Tolerability Of Empagliflozin Research Articles

Safety of Empagliflozin: An Individual Participant-Level Data Meta-Analysis from Four Large Trials.

Empagliflozin is a sodium-glucose co-transporter-2 inhibitor used to treat type 2 diabetes (T2D) to improve glycemic control, reduce risk of cardiovascular death in patients with T2D, and treat patients with symptomatic chronic heart failure (HF) and chronic kidney disease (CKD). The safety profile of empagliflozin is well documented, although adverse events (AEs) remain of interest to clinicians. This study provides an up-to-date safety evaluation of empagliflozin. Data were pooled from four long-term trials which included: patients with T2D and established cardiovascular disease (EMPA-REG OUTCOME), patients with HF, with/without diabetes (EMPEROR-Reduced and EMPEROR-Preserved), and patients with CKD, with/without diabetes (EMPA-KIDNEY). Since three of the four trials evaluated empagliflozin 10mg, the meta-analysis was restricted to this dose. Total trial medication exposure was 19,727 patient-years for patients who received empagliflozin (n = 10,472) and 19,447 patient-years for placebo (n = 10,461). The percentages of patients with serious AEs, fatal AEs, and AEs leading to discontinuation were similar for both groups. The incidences of serious urinary tract infection and serious pyelonephritis or urosepsis were similar for both groups but higher for women taking empagliflozin versus placebo. Serious genital infections were not increased with empagliflozin versus placebo. There was a slight increase in ketoacidosis and serious volume depletion in patients who received empagliflozin versus placebo. The occurrence of serious acute kidney injury was lower with empagliflozin versus placebo. Empagliflozin was not associated with an increased incidence of severe hypoglycemia, bone fractures, or lower limb amputations. Empagliflozin is therefore considered safe in people without diabetes, the elderly, patients with very low estimated glomerular filtration rate, low body mass index, and HF. Safety is unaltered by blood pressure, concomitant medication for hypertension, HF, and immunosuppression. This meta-analysis of long-term safety data extends current knowledge and confirms the safety and tolerability of empagliflozin.

Safety and tolerability of Empagliflozin use during the holy month of Ramadan by fasting patients with type 2 diabetes: A prospective cohort study

BackgroundType 2 Diabetes Mellitus (T2DM) patients are exposed to a 7.5 times higher risk of hypoglycemia while fasting during Ramadan. Relevant diabetes guidelines prioritize the use of SGLT2 inhibitors over other classes. There is a great need to enrich data on their safe and effective use by fasting patients at greater risk of hypoglycemia. Therefore, this study aims to assess the safety and tolerability of Empagliflozin in T2DM Muslim patients during Ramadan. MethodologyA prospective cohort study was conducted for adult Muslim T2DM patients. Patients who met the inclusion criteria were categorized into two sub-cohorts based on Empagliflozin use during Ramadan (Control versus Empagliflozin). The primary outcomes were the incidence of hypoglycemia symptoms and confirmed hypoglycemia. Other outcomes were secondary. All patients were followed up to eight weeks post-Ramadan. A propensity score (PS) matching and Risk Ratio (RR) were used to report the outcomes. ResultsAmong 1104 patients with T2DM who were screened, 220 patients were included, and Empagliflozin was given to 89 patients as an add-on to OHDs. After matching with PS (1:1 ratio), the two groups were comparable. The use of other OHDs, such as sulfonylurea, DPP4 inhibitors, and Biguanides, was not statistically different between the two groups. The risk of hypoglycemia symptoms during Ramadan was lower in patients who received Empagliflozin than in the control group (RR 0.48 CI 0.26, 0.89; p-value = 0.02). Additionally, the risk of confirmed hypoglycemia was not statistically significant between the two groups (RR 1.09 CI 0.37, 3.22; p-value = 0.89). ConclusionEmpagliflozin use during Ramadan fasting was associated with a lower risk of hypoglycemia symptoms and higher tolerability. Further randomized control trials are required to confirm these findings.

