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Empagliflozin as adjunct to insulin in Japanese participants with type 1 diabetes: Results of a 4-week, double-blind, randomized, placebo-controlled phase 2 trial.

ABSTRACT: AIMS:This phase 2, double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov NCT02702011) with 4 sites in Japan investigated the pharmacodynamics (PD), pharmacokinetics (PK) and safety profile of empagliflozin in Japanese participants with type 1 diabetes mellitus (T1DM) as adjunctive therapy to insulin. MATERIALS AND METHODS:Participants using multiple daily injections of insulin for ?12 months, with HbA1c of 7.5%-10.0%, entered a 2-week, open-label, placebo run-in period, followed by a 4-week, double-blind period during which participants were randomized 1:1:1:1 to receive empagliflozin 2.5 mg (n = 13), empagliflozin 10 mg (n = 12), empagliflozin 25 mg (n = 12) or placebo (n = 11). The primary objective was to assess the effect of empagliflozin vs placebo on urinary glucose excretion (UGE) after 7 days of treatment. RESULTS:PD: Empagliflozin resulted in a dose-dependent significant increase in 24-hour UGE compared with placebo (UGE placebo-corrected mean [95% confidence interval] change from baseline: 2.5 mg, 65.10 [43.29, 86.90] g/24 h; 10 mg, 81.19 [58.80, 103.58] g/24 h; 25 mg, 98.11 [75.91, 120.31] g/24 h). After 4 weeks of treatment, UGE increase was associated with improved glycaemic control, reduced body weight and decreased insulin needs. Empagliflozin treatment also resulted in dose-dependent increases in serum ketone bodies and free fatty acids. PK: Plasma empagliflozin levels increased in a dose-dependent manner and peaked at 1.5 hours. In this short study, empagliflozin was well tolerated, with no increase in rate of hypoglycaemia and no diabetic ketoacidosis events reported. CONCLUSIONS:Based on this short-duration phase 2 study, the PK/PD profile of empagliflozin in Japanese participants with T1DM is comparable to that of non-Japanese participants.

SUBMITTER: Shimada A

PROVIDER: S-EPMC6099358 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Empagliflozin as adjunct to insulin in Japanese participants with type 1 diabetes: Results of a 4-week, double-blind, randomized, placebo-controlled phase 2 trial.

Shimada Akira A Hanafusa Toshiaki T Yasui Atsutaka A Lee Ganghyuck G Taneda Yusuke Y Sarashina Akiko A Shiki Kosuke K George Jyothis J Soleymanlou Nima N Marquard Jan J

Diabetes, obesity & metabolism 20180605 9

<h4>Aims</h4>This phase 2, double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov NCT02702011) with 4 sites in Japan investigated the pharmacodynamics (PD), pharmacokinetics (PK) and safety profile of empagliflozin in Japanese participants with type 1 diabetes mellitus (T1DM) as adjunctive therapy to insulin.<h4>Materials and methods</h4>Participants using multiple daily injections of insulin for ≥12 months, with HbA1c of 7.5%-10.0%, entered a 2-week, open-label, placebo run-in p ...[more]

PMID: 29766633

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Project description:BackgroundThis study evaluated the effect of empagliflozin on postprandial glucose (PPG) and 24-hour glucose variability in Japanese patients with type 2 diabetes mellitus (T2DM).MethodsPatients (N = 60; baseline mean [SD] HbA1c 7.91 [0.80]%; body mass index 24.3 [3.2] kg/m(2)) were randomized to receive empagliflozin 10 mg (n = 20), empagliflozin 25 mg (n = 19) or placebo (n = 21) once daily as monotherapy for 28 days. A meal tolerance test and continuous glucose monitoring (CGM) for 24 hours were performed at baseline and on days 1 and 28. The primary endpoint was change from baseline in area under the glucose concentration-time curve 3 hours after breakfast (AUC1-4h for PPG) at day 28.ResultsAdjusted mean (95%) differences versus placebo in changes from baseline in AUC1-4h for PPG at day 1 were -97.1 (-126.5, -67.8) mg · h/dl with empagliflozin 10 mg and -91.6 (-120.4, -62.8) mg · h/dl with empagliflozin 25 mg (both p < 0.001 versus placebo) and at day 28 were -85.5 (-126.0, -45.0) mg · h/dl with empagliflozin 10 mg and -104.9 (-144.8, -65.0) mg · h/dl with empagliflozin 25 mg (both p < 0.001 versus placebo). Adjusted mean (95% CI) differences versus placebo in change from baseline in 24-hour mean glucose (CGM) at day 1 were -20.8 (-27.0, -14.7) mg/dl with empagliflozin 10 mg and -23.9 (-30.0, -17.9) mg/dl with empagliflozin 25 mg (both p < 0.001 versus placebo) and at day 28 were -24.5 (-35.4, -13.6) mg/dl with empagliflozin 10 mg and -31.7 (-42.5,-20.9) mg/dl with empagliflozin 25 mg (both p < 0.001 versus placebo). Changes from baseline in mean amplitude of glucose excursions (MAGE; CGM) were not significantly different with either empagliflozin dose versus placebo at either timepoint. Curves of mean glucose (CGM) did not change between baseline and day 1 or 28 with placebo, but shifted downward with empagliflozin. Percentage of time with glucose ≥70 to <180 mg/dl increased from 52.0% at baseline to 77.0% at day 28 with empagliflozin 10 mg and from 55.0% to 81.1% with empagliflozin 25 mg, without increasing time spent with hypoglycemia.ConclusionEmpagliflozin for 28 days reduced PPG from the first day and improved daily blood glucose control in Japanese patients with T2DM.Trial registrationClinicaltrials.gov NCT01947855.

