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Background: Doubling of serum creatinine [equivalent to 57% reduction in estimated glomerular filtration rate (eGFR)] is an established surrogate for end-stage kidney disease (ESKD); however, this endpoint necessitates lengthy follow-up and large sample sizes in clinical trials. We explored whether alternative eGFR decline thresholds provide more feasible surrogate kidney endpoints., Methods: The study involved post hoc analysis of the EMPA-REG OUTCOME® trial. Adults with type 2 diabetes, high cardiovascular risk and eGFR ≥30 mL/min/1.73 m2 were assigned empagliflozin 10 mg or 25 mg (n = 4687) or placebo (n = 2333), on top of standard of care. We assessed composite endpoints incorporating different eGFR decline thresholds (≥30, ≥40, ≥50 or ≥57%) combined with initiation of renal replacement therapy (RRT) or renal death. This trial is registered with ClinicalTrials.gov (NCT01131676)., Results: Empagliflozin versus placebo significantly lowered the risk of decline in eGFR for each threshold listed above, combined with initiation of RRT or renal death, ranging from a hazard ratio (HR) of 0.81 [95% confidence interval (CI) 0.72-0.91] for endpoints based on 30% eGFR decline to an HR of 0.37 (0.23-0.61) for endpoints based on 57% eGFR decline. Lower thresholds (e.g. 30%) were associated with higher event rates but weaker treatment effects. The time to the 95% CI of the HR falling to <1.0 decreased with increasing eGFR threshold., Conclusions: The composite of 40% decline in eGFR, ESKD or renal death appears to provide reliable results similar to the traditional 57% decline in eGFR., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Aim: To report results at week 208, including a 104-week masked extension, of the EMPA-REG H2H-SU trial in patients with type 2 diabetes with inadequate glycaemic control on metformin, in which empagliflozin 25 mg given for 104 weeks provided a sustained reduction in glycated haemoglobin (HbA1c) with a small but statistically significant benefit vs glimepiride, sustained reductions in weight and blood pressure, and low risk of hypoglycaemia., Research Design and Methods: Patients with type 2 diabetes and HbA1c 53-86 mmol/mol (7% to 10%) were randomized to empagliflozin 25 mg or glimepiride 1 to 4 mg for 104 weeks as add-on to metformin. Patients who completed the randomized treatment period could participate in a 104-week extension in which they continued the double-blind treatment allocated at randomization., Results: Of 765 and 780 patients treated with empagliflozin and glimepiride, 576 and 549 patients, respectively, entered the extension period of the study. At week 208, the adjusted mean difference in change from baseline in HbA1c with empagliflozin vs glimepiride was -1.96 mmol/mol, 95% CI -3.57, -0.35 (-0.18%, 95% CI -0.33, -0.03); P = 0.0172. Rescue therapy was given to 23% of patients on empagliflozin and 34% on glimepiride (odds ratio 0.56 [95% CI 0.45, 0.71]; P < 0.0001). Confirmed hypoglycaemic adverse events (plasma glucose ≤3.9 mmol/L and/or requiring assistance) occurred in 3% of patients on empagliflozin and 28% on glimepiride (odds ratio 0.08 [95% CI 0.05, 0.13]; P < 0.0001)., Conclusions: In patients with type 2 diabetes, empagliflozin 25 mg as add-on to metformin for 208 weeks reduced HbA1c with a significantly lower risk of hypoglycaemia and a significantly smaller proportion of patients receiving rescue therapy compared with glimepiride., (© 2018 John Wiley & Sons Ltd.)

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 <0.001). However, annual mean slope (ml/min per 1.73 m 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 <0.001). After drug cessation, the adjusted mean eGFR slope (ml/min per 1.73 m 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 <0.001). Results were consistent across patient subgroups at higher CKD risk., Conclusions: The hemodynamic effects of empagliflozin, associated with reduction in intraglomerular pressure, may contribute to long-term preservation of kidney function., (Copyright © 2018 by the American Society of Nephrology.)

Objective: To assess the effect of empagliflozin on bone fractures and bone mineral density in patients with type 2 diabetes in pooled placebo-controlled trial data and a head-to-head study versus glimepiride., Research Design and Methods: Pooled data were analyzed from patients who were randomized 1:1:1 to empagliflozin 10 mg, empagliflozin 25 mg, or placebo in phase I-III clinical trials. Data were also analyzed from the EMPA-REG H2H-SU trial in which patients received empagliflozin 25 mg or glimepiride as an add-on to metformin for 104 weeks with a 104-week extension. Bone fracture adverse events (AEs) were evaluated through a search of investigator-reported (nonadjudicated) events., Results: In the pooled analysis, bone fracture AEs were reported in 119 of 4,221 (2.8%), 105 of 4,196 (2.5%), and 123 of 4,203 (2.9%) patients in the empagliflozin 10 mg, empagliflozin 25 mg, and placebo groups, respectively (rates of 1.55, 1.36, and 1.69/100 patient-years, respectively). In the EMPA-REG H2H-SU trial, bone fracture AEs were reported in 31 of 765 (4.1%) patients receiving empagliflozin 25 mg and in 33 of 780 (4.2%) patients receiving glimepiride (rates of 1.28 and 1.40/100 patient-years, respectively)., Conclusions: Empagliflozin did not increase the risk of bone fracture compared with placebo in a pooled analysis of >12,000 patients or compared with glimepiride in a 4-year head-to-head study., (© 2018 by the American Diabetes Association.)

Aims: Empagliflozin reduced the risk of cardiovascular (CV) death and heart failure (HF) hospitalizations in patients with type 2 diabetes (T2D) and established CV disease (CVD) in the EMPA-REG OUTCOME® trial. We investigated whether the benefit of empagliflozin was observed across the spectrum of HF risk., Methods and Results: Seven thousand and twenty patients with T2D (HbA1c 7-10% and eGFR > 30 mL/min/1.73 m2) were treated with empagliflozin 10 or 25 mg, or placebo once daily and followed for median 3.1 years. In patients without HF at baseline (89.9%), we derived the 5-year risk for incident HF using the 9-variable Health ABC HF Risk score [classified as low-to-average (<10%), high (10-20%), and very high (≥ 20%)]. Overall, 67.2% of the population had low-to-average, 24.2% high, and 5.1% very high 5-year HF risk. Across these groups, the effect on CV death and HF hospitalization with empagliflozin was consistent [hazard ratio 0.71 (95% confidence interval: 0.52, 0.96), 0.52 (0.36, 0.75), and 0.55 (0.30, 1.00), respectively]. Effects on CV death in the ostensibly highest HF risk group (HF at baseline and/or incident HF during the trial) in whom 37.9% of the overall CV deaths occurred, was also beneficial [0.67 (0.47, 0.97)], yet, similar benefits were seen in the lower risk patients., Conclusion: In patients with T2D and established CVD, a sizeable proportion without HF at baseline are at high or very high risk for HF outcomes, indicating the need for active case finding in this patient population. Empagliflozin consistently improved HF outcomes both in patients at low or high HF risk., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Background: Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduced cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus and established cardiovascular disease in the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients). Urinary glucose excretion with empagliflozin decreases with declining renal function, resulting in less potency for glucose lowering in patients with kidney disease. We investigated the effects of empagliflozin on clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease., Methods: Patients with type 2 diabetes mellitus, established cardiovascular disease, and estimated glomerular filtration rate (eGFR) ≥30 mL·min -1 ·1.73 m -2 at screening were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily in addition to standard of care. We analyzed cardiovascular death, hospitalization for heart failure, all-cause hospitalization, and all-cause mortality in patients with prevalent kidney disease (defined as eGFR <60 mL·min -1 ·1.73 m -2 and/or urine albumin-creatinine ratio >300 mg/g) at baseline. Additional analyses were performed in subgroups by baseline eGFR (<45, 45-<60, 60-<90, ≥90 mL·min -1 ·1.73 m -2 ) and baseline urine albumin-creatinine ratio (>300, 30-≤300, <30 mg/g)., Results: Of 7020 patients treated, 2250 patients had prevalent kidney disease at baseline, of whom 67% had a diagnosis of type 2 diabetes mellitus for >10 years, 58% were receiving insulin, and 84% were taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. In patients with prevalent kidney disease at baseline, empagliflozin reduced the risk of cardiovascular death by 29% compared with placebo (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52-0.98), the risk of all-cause mortality by 24% (HR, 0.76; 95% CI, 0.59-0.99), the risk of hospitalization for heart failure by 39% (HR, 0.61; 95% CI, 0.42-0.87), and the risk of all-cause hospitalization by 19% (HR, 0.81; 95% CI, 0.72-0.92). Effects of empagliflozin on these outcomes were consistent across categories of eGFR and urine albumin-creatinine ratio at baseline and across the 2 doses studied. The adverse event profile of empagliflozin in patients with eGFR <60 mL·min -1 ·1.73 m -2 was consistent with the overall trial population., Conclusions: Empagliflozin improved clinical outcomes and reduced mortality in vulnerable patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01131676., (© 2017 American Heart Association, Inc.)

