Dataset Information

Population Pharmacokinetics and Exposure-Response (Efficacy and Safety/Tolerability) of Empagliflozin in Patients with Type 2 Diabetes.

ABSTRACT:

Introduction

The aim of the analysis was to characterize the population pharmacokinetics (PKs) and exposure-response (E-R) for efficacy (fasting plasma glucose, glycated hemoglobin) and safety/tolerability [hypoglycemia, genital infections, urinary tract infection (UTI), and volume depletion] of the sodium glucose cotransporter 2 inhibitor, empagliflozin, in patients with type 2 diabetes mellitus. This study extends the findings of previous analyses which described the PK and pharmacodynamics (PD) using early clinical studies of up to 12 weeks in duration.

Methods

Population pharmacokinetic and E-R models were developed based on two Phase I, four Phase II, and four Phase III studies.

Results

Variability in empagliflozin exposure was primarily affected by estimated glomerular filtration rate (eGFR) (less than twofold increase in exposure in patients with severe renal impairment). Consistent with its mode of action, the efficacy of empagliflozin was increased with elevated baseline plasma glucose levels and attenuated with decreasing renal function, but was still maintained to nearly half the maximal effect with eGFR as low as 30 mL/min/1.73 m(2). All other investigated covariates, including sex, body mass index, race, and age did not alter the PK or efficacy of empagliflozin to a clinically relevant extent. Compared with placebo, empagliflozin administration was associated with an exposure-independent increase in the incidence of genital infections and no significant change in the risk of UTI, hypoglycemia, or volume depletion.

Conclusion

Based on the results from the PK and E-R analysis, no dose adjustment is required for empagliflozin in the patient population for which the drug is approved.

Funding

Boehringer Ingelheim.

SUBMITTER: Baron KT

PROVIDER: S-EPMC5014782 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionThe aim of this analysis was to characterize the safety and tolerability of empagliflozin in patients with type 2 diabetes mellitus (T2DM) who were randomized to empagliflozin (10/25 mg) or placebo in clinical trials.MethodsPooled data from 20 trials were analyzed for patients with T2DM treated with empagliflozin 10 mg (n = 4858), empagliflozin 25 mg (n = 5057), or placebo (n = 4904). The dataset comprised 15 randomized phase I-III trials, an extension trial and dose escalation studies. Adverse events (AEs) were assessed descriptively in participants who took ≥ 1 dose of study drug. AE incidence rates per 100 patient-years were calculated to adjust for differences in drug exposure between trials.ResultsTotal exposure was 16,480 and 7857 patient-years in the pooled empagliflozin 10/25 mg and placebo groups, respectively. The incidence of any AEs, AEs leading to treatment discontinuation, severe AEs, and serious AEs was similar across groups. The frequency of serious AEs requiring hospitalization was 18.6% for the empagliflozin 10/25 mg group and 21.3% for the placebo group. The empagliflozin 10/25 mg group was not associated with a higher rate of confirmed hypoglycemia versus placebo, except in patients co-administered insulin and/or a sulfonylurea (31.5% vs. 30.2%, respectively). The incidence of events consistent with urinary tract infections (UTI) was also similar for the empagliflozin 10/25 mg group versus placebo (9.27 vs. 9.70/100 patient-years, respectively). History of UTI was identified as a risk factor for UTI during treatment. Events consistent with genital infections occurred more frequently with empagliflozin 10/25 mg than placebo (3.54 vs. 0.95/100 patient-years, respectively). The frequency of AEs consistent with volume depletion was similar across groups, but higher with empagliflozin 10/25 mg than placebo in patients aged 75 to < 85 years and those on loop diuretics at baseline.ConclusionThis comprehensive analysis confirms that both empagliflozin 10 mg and 25 mg are well tolerated in patients with T2DM, reinforcing the established clinical safety profile of empagliflozin.

Project description:IntroductionWe characterized the safety and tolerability of empagliflozin in patients with type 2 diabetes (T2DM) randomized 1:1:1 to placebo, empagliflozin 10 mg, or empagliflozin 25 mg in clinical trials.MethodsPooled data were analyzed from patients with T2DM treated with placebo (N = 4203), empagliflozin 10 mg (N = 4221), or empagliflozin 25 mg (N = 4196) in 15 randomized phase I-III trials plus four extension studies. Adverse events (AEs) were assessed descriptively in participants who took at least one dose of study drug. AE incidence rates per 100 patient-years were calculated to adjust for differences in drug exposure between trials.ResultsTotal exposure was 7369, 7782, and 7754 patient-years in the placebo, empagliflozin 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 participants treated with empagliflozin vs. placebo. Empagliflozin was not associated with an increased risk of hypoglycemia vs. placebo, except in participants on background sulfonylurea. The incidence of events consistent with urinary tract infection was similar across treatment groups (8.7-9.5/100 patient-years). Events consistent with genital infection occurred more frequently in participants treated with empagliflozin 10 and 25 mg (3.5 and 3.4/100 patient-years, respectively) than placebo (0.9/100 patient-years). The incidence of AEs consistent with volume depletion was similar across treatment groups (1.7-1.9/100 patient-years) but was higher with empagliflozin 10 mg and 25 mg vs. placebo in participants aged 75 years or older (3.2 and 3.0 vs. 2.3/100 patient-years, respectively). The rates of bone fractures, cancer events, renal AEs, venous thromboembolic events, hepatic injury, acute pancreatitis, lower limb amputations, and diabetic ketoacidosis were similar across treatment groups.ConclusionThis analysis of pooled safety data based on more than 15,000 patient-years' exposure supports a favorable benefit-risk profile of empagliflozin in patients with T2DM.FundingBoehringer Ingelheim Pharma GmbH.

Project description: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.