselAbstract:Abstract Introduction Following the results of the EMPA-REG Outcome trial, we hypothesized that Empagliflozin, a highly potent and specific sodium/glucose cotransporteur 2 inhibitor, could improve type 2 diabetes mellitus (T2DM)-associated erectile dysfunction (ED), a highly prevalent complication of T2DM, very often coexisting with cardiovascular complications and considered as a prognostic factor of cardiovascular disease in men with diabetes. Aim To investigate the effects of chronic treatment with Empagliflozin on ED in a T2DM rat model in the presence or absence of sildenafil. Methods Male Goto-Kakizaki (GK), a model of T2DM, and age-matched Wistar rats received placebo or Empagliflozin treatment at 25.3 ± 0.9 mg/kg/d for 4 weeks. Then, the in vivo effect of Empagliflozin on erectile function was assessed by electrical stimulation of the cavernous nerve at different frequencies under anesthesia in the presence or absence of acute intravenous injection of sildenafil. Endothelium-dependent, -independent, and nitrergic relaxations of cavernosal strips from the rats were studied. Main Outcome Measures Body weight, food consumption, metabolic parameters, plasma inflammation biomarkers, and in vivo erectile responses elicited by electrical stimulation of the cavernous nerve in Empagliflozin-treated and untreated GK rats and control Wistar rats were assessed and followed by concentration or frequency response curves to endothelium-dependent, -independent, and nitrergic relaxations of cavernosal strips from these rats. Results Chronic Empagliflozin followed by acute sildenafil significantly improved erectile responses in adult GK rats (n = 12–15/group). Ratios of intracavernous pressure and area under the curve/mean arterial pressure during the electrical stimulation were significantly increased in Empagliflozin-treated vs untreated GK rats. Nitrergic relaxations of cavernosal strips from GK rats were significantly increased with Empagliflozin compared with placebo. Moreover, the effect of sildenafil on erectile function was not altered by Empagliflozin treatment. Clinical Implications Empagliflozin may benefit T2DM patient with ED. Strengths & Limitations The mechanism(s) by which Empagliflozin shows favorable effect on erectile function in GK rats needs to be further elucidated. Conclusion Empagliflozin shows favorable effect on erectile function in diabetic GK rats mediated by an improvement of nitrergic relaxation of erectile tissue. Whether this favorable effect on ED in the experimental context of T2DM is due to better glycemic control or to another effect of Empagliflozin deserves further investigation. Assaly R, Gorny D, Compagnie S, et al. The Favorable Effect of Empagliflozin on Erectile Function in an Experimental Model of Type 2 Diabetes. J Sex Med 2018;15:1224–1234.
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Empagliflozin Improves Left Ventricular Diastolic Dysfunction in a Genetic Model of Type 2 Diabetes.
Cardiovascular Drugs and Therapy, 2017Co-Authors: Nadjib Hammoudi, Eric Mayoux, Dongtak Jeong, Rajvir Singh, Ahmed Farhat, Michel Komajda, Roger J. Hajjar, Djamel LebecheAbstract:Cardiovascular (CV) diseases in type 2 diabetes (T2DM) represent an enormous burden with high mortality and morbidity. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently emerged as a new antidiabetic class that improves glucose control, as well as body weight and blood pressure with no increased risk of hypoglycemia. The first CV outcome study terminated with Empagliflozin, a specific SGLT2 inhibitor, has shown a reduction in CV mortality and in heart failure hospitalization, suggesting a beneficial impact on cardiac function which remains to be demonstrated. This study was designed to examine the chronic effect of Empagliflozin on left ventricular (LV) systolic and diastolic functions in a genetic model of T2DM, ob/ob mice. Cardiac phenotype was characterized by echocardiography, in vivo hemodynamics, histology, and molecular profiling. Our results demonstrate that Empagliflozin significantly lowered HbA1c and slightly reduced body weight compared to vehicle treatment with no obvious changes in insulin levels. Empagliflozin also improved LV maximum pressure and in vivo indices of diastolic function. While systolic function was grossly not affected in both groups at steady state, response to dobutamine stimulation was significantly improved in the Empagliflozin-treated group, suggesting amelioration of contractile reserve. This was paralleled by an increase in phospholamban (PLN) phosphorylation and increased SERCA2a/PLN ratio, indicative of enhanced SERCA2a function, further supporting improved cardiac relaxation and diastolic function. In addition, Empagliflozin reconciled diabetes-associated increase in MAPKs and dysregulated phosphorylation of IRS1 and Akt, leading to improvement in myocardial insulin sensitivity and glucose utilization. The data show that chronic treatment with Empagliflozin improves diastolic function, preserves calcium handling and growth signaling pathways and attenuates myocardial insulin resistance in ob/ob mice, findings suggestive of a potential clinical utility for Empagliflozin in the treatment of diastolic dysfunction.