Efficacy and safety of combination of empagliflozin and metformin with combination of sitagliptin and metformin during Ramadan: an observational study

BackgroundManagement of diabetes during fasting is a clinical challenge. Sodium glucose co-transporter -2 inhibitors (SGLT2i) are considered safe with a low risk of hypoglycemia. However, studies on SGLT2i are scarce. This study was designed to compare the efficacy, safety, and tolerability of empagliflozin with metformin during Ramadan in comparison with sitagliptin and metformin.MethodsIt was a prospective, observational study, conducted at 11 different sites all across Pakistan on an outpatient basis during Ramadan (May 2021–June 2021). including 132 patients, 88 who received metformin and sitagliptin, and 44 patients who received metformin and empagliflozin.ResultsPatients of the SGLT-2i group experienced similar symptomatic hypoglycemic episodes (15.9%) as the sitagliptin group. There was an improvement in blood sugar levels after the use of SGLT-2i (RBS 181 ± 64 before Ramadan vs 162 ± 53 after Ramadan). HbA1c also improved after the use of SGLT-2i before and after Ramadan (7.2 ± 0.8 vs 6.9 ± 0.9 for Metformin + Empagliflozin and 7.8 ± 1.5 vs 7.6 ± 1.6 for Metformin and sitagliptin). Weight and BMI improved after the use of SGLT-2i (BMI 36.5 ± 4.8 before Ramadan and 33.7 ± 2.4 after Ramadan). There were no reported cases of urinary tract infection in the empagliflozin group.ConclusionSGLT-2 inhibitors combined with metformin for patients with diabetes during Ramadan fasting is as effective, safe and well tolerated as DPP4 combined with metformin.

Safety and tolerability of empagliflozin and linagliptin combination therapy in patients with type 2 diabetes mellitus: a pooled analysis of data from five randomized, controlled clinical trials

ABSTRACT Objectives The fixed-dose combination of empagliflozin and linagliptin, two glucose-lowering drugs prescribed for type 2 diabetes mellitus, has demonstrated good tolerability in phase III clinical trials. To further evaluate the safety profile of this combination, the data from these trials were pooled and analyzed. Methods This was a post-hoc pooled analysis of five randomized, double-blind, clinical trials of the empagliflozin/linagliptin fixed-dose combination. Data for adverse events and laboratory parameters were evaluated. Results The analysis included 2895 patients: 1410, 1015, and 470 receiving the empagliflozin/linagliptin combination, empagliflozin monotherapy, and linagliptin monotherapy, respectively. Overall, the incidence of adverse events with the empagliflozin/linagliptin combination was similar to that with empagliflozin or linagliptin alone. Fewer than 2% of patients experienced hypoglycemia, and its incidence was similar across treatment groups. Genital infections occurred in more patients receiving empagliflozin/linagliptin (3.0%) or empagliflozin monotherapy (5.1%) than in those receiving linagliptin monotherapy (1.9%). No cases of Fournier’s gangrene, diabetic ketoacidosis, or pemphigoid occurred, and no clinically relevant mean changes in laboratory parameters were noted. Conclusion The safety profile of the fixed-dose combination of empagliflozin and linagliptin was similar to the individual monotherapies. No new safety signals were identified.

An evaluation of empagliflozin and it’s applicability to hypertension as a therapeutic option

