Dataset Information

Effects of Ertugliflozin on Liver Enzymes in Patients with Type 2 Diabetes: A Post-Hoc Pooled Analysis of Phase 3 Trials.

ABSTRACT:

Introduction

This post hoc exploratory analysis examined the effects of ertugliflozin on liver enzymes in patients with type 2 diabetes mellitus (T2DM).

Methods

Data were pooled from seven randomized, double-blind VERTIS phase 3 trials that evaluated ertugliflozin (5 mg and 15 mg) versus non-ertugliflozin (placebo, glimepiride, or sitagliptin) treatment in patients with T2DM. Change from baseline at week 52 of treatment in alanine and aspartate aminotransferase (ALT and AST, respectively) serum levels (overall and categorized into tertiles by baseline ALT and AST), Fibrosis-4 Index (FIB-4), glycated hemoglobin (HbA1c), and body weight were evaluated, along with the association between changes in ALT and AST and changes in HbA1c and body weight by treatment.

Results

Baseline characteristics were balanced across treatment groups (ertugliflozin 5 mg, n?=?1716; ertugliflozin 15 mg, n?=?1693; non-ertugliflozin, n?=?1450). At week 52 of treatment, serum levels of ALT and AST were reduced in patients in the ertugliflozin treatment groups (5 and 15 mg, respectively) compared with those in the non-ertugliflozin group. The comparator-adjusted mean (95% confidence interval [CI]) difference in change from baseline at week 52 for ALT was -?3.35 (-?4.40, -?2.31) IU/L for ertugliflozin 5 mg and -?4.08 (-?5.13, -?3.03) IU/L for ertugliflozin 15 mg; for AST, the respective values were -?1.81 (-?2.50, -?1.11) IU/L and -?2.12 (-?2.82, -?1.42) IU/L. The effects of ertugliflozin were detected across all baseline ALT and AST tertiles, with the highest tertile showing the greatest treatment differences. No meaningful differences were observed between treatment groups for FIB-4. Changes in ALT and AST showed a weak but statistically significant association with changes in HbA1c and body weight in all treatment groups.

Conclusions

Treatment with ertugliflozin resulted in a reduction in the levels of hepatic transaminases compared with the non-ertugliflozin group after 52 weeks of treatment. Changes in body weight and HbA1c contributed at least in part to the effects of ertugliflozin on liver enzymes.

Trial registration

Clinicaltrials.gov registry numbers: NCT02033889, NCT01958671, NCT02036515, NCT01986855, NCT02099110, NCT02226003, NCT01999218.

SUBMITTER: Gallo S

PROVIDER: S-EPMC7376773 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Effects of Ertugliflozin on Liver Enzymes in Patients with Type 2 Diabetes: A Post-Hoc Pooled Analysis of Phase 3 Trials.

Gallo Silvina S Calle Roberto A RA Terra Steven G SG Pong Annpey A Tarasenko Lisa L Raji Annaswamy A

Diabetes therapy : research, treatment and education of diabetes and related disorders 20200709 8

<h4>Introduction</h4>This post hoc exploratory analysis examined the effects of ertugliflozin on liver enzymes in patients with type 2 diabetes mellitus (T2DM).<h4>Methods</h4>Data were pooled from seven randomized, double-blind VERTIS phase 3 trials that evaluated ertugliflozin (5 mg and 15 mg) versus non-ertugliflozin (placebo, glimepiride, or sitagliptin) treatment in patients with T2DM. Change from baseline at week 52 of treatment in alanine and aspartate aminotransferase (ALT and AST, respe ...[more]