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sglt2 inhibition by Empagliflozin promotes fat utilization and browning and attenuates inflammation and insulin resistance by polarizing m2 macrophages in diet induced obese mice
EBioMedicine, 2017Co-Authors: Naoto Nagata, Eric Mayoux, Mayumi Nagashimada, Fen Zhuge, Guanliang Chen, Shuichi Kaneko, Tsuguhito OtaAbstract:Abstract Sodium-glucose cotransporter (SGLT) 2 inhibitors increase urinary glucose excretion (UGE), leading to blood glucose reductions and weight loss. However, the impacts of SGLT2 inhibition on energy homeostasis and obesity-induced insulin resistance are less well known. Here, we show that Empagliflozin, a SGLT2 inhibitor, enhanced energy expenditure and attenuated inflammation and insulin resistance in high-fat-diet-induced obese (DIO) mice. C57BL/6J mice were pair-fed a high-fat diet (HFD) or a HFD with Empagliflozin for 16weeks. Empagliflozin administration increased UGE in the DIO mice, whereas it suppressed HFD-induced weight gain, insulin resistance, and hepatic steatosis. Moreover, Empagliflozin shifted energy metabolism towards fat utilization, elevated AMP-activated protein kinase and acetyl-CoA carbolxylase phosphorylation in skeletal muscle, and increased hepatic and plasma fibroblast growth factor 21 levels. Importantly, Empagliflozin increased energy expenditure, heat production, and the expression of uncoupling protein 1 in brown fat and in inguinal and epididymal white adipose tissue (WAT). Furthermore, Empagliflozin reduced M1-polarized macrophage accumulation while inducing the anti-inflammatory M2 phenotype of macrophages within WAT and liver, lowering plasma TNFα levels and attenuating obesity-related chronic inflammation. Thus, Empagliflozin suppressed weight gain by enhancing fat utilization and browning and attenuated obesity-induced inflammation and insulin resistance by polarizing M2 macrophages in WAT and liver.
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Empagliflozin Protects against Diet-Induced NLRP-3 Inflammasome Activation and Lipid Accumulation.
Journal of Pharmacology and Experimental Therapeutics, 2016Co-Authors: Elisa Benetti, Eric Mayoux, Raffaella Mastrocola, G Vitarelli, Juan Carlos Cutrin, Debora Nigro, Fausto Chiazza, Massimo Collino, Roberto FantozziAbstract:The aim of this study was to evaluate the effects of chronic treatment with Empagliflozin, a potent and selective sodium glucose cotransporter-2 inhibitor, in a murine model of diet-induced obesity and insulin resistance, focusing on drug effects on body weight reduction and nucleotide-binding domain, leucine-rich repeat containing protein (NLRP)-3 inflammasome activation, which have never been investigated to date. Male C57BL/6 mice were fed control or a high fat–high sugar (HFHS) diet for 4 months. Over the last 2 months, subsets of animals were treated with Empagliflozin (1–10 mg/kg) added to the diet. Empagliflozin evoked body weight reduction ( P < 0.001 for the highest dose) and positive effects on fasting glycemia and homeostasis model assessment of insulin resistance. In addition, the drug was able to reduce renal tubular damage and liver triglycerides level in a dose-dependent manner. Interestingly, Empagliflozin also decreased cardiac lipid accumulation. Moreover, diet-induced activation of NLRP-3 in kidney and liver (not observed in the heart) was dose-dependently attenuated by Empagliflozin. Our results clearly demonstrate the ability of Empagliflozin to counteract the deleterious effects evoked by chronic exposure to HFHS diet. Most notably, Empagliflozin treatment was associated with NLRP-3 inflammasome signaling modulation, suggesting that this inhibition may contribute to the drug therapeutic effects.