ABSTRACT Introduction Sodium-glucose cotransporter 2 (SGLT2) inhibitors such as Empagliflozin are novel antihyperglycemic drugs approved for the treatment of type 2 diabetes (T2D). In addition to its glucose-lowering effects, Empagliflozin promotes weight loss, blood pressure reduction, and other beneficial metabolic benefits. Areas covered This review outlines the pharmacokinetics, pharmacodynamics, safety, and tolerability of Empagliflozin and discusses its role in diabetes-associated hypertension. Expert opinion Empagliflozin was the first in class to not only demonstrate safety of SGLT2 inhibition but also cardio- and reno-protective effects in an adequately powered cardiovascular outcome trial. The EMPA-REG study showed significant reductions in mortality from cardiovascular causes, hospitalization for heart failure, and progression of diabetic kidney disease. These benefits cannot be attributed to glycemic control alone, suggesting the involvement of other SGLT2 inhibition-mediated mechanisms. Recent data suggests the potential utility of SGLT2 inhibition in other conditions including type 1 diabetes (T1D) and non-diabetic heart failure patients with clinical trials currently being conducted. In concert with ongoing pre-clinical investigations to unravel the mechanisms contributing to cardiorenal protection, the full therapeutic potential of SGLT2 inhibition will become apparent over the next few years and promises to be one of the major success stories in clinical medicine. Abbreviations T1D: type 1 diabetes; T2D: type 2 diabetes; SGLT2: sodium-glucose cotransporter 2; CVD: cardiovascular disease; SBP: systolic blood pressure; DBP: diastolic blood pressure; SNS: sympathetic nervous system; BP: blood pressure; CV: cardiovascular; ZDF: Zucker diabetic fatty; CKD: chronic kidney disease; FDA: Food and Drug Administration

Efficacy and safety of empagliflozin for type 2 diabetes mellitus: Meta-analysis of randomized controlled trials.

Background:This study was designed to evaluate the efficiency and tolerability of empagliflozin (EMPA) as monotherapy or add-on to existing therapy in patients with type 2 diabetes mellitus (T2DM).Methods:Randomized controlled trials (RCTs) comparing efficacy and safety of EMPA vs placebo or EMPA plus other antidiabetes drugs vs placebo plus other oral antidiabetes drugs (OADs) in T2DM were recruited from electronic database Pubmed, Web of Knowledge, and Cochrane Central Register of Controlled Trials (CENTRAL), supplemented by a hand search of the reference lists of selected articles. Main effect sizes were change from baseline on glycemia control, body weight, blood pressure, and complications (i.e., incidence of urinary and genital tract infections, and morbidity of hypoglycemia and hyperglycemia). Random-effects model was used to account for clinical or methodologic heterogeneity across studies.Results:Fifteen RCTs with a total number of 7891 individuals (5374 in EMPA group and 2517 in control group) were suitable for this meta-analysis. The results demonstrated that significant improvements in glycemia control, body weight, and blood pressure were associated with EMPA application (i.e., monotherapy and add-on therapy) in patient with T2DM when compared with placebo. Meanwhile, EMPA 10 and 20 mg improved glycemia, body weight, and blood pressure control for patients with T2DM. There was no significant difference in incidence of hypoglycemia and urinary tract infections across EMPA and placebo group. Significant reduced risk of hyperglycemia was revealed in EMPA group vs placebo (risk ratio: 0.34, 95%confidence interval: 0.23–0.49, P < .00001), except in patients on background insulin therapy. However, increased risk of genital infection was noted across EMPA vs placebo (risk ratio: 2.59, 95% confidence interval: 1.80–3.71, P < .00001).Conclusion:Our evidence supports the application of EMPA in treatment of patients with T2DM who are obesity or at risk of weight gain.

Safety and tolerability of empagliflozin in East Asian patients with type 2 diabetes: Pooled analysis of phase I-III clinical trials.

Aims/IntroductionWe investigated the safety and tolerability of empagliflozin (EMPA) in East Asian patients with type 2 diabetes.Materials and MethodsData were pooled from participants with type 2 diabetes evenly randomized to a placebo, EMPA 10 mg or EMPA 25 mg in 15 phase I–III trials. Adverse events (AEs) were analyzed in the subgroup of trial participants from East Asian countries/regions.ResultsIn total, 709, 724 and 708 East Asian trial participants with type 2 diabetes received a placebo, EMPA 10 mg and EMPA 25 mg, respectively; total exposure was 953, 1,072, and 1,033 patient‐years in these groups, respectively. The EMPA and placebo groups had similar incidences of severe AEs, serious AEs and AEs leading to discontinuation. Incidences of hypoglycemia differed according to anti‐diabetes medication used at baseline. Higher rates of events consistent with genital infection were observed with EMPA (EMPA 1.5–1.7/100, placebo 0.2/100 patient‐years). Rates of AEs consistent with volume depletion were comparable among treatment groups (0.8–1.4/100 patient‐years), but in trial participants aged ≥65 years, the rate was greater with EMPA 25 mg (EMPA 25 mg 3.5/100, placebo 2.0/100 patient‐years). Incidences of events consistent with urinary tract infection, thromboembolic events, renal events, hepatic AEs, diabetic ketoacidosis, fractures and lower limb amputation were similar between EMPA and the placebo.ConclusionsIn the present pooled analysis, EMPA was well tolerated in East Asian type 2 diabetes patients based on >2,100 patient‐years’ exposure, consistent with results from the overall analysis population.