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., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Heart failure (HF) and type 2 diabetes mellitus (T2DM) are both growing public health concerns contributing to major medical and economic burdens to society. T2DM increases the risk of HF, frequently occurs concomitantly with HF, and worsens the prognosis of HF. Several anti-hyperglycaemic medications have been associated with a concern for worse HF outcomes. More recently, the results of the EMPA-REG OUTCOME trial showed that the sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin was associated with a pronounced and precocious 38% reduction in cardiovascular mortality in subjects with T2DM and established cardiovascular disease [Correction added on 8 September 2017, after first online publication: "32%" in the previous sentence was corrected to "38%"]. These benefits were more related to a reduction in incident HF events rather than to ischaemic vascular endpoints. Several mechanisms have been put forward to explain these benefits, which also raise the possibility of using these drugs as therapies not only in the prevention of HF, but also for the treatment of patients with established HF regardless of the presence or absence of diabetes. Several large trials are currently exploring this postulate., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

In the EMPA-REG BP trial, empagliflozin significantly reduced systolic and diastolic blood pressure (SBP and DBP) compared with placebo at week 12 in patients with type 2 diabetes mellitus (T2DM) and hypertension. In a post-hoc analysis, we assessed the effect of empagliflozin on SBP and DBP using 24-hour ambulatory BP monitoring in patients categorized as dippers (sleep-time mean SBP ≤ 90% of awake-time mean; n = 417) or non-dippers (sleep-time mean SBP > 90% of awake-time mean; n = 350). In dippers, adjusted mean (SE) changes from baseline in mean 24-hour SBP (mm Hg) at week 12 were -0.2 (0.7) with placebo vs -3.8 (0.6) and -3.9 (0.7) with empagliflozin 10 and 25 mg, respectively (both P  < .001 vs placebo). In non-dippers, these changes were 1.0 (0.7) with placebo vs -1.6 (0.7) with empagliflozin 10 mg ( P  = .013 vs placebo) and -3.8 (0.7) with empagliflozin 25 mg ( P  < .001 vs placebo). In both dippers and non-dippers, SBP and DBP patterns over 24 hours were maintained. There were no clinically relevant changes in heart rate with empagliflozin. In conclusion, empagliflozin significantly reduced mean 24-hour SBP compared with placebo in dippers and non-dippers., (© 2017 John Wiley & Sons Ltd.)

Inhibition of sodium glucose cotransporter 2 with empagliflozin results in caloric loss by increasing urinary glucose excretion and has a mild diuretic effect. Diuretic effects are usually associated with reflex-mediated increases in sympathetic tone, whereas caloric loss is associated with decreased sympathetic tone. In an open-label trial, muscle sympathetic nerve activity (MSNA) (burst frequency, burst incidence, and total MSNA) was assessed using microneurography performed off-treatment and on day 4 of treatment with empagliflozin 25 mg once daily in 22 metformin-treated patients with type II diabetes (mean [range] age 54 [40-65] years). Systolic and diastolic blood pressure (BP), heart rate, urine volume, and body weight were assessed before and on day 4 (BP, heart rate), day 5 (urine volume), or day 6 (body weight) of treatment with empagliflozin. After 4 days of treatment with empagliflozin, no significant changes in MSNA were apparent despite a numerical increase in urine volume, numerical reductions in BP, and significant weight loss. There were no clinically relevant changes in heart rate. Empagliflozin is not associated with clinically relevant reflex-mediated sympathetic activation in contrast to increases observed with diuretics in other studies. Our study suggests a novel mechanism through which sodium glucose cotransporter 2 inhibition affects human autonomic cardiovascular regulation., (Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

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., (© 2017 The Authors.)

Objective: Inhibition of the renal sodium-glucose cotransporter 2 (SGLT2) is a novel concept in the therapy of diabetes mellitus. In this study, we first assessed whether common single nucleotide polymorphisms (SNPs) in the SGLT2-encoding gene SLC5A2 affect diabetes-related metabolic traits in subjects at risk for type 2 diabetes and, second, whether these have pharmacogenetic relevance by interfering with the response to empagliflozin treatment in patients with type 2 diabetes., Patients and Methods: Samples from a metabolically well-phenotyped cross-sectional study population (total N=2600) at increased risk for type 2 diabetes and pooled pharmacogenetic samples from patients from four phase III trials of empagliflozin (in total: 603 receiving empagliflozin, 305 receiving placebo) were genotyped for five common SNPs (minor allele frequencies ≥5%) present in the SLC5A2 gene locus., Results: In the cross-sectional study, none of the SLC5A2 SNPs significantly influenced metabolic traits such as body fat, insulin sensitivity/resistance, insulin release, HbA1c, plasma glucose, or systolic blood pressure when multiple testing was taken into account (all P≥0.0083). Further, no relevant effect on response to treatment with empagliflozin on HbA1c, fasting glucose, weight, or systolic blood pressure was observed for the SNPs tested in the pharmacogenetic study., Conclusion: Common genetic variants in the SLC5A2 gene neither affects diabetes-related metabolic traits nor have a clinically relevant impact on response to treatment with the SGLT2 inhibitor empagliflozin.

Aim: To evaluate the efficacy and safety of linagliptin vs placebo as add-on to empagliflozin and metformin in patients with type 2 diabetes., Materials and Methods: Patients with inadequate glycaemic control despite stable-dose metformin received open-label empagliflozin 10 mg (study 1) or 25 mg (study 2) as add-on therapy for 16 weeks. Subsequently, those with HbA1c ≥7.0 and ≤10.5% (>53 and ≤91 mmol/mol) (N = 482) were randomized to 24 weeks' double-blind, double-dummy treatment with linagliptin 5 mg or placebo in study 1, or to linagliptin 5 mg or placebo in study 2; all patients continued treatment with metformin and empagliflozin 10 mg (study 1) or metformin and empagliflozin 25 mg (study 2). The primary endpoint was change from baseline (defined as the last value before first intake of randomized, double-blind treatment) in HbA1c at week 24., Results: At week 24, HbA1c (mean baseline 7.82-8.04 [62-64 mmol/mol]) was significantly reduced with linagliptin vs placebo; adjusted mean (SE) differences in change from baseline in HbA1c with linagliptin vs placebo were -.32% (.10) (-3.59 [1.08] mmol/mol) ( P = .001) for patients on empagliflozin 10 mg and metformin, and -0.47% (0.10) (-5.15 [1.04] mmol/mol) ( P < 0.001) for patients on empagliflozin 25 mg and metformin. Adverse events were reported in more patients receiving placebo than in those receiving linagliptin: 55.5% vs 48.4% in study 1 and 58.9% vs 52.7% in study 2., Conclusions: Linagliptin as add-on to empagliflozin and metformin for 24 weeks improved glycaemic control vs placebo, and was well tolerated., (© 2016 John Wiley & Sons Ltd.)

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.

Background: We evaluated the effect of empagliflozin as adjunct to insulin on 24-h glucose exposure and variability in patients with type 1 diabetes., Methods: Patients (N = 75) with HbA 1c ≥7.5% to ≤10.5% were randomized to receive empagliflozin 2.5 mg, empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily as adjunct to insulin for 4 weeks. Insulin dose was to be kept as stable as possible during week 1 of treatment and was freely adjustable thereafter. Markers of glucose exposure and variability were assessed from 7-day blinded continuous glucose monitoring intervals. This study is completed ( ClinicalTrials.gov NCT01969747)., Results: Empagliflozin reduced hourly mean glucose area under the median curve over 24 h versus placebo within week 1 (adjusted mean differences: -12.2 mg/dL·h [95% confidence interval -23.9 to -0.5], -30.2 mg/dL·h [-42.2 to -18.2], and -33.0 mg/dL·h [-44.8 to -21.1] with empagliflozin 2.5, 10, and 25 mg, respectively; all P < 0.05) and increased time in glucose target range (>70 to ≤180 mg/dL). Results were sustained to week 4 with empagliflozin 25 mg. All empagliflozin doses significantly reduced glucose variability (interquartile range and mean amplitude of glucose excursions) versus placebo at weeks 1 and 4. Except for small increases in hours per day with glucose ≤70 mg/dL during the stable insulin period, empagliflozin did not increase time in hypoglycemia compared with placebo., Conclusions: In patients with type 1 diabetes, empagliflozin as adjunct to insulin decreased glucose exposure and variability and increased time in glucose target range.

