Dataset Information

A Phase 1 Multiple Dose Study of Tirzepatide in Chinese Patients with Type 2 Diabetes.

ABSTRACT:

Introduction

To investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of tirzepatide in Chinese patients with type 2 diabetes (T2D).

Methods

In this phase 1, double-blind, placebo-controlled, multiple dose study, patients were randomized into one of two cohorts to receive once-weekly subcutaneous tirzepatide or placebo. The initial tirzepatide dose in both cohorts was 2.5 mg, which was increased by 2.5 mg every 4 weeks to a maximum final dose of 10.0 mg at week 16 (Cohort 1) or 15.0 mg at week 24 (Cohort 2). The primary outcome was the safety and tolerability of tirzepatide.

Results

Twenty-four patients were randomized (tirzepatide 2.5-10.0 mg: n = 10, tirzepatide 2.5-15.0 mg: n = 10, placebo: n = 4); 22 completed the study. The most frequently reported treatment-emergent adverse events (TEAEs) among patients receiving tirzepatide were diarrhea and decreased appetite; most TEAEs were mild and resolved spontaneously with no serious adverse events reported in the tirzepatide groups and one in the placebo group. The plasma concentration half-life of tirzepatide was approximately 5-6 days. Mean glycated hemoglobin (HbA1c) decreased over time from baseline in the 2.5-10.0 mg (- 2.4%) and 2.5-15.0 mg (- 1.6%) tirzepatide groups, at week 16 and week 24, respectively, but remained steady in patients receiving placebo. Body weight decreased from baseline by - 4.2 kg at week 16 in the tirzepatide 2.5-10.0 mg group and by - 6.7 kg at week 24 in the 2.5-15.0 mg group. Mean fasting plasma glucose levels fell from baseline by - 4.6 mmol/L in the tirzepatide 2.5-10.0 mg group at week 16 and by - 3.7 mmol/L at week 24 in the tirzepatide 2.5-15.0 mg group.

Conclusions

Tirzepatide was well tolerated in this population of Chinese patients with T2D. The safety, tolerability, PK, and PD profile of tirzepatide support once-weekly dosing in this population.

Clinical trial registration

ClinicalTrials.gov: NCT04235959.

SUBMITTER: Feng P

PROVIDER: S-EPMC10329955 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

A Phase 1 Multiple Dose Study of Tirzepatide in Chinese Patients with Type 2 Diabetes.

Feng Ping P Sheng Xiaoyan X Ji Yongjia Y Urva Shweta S Wang Feng F Miller Sheila S Qian Chenxi C An Zhenmei Z Cui Yimin Y

Advances in therapy 20230607 8

<h4>Introduction</h4>To investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of tirzepatide in Chinese patients with type 2 diabetes (T2D).<h4>Methods</h4>In this phase 1, double-blind, placebo-controlled, multiple dose study, patients were randomized into one of two cohorts to receive once-weekly subcutaneous tirzepatide or placebo. The initial tirzepatide dose in both cohorts was 2.5 mg, which was increased by 2.5 mg every 4 weeks to a maximum final dose of 10 ...[more]