PMID: 32648108

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Project description:BackgroundThe efficacy of ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, for glycemic and blood pressure (BP) control has been demonstrated in phase 3 studies. To further evaluate the effects of ertugliflozin on BP and other hemodynamic parameters, an analysis was conducted on the pooled patient populations from these studies.MethodsThis was a post hoc analysis of data from three phase 3 studies (NCT01958671, NCT02033889, and NCT02036515) of adults with type 2 diabetes mellitus who received placebo, ertugliflozin 5 mg, or ertugliflozin 15 mg. Outcomes at 26 weeks were analyzed for the pooled population and according to relevant baseline factors, including BP.ResultsOf the 1544 patients included (placebo, n = 515; ertugliflozin 5 mg, n = 519; ertugliflozin 15 mg, n = 510), most (67.4-69.0%) had hypertension at baseline. Mean baseline BP was similar across treatment groups (placebo, 129.7/78.0 mmHg; ertugliflozin 5 mg, 131.0/78.4 mmHg; ertugliflozin 15 mg, 130.5/78.4 mmHg). At Week 26, placebo-adjusted least squares (LS) mean changes (95% confidence intervals [CI]) from baseline in systolic BP (SBP) were - 3.7 mmHg (- 5.1, - 2.3) for both ertugliflozin doses. Reductions were consistent across all baseline subgroups. At Week 26, more patients with a baseline SBP ≥ 130 mmHg had a SBP < 130 mmHg with ertugliflozin (38.7% both doses) than with placebo (24.0%), and more patients with a baseline SBP ≥ 140 mmHg attained a SBP < 140 mmHg with ertugliflozin (59.5% [5 mg] and 66.7% [15 mg]) than with placebo (43.8%). Placebo-adjusted LS mean changes (95% CI) in diastolic BP (DBP) with ertugliflozin 5 mg and 15 mg were - 1.8 mmHg (- 2.7, - 0.9) and - 1.6 mmHg (- 2.5, - 0.7), respectively, and in pulse rate were - 1.3 beats per minute (bpm) (- 2.2, - 0.3) and - 1.5 bpm (- 2.5, - 0.6), respectively. Greater reductions in pulse pressure, mean arterial pressure, and double product were observed with ertugliflozin than with placebo. Incidence of adverse event-related osmotic diuresis was low, but greater with ertugliflozin (2.9% [5 mg], 2.4% [15 mg]) than placebo (1.0%).ConclusionErtugliflozin treatment led to reductions in SBP, DBP, and pulse rate relative to placebo. Reductions in SBP were generally consistent across the subgroups evaluated. Trial registration NCT01958671; NCT02033889; NCT02036515.

Project description:INTRODUCTION:The sodium-glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin is approved for the treatment of adults with type 2 diabetes mellitus (T2DM). This analysis was conducted on safety data pooled from phase 3 studies using ertugliflozin 5 mg or 15 mg versus placebo or an active comparator. METHODS:The placebo pool (n = 1544) comprised data from three similarly designed 26-week placebo-controlled studies. The broad pool (n = 4849) comprised these three placebo-controlled studies plus four placebo- or active-controlled studies with treatment durations of up to 104 weeks. RESULTS:In the placebo pool, there were no notable differences across groups in the incidence of adverse events (AEs), serious AEs, or AEs resulting in discontinuation from study medication, while associations were observed with genital mycotic infection in both females (3.0%, 9.1%, and 12.2% in the placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg groups, respectively) and males (0.4%, 3.7%, 4.2%), thirst (0.2%, 1.3%, 1.0%), and increased urination (1.0%, 2.7%, 2.4%). In the broad pool, volume depletion was increased with ertugliflozin in patients with estimated glomerular filtration rate < 60 ml/min/1.73 m2, aged ≥ 65 years, or who were taking diuretics. Ertugliflozin was not associated with increased urinary tract infection, fracture, hypoglycemia, pancreatitis, renal or hepatic injury, hypersensitivity, malignancy, or venous thromboembolism. Small numbers of patients were reported with lower limb amputation [0.1% (non-ertugliflozin group), 0.2% (ertugliflozin 5 mg), 0.5% (ertugliflozin 15 mg)]. There were three cases of ketoacidosis (all ertugliflozin 15 mg) and no cases of Fournier's gangrene. CONCLUSION:This pooled analysis showed that ertugliflozin was generally well tolerated in a large population of patients with T2DM with and without moderate renal impairment who were taking a range of background diabetes medications including insulin and insulin secretagogs, with results that are generally consistent with those for other SGLT2 inhibitors. TRIAL REGISTRATION:Clinicaltrials.gov indentifier, NCT02033889, NCT01958671, NCT02036515, NCT01986855, NCT02099110, NCT02226003, NCT01999218.