In the EMPA-REG BP trial, empagliflozin 10 mg and 25 mg once daily reduced glycohemoglobin, blood pressure (BP), and weight versus placebo in patients with type 2 diabetes mellitus and hypertension. Patients received placebo (n=271), empagliflozin 10 mg (n=276), or empagliflozin 25 mg (n=276) for 12 weeks (n=full analysis set). This present analysis investigated changes from baseline to week 12 in mean 24-hour systolic BP (SBP) and diastolic BP (DBP) in patients receiving 0, 1, or ≥2 antihypertensive medications and patients receiving/not receiving diuretics or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Compared with placebo, empagliflozin 10 mg and 25 mg reduced mean 24-hour SBP/DBP in patients receiving 0 (10 mg: -3.89/-2.58 mm Hg; 25 mg: -3.77/-2.45 mm Hg), 1 (10 mg: -4.74/-1.97 mm Hg; 25 mg: -4.27/-1.81 mm Hg), or ≥2 (10 mg: -2.36/-0.68 mm Hg; 25 mg: -4.17/-1.54 mm Hg) antihypertensives. The effect of empagliflozin was not significantly different between subgroups by number of antihypertensives for changes in SBP (interaction P value 0.448) or DBP (interaction P value 0.498). Empagliflozin reduced 24-hour mean SBP/DBP irrespective of diuretic or angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, with no significant difference between subgroups by use/no use of diuretics (interaction P values 0.380 [systolic]; 0.240 [diastolic]) or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (interaction P values 0.900 [systolic]; 0.359 [diastolic]). In conclusion, in patients with type 2 diabetes mellitus and hypertension, empagliflozin for 12 weeks reduced SBP and DBP versus placebo, irrespective of the number of antihypertensives and use of diuretics or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers., Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT01370005., (© 2016 American Heart Association, Inc.)

Purpose: Our aim was to investigate the effects of the sodium glucose cotransporter 2 inhibitor empagliflozin on urinary and serum glucose and electrolytes, urinary volume, osmolality, and the renin-angiotensin system in patients with type 2 diabetes., Methods: In an open-label study, 22 patients receiving metformin (median age 56 years; range 40-65 years) received empagliflozin 25 mg once daily for 5 days. Food, fluid, and sodium intake were standardized for 3 days before and during treatment., Findings: Twenty patients completed treatment. After single and multiple doses of empagliflozin, mean (SE) changes from baseline in 24-hour urinary glucose excretion were 463.3 (57.3) mmol/d and 599.5 (60.0) mmol/d, respectively (83.5 [10.3] g/d and 108.0 [10.8] g/d, respectively) (both P < 0.001), and in fasting serum glucose concentration were -1.8 (0.4) mmol/L and -1.1 (0.3) mmol/L, respectively (both P < 0.001). After a single dose, mean (SE) change from baseline in urine sodium excretion was 45.3 (9.6) mmol/d (P < 0.001), and in urine volume was 341.0 (140.5) g/d (P = 0.025), but there were no changes compared with baseline in either parameter after multiple doses. There were no changes in plasma renin or serum aldosterone with single or multiple doses of empagliflozin. There was a nonsignificant reduction in weight after a single dose of empagliflozin and a mean (SE) change of -1.4 (0.5) kg after multiple doses (P = 0.020)., Implications: Empagliflozin 25 mg increased urinary glucose excretion and decreased serum glucose and weight with transient natriuresis and increases in urine volume, without significant changes in the renin-angiotensin system. Clinicaltrials.gov Identifier: NCT01276288., (Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.)

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-naïve 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 < 0.001) and with metformin twice-daily regimens (P < 0.01). Reductions in weight at week 24 were significantly greater with empagliflozin + metformin twice-daily regimens (range -2.8 to -3.8 kg) than with metformin twice-daily regimens (-0.5 to -1.3 kg) (P < 0.001 for all). Adverse event (AE) rates were similar across groups (56.7-66.3%). No hypoglycemic AEs required assistance., 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., (© 2016 by the American Diabetes Association.)

Aim: To assess the effect of empagliflozin on cardiovascular (CV) risk in patients with type 2 diabetes (T2DM) through a meta-analysis of data from eight placebo-controlled trials., Methods: Data were analysed from eight randomized placebo-controlled trials undertaken to investigate the efficacy and safety of empagliflozin 10 and 25 mg once daily in patients with T2DM, comprising patients at low/medium and high CV risk. Suspected CV events were prospectively adjudicated. The empagliflozin 10 and 25 mg groups were pooled for the primary analysis. The primary endpoint was a composite of CV death, non-fatal myocardial infarction (MI), non-fatal stroke and hospitalization for unstable angina [4-point major adverse CV events (MACE)]. The secondary endpoint was a composite of CV death, non-fatal MI and non-fatal stroke (3-point MACE). Risk estimates were calculated using Cox regression analysis., Results: A total of 3835 patients received placebo and 7457 received empagliflozin. Total exposure was 7448.3 years for placebo and 15482.1 years for empagliflozin. Four-point MACE occurred in 365 (9.5%) patients receiving placebo and 635 (8.5%) patients receiving empagliflozin [hazard ratio for empagliflozin vs. placebo 0.86 (95% CI 0.76, 0.98)]. Three-point MACE occurred in 307 (8.0%) patients receiving placebo and 522 (7.0%) patients receiving empagliflozin [hazard ratio for empagliflozin vs. placebo 0.84 (95% CI 0.73, 0.96)]., Conclusions: In a meta-analysis of data from eight randomized trials involving 11 292 patients with T2DM at low/medium or high CV risk, empagliflozin was associated with a reduced risk of 4-point MACE and 3-point MACE compared with placebo., (© 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

We investigated the efficacy and safety of empagliflozin over 24 weeks in Asian patients with type 2 diabetes (T2DM) using pooled data from four phase III trials. In these trials, patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg or placebo as monotherapy or add-on to metformin, metformin plus sulphonylurea or pioglitazone ± metformin. In total, 1326 patients from Asia received ≥1 dose of study drug. At week 24, adjusted mean differences versus placebo in change from baseline in glycated haemoglobin (HbA1c) were -0.66% [95% confidence interval (CI) -0.76, -0.56] and -0.73% (95% CI -0.83, -0.64) and in weight were -1.6 kg (95% CI -1.9, -1.3) and -1.8 kg (95% CI -2.1, -1.5) with empagliflozin 10 and 25 mg, respectively (all p < 0.001). Empagliflozin significantly reduced systolic and diastolic blood pressure. The proportion of patients reporting ≥1 adverse event was similar across treatment groups, but events consistent with genital infection were more common in patients treated with empagliflozin 10 mg (3.4%) or 25 mg (2.3%) than placebo (0.9%). Thus in Asian patients with T2DM, empagliflozin reduced HbA1c, weight and blood pressure, and was well tolerated., (© 2016 John Wiley & Sons Ltd.)

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., (Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.)

Aims/hypothesis: Sodium glucose cotransporter 2 (SGLT2) inhibition lowers HbA1c, systolic BP (SBP) and weight in patients with type 2 diabetes and reduces renal hyperfiltration associated with type 1 diabetes, suggesting decreased intraglomerular hypertension. As lowering HbA1c, SBP, weight and intraglomerular pressure is associated with anti-albuminuric effects in diabetes, we hypothesised that SGLT2 inhibition would reduce the urine albumin-to-creatinine ratio (UACR) to a clinically meaningful extent., Methods: We examined the effect of the SGLT2 inhibitor empagliflozin on UACR by pooling data from patients with type 2 diabetes and prevalent microalbuminuria (UACR = 30-300 mg/g; n = 636) or macroalbuminuria (UACR > 300 mg/g; n = 215) who participated in one of five phase III randomised clinical trials. Primary assessment was defined as percentage change in geometric mean UACR from baseline to week 24., Results: After controlling for clinical confounders including baseline log-transformed UACR, HbA1c, SBP and estimated GFR (according to the Modification of Diet in Renal Disease [MDRD] formula), treatment with empagliflozin significantly reduced UACR in patients with microalbuminuria (-32% vs placebo; p < 0.001) or macroalbuminuria (-41% vs placebo; p < 0.001). Intriguingly, in regression models, most of the UACR-lowering effect with empagliflozin was not explained by SGLT2 inhibition-related improvements in HbA1c, SBP or weight., Conclusions/interpretation: In patients with type 2 diabetes and either micro- or macroalbuminuria, empagliflozin reduced UACR by a clinically meaningful amount. This effect was largely independent of the known metabolic or systemic haemodynamic effects of this drug class. Our results further support a direct renal effect of SGLT2 inhibitors. Prospective studies are needed to explore the potential of this intervention to alter the course of kidney disease in high-risk patients with diabetes., Trial Registration: Clinicaltrials.gov NCT01177813 (study 1); NCT01159600 (study 2); NCT01159600 (study 3); NCT01210001 (study 4); and NCT01164501 (study 5).