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Empagliflozin via switching metabolism toward lipid utilization moderately increases ldl cholesterol levels through reduced ldl catabolism
Diabetes, 2016Co-Authors: Francois Briand, Michael Mark, Eric Mayoux, Emmanuel Brousseau, Noemie Burr, Isabelle Urbain, Clement Costard, Thierry SulpiceAbstract:In clinical trials, a small increase in LDL cholesterol has been reported with sodium-glucose cotransporter 2 (SGLT2) inhibitors. The mechanisms by which the SGLT2 inhibitor Empagliflozin increases LDL cholesterol levels were investigated in hamsters with diet-induced dyslipidemia. Compared with vehicle, Empagliflozin 30 mg/kg/day for 2 weeks significantly reduced fasting blood glucose by 18%, with significant increase in fasting plasma LDL cholesterol, free fatty acids, and total ketone bodies by 25, 49, and 116%, respectively. In fasting conditions, glycogen hepatic levels were further reduced by 84% with Empagliflozin, while 3-hydroxy-3-methylglutaryl-CoA reductase activity and total cholesterol hepatic levels were 31 and 10% higher, respectively (both P < 0.05 vs. vehicle). A significant 20% reduction in hepatic LDL receptor protein expression was also observed with Empagliflozin. Importantly, none of these parameters were changed by Empagliflozin in fed conditions. Empagliflozin significantly reduced the catabolism of (3)H-cholesteryl oleate-labeled LDL injected intravenously by 20%, indicating that Empagliflozin raises LDL levels through reduced catabolism. Unexpectedly, Empagliflozin also reduced intestinal cholesterol absorption in vivo, which led to a significant increase in LDL- and macrophage-derived cholesterol fecal excretion (both P < 0.05 vs. vehicle). These data suggest that Empagliflozin, by switching energy metabolism from carbohydrate to lipid utilization, moderately increases ketone production and LDL cholesterol levels. Interestingly, Empagliflozin also reduces intestinal cholesterol absorption, which in turn promotes LDL- and macrophage-derived cholesterol fecal excretion.
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the sodium glucose cotransporter type 2 inhibitor Empagliflozin preserves β cell mass and restores glucose homeostasis in the male zucker diabetic fatty rat
Journal of Pharmacology and Experimental Therapeutics, 2014Co-Authors: Henrik H Hansen, Thomas Klein, Michael Mark, Jacob Jelsing, Carl Frederik Hansen, Gitte Hansen, Niels Vrang, Eric MayouxAbstract:Type 2 diabetes is characterized by impaired β-cell function associated with progressive reduction of insulin secretion and β-cell mass. Evidently, there is an unmet need for treatments with greater sustainability in β-cell protection and anti-diabetic efficacy. Through an insulin and β-cell independent mechanism, Empagliflozin, a specific sodium glucose co-transporter type-2 (SGLT-2) inhibitor, may potentially provide longer efficacy. This study compared the anti-diabetic durability of Empagliflozin treatment (10 mg/kg, p.o.) against glibenclamide (3 mg/kg, p.o.) and liraglutide (0.2 mg/kg, s.c.) on deficient glucose homeostasis and β-cell function in Zucker diabetic Fatty (ZDF) rats. Empagliflozin and liraglutide led to marked improvements in fed glucose and HbA1c levels, as well as impeding a progressive decline in insulin levels. In contrast, glibenclamide was ineffective. Whereas the effects of liraglutide were less pronounced at week 8 of treatment compared to week 4, those of Empagliflozin remained stable throughout the study period. Similarly, Empagliflozin improved glucose tolerance and preserved insulin secretion after both 4 and 8 weeks of treatment. These effects were reflected by a less reduction in β-cell mass with Empagliflozin or liraglutide at week 4, while only Empagliflozin showed β-cell sparing effects at week 8. While this study cannot be used to dissociate the absolute anti-diabetic efficacy among those different mechanisms of action, the study demonstrates that Empagliflozin exerts a more sustained improvement of glucose homeostasis and β-cell protection ZDF rats. In comparison to other type 2 diabetic treatments, SGLT-2 inhibitors may through insulin-independent pathways thus enhance durability of β-cell protection and anti-diabetic efficacy.