Project description:IntroductionThe ADA-EASD consensus report recommends using glucagon-like peptide-1 receptor agonists (GLP-1RAs) as the first injectable therapy prior to basal insulin in most patients with type 2 diabetes (T2D) not at glycemic goals after oral anti-hyperglycemia medications (OH). The objective of this analysis was to assess the glycemic efficacy of once-weekly dulaglutide 1.5 mg in patients with T2D when added on a background of commonly used OH regimens.MethodsPatients from seven phase 3 AWARD [Assessment of Weekly AdministRation of LY2189265 (Dulaglutide) in Diabetes] trials, where once-weekly dulaglutide 1.5 mg was added to OHs, were pooled into the following categories based on OH regimens: metformin (MET), sulfonylurea (SU), MET + SU, MET + pioglitazone, and MET + SGLT2i. Change from baseline in glycated hemoglobin A1c (HbA1c), fasting serum glucose and body weight, proportion of patients reaching target HbA1c < 7%, and safety parameters were assessed.ResultsA total of 1784 patients treated with once-weekly dulaglutide 1.5 mg were included in this analysis. Baseline characteristics of the overall population were (mean ± standard deviation): age, 55.4 ± 9.8 years, HbA1c: 8.2 ± 1.0%, body mass index: 31.4 ± 5.4 kg/m2, duration of diabetes: 8.0 ± 5.6 years, and 878 (49.2%) were female. At 6 months, the addition of once-weekly dulaglutide 1.5 mg to various OH regimens significantly reduced HbA1c (- 1.3 to - 1.6%) and fasting blood glucose (- 29 to - 45 mg/dl) from baseline in all groups (p < 0.001), with 39-61% and 52-76% of these patients achieving HbA1c targets of ≤ 6.5% and < 7%, respectively. Significant reductions in body weight (- 0.8 to - 2.9 kg) were also observed in all groups (p < 0.001). Nausea, vomiting, and diarrhea were reported by 10-35%, 4-19%, and 6-28% of patients, respectively. Severe hypoglycemia occurred in one patient (MET + SU).ConclusionThe addition of a once-weekly GLP-1RA, dulaglutide, demonstrated clinically meaningful HbA1c reduction in patients with T2D on different background OH regimens, making it an effective first injectable option.FundingEli Lilly and Company.

Project description:Aims/hypothesisThis study aimed to evaluate the effect of ertugliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on eGFR and albuminuria (urine albumin/creatinine ratio [UACR]) vs glimepiride or placebo/glimepiride (non-ertugliflozin) over 104 weeks of treatment in participants with type 2 diabetes mellitus, using pooled data from two randomised controlled, active comparator studies from the eValuation of ERTugliflozin effIcacy and Safety (VERTIS) programme (Clinicaltrials.gov NCT01999218 [VERTIS SU] and NCT02033889 [VERTIS MET]). In the VERTIS SU study, ertugliflozin was evaluated vs glimepiride over 104 weeks. In the VERTIS MET study, ertugliflozin was evaluated vs placebo over 26 weeks; eligible participants were switched from placebo to blinded glimepiride from week 26 to week 104. The glycaemic efficacy of ertugliflozin vs non-ertugliflozin was also assessed in the pooled population.MethodsPost hoc, exploratory analysis was used to investigate mean changes from baseline in eGFR and UACR over 104 weeks.ResultsOverall, mean (SD) baseline eGFR was 88.2 (18.8) ml min-1 (1.73 m)-2 and geometric mean (95% CI) of baseline UACR was 1.31 mg/mmol (1.23, 1.38). At week 6, the changes in eGFR from baseline were -2.3, -2.7 and -0.7 ml min-1 (1.73 m)-2 for the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Mean eGFR in the ertugliflozin groups increased over time thereafter, while it decreased in the non-ertugliflozin group. Week 104 changes in eGFR from baseline were -0.2, 0.1 and -2.0 ml min-1 (1.73 m)-2 for the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Among 415 patients (21.4% of the cohort) with albuminuria at baseline, the ertugliflozin groups had greater reductions in UACR at all measured time points up to week 104. At week 104, the non-ertugliflozin-corrected difference in UACR (95% CI) was -29.5% (-44.8, -9.8; p < 0.01) for ertugliflozin 5 mg and -37.6% (-51.8, -19.2; p < 0.001) for ertugliflozin 15 mg. Least squares mean changes from baseline in HbA1c (mmol/mol [95% CI]) at week 104 were similar between treatment groups: -6.84 (-7.64, -6.03), -7.74 (-8.54, -6.94) and -6.84 (-7.65, -6.03) in the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Least squares mean changes from baseline in HbA1c (% [95% CI]) at week 104 were: -0.63 (-0.70, -0.55), -0.71 (-0.78, -0.64) and -0.63 (-0.70, -0.55) in the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively.Conclusions/interpretationErtugliflozin reduced eGFR at week 6, consistent with the known pharmacodynamic effects of SGLT2 inhibitors on renal function. Over 104 weeks, eGFR values returned to baseline and were higher with ertugliflozin compared with non-ertugliflozin treatment, even though changes in HbA1c did not differ between the groups. Ertugliflozin reduced UACR in patients with baseline albuminuria.Trial registrationclinicaltrials.gov NCT01999218 and NCT02033889.