Background: Diabetes confers an increased risk of adverse cardiovascular and renal events. In the EMPA-REG OUTCOME trial, empagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduced the risk of major adverse cardiovascular events in patients with type 2 diabetes at high risk for cardiovascular events. We wanted to determine the long-term renal effects of empagliflozin, an analysis that was a prespecified component of the secondary microvascular outcome of that trial., Methods: We randomly assigned patients with type 2 diabetes and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m(2) of body-surface area to receive either empagliflozin (at a dose of 10 mg or 25 mg) or placebo once daily. Prespecified renal outcomes included incident or worsening nephropathy (progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease) and incident albuminuria., Results: Incident or worsening nephropathy occurred in 525 of 4124 patients (12.7%) in the empagliflozin group and in 388 of 2061 (18.8%) in the placebo group (hazard ratio in the empagliflozin group, 0.61; 95% confidence interval, 0.53 to 0.70; P<0.001). Doubling of the serum creatinine level occurred in 70 of 4645 patients (1.5%) in the empagliflozin group and in 60 of 2323 (2.6%) in the placebo group, a significant relative risk reduction of 44%. Renal-replacement therapy was initiated in 13 of 4687 patients (0.3%) in the empagliflozin group and in 14 of 2333 patients (0.6%) in the placebo group, representing a 55% lower relative risk in the empagliflozin group. There was no significant between-group difference in the rate of incident albuminuria. The adverse-event profile of empagliflozin in patients with impaired kidney function at baseline was similar to that reported in the overall trial population., Conclusions: In patients with type 2 diabetes at high cardiovascular risk, empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care. (Funded by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.).

Purpose: The aim of this analysis was to establish the safety profile and tolerability of empagliflozin in patients with type 2 diabetes mellitus (T2DM) according to pooled data from several clinical trials., Methods: Pooled data were analyzed from patients with T2DM treated with placebo (n = 3695), empagliflozin 10 mg (n = 3806), or empagliflozin 25 mg (n = 4782) in 17 randomized, Phase I, II, and III clinical trials plus 6 extension studies. Adverse events (AEs) were assessed descriptively in patients who took ≥1 dose of the study drug. AE incidence rates per 100 patient-years were calculated to adjust for differences in drug exposure across trials., Findings: Total exposure was 3254, 3840, and 5649 patient-years in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg groups, respectively. The incidence of any AEs, AEs leading to treatment discontinuation, severe AEs, and serious AEs was no higher in patients treated with empagliflozin than with placebo. Empagliflozin was not associated with an increased risk of hypoglycemia versus placebo, except in patients on background sulfonylurea and/or insulin. The incidence of events consistent with urinary tract infection was similar across treatment groups (9.4-11.3/100 patient-years); 0.4%, 0.2%, and 0.3% of patients in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg groups, respectively, had urinary tract infections that required or prolonged hospitalization. The incidence of events consistent with genital infection was higher in patients treated with empagliflozin (4.7 and 5.0/100 patient-years for empagliflozin 10 and 25 mg, respectively) than placebo (1.3/100 patient-years), but only 0.1%, 0.1%, and <0.1% in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg groups, respectively, had genital infections that required or prolonged hospitalization. The incidence of AEs consistent with volume depletion was similar with placebo, empagliflozin 10 mg, and empagliflozin 25 mg (1.6, 1.5, and 1.3/100 patient-years, respectively) and was higher with empagliflozin 25 mg than placebo or empagliflozin 10 mg in patients aged >75 years (4.4 vs 2.3 and 2.5/100 patient-years, respectively). The incidences of bone fractures, malignancies, decreased renal function, hepatic injury, venous thromboembolic events, and diabetic ketoacidosis were low and similar across the treatment groups., Implications: In this predefined analysis that was based on >9000 patient-years' exposure to empagliflozin, empagliflozin 10 mg, and empagliflozin 25 mg were well tolerated in patients with T2DM., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims/hypothesis: Sodium glucose co-transporter 2 (SGLT2) inhibitors lower glycaemia by inducing glycosuria, but raise endogenous glucose production (EGP). Metformin lowers glycaemia mainly by suppressing EGP. We compared the effects of the SGLT2 inhibitor empagliflozin in treatment-naive (TN) and metformin pretreated (Met) patients with type 2 diabetes., Methods: A total of 32 TN and 34 patients on a stable dose of metformin, two subgroups of a study that we previously reported, received a mixed meal with double-tracer glucose administration and indirect calorimetry at baseline, after a single 25 mg dose of empagliflozin, and after 4 weeks of treatment with empagliflozin 25 mg/day., Results: At baseline, compared with the TN group, the Met group had higher fasting glycaemia (9.1 ± 1.7 vs 8.2 ± 1.3 mmol/l), lower fasting and postmeal insulin secretion, lower beta cell glucose sensitivity (37 [18] vs 58 [43] pmol min(-1) m(-2) [mmol/l](-1), median [interquartile range]) and insulin:glucagon ratio, and higher fasting EGP (15.9 [4.3] vs 12.1 [2.7] μmol kgFFM (-1) min(-1)). Change from baseline in fasting EGP after single dose and 4 weeks of treatment with empagliflozin was similar in the Met and TN groups (19.6 [4.2] and 19.0 [2.3] in Met vs 16.2 [3.6] and 15.5 [3.2] μmol kgFFM (-1) min(-1) in TN for acute and chronic dosing, respectively). Beta cell glucose sensitivity increased less in Met than TN patients, whereas substrate utilisation shifted from carbohydrate to fat more in Met than TN patients., Conclusions/interpretation: At baseline, Met patients with type 2 diabetes had more advanced disease than TN patients, featuring worse beta cell function and higher EGP. Empagliflozin induced similar glycosuria and metabolic and hormonal responses in Met and TN patients., Trial Registration: ClinicalTrials.gov NCT01248364; European Union Clinical Trials Register 2010-018708-99.

Aims: To determine the effects of empagliflozin on adiposity indices among patients with type 2 diabetes mellitus., Methods: Changes in weight, waist circumference, estimated total body fat, index of central obesity and visceral adiposity index were assessed using analysis of covariance and testing of treatment by strata for age, sex and baseline waist circumference in patients with type 2 diabetes mellitus randomized to blinded treatment with empagliflozin versus placebo in clinical trials of 12 weeks (cohort 1) or 24 weeks (cohort 2) duration., Results: This study comprised 3300 patients (cohort 1, N = 823; cohort 2, N = 2477). Empagliflozin reduced weight, waist circumference and adiposity indices versus placebo in both cohorts. Adjusted mean (95% confidence interval) change from baseline in empagliflozin versus placebo was -1.7 kg (-2.1 to -1.4 kg) and -1.9 kg (-2.1 to -1.7 kg) for body weight (p < 0.001); -1.3 cm (-1.8 to -0.7 cm) and -1.3 cm (-1.7 to -1.0 cm) for waist circumference (p < 0.001); -0.2% (-0.7% to 0.3%; p = 0.45) and -0.3% (-0.7% to 0.0%; p = 0.08) for estimated total body fat; -0.007 (-0.011 to -0.004) and -0.008 (-0.010 to -0.006) for index of central obesity (p < 0.001); and -0.3 (-0.5 to 0.0; p = 0.07) and -0.4 (-0.7 to -0.1; p = 0.003) for visceral adiposity index in cohorts 1 and 2, respectively. Adipose reductions were seen across most age, sex and waist circumference subgroups., Conclusion: Empagliflozin significantly reduced weight and adiposity indices with the potential to improve cardiometabolic risk among patients with type 2 diabetes mellitus., (© The Author(s) 2015.)

Background: To investigate the long-term efficacy and safety of empagliflozin monotherapy compared with placebo and sitagliptin in drug-naïve patients with type 2 diabetes mellitus., Methods: Of 899 patients randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, placebo, or sitagliptin 100 mg once daily for 24 weeks, 615 continued in a double-blind extension trial for ≥52 weeks. Exploratory endpoints included changes from baseline in HbA1c, weight and blood pressure at week 76., Results: Compared with placebo, adjusted mean changes from baseline in HbA1c at week 76 were -0.78 % (95 % CI -0.94, -0.63; p < 0.001) and -0.89 % (95 % CI -1.04, -0.73; p < 0.001) for empagliflozin 10 mg and 25 mg, respectively. Compared with placebo, adjusted mean changes from baseline in weight at week 76 were -1.8 kg (95 % CI -2.4, -1.3; p < 0.001) and -2.0 kg (95 % CI -2.6, -1.5; p < 0.001) for empagliflozin 10 mg and 25 mg, respectively. Empagliflozin led to reductions in systolic blood pressure (SBP) compared with placebo in the primary analysis but not in sensitivity analyses. Compared with sitagliptin, empagliflozin 25 mg reduced HbA1c and both empagliflozin doses reduced weight and SBP. Adverse events (AEs) were reported in 76.8, 78.0, 76.4 and 72.2 % of patients on empagliflozin 10 mg, empagliflozin 25 mg, placebo and sitagliptin, respectively. Confirmed hypoglycaemic AEs (glucose ≤3.9 mmol/l and/or requiring assistance) were reported in two patients (0.9 %) per treatment group., Conclusions: Empagliflozin monotherapy for ≥76 weeks was well tolerated and led to sustained reductions in HbA1c and weight compared with placebo., Trial Registration: clinicaltrials.gov NCT01289990.