PMID: 37285081

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Project description:IntroductionThe presence of metabolic abnormalities in patients with type 2 diabetes (T2D) increases the risk of cardiovascular disease and other comorbidities. This analysis compared the effects of tirzepatide (5, 10, and 15 mg) and dulaglutide 0.75 mg on the prevalence of metabolic abnormalities in Japanese patients with T2D.MethodsThis was a post hoc analysis of SURPASS J-mono, a multicenter, randomized, double-blind, active-controlled, parallel-group, phase 3 trial that compared the efficacy and safety of tirzepatide monotherapy (5, 10, and 15 mg) to dulaglutide 0.75 mg in Japanese patients with T2D. Thresholds for abnormalities were based on the Japanese criteria for metabolic syndrome. Proportions of participants meeting a composite endpoint (visceral fat accumulation measured by waist circumference plus two or more of dyslipidemia, hypertension, or hyperglycemia) or individual component thresholds were calculated at baseline and week 52 for the overall population and for baseline body mass index (BMI) subgroups (< 25, 25 to < 30, and ≥ 30 kg/m2).ResultsOf 636 randomized participants, 431 (67.8%) met the composite endpoint at baseline, with similar findings observed across treatment arms. At week 52, the proportion of participants on treatment that met the composite endpoint was 31.7%, 23.0%, and 14.2% in the tirzepatide 5-, 10-, and 15-mg arms, respectively, and 56.5% in the dulaglutide arm (p < 0.001). A higher proportion met the composite endpoint at baseline in the BMI 25 to < 30 and ≥ 30 kg/m2 subgroups (73.2-79.3%) compared with the < 25 kg/m2 subgroup (45.3%), with reductions observed across all BMI subgroups treated with tirzepatide. The proportion of participants with individual metabolic abnormalities showed similar trends to those observed for the composite endpoint. Tirzepatide was consistently superior to dulaglutide across all assessments.ConclusionsTirzepatide reduced the prevalence of multiple metabolic abnormalities, indicating tirzepatide may have metabolic benefit in Japanese patients with T2D.Trial registrationClinicalTrials.gov, NCT03861052.

Project description:BackgroundTirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide/ glucagon-like peptide-1 receptor agonist, is approved in the United States, Europe and Japan for the treatment of type 2 diabetes. Across the SURPASS-1 to -5 clinical studies, tirzepatide 5, 10 and 15 mg demonstrated significant improvements in glycated haemoglobin A1c (HbA1c) (- 1.9 to - 2.6%), body weight (- 6.6 to - 13.9%) and systolic blood pressure (SBP) (- 2.8 to - 12.6 mmHg) at the end of study treatment.MethodsPost-hoc mediation analyses were conducted to evaluate weight-loss dependent and weight-loss independent effects of tirzepatide on SBP reductions across the 5 SURPASS studies. The safety population (all randomized patients who took at least 1 dose of study drug) of each study was analyzed. Additional analyses were conducted at individual study level or pooled across 5 SURPASS trials.ResultsThe difference in mean SBP change from baseline at 40 weeks (total effect) between the tirzepatide and comparator groups was - 1.3 to - 5.1 mmHg (tirzepatide 5 mg), - 1.7 to - 6.5 mmHg (tirzepatide 10 mg) and - 3.1 to - 11.5 mmHg (tirzepatide 15 mg). These SBP reductions were primarily mediated through weight loss, with different degrees of contributions from weight-loss independent effects across the different trials. In the SURPASS-4 study, which enrolled patients with established cardiovascular disease, weight-loss independent effects explained 33% to 57% of difference in SBP change between tirzepatide and insulin glargine groups. In a pooled analysis of the SURPASS-1 to -5 studies, there was a significant (p < 0.001) but weak correlation (r = 0.18 to 0.22) between change in body weight and SBP. Reductions in SBP with tirzepatide were not dependent on concomitant antihypertensive medications at baseline as similar reductions were observed whether participants were receiving them or not (interaction p = 0.77). The largest SBP reductions were observed in the highest baseline category (> 140 mmHg), while those in the first quartile of baseline SBP category (< 122 mmHg) observed no further decrease in SBP.ConclusionsTirzepatide-induced SBP reduction was primarily mediated through weight loss, with different degrees of contributions from weight-loss independent effects across the different trials. SBP reduction was not dependent on antihypertensive medication use but dependent on baseline SBP value, alleviating theoretical concerns of hypotension.

Dataset Information

A Phase 1 Multiple Dose Study of Tirzepatide in Chinese Patients with Type 2 Diabetes.

Introduction

Methods

Results

Conclusions

Clinical trial registration

Publications

A Phase 1 Multiple Dose Study of Tirzepatide in Chinese Patients with Type 2 Diabetes.

Similar Datasets

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