Project description:IntroductionOrlistat is an inhibitor of pancreatic lipase and is used as an anti-obesity drug in many countries. However, there are no data available regarding the effects of orlistat on visceral fat accumulation in Japanese subjects. Therefore, this comparative, placebo-controlled, double-blind, randomized study aimed to evaluate the efficacy and safety of orlistat in Japanese participants with excessive visceral fat accumulation and without dyslipidemia, diabetes mellitus, and hypertension ("metabolic diseases").MethodsThe study population included Japanese participants with excessive visceral fat accumulation (waist circumference ≥ 85 cm in males and ≥ 90 cm in females, which corresponds to a visceral fat area of 100 cm2) and without metabolic diseases. Following a 12-week observation term, participants were randomized to the orlistat 60 mg group (n = 100) or placebo group (n = 100). Both drugs were administered orally three times daily for 24 weeks. Participants were also counseled to improve their diet and to maintain exercise throughout the study. Visceral fat area, subcutaneous fat area, waist circumference, body weight, body mass index, adverse reactions, laboratory tests, and blood pressure were regularly assessed.ResultsVisceral fat area, waist circumference, and body weight were significantly reduced in the orlistat group (mean ± standard error, - 13.50 ± 1.52%, - 2.51 ± 0.25%, and - 2.79 ± 0.30%, respectively) compared to the placebo group (- 5.45 ± 1.50%, - 1.55 ± 0.26%, and - 1.22 ± 0.28%, respectively) at the last assessment. The main adverse reactions were defecation-related symptoms including oily spotting and flatus with discharge, resulting from the pharmacological effects of orlistat. Most adverse reactions were mild, and none were serious or severe.ConclusionOrlistat administration reduced visceral fat area, waist circumference, and body weight in Japanese participants with excessive visceral fat and without metabolic diseases. In addition, safety was confirmed with a tolerable profile. Orlistat may be useful to reduce excessive visceral fat accumulation when used in combination with diet and exercise.Trial registrationJapan Pharmaceutical Information Center identifier, JapicCTI-184005.FundingTaisho Pharmaceutical Co., Ltd.

Project description:Abstract In this 56-week, randomized, double-blind, US-based multicenter trial (NCT02963935) we investigated the effects of liraglutide 3.0 mg vs placebo, as adjunct to intensive behavior therapy (IBT) (i.e. reduced calorie intake, increased physical activity [max target: 250 min/week], and 23 counseling sessions). Here we report the effects of treatment on weight change (co-primary endpoints: mean change in body weight [%] and proportion of individuals losing ≥5%), glycemic variables, cardiometabolic risk factors, safety and tolerability. Individuals aged ≥18 years with a body mass index (BMI) ≥30 kg/m2 and without diabetes were randomized 1:1 to liraglutide 3.0 mg or placebo along with IBT. Continuous and categorical variables were calculated using analysis of covariance (ANCOVA) and logistic regression respectively, with treatment, gender and BMI as factors and baseline endpoint as a covariate. Missing values were handled using a jump-to-reference multiple imputation model. There were 282 individuals in the full analysis set; 142 were randomized to liraglutide 3.0 mg (45 y, 16% male, 109 kg, 39 kg/m2) and 140 to placebo (49 y, 17% male, 107 kg, 39 kg/m2); 99% and 93% completed the trial, respectively. The intention to treat analysis demonstrated weight loss at 56 weeks of 7.5% with liraglutide 3.0 mg and 4.0% with placebo (estimated treatment difference (ETD) [95% CI], 3.5% [5.3, 1.6]; p=0.0003). Weight loss in individuals on trial product at 56 weeks was 9.1% (n=114) and 4.8% (n=103), respectively. The proportion of individuals achieving ≥5% weight loss was 61.5% with liraglutide 3.0 mg and 38.8% with placebo (estimated odds ratio (OR) 2.5 [1.5, 4.1], p=0.0003). The proportion who lost >10% was 30.5% and 19.8% (OR 1.8 [1.01, 3.1], p=0.0469), and >15% was 18.1% and 8.9% (OR 2.3 [1.1, 4.7], p=0.0311, respectively. Change in waist circumference was -9.4 cm with liraglutide 3.0 mg vs -6.7 cm with placebo (ETD -2.7 cm [-4.7, -0.8], p=0.006). Significant improvements at 56 weeks were seen for liraglutide 3.0 mg vs placebo in both HbA1c (ETD -0.10% [-0.16, -0.04], p=0.0008) and fasting plasma glucose (ETD ‑0.23 mmol/L [-0.36, -0.11] p=0.0002). Blood pressure (BP) reductions were observed in both treatment arms at 56 weeks, but there were no significant differences between groups in systolic (ETD -2.2 mmHg [‑4.9, 0.5], p=0.11) or diastolic BP (ETD -0.2 mmHg [‑2.2, 1.8], p=0.87), or heart rate (ETD 1.3 bpm [-0.8, 3.4], p=0.23). Lipids were improved vs baseline but no significant differences between treatment arms were observed at 56 weeks (all p>0.05). Liraglutide 3.0 mg was generally well tolerated and no new safety signals were observed in this study. The most frequent adverse events were gastrointestinal (liraglutide 3.0 mg: 71%; placebo: 49%). In conclusion, liraglutide 3.0 mg as an adjunct to IBT resulted in significantly greater weight loss, as compared to IBT and placebo. Supported by Novo Nordisk.

Dataset Information

Empagliflozin as adjunct to insulin in Japanese participants with type 1 diabetes: Results of a 4-week, double-blind, randomized, placebo-controlled phase 2 trial.

Publications

Empagliflozin as adjunct to insulin in Japanese participants with type 1 diabetes: Results of a 4-week, double-blind, randomized, placebo-controlled phase 2 trial.

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