Safety and Tolerability of Empagliflozin in East Asian Patients with Type 2 Diabetes—Pooled Analysis of Phase I-III Clinical Trials

Aims/Introduction: As the pathophysiology of type 2 diabetes (T2DM) differs in East Asian patients compared with that in other ethnic groups, a comprehensive evaluation of the safety of empagliflozin (EMPA) in East Asian patients is desirable to inform clinical practice in the patient population. We therefore investigated the safety and tolerability of EMPA in East Asian patients with T2DM. Materials and Methods: Data were pooled from patients with T2DM treated with placebo, EMPA 10 mg or 25 mg in 15 Phase I-III trials plus 4 extension studies. Adverse events (AEs) were analyzed in the subgroup of patients from East Asian countries. (China, Hong Kong, Japan, Korea, Taiwan) (N=2141). Results: Total exposure was 953, 1072, and 1033 patient-years in the placebo, EMPA 10 mg, and 25 mg groups, respectively. The incidence of any AEs, severe AEs, serious AEs, and AEs leading to discontinuation was no higher in patients who were treated with either dose of EMPA than in those treated with placebo. The incidence of hypoglycemia differed according to glucose-lowering medications used at baseline. Events consistent with urinary tract infection occurred less frequently with EMPA than placebo (5.3-5.8 vs. 7.2/100 patient-years). Events consistent with genital infection occurred more frequently with EMPA than placebo (1.5-1.7 vs. 0.2/100 patient-years). The incidence of AEs consistent with volume depletion was similar across treatment groups (0.8-1.4/100 patient-years). Rates of bone fractures, renal AEs, venous thromboembolic events, hepatic injury, lower limb amputation and diabetic ketoacidosis were similar or no higher with EMPA vs. placebo. Conclusions: In this pooled analysis, EMPA was well tolerated in the East Asian patients with T2DM based on &amp;gt;3,000 patient-years’ exposure, consistent with results from the overall analysis population. The result was in line with package inserts in East Asian countries and did not raise new safety concerns. Disclosure A. Yasui: Employee; Self; Nippon Boehringer Ingelheim Co. Ltd. D. Yabe: Speaker's Bureau; Self; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd.. Research Support; Self; Nippon Boehringer Ingelheim Co. Ltd., Eli Lilly and Company, MSD K.K., Ono Pharmaceutical Co., Ltd., Arkray, Inc., Taisho Toyama Pharmaceutical Co., Ltd., Novo Vordisk Pharma Ltd., Takeda Pharamaceutical Co., Ltd. L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Eli Lilly and Company, Bristol-Myers Squibb Company, Novartis AG, Novo Nordisk A/S, Merck &amp; Co., Inc., Bayer AG, Merck Sharp &amp; Dohme Corp., Takeda Development Center Asia, Pte. Ltd., Sanofi, Roche Pharma, Boehringer Ingelheim GmbH. Research Support; Self; AstraZeneca, Roche Pharma, Sanofi, Merck Sharp &amp; Dohme Corp., Novartis AG, Eli Lilly and Company, Bristol-Myers Squibb Company. M. Lee: None. R.C. Ma: Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp &amp; Dohme Corp., Pfizer Inc.. Advisory Panel; Self; Boehringer Ingelheim GmbH, Nippon Boehringer Ingelheim Co. Ltd. T. Chang: Stock/Shareholder; Self; Novo Nordisk A/S. Advisory Panel; Self; Nippon Boehringer Ingelheim Co. Ltd. T. Okamura: Employee; Self; Nippon Boehringer Ingelheim Co. Ltd. C. Zeller: Employee; Self; Boehringer Ingelheim Pharma GmbH &amp; Co. KG. S. Kaspers: Employee; Self; Boehringer Ingelheim GmbH. J. Lee: Employee; Self; Boehringer Ingelheim GmbH. S. Kohler: Employee; Self; Boehringer Ingelheim GmbH. Y. Seino: Speaker's Bureau; Self; MSD K.K., Kao Corporation, Taisho Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Taisho Toyama Pharamceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Nippon Becton Dickinson Co., Ltd., Novo Nordisk Pharma Ltd.. Research Support; Self; Terumo Medical Corporation, Bayer Yakuhin, Ltd., Boehringer Ingelheim GmbH, Arkray, Inc., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Novo Nordisk Pharma Ltd..