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Empagliflozin a novel potent and selective sglt 2 inhibitor improves glycaemic control alone and in combination with insulin in streptozotocin induced diabetic rats a model of type 1 diabetes mellitus
Diabetes Obesity and Metabolism, 2012Co-Authors: Gerd Luippold, Michael Mark, Thomas Klein, Rolf GremplerAbstract:Aim: Sodium glucose cotransporter-2 (SGLT-2) is key to reabsorption of glucose in the kidney. SGLT-2 inhibitors are in clinical development for treatment of type 2 diabetes mellitus (T2DM). The mechanism may be of value also in the treatment of type 1 diabetes mellitus (T1DM). This study investigated effects of the SGLT-2 inhibitor, Empagliflozin, alone and in combination with insulin, on glucose homeostasis in an animal model of T1DM. Methods: Sprague–Dawley rats were administered a single intraperitoneal injection of streptozotocin (STZ; 60 mg/kg). Acutely, STZ rats received two doses of insulin glargine with or without Empagliflozin, and blood glucose was measured. In a subchronic study, STZ rats received Empagliflozin alone, one or two insulin-releasing implants or a combination of one implant and Empagliflozin over 28 days; blood glucose and HbA1c were measured. Results: In the acute setting, Empagliflozin in combination with 1.5 IU insulin induced a similar glucose-lowering effect as 6 IU insulin. Both interventions were more efficacious than monotherapy with 1.5 IU insulin. In the subchronic study, 12-h blood glucose profile on day 28 in the combination group was lower than with one implant, and similar to two implants. Plasma HbA1c was improved in the combination group and in animals with two implants. Conclusions: Empagliflozin reduced blood glucose levels in a T1DM animal model. Empagliflozin combined with low-dose insulin showed comparable glucose-lowering efficacy to treatment with high-dose insulin. Our data suggest that Empagliflozin is an efficacious adjunctive-to-insulin therapy with the clinical potential for the treatment of T1DM.
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long term treatment with Empagliflozin a novel potent and selective sglt 2 inhibitor improves glycaemic control and features of metabolic syndrome in diabetic rats
Diabetes Obesity and Metabolism, 2012Co-Authors: Leo Thomas, Rolf Grempler, Matthias Eckhardt, Frank Himmelsbach, Achim Sauer, Thomas Klein, Peter Eickelmann, Michael MarkAbstract:Empagliflozin is a potent, selective sodium glucose co-transporter-2 inhibitor that is in development for the treatment of type 2 diabetes. This series of studies was conducted to assess the in vivo pharmacological effects of single or multiple doses of Empagliflozin in Zucker diabetic fatty rats. Single doses of Empagliflozin resulted in dose-dependent increases in urinary glucose excretion and reductions in blood glucose levels. After multiple doses (5 weeks), fasting blood glucose levels were reduced by 26 and 39% with 1 and 3 mg/kg Empagliflozin, respectively, relative to vehicle. After 5 weeks, HbA1c levels were reduced (from a baseline of 7.9%) by 0.3 and 1.1% with 1 and 3 mg/kg Empagliflozin, respectively, versus an increase of 1.1% with vehicle. Hyperinsulinaemic-euglycaemic clamp indicated improved insulin sensitivity with Empagliflozin after multiple doses versus vehicle. These findings support the development of Empagliflozin for the treatment of type 2 diabetes.
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Empagliflozin a novel selective sodium glucose cotransporter 2 sglt 2 inhibitor characterisation and comparison with other sglt 2 inhibitors
Diabetes Obesity and Metabolism, 2012Co-Authors: Rolf Grempler, Leo Thomas, Matthias Eckhardt, Frank Himmelsbach, Achim Sauer, Thomas Klein, Michael Mark, D E Sharp, Remko Bakker, Peter EickelmannAbstract:Aims: Empagliflozin is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor in clinical development for the treatment of type 2 diabetes mellitus. This study assessed pharmacological properties of Empagliflozin in vitro and pharmacokinetic properties in vivo and compared its potency and selectivity with other SGLT-2 inhibitors. Methods: [14C]-alpha-methyl glucopyranoside (AMG) uptake experiments were performed with stable cell lines over-expressing human (h) SGLT-1, 2 and 4. Two new cell lines over-expressing hSGLT-5 and hSGLT-6 were established and [14C]-mannose and [14C]-myo-inositol uptake assays developed. Binding kinetics were analysed using a radioligand binding assay with [3H]-labelled Empagliflozin and HEK293-hSGLT-2 cell membranes. Acute in vivo assessment of pharmacokinetics was performed with normoglycaemic beagle dogs and Zucker diabetic fatty (ZDF) rats. Results: Empagliflozin has an IC50 of 3.1 nM for hSGLT-2. Its binding to SGLT-2 is competitive with glucose (half-life approximately 1 h). Compared with other SGLT-2 inhibitors, Empagliflozin has a high degree of selectivity over SGLT-1, 4, 5 and 6. Species differences in SGLT-1 selectivity were identified. Empagliflozin pharmacokinetics in ZDF rats were characterised by moderate total plasma clearance (CL) and bioavailability (BA), while in beagle dogs CL was low and BA was high. Conclusions: Empagliflozin is a potent and competitive SGLT-2 inhibitor with an excellent selectivity profile and the highest selectivity window of the tested SGLT-2 inhibitors over hSGLT-1. Empagliflozin represents an innovative therapeutic approach to treat diabetes.