Aims: To determine the effects of empagliflozin on blood pressure (BP) and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes mellitus (T2DM)., Methods: We conducted a post hoc analysis of data from a phase III trial in patients with T2DM and hypertension receiving 12 weeks' empagliflozin and four phase III trials in patients with T2DM receiving 24 weeks' empagliflozin (cohort 1, n = 823; cohort 2, n = 2477). BP was measured using 24-h BP monitoring (cohort 1) or seated office measurements (cohort 2)., Results: Empagliflozin reduced systolic BP (SBP) and diastolic BP in both cohorts (p < 0.001 vs placebo), without increasing heart rate. Empagliflozin reduced pulse pressure (PP; adjusted mean difference vs placebo cohort 1: -2.3 mmHg; cohort 2: -2.3 mmHg), mean arterial pressure (MAP; cohort 1, -2.3 mmHg; cohort 2, -2.1 mmHg) and double product (cohort 1, -385 mmHg × bpm; cohort 2, -369 mmHg × bpm) all p < 0.001 vs placebo. There was a trend towards a reduction in the ambulatory arterial stiffness index (AASI) with empagliflozin in cohort 1 (p = 0.059 vs placebo). AASI was not measured in cohort 2. Subgroup analyses showed that there were greater reductions in PP with increasing baseline SBP in cohort 1 (p = 0.092). In cohort 2, greater reductions in MAP were achieved in patients with higher baseline SBP (p = 0.027) and greater reductions in PP were observed in older patients (p = 0.011)., Conclusions: Empagliflozin reduced BP and had favourable effects on markers of arterial stiffness and vascular resistance., (© 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To investigate the long-term efficacy and safety of empagliflozin as add-on to metformin in people with Type 2 diabetes., Methods: Of 637 participants treated with empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily for 24 weeks, 463 (72.7%) were treated in a double-blind extension trial for ≥ 52 weeks. Prespecified exploratory endpoints included changes from baseline in HbA1c , weight and blood pressure at week 76., Results: Compared with placebo, adjusted mean changes from baseline in HbA1c (overall baseline mean ± sd 63 ± 9 mmol/mol [7.9 ± 0.9%]) were -7 mmol/mol [(-0.6%) 95% CI -8, -5 mmol/mol (-0.8, -0.5%); P < 0.001] and -8 mmol/mol [(-0.7%) 95% CI -10, -6 mmol/mol (-0.9, -0.6%); P < 0.001], for empagliflozin 10 mg and 25 mg, respectively. Compared with placebo, adjusted mean changes from baseline in weight were -1.9 kg (95% CI -2.5, -1.3; P < 0.001) and -2.2 kg (95% CI -2.8, -1.6; P < 0.001) for empagliflozin 10 mg and 25 mg, respectively. Empagliflozin led to sustained reductions in systolic blood pressure vs. placebo. Adverse events were reported in 77.7, 80.2 and 72.0% of participants on placebo, empagliflozin 10 mg and empagliflozin 25 mg, respectively. Confirmed hypoglycaemic adverse events (glucose ≤ 3.9 mmol/l and/or event requiring assistance) were reported in 3.4, 4.1 and 4.2% of participants in these groups, respectively., Conclusions: In people with Type 2 diabetes, empagliflozin 10 mg and 25 mg given as add-on to metformin for 76 weeks were well tolerated and led to sustained reductions in HbA1c , weight and systolic blood pressure., (© 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.)

Background: The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known., Methods: We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina., Results: A total of 7020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99; P=0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction). There was no significant between-group difference in the key secondary outcome (P=0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events., Conclusions: Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care. (Funded by Boehringer Ingelheim and Eli Lilly; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.).

Background: We recently reported improved glycemic control with reduced insulin dose in subjects with type 1 diabetes treated with the sodium glucose co-transporter-2 inhibitor empagliflozin. To further characterize the effects, we analyzed diurnal glycemic patterns by continuous glucose monitoring (CGM)., Methods: In an 8-week single-arm open-label pilot study of empagliflozin, we compared ambulatory glucose profiles produced from CGM data during 2-week intervals in a placebo run-in baseline period, end-of-treatment, and post-treatment. Change in glycemic exposure was evaluated by area under the median curve according to time of day (AUCTOTAL 12:00am-11:55pm; AUCDAY 7:05am-10:55pm, AUCNIGHT 11:00pm-7:00am), as well as glycemic variability, glycemic stability and time-in-target (≥70 to ≤140mg/dL)., Results: The 40 patients (26 on insulin pump) were aged 24±5 years and BMI 24.5±3.2 kg/m2. Consistent with the observed HbA1c decrease (8.0±0.9% to 7.6±0.9%, p<0.0001), normalized AUCTOTAL CGM decreased from 153.7±25.4 to 149.0±30.2mg/dL∙h at end-of-treatment (p = 0.31), and significantly increased post-treatment (164.1±29.5mg/dL∙h, p = 0.02). The numerical decrease in normalized AUCNIGHT (152.0±36.6 to 141.9±34.4mg/dL∙h, p = 0.13) exceeded AUCDAY (154.5±24.5 to 152.6±30.4mg/dL∙h, p = 0.65). Trends toward lower glycemic variability (83.1±18.9 to 75.6±28.6mg/dL, p = 0.06) and little change in glycemic stability (10.8±3.6 to 10.3±4.5mg/dL/h, p = 0.51) were observed. When empagliflozin was discontinued, these worsened relative to baseline (89.3±19.3mg/dL, p = 0.04 and 11.8±3.7mg/dL/hr, p = 0.08). Time-in-target numerically increased (40.2±11.9 to 43.1±13.5%, p = 0.69) at end-of-treatment but reversed post-treatment. Findings were similar on stratification of pump and MDI subjects., Conclusions: We observed that empagliflozin was associated with patterns of improved nighttime glycemia more prominent than daytime., Trial Registration: Clinicaltrials.gov NCT01392560.

Aims: To investigate the pharmacodynamics, efficacy and safety of empagliflozin as adjunct to insulin in patients with type 1 diabetes., Methods: A total of 75 patients with glycated haemoglobin (HbA1c) concentrations of ≥7.5 to ≤10.5% (≥58 to ≤91 mmol/mol) were randomized to receive once-daily empagliflozin 2.5 mg, empagliflozin 10 mg, empagliflozin 25 mg, or placebo as adjunct to insulin for 28 days. Insulin dose was to be kept as stable as possible for 7 days then adjusted, at the investigator's discretion, to achieve optimum glycaemic control. The primary exploratory endpoint was change from baseline in 24-h urinary glucose excretion (UGE) on day 7., Results: Empagliflozin significantly increased 24-h UGE versus placebo on days 7 and 28. On day 28, adjusted mean differences with empagliflozin versus placebo in changes from baseline in: HbA1c were -0.35 to -0.49% (-3.8 to -5.4 mmol/mol; all p < 0.05 vs. placebo); total daily insulin dose -0.07 to -0.09 U/kg (all p<0.05 vs placebo); and weight were -1.5 to -1.9 kg (all p < 0.001 vs. placebo). In the placebo, empagliflozin 2.5, 10 and 25 mg groups, respectively, adverse events were reported in 94.7, 89.5, 78.9 and 100.0% of patients, and the rate of symptomatic hypoglycaemic episodes with glucose ≤3.0 mmol/l not requiring assistance was 1.0, 0.4, 0.5 and 0.8 episodes per 30 days., Conclusions: In patients with type 1 diabetes, empagliflozin for 28 days as adjunct to insulin increased UGE, improved HbA1c and reduced weight with lower insulin doses compared with placebo and without increasing hypoglycaemia., (© 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To investigate the efficacy and tolerability of empagliflozin added to basal insulin-treated type 2 diabetes., Methods: Patients inadequately controlled [glycated haemoglobin (HbA1c) >7 to ≤10% (>53 to ≤86 mmol/mol)] on basal insulin (glargine, detemir, NPH) were randomized to empagliflozin 10 mg (n = 169), empagliflozin 25 mg (n = 155) or placebo (n = 170) for 78 weeks. The baseline characteristics were balanced among the groups [mean HbA1c 8.2% (67 mmol/mol), BMI 32.2 kg/m(2) ]. The basal insulin dose was to remain constant for 18 weeks, then could be adjusted at investigator's discretion. The primary endpoint was change from baseline in HbA1c at week 18. Key secondary endpoints were changes from baseline in HbA1c and insulin dose at week 78., Results: At week 18, the adjusted mean ± standard error changes from baseline in HbA1c were 0.0 ± 0.1% (-0.1 ± 0.8 mmol/mol) for placebo, compared with -0.6 ± 0.1% (-6.2 ± 0.8 mmol/mol) and -0.7 ± 0.1% (-7.8 ± 0.8 mmol/mol) for empagliflozin 10 and 25 mg, respectively (both p < 0.001). At week 78, empagliflozin 10 and 25 mg significantly reduced HbA1c, insulin dose and weight vs placebo (all p < 0.01), and empagliflozin 10 mg significantly reduced systolic blood pressure vs placebo (p = 0.004). Similar percentages of patients had confirmed hypoglycaemia in all groups (35-36%). Events consistent with urinary tract infection were reported in 9, 15 and 12% of patients on placebo, empagliflozin 10 and 25 mg, and events consistent with genital infection were reported in 2, 8 and 5%, respectively., Conclusions: Empagliflozin for 78 weeks added to basal insulin improved glycaemic control and reduced weight with a similar risk of hypoglycaemia to placebo., (© 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