Project description:INTRODUCTION:Gastrointestinal (GI) events are a common side effect of glucagon-like peptide 1 (GLP-1) receptor agonists (RA) class. This post hoc analysis assessed the characteristics of GI adverse events in Chinese patients with type 2 diabetes (T2D) who were treated with once-weekly dulaglutide from two randomized clinical trials. METHODS:Chinese patients with T2D, treated with once-weekly dulaglutide (1.5 mg and 0.75 mg) from two phase III multicenter trials (AWARD-CHN1 and AWARD-CHN2) were included. Descriptive statistics were used to present the data. The characteristics (incidence, severity, onset, duration, and time of occurrence) of GI adverse events reported through 26 weeks in a Chinese subpopulation from the two trials were investigated. RESULTS:A total of 787 Chinese patients with T2D were included in this analysis. Up to week 26, 225 patients (28.6%) reported at least one GI treatment-emergent adverse event (TEAE). The most frequently reported GI TEAEs were diarrhea (13.1%), nausea (6.6%), abdominal distension (6.4%), and vomiting (3.0%), with most being categorized as mild to moderate in severity in proportions of 92%, 88%, 94%, and 83%, respectively. A total of 12 patients (1.5%) discontinued the dulaglutide treatment as a result of GI TEAEs. The median duration of the first reported GI TEAEs was 4.0, 5.0, 12.5, and 4.0 days for diarrhea, nausea, abdominal distension, and vomiting, respectively. The incidence of GI TEAEs was more frequent during the first 2 weeks of dulaglutide treatment; however, the incidence declined rapidly after 2 weeks and remained low until week 26. CONCLUSIONS:Most of the GI TEAEs associated with once-weekly dulaglutide (1.5 mg and 0.75 mg) were mild to moderate in severity. The incidence of GI TEAEs was more pronounced during the first 2 weeks of dulaglutide treatment but declined rapidly as treatment continued, and was low at week 26, indicating that dulaglutide was well tolerated in Chinese patients with T2D. TRIAL REGISTRATION:NCT01648582 and NCT01644500.

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Project description:IntroductionIpragliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). The objective of this pooled analysis was to characterise the safety profile of ipragliflozin based on safety data from published randomised controlled trials.MethodsSafety data from 12 randomised, phase II/III/IV placebo-controlled, parallel group, comparative studies of ipragliflozin in patients with T2DM were pooled. Treatment-emergent adverse events (TEAEs) were analysed for patients who had received at least one dose of ipragliflozin 50 mg (n = 1209) or placebo (n = 796) in studies lasting for up to 24 weeks. TEAEs of special interest and serious adverse events (SAEs) were assessed, as well as abnormal laboratory test and vital sign measurements.ResultsThe overall incidences of TEAEs and SAEs between the ipragliflozin and placebo groups were similar, 63.8% vs 59.3% and 2.5% vs 3.3%, respectively. The incidence of TEAEs leading to permanent discontinuation was lower for ipragliflozin (3.6%) than placebo (6.5%). The incidences of TEAEs of special interest including those related to urinary tract infection, cardiovascular events, renal disorder, fracture, malignant tumours and hypoglycaemia were also similar between the groups. Genital infections were more frequent with ipragliflozin (2.4%) than placebo (0.6%), as were pollakiuria/polyuria (6.0% vs 2.0%), volume depletion (4.9% vs 1.8%) and skin/subcutaneous tissue disorders (7.7% vs 4.4%). There were no reported cases of diabetic ketoacidosis, fractures, lower-limb amputation or Fournier's gangrene in ipragliflozin-treated patients across the 12 studies.ConclusionIn randomised, placebo-controlled trials of patients with T2DM, ipragliflozin was well tolerated, with a similar overall incidence of TEAEs to placebo. No new safety signals were observed.Trial registration numbersNCT01071850, NCT00621868, NCT01057628, NCT01117584, NCT01135433, NCT01225081, NCT01242215, NCT02175784, NCT01505426, NCT02452632, NCT02794792, NCT01316094.FundingAstellas Pharma Inc.

Dataset Information

Effects of Ertugliflozin on Liver Enzymes in Patients with Type 2 Diabetes: A Post-Hoc Pooled Analysis of Phase 3 Trials.

Introduction

Methods

Results

Conclusions

Trial registration

Publications

Effects of Ertugliflozin on Liver Enzymes in Patients with Type 2 Diabetes: A Post-Hoc Pooled Analysis of Phase 3 Trials.

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