Safety and tolerability of empagliflozin in patients with type 2 diabetes

Aim: To assess the safety and tolerability of empagliflozin using data pooled from Phase I, II and III trials in patients with type 2 diabetes (T2DM).

Safety and Tolerability of Empagliflozin in Patients with Type 2 Diabetes

PurposeThe 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. MethodsPooled 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. FindingsTotal 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. ImplicationsIn 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.

Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial.

To investigate the efficacy and tolerability of empagliflozin as an add-on to metformin therapy in patients with type 2 diabetes. Patients with HbA1c levels of ≥7% to ≤ 10% (≥53 to ≤86 mmol/mol) while receiving metformin (≥1,500 mg/day) were randomized and treated with once-daily treatment with empagliflozin 10 mg (n = 217), empagliflozin 25 mg (n = 213), or placebo (n = 207) for 24 weeks. The primary end point was the change in HbA1c level from baseline at week 24. Key secondary end points were changes from baseline in weight and mean daily glucose (MDG) at week 24. At week 24, adjusted mean (SE) changes from baseline in HbA1c were -0.13% (0.05)% (-1.4 [0.5] mmol/mol) with placebo, -0.70% (0.05)% (-7.7 [0.5] mmol/mol) with empagliflozin 10 mg, and -0.77% (0.05)% (-8.4 [0.5] mmol/mol) with empagliflozin 25 mg (both P < 0.001). Empagliflozin significantly reduced MDG level and systolic and diastolic blood pressure (BP) versus placebo. Adjusted mean (SE) changes from baseline in weight were -0.45 kg (0.17 kg) with placebo, -2.08 kg (0.17 kg) with empagliflozin 10 mg, and -2.46 kg (0.17 kg) with empagliflozin 25 mg (both P < 0.001). Adverse events (AEs) were similar across groups (placebo 58.7%; empagliflozin 49.5-57.1%). Confirmed hypoglycemic AEs were reported in 0.5%, 1.8%, and 1.4% of patients receiving placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Events consistent with urinary tract infections were reported in 4.9%, 5.1%, and 5.6% of patients, and events consistent with genital infections were reported in 0%, 3.7%, and 4.7% of patients, respectively. Empagliflozin 10 and 25 mg for 24 weeks as add-on to metformin therapy significantly improved glycemic control, weight, and BP, and were well-tolerated.

Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial.