This study investigated the long-term efficacy and safety of empagliflozin as add-on to metformin plus sulphonylurea in patients with type 2 diabetes mellitus (T2DM). Of 666 patients treated with empagliflozin 10 mg, empagliflozin 25 mg or placebo once daily for 24 weeks, 472 patients (70.9%) were treated in a double-blind extension trial for ≥52 weeks. Pre-specified exploratory endpoints included changes from baseline in HbA(1c), weight and blood pressure at week 76. At week 76, adjusted mean differences versus placebo in change from baseline in HbA(1c) were -0.7% (-8 mmol/mol) with empagliflozin 10 mg or 25 mg (both p<0.001), in weight were -1.8 kg and -1.6 kg with empagliflozin 10 mg and 25 mg, respectively (both p<0.001), and in systolic blood pressure (SBP) were -2.2 mmHg with empagliflozin 10 mg (p=0.021) and -2.1 mmHg with empagliflozin 25 mg (p=0.029). Sensitivity analyses provided consistent results for HbA1c and weight, but showed no significant difference between empagliflozin and placebo in change from baseline in SBP. Adverse events (AEs) were reported in 81.7%, 82.0% and 81.3% of patients on empagliflozin 10 mg, 25 mg and placebo, respectively. Confirmed hypoglycaemic AEs (glucose ≤3.9 mmol/l and/or requiring assistance) were reported in 23.7%, 19.4% and 15.6% of patients on empagliflozin 10 mg, 25 mg and placebo, respectively; one patient each on empagliflozin 10mg and placebo required assistance. In conclusion, empagliflozin as add-on to metformin plus sulphonylurea for 76 weeks was well tolerated and led to sustained reductions in HbA1c and weight versus placebo. CLINICALTRIALS.GOV: NCT01289990., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To investigate the long-term efficacy and safety of empagliflozin as add-on therapy to pioglitazone with or without metformin in patients with type 2 diabetes mellitus., Methods: Of 498 patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily for 24 weeks in the EMPA-REG PIO™ study, 305 (61.2%) were treated in a double-blind extension trial for ≥52 weeks (total duration ≥76 weeks). Exploratory end points at week 76 included changes from baseline in glycosylated hemoglobin (HbA1c), weight, and blood pressure assessed using ANCOVA in patients who received ≥1 dose of study drug and had a baseline HbA1c measurement in the initial study., Findings: Compared with placebo, adjusted mean (95% CI) changes from baseline in HbA1c level at week 76 were -0.59% (-0.79% to -0.40%; P < 0.001) for empagliflozin 10 mg (-6.5 [-8.6 to -4.4] mmol/mol) and -0.69% (-0.88% to -0.50%; P < 0.001) for empagliflozin 25 mg (-7.5 [-9.6 to -5.4] mmol/mol). Compared with placebo, adjusted mean (95% CI) changes from baseline in weight at week 76 were -2.0 kg (-2.7 to -1.2 kg; P < 0.001) and -1.7 kg (-2.4 -1.0 kg; P < 0.001) for empagliflozin 10 mg and 25 mg, respectively. Compared with placebo, only empagliflozin 25 mg led to significant reductions in systolic blood pressure (adjusted mean [95% CI] change: -3.7 mmHg [-6.1 to -1.3 mmHg]; P = 0.003) and diastolic blood pressure (adjusted mean [95% CI] change: -2.2 mmHg [-3.7 to -0.7 mmHg]; P = 0.004). Sensitivity analyses were consistent with these results for HbA1c level, fasting plasma glucose concentration, and weight, but revealed no significant difference between empagliflozin and placebo in change from baseline in systolic or diastolic blood pressure at week 76. Confirmed hypoglycemic adverse events (glucose ≤3.9 mmol/L and/or requiring assistance) were reported in 4.2%, 1.8%, and 3.0% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively; 1 patient each taking placebo and empagliflozin 25 mg required assistance. Adverse events consistent with urinary tract infection were reported in 26.7%, 22.4%, and 22.0% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Adverse events consistent with genital infection were reported in 3.0%, 10.3%, and 4.2% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively., Implications: Empagliflozin 10 mg or 25 mg as add-on therapy to pioglitazone with or without metformin for 76 weeks was well tolerated and led to sustained reductions in HbA1c and weight compared with placebo in patients with type 2 diabetes. ClinicalTrials.gov identifier: NCT01210001., (Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.)

Purpose: The aim was to investigate the effects of coadministration of the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin with the thiazolidinedione pioglitazone., Methods: In study 1, 20 healthy volunteers received 50 mg of empagliflozin alone for 5 days, followed by 50 mg of empagliflozin coadministered with 45 mg of pioglitazone for 7 days and 45 mg of pioglitazone alone for 7 days in 1 of 2 treatment sequences. In study 2, 20 volunteers received 45 mg of pioglitazone alone for 7 days and 10, 25, and 50 mg of empagliflozin for 9 days coadministered with 45 mg of pioglitazone for the first 7 days in 1 of 4 treatment sequences., Findings: Pioglitazone exposure (Cmax and AUC) increased when coadministered with empagliflozin versus monotherapy in study 1. The geometric mean ratio (GMR) for pioglitazone Cmax at steady state (Cmax,ss) and for AUC during the dosing interval at steady state (AUCτ,ss) when coadministered with empagliflozin versus administration alone was 187.89% (95% CI, 166.35%-212.23%) and 157.97% (95% CI, 148.02%-168.58%), respectively. Because an increase in pioglitazone exposure was not expected, based on in vitro data, a second study was conducted with the empagliflozin doses tested in Phase III trials. In study 2, pioglitazone exposure decreased marginally when coadministered with empagliflozin. The GMR for pioglitazone Cmax,ss when coadministered with empagliflozin versus administration alone was 87.74% (95% CI, 73.88%-104.21%) with empagliflozin 10 mg, 90.23% (95% CI, 66.84%-121.82%) with empagliflozin 25 mg, and 89.85% (95% CI, 71.03%-113.66%) with empagliflozin 50 mg. The GMR for pioglitazone AUCτ,ss when coadministered with empagliflozin versus administration alone was 90.01% (95% CI, 77.91%-103.99%) with empagliflozin 10 mg, 88.98% (95% CI, 72.69%-108.92%) with empagliflozin 25 mg, and 91.10% (95% CI, 77.40%-107.22%) with empagliflozin 50 mg. The effects of empagliflozin on pioglitazone exposure are not considered to be clinically relevant. Empagliflozin exposure was unaffected by coadministration with pioglitazone. Empagliflozin and pioglitazone were well tolerated when administered alone or in combination. In study 1, adverse events were reported in 1 of 19 participants on empagliflozin 50 mg alone, 4 of 20 on pioglitazone alone, and 5 of 18 on combination treatment. In study 2, adverse events were reported in 8 of 20 participants on pioglitazone alone, 10 of 18 when coadministered with empagliflozin 10 mg, 5 of 17 when coadministered with empagliflozin 25 mg, and 6 of 16 when coadministered with empagliflozin 50 mg., Implications: These results indicate that pioglitazone and empagliflozin can be coadministered without dose adjustments. EudraCT identifiers: 2008-006087-11 (study 1) and 2009-018089-36 (study 2)., (Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.)