OBJECTIVETo investigate the efficacy and tolerability of empagliflozin as add-on to metformin and sulfonylurea in patients with type 2 diabetes.RESEARCH DESIGN AND METHODSPatients inadequately controlled on metformin and sulfonylurea (HbA1c ≥7 to ≤10%) were randomized and treated with once-daily empagliflozin 10 mg (n = 225), empagliflozin 25 mg (n = 216), or placebo (n = 225) for 24 weeks. The primary end point was change from baseline in HbA1c at week 24. Key secondary end points were changes from baseline in weight and mean daily glucose (MDG) at week 24.RESULTSAt week 24, adjusted mean (SE) changes from baseline in HbA1c were −0.17% (0.05) for placebo vs. −0.82% (0.05) and −0.77% (0.05) for empagliflozin 10 and 25 mg, respectively (both P < 0.001). Empagliflozin significantly reduced MDG, weight, and systolic (but not diastolic) blood pressure versus placebo. Adverse events were reported in 62.7, 67.9, and 64.1% of patients on placebo and empagliflozin 10 and 25 mg, respectively. Events consistent with urinary tract infection were reported in 8.0, 10.3, and 8.3% of patients on placebo and empagliflozin 10 and 25 mg, respectively (females: 13.3, 18.0, and 17.5%, respectively; males: 2.7, 2.7, and 0%, respectively). Events consistent with genital infection were reported in 0.9, 2.7, and 2.3% of patients on placebo and empagliflozin 10 and 25 mg, respectively (females: 0.9, 4.5, and 3.9%, respectively; males: 0.9% in each group).CONCLUSIONSEmpagliflozin 10 and 25 mg for 24 weeks as add-on to metformin plus sulfonylurea improved glycemic control, weight, and systolic blood pressure and were well tolerated.

Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial

We aimed to investigate the efficacy and tolerability of empagliflozin, an oral, potent, and selective inhibitor of sodium-glucose co-transporter 2, in patients with type 2 diabetes who had not received drug treatment in the preceding 12 weeks. In our multicentre, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) who had not received oral or injected anti-diabetes treatment in the previous 12 weeks. Eligible patients had HbA1c concentrations of 7-10%. We randomly allocated patients (1:1:1:1) with a computer-generated random sequence, stratified by region, HbA1c, and estimated glomerular filtration rate at screening, to placebo, empagliflozin 10 mg, empagliflozin 25 mg, or sitagliptin 100 mg once daily for 24 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c at week 24 by ANCOVA in all randomly allocated patients who were treated with at least one dose of study drug and had a baseline HbA1c value. This study is completed and registered with ClinicalTrials.gov, number NCT01177813. Between Aug 12, 2010, and March 19, 2012, we randomly allocated 228 patients to receive placebo, 224 to receive empagliflozin 10 mg, 224 to receive empagliflozin 25 mg, and 223 to receive sitagliptin. Compared with placebo, adjusted mean differences in change from baseline HbA1c at week 24 were -0·74% (95% CI -0·88 to -0·59; p<0·0001) for empagliflozin 10 mg, -0·85% (-0·99 to -0·71; p<0·0001) for empagliflozin 25 mg, and -0·73% (-0·88 to -0·59; p<0·0001) for sitagliptin. 140 (61%) patients in the placebo group reported adverse events (four [2%] severe and six [3%] serious), as did 123 (55%) patients in the empagliflozin 10 mg group (eight [4%] severe and eight [4%] serious), 135 (60%) patients in the empagliflozin 25 mg group (seven [3%] severe and five [2%] serious), and 119 (53%) patients in the sitagliptin group (five [2%] severe and six [3%] serious). Empagliflozin provides a tolerable and efficacious strategy to reduce HbA1c in patients with type 2 diabetes who had not previously received drug treatment. Boehringer Ingelheim and Eli Lilly.

Empagliflozin improves glycaemic and weight control as add‐on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24‐week, randomized, placebo‐controlled trial

This study investigated the efficacy and tolerability of empagliflozin as add-on to pioglitazone ± metformin in patients with type 2 diabetes (T2DM). Patients with HbA1c ≥7 and ≤10% were randomized and treated with once daily empagliflozin 10 mg (n = 165), empagliflozin 25 mg (n = 168) or placebo (n = 165) as add-on to pioglitazone ± metformin for 24 weeks. Endpoints included changes from baseline in HbA1c (primary endpoint), fasting plasma glucose (FPG) and body weight at week 24. Adjusted mean ± standard error changes in HbA1c were -0.6 ± 0.07% and -0.7 ± 0.07% with empagliflozin 10 mg and 25 mg, respectively, vs. -0.1 ± 0.07% with placebo (both p < 0.001). More patients with HbA1c ≥7% at baseline achieved HbA1c <7% with empagliflozin 10 mg (23.8%) and 25 mg (30.0%) vs. placebo (7.7%) (both p < 0.001). FPG decreased with empagliflozin (-0.94 mmol/l for 10 mg and -1.22 mmol/l for 25 mg) and increased with placebo (+0.36 mmol/l; both p < 0.001). Adjusted mean ± standard error changes in weight were -1.62 ± 0.21 kg and -1.47 ± 0.21 kg with empagliflozin 10 mg and 25 mg, respectively, vs. +0.34 ± 0.21 kg with placebo (both p < 0.001). Similar proportions of patients reported adverse events with empagliflozin (67.3-71.4%) and placebo (72.7%). Confirmed hypoglycaemia was reported by 1.2-2.4% of patients on empagliflozin and 1.8% on placebo. Empagliflozin 10 mg and 25 mg once daily for 24 weeks as add-on to pioglitazone ± metformin reduced HbA1c, FPG and weight and were well tolerated in patients with T2DM.

Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment

This open-label, parallel-group study investigated the effect of various degrees of hepatic impairment on the pharmacokinetics, safety and tolerability of the sodium glucose cotransporter 2 inhibitor empagliflozin. Thirty-six subjects [8 each with mild, moderate or severe hepatic impairment (Child-Pugh classification), and 12 matched controls with normal hepatic function] received a single 50 mg dose of empagliflozin. Empagliflozin was rapidly absorbed. After reaching peak levels, plasma drug concentrations declined in a biphasic fashion. Compared with subjects with normal hepatic function, geometric mean ratios (90% confidence interval) of AUC(0-∞) and C(max) were 123.15% (98.89-153.36) and 103.81% (82.29-130.95), respectively, in patients with mild hepatic impairment, 146.97% (118.02-183.02) and 123.31% (97.74-155.55), respectively, in patients with moderate hepatic impairment, and 174.70% (140.29-217.55) and 148.41% (117.65-187.23), respectively, in patients with severe hepatic impairment. Adverse events, all mild or moderate in intensity, were reported in three subjects with moderate hepatic impairment, two subjects with severe hepatic impairment and six subjects with normal hepatic function. Empagliflozin was well tolerated in subjects with hepatic impairment. Increases in empagliflozin exposure were less than twofold in patients with hepatic impairment; therefore no dose adjustment of empagliflozin is required in patients with hepatic impairment.

Pharmacokinetics, pharmacodynamics, safety and tolerability of 4weeks' treatment with empagliflozin in Japanese patients with type 2 diabetes mellitus.

To evaluate the pharmacodynamics, pharmacokinetics, safety and tolerability of empagliflozin in Japanese patients with type 2 diabetes mellitus. In this 4-week, multiple dose, randomized, parallel-group, double-blind, placebo-controlled trial, patients (n=100) were randomized to receive 1, 5, 10 or 25mg of empagliflozin, or placebo once daily. Key end-points were urinary glucose excretion (UGE), fasting plasma glucose (FPG) and eight-point glucose profile. Data are presented for 1, 5, 10, 25mg of empagliflozin and placebo groups, respectively. Adjusted mean changes from baseline to day27 in UGE were 40.8, 77.1, 80.9, 93.0 and -2.1g (P<0.0001 for all empagliflozin groups vs placebo). Adjusted mean changes from baseline to day 28 in FPG were -1.56, -1.96, -2.31, -2.37 and -0.86mmol/L (P<0.01 for all empagliflozin groups vs placebo). Adjusted mean changes from baseline to day27 in eight-point glucose profile were -1.96, -2.21, -2.42, -2.54 and -0.97mmol/L (P<0.01 for all empagliflozin groups vs placebo). Empagliflozin reached peak plasma concentration 1.5-2h after dosing. Mean steady state terminal elimination half-lives ranged from 13.2 to 18.0h. Of 100 patients, 25 experienced an adverse event, occurring more frequently for empagliflozin (29.1%) than placebo (9.5%); frequency was not dose related. In Japanese patients with type 2 diabetes mellitus, empagliflozin at doses up to 25mg once daily for 4weeks was well tolerated and resulted in significant improvements in glycemic control compared with placebo. This trial was registered with ClinicalTrials.gov (no. NCT00885118).