Aims: To evaluate the safety and efficacy of empagliflozin for 52 weeks as add-on to one other oral antidiabetes therapy in Japanese patients with type 2 diabetes mellitus (T2DM)., Methods: Patients on biguanide (n = 133), thiazolidinedione (n = 273), α-glucosidase inhibitor (n = 139), dipeptidyl-peptidase-4 inhibitor (n = 139) or glinide (n = 140) were randomized 1 : 1 to receive empagliflozin 10 or 25 mg double-blind as add-on therapy for 52 weeks. Patients on sulphonylurea (SU; n = 336) were randomized 2 : 2 : 1 to receive empagliflozin 10 or 25 mg double-blind or open-label metformin as add-on therapy for 52 weeks. The primary objective was to evaluate safety. Change from baseline in glycated haemoglobin (HbA1c) at week 52 was a secondary endpoint., Results: Adverse events (AEs) were reported in 67.6-84.6% of patients receiving empagliflozin. Confirmed hypoglycaemic AEs (plasma glucose ≤70 mg/dl and/or requiring assistance) were reported in 4.4 and 6.6%, respectively, of patients receiving empagliflozin 10 and 25 mg as add-on to SU and in 0.0 to 2.9%, respectively, of patients receiving empagliflozin 10 and 25 mg as add-on to other therapies. Baseline mean ± standard deviation HbA1c ranged from 7.51 ± 0.73 to 8.06 ± 0.76% across background therapy groups. At week 52, adjusted mean ± standard error changes from baseline in HbA1c ranged from -0.77 ± 0.06 to -1.00 ± 0.06% in patients receiving empagliflozin., Conclusions: In Japanese patients with T2DM, empagliflozin 10 and 25 mg as add-on to one other oral antidiabetes therapy for 52 weeks were well tolerated and were associated with clinically meaningful reductions in HbA1c., (© 2015 John Wiley & Sons Ltd.)

Patients with type 2 diabetes mellitus (T2DM) with a glycated haemoglobin (HbA1c) level ≥7 and ≤10% were randomized to receive empagliflozin 12.5 mg twice daily (n = 219), 25 mg once daily (n = 218), 5 mg twice daily (n = 219) or 10 mg once daily (n = 220), or placebo (n = 107) as add-on to stable-dose metformin immediate release (IR) twice daily for 16 weeks. The primary endpoint was change from baseline in HbA1c at week 16. At week 16, change from baseline in HbA1c with empagliflozin twice daily was non-inferior to empagliflozin once daily and vice versa. The adjusted mean (95% confidence interval) difference in change from baseline in HbA1c with empagliflozin 12.5 mg twice daily versus 25 mg once daily was -0.11% (-0.26, 0.03), and with empagliflozin 5 mg twice daily versus 10 mg once daily it was -0.02% (-0.16, 0.13). All empagliflozin regimens were well tolerated; thus, when used as add-on to metformin IR in patients with T2DM, the therapeutic effect of empagliflozin twice-daily and once-daily regimens can be considered equivalent., (© 2015 John Wiley & Sons Ltd.)

Introduction: The aim of this randomized, double-blind, parallel-group study was to investigate the safety and efficacy of empagliflozin monotherapy for 52 weeks in Japanese patients with type 2 diabetes (T2DM)., Methods: In a 12-week dose-finding period, patients [N = 547; mean baseline glycosylated hemoglobin (HbA1c) 7.92-8.02%] received empagliflozin (5, 10, 25, or 50 mg) or placebo. In a 40-week extension period, patients on empagliflozin 10 or 25 mg continued the same treatment and patients on other doses were reallocated to empagliflozin 10 or 25 mg. Outcomes at week 52 included changes from baseline in HbA1c, fasting plasma glucose (FPG), weight and blood pressure (BP) in patients who received empagliflozin 10 or 25 mg in both the initial 12 weeks and the extension and safety in patients treated with ≥1 dose of empagliflozin 10 or 25 mg., Results: Adjusted mean ± SE changes in HbA1c from baseline at week 52 were -0.67 ± 0.09% and -0.86 ± 0.09%, in FPG were -24.7 ± 3.2 mg/dL and -31.3 ± 3.4 mg/dL, and in body weight were -3.1 ± 0.4 kg and -3.1 ± 0.4 kg, with empagliflozin 10 and 25 mg, respectively. Both doses reduced systolic and diastolic BP. Adverse events were reported in 70.8% and 66.8% of patients on empagliflozin 10 and 25 mg, respectively. Confirmed hypoglycemic adverse events (plasma glucose ≤70 mg/dL and/or requiring assistance) were reported in one patient per group., Conclusion: Empagliflozin monotherapy for 52 weeks led to sustained reductions in HbA1c, FPG, weight and BP and was well tolerated in Japanese patients with T2DM., Funding: Boehringer Ingelheim and Eli Lilly and Company.

Purpose: Empagliflozin is a potent, selective sodium glucose cotransporter 2 inhibitor approved for the treatment of type 2 diabetes mellitus. Thiazide or loop diuretics are commonly prescribed in patients with type 2 diabetes mellitus. This study investigated potential pharmacokinetic drug-drug interactions between empagliflozin and hydrochlorothiazide (HCTZ) or torasemide (TOR)., Methods: This was an open-label, crossover study. Patients with type 2 diabetes mellitus were randomized to receive empagliflozin 25 mg once daily for 5 days and either HCTZ 25 mg once daily for 4 days followed by HCTZ 25 mg once daily plus empagliflozin 25 mg once daily for 5 days or TOR 5 mg once daily for 4 days followed by TOR 5 mg once daily plus empagliflozin once daily for 5 days in 1 of 4 sequences, with at least a 7-day washout period between treatments. Pharmacokinetic parameters of empagliflozin, HCTZ, and TOR were assessed and standard bioequivalence criteria (80%-125%) were applied. Tolerability assessments included the frequency of adverse events and an investigator assessment of global tolerability., Findings: Mean (SD) age of the 22 patients treated was 54.0 (8.1) years and body mass index was 27.1 (3.7) kg/m(2). Coadministration of empagliflozin with HCTZ or TOR had no effect on exposure to empagliflozin, HCTZ, or TOR. Geometric mean ratios (90% CIs) for empagliflozin AUC over a uniform dosing interval and Cmax at steady state were 107.1% (90% CI, 97.1-118.1) and 102.8% (90% CI, 88.6-119.3), respectively, when coadministered with HCTZ versus administration alone, and 107.8% (90% CI, 100.1-116.1) and 107.5% (90% CI, 97.9-118.0), respectively, when coadministered with TOR versus administration alone. For HCTZ, the geometric mean ratios for AUC over a uniform dosing interval and Cmax at steady state were 96.3% (90% CI, 89.1-104.0) and 101.8% (90% CI, 88.6-116.9), respectively, and for TOR were 101.4% (90% CI, 99.1-103.9) and 104.4% (90% CI, 93.8-116.3), respectively, for combined treatment versus administration alone. The pharmacokinetic profiles of empagliflozin, HCTZ, and TOR were similar after administration alone and in combination. Global tolerability was good for all patients after each treatment, and no severe or serious adverse events were reported., Implications: No pharmacokinetic drug-drug interaction was observed between empagliflozin and HCTZ or TOR. ClinicalTrials.gov identifier: NCT01276288., (Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.)

Objective: To evaluate the efficacy and safety of combinations of empagliflozin/linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin., Research Design and Methods: Subjects were randomized to a combination of empagliflozin 25 mg/linagliptin 5 mg (n = 137), empagliflozin 10 mg/linagliptin 5 mg (n = 136), empagliflozin 25 mg (n = 141), empagliflozin 10 mg (n = 140), or linagliptin 5 mg (n = 132) as add-on to metformin for 52 weeks. The primary end point was change from baseline in HbA1c at week 24., Results: At week 24, reductions in HbA1c (mean baseline 7.90-8.02% [62.8-64.1 mmol/mol]) with empagliflozin/linagliptin were superior to those with empagliflozin or linagliptin alone as add-on to metformin; adjusted mean (SE) changes from baseline were -1.19% (0.06) (-13.1 mmol/mol [0.7]) with empagliflozin 25 mg/linagliptin 5 mg, -1.08% (0.06) (-11.8 mmol/mol [0.7]) with empagliflozin 10 mg/linagliptin 5 mg, -0.62% (0.06) (-6.8 mmol/mol [0.7]) with empagliflozin 25 mg, -0.66% (0.06) (-7.2 mmol/mol [0.7]) with empagliflozin 10 mg, and -0.70% (0.06) (-7.6 mmol/mol [0.7]) with linagliptin 5 mg (P < 0.001 for all comparisons). In these groups, respectively, 61.8, 57.8, 32.6, 28.0, and 36.1% of subjects with baseline HbA1c ≥7% (≥53 mmol/mol) had HbA1c <7% (<53 mmol/mol) at week 24. Efficacy was maintained at week 52. The proportion of subjects with adverse events (AEs) over 52 weeks was similar across treatment arms (68.6-73.0%), with no hypoglycemic AEs requiring assistance., Conclusions: Combinations of empagliflozin/linagliptin as second-line therapy for 52 weeks significantly reduced HbA1c compared with the individual components and were well tolerated., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: To investigate the efficacy, safety, and tolerability of empagliflozin in patients with type 2 diabetes and hypertension., Research Design and Methods: Patients (N = 825) with type 2 diabetes and hypertension (mean seated systolic blood pressure [SBP] 130-159 mmHg and diastolic blood pressure [DBP] 80-99 mmHg) were randomized (double blind) to 10 mg or 25 mg empagliflozin or placebo once daily for 12 weeks., Results: At week 12, adjusted mean difference versus placebo in change from baseline in mean 24-h SBP (ambulatory blood pressure monitoring [ABPM]) was -3.44 mmHg (95% CI -4.78, -2.09) with 10 mg empagliflozin and -4.16 mmHg (-5.50, -2.83) with 25 mg empagliflozin (both P < 0.001). At week 12, adjusted mean difference versus placebo in change from baseline in mean 24-h DBP (ABPM) was -1.36 mmHg (95% CI -2.15, -0.56) with 10 mg empagliflozin and -1.72 mmHg (95% CI -2.51, -0.93) with 25 mg empagliflozin (both P < 0.001). Changes in office BP were consistent with ABPM. Adjusted mean difference versus placebo in change from baseline in HbA1c at week 12 was -0.62% (95% CI -0.72, -0.52) (-6.8 mmol/mol [95% CI -7.9, -5.7]) with 10 mg empagliflozin and -0.65% (95% CI -0.75, -0.55) (-7.1 mmol/mol [95% CI -8.2, -6.0]) with 25 mg empagliflozin (both P < 0.001). Empagliflozin was well tolerated. One patient on placebo and one patient on 10 mg empagliflozin reported events consistent with volume depletion., Conclusions: Empagliflozin was associated with significant and clinically meaningful reductions in BP and HbA1c versus placebo and was well tolerated in patients with type 2 diabetes and hypertension., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: To evaluate the efficacy and safety of empagliflozin/linagliptin in subjects with type 2 diabetes., Research Design and Methods: Subjects not receiving antidiabetes therapy for ≥12 weeks were randomized to empagliflozin 25 mg/linagliptin 5 mg (n = 137), empagliflozin 10 mg/linagliptin 5 mg (n = 136), empagliflozin 25 mg (n = 135), empagliflozin 10 mg (n = 134), or linagliptin 5 mg (n = 135) for 52 weeks. The primary end point was change from baseline in HbA1c at week 24., Results: Mean HbA1c at baseline was 7.99-8.05% (64 mmol/mol). At week 24, adjusted mean (SE) changes from baseline in HbA1c with empagliflozin 25 mg/linagliptin 5 mg, empagliflozin 10 mg/linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and linagliptin 5 mg were -1.08 (0.06)% (-11.8 [0.7] mmol/mol), -1.24 (0.06)% (-13.6 [0.7] mmol/mol), -0.95 (0.06)% (-10.4 [0.7] mmol/mol), -0.83 (0.06)% (-9.1 [0.7] mmol/mol), and -0.67 (0.06)% (-7.3 [0.7] mmol/mol), respectively. Reductions in HbA1c were significantly greater for empagliflozin 25 mg/linagliptin 5 mg compared with linagliptin 5 mg (P < 0.001) but not compared with empagliflozin 25 mg and were significantly greater for empagliflozin 10 mg/linagliptin 5 mg compared with the individual components (P < 0.001 for both). At week 24, 55.4%, 62.3%, 41.5%, 38.8%, and 32.3% of subjects with baseline HbA1c ≥7% (≥53 mmol/mol) reached HbA1c <7% with empagliflozin 25 mg/linagliptin 5 mg, empagliflozin 10 mg/linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and linagliptin 5 mg, respectively. Efficacy was maintained at week 52. The proportion of subjects with adverse events (AEs) over 52 weeks was similar across groups (68.9-81.5%), with no confirmed hypoglycemic AEs., Conclusions: Reductions from baseline in HbA1c with empagliflozin/linagliptin were significantly different versus linagliptin and empagliflozin 10 mg but not versus empagliflozin 25 mg. Empagliflozin/linagliptin was well tolerated., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

1. The absorption, biotransformation and excretion of empagliflozin, an SGLT2 inhibitor, were evaluated in eight healthy subjects following a single 50 mg oral dose of empagliflozin containing ∼100 µCi [(14)C]-empagliflozin. 2. Radioactivity was rapidly absorbed, with plasma levels peaking 1 h post-dose. Total exposure was lower in blood versus plasma, consistent with moderate (28.6-36.8%) red blood cell partitioning. Protein binding was 80.3-86.2%. 3. Most of the radioactive dose was recovered in urine (54.4%) and faeces (41.1%). Unchanged empagliflozin was the most abundant drug-related component in plasma, representing 75.5-77.4% of plasma radioactivity and 79.6% plasma radioactivity AUC0-12 h. Unchanged empagliflozin was the most abundant drug-related component in urine and faeces, representing 43.5% (23.7% of dose) and 82.9% (34.1% of dose) of radioactivity in urine and faeces, respectively. Six metabolites were identified in plasma: three glucuronide conjugates representing 4.7-7.1% of AUC0-12 h and three less abundant metabolites (<0.2-1.9% AUC0-12 h). The most abundant metabolites in urine were two glucuronide conjugates (7.8-13.2% of dose) and in faeces was a tetrahydrofuran ring-opened carboxylic acid metabolite (1.9% of dose). 4. To conclude, empagliflozin was rapidly absorbed and excreted primarily unchanged in urine and faeces. Unchanged parent was the major drug-related component in plasma. Metabolism was primarily via glucuronide conjugation.

Aims: To provide model-based clinical development decision support including dose selection guidance for empagliflozin, an orally administered sodium glucose cotransporter 2 inhibitor, through developed exposure-response (E-R) models for efficacy and tolerability in patients with type 2 diabetes mellitus (T2DM)., Methods: Five randomized, placebo-controlled, multiple oral dose studies of empagliflozin in patients with T2DM (n = 974; 1-100 mg once daily, duration ≤12 weeks) were used to develop E-R models for efficacy (glycosylated haemoglobin [HbA1c ], fasting plasma glucose [FPG] and urinary glucose excretion). Two studies (n = 748, 12 weeks) were used to evaluate tolerability E-R., Results: The efficacy model predicted maximal decreases in FPG and HbA1c of 16% and 0.6%, respectively, assuming a baseline FPG concentration of 8 mm (144 mg dl(-1) ) and 10-25 mg every day empagliflozin targeted 80-90% of these maximums. Increases in exposure had no effect on incidence rates of hypoglycaemia (n = 4), urinary tract infection (n = 17) or genital/vulvovaginal-related (n = 16) events, although low prevalence rates may have precluded more accurate evaluation., Conclusions: E-R analyses indicated that 10 and 25 mg once daily empagliflozin doses achieved near maximal glucose lowering efficacy., (© 2014 The British Pharmacological Society.)

Purpose: The purpose of this study was to assess the effect of renal impairment on the pharmacokinetic, pharmacodynamic, and safety profiles of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in Japanese patients with type 2 diabetes mellitus (T2DM)., Methods: In an open-label, parallel-group study, 32 Japanese patients with T2DM and different degrees of renal function (n = 8 per renal function category: normal renal function, estimated glomerular filtration rate [eGFR; Japanese equation] ≥90 mL/min/1.73 m(2); mild renal impairment, eGFR of 60-<90 mL/min/1.73 m(2); moderate renal impairment, eGFR of 30-<60 mL/min/1.73 m(2); and severe renal impairment, eGFR of 15-<30 mL/min/1.73 m(2)) received a single 25 mg dose of empagliflozin., Findings: Empagliflozin exposure increased with increasing renal impairment. Maximum empagliflozin plasma concentrations were similar among all renal function groups. Adjusted geometric mean ratios for extent of exposure (AUC0-∞) to empagliflozin versus normal renal function were 128.8% (95% CI, 106.0-156.6%), 143.8% (95% CI, 118.3-174.8%), and 152.3% (95% CI, 125.3-185.2%) for patients with mild, moderate, and severe renal impairment, respectively. Decreases in renal clearance of empagliflozin correlated with eGFR. Urinary glucose excretion decreased with increasing renal impairment and correlated with eGFR (adjusted mean [SE] change from baseline: 75.0 [4.84] g, 62.6 [5.75] g, 57.9 [4.86] g, and 23.7 [5.24] g for patients with normal renal function and mild, moderate, and severe renal impairment, respectively). Only 2 patients (6%) had adverse events; both were mild., Implications: Pharmacokinetic data suggest that no dose adjustment of empagliflozin is necessary in Japanese patients with T2DM and renal impairment because increases in exposure were <2-fold. Urinary glucose excretion decreased with increasing renal impairment. ClinicalTrials.gov identifier: NCT01581658., (Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.)