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Biliary effects of liraglutide and sitagliptin, a 12-week randomized placebo-controlled trial in type 2 diabetes patients.

ABSTRACT: AIMS:Treatment with glucagon-like peptide (GLP)-1 receptor agonists or dipeptidyl peptidase (DPP)-4 inhibitors might increase gallstone formation; however, the mechanisms involved are unknown. We aimed to assess the effects of these drugs on gallbladder volume and bile acid profile. MATERIALS AND METHODS:A total of 57 type 2 diabetes patients (mean?±?SD age, 62.8?±?6.9?years; BMI, 31.8?±?4.1?kg/m2 ; HbA1c, 7.3%?±?0.6%), treated with metformin and/or sulfonylureas, were included in this 12-week randomized, placebo-controlled, double-blind, single-centre trial between July 2013 and August 2015 at the VU University Medical Center, the Netherlands. Patients received the GLP-1 receptor agonist liraglutide, the DPP-4 inhibitor sitagliptin or matching placebo for 12?weeks. Gallbladder fasting volume and ejection fraction were measured using ultrasonography after a high-fat meal. Serum bile acids were measured in the fasting and postprandial state and in faecal samples. The trial was registered at ClinicalTrials.gov (NCT01744236). RESULTS:Neither liraglutide nor sitagliptin had an effect on gallbladder fasting volume and ejection fraction (p?>?.05). Liraglutide increased serum levels of deoxycholic acid in the fasting state [0.20?µmol/L (95% CI 0.027-0.376), p?=?0.024] and postprandial state [AUC 40.71 (13.22-68.21), p?=?0.005] and in faeces [ratio 1.5 (1.03-2.19); p?=?0.035]. Sitagliptin had no effect on serum bile acids, but increased faecal levels of chenodeoxycholic acid [ratio 3.42 (1.33-8.79), p?=?0.012], cholic acid [ratio 3.32 (1.26-8.87), p?=?0.017] and ursodeoxycholic acid [ratio 3.81 (1.44-10.14), p?=?0.008]. CONCLUSIONS:Neither liraglutide nor sitagliptin has an effect on gallbladder volume. Observed changes in bile acids with liraglutide suggest alterations in the intestinal microbiome, while sitagliptin appears to increase hepatic bile acid production.

SUBMITTER: Smits MM

PROVIDER: S-EPMC5129471 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Biliary effects of liraglutide and sitagliptin, a 12-week randomized placebo-controlled trial in type 2 diabetes patients.

Smits Mark M MM Tonneijck Lennart L Muskiet Marcel H A MH Hoekstra Trynke T Kramer Mark H H MH Diamant Michaela M Nieuwdorp Max M Groen Albert K AK Cahen Djuna L DL van Raalte Daniël H DH

Diabetes, obesity & metabolism 20160830 12

<h4>Aims</h4>Treatment with glucagon-like peptide (GLP)-1 receptor agonists or dipeptidyl peptidase (DPP)-4 inhibitors might increase gallstone formation; however, the mechanisms involved are unknown. We aimed to assess the effects of these drugs on gallbladder volume and bile acid profile.<h4>Materials and methods</h4>A total of 57 type 2 diabetes patients (mean ± SD age, 62.8 ± 6.9 years; BMI, 31.8 ± 4.1 kg/m<sup>2</sup> ; HbA1c, 7.3% ± 0.6%), treated with metformin and/or sulfonylureas, were ...[more]

PMID: 27451030

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Project description:Abstract Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) reduce glycated hemoglobin (HbA1c), but randomized controlled trial data on their combined use are limited. The LIRA-ADD2SGLT2i trial compared the effect on glycemic control of liraglutide 1.8 mg/day (a GLP-1 analog) vs placebo as add-on to SGLT2i ± metformin in patients with type 2 diabetes (T2D). In this phase 3b trial, patients with T2D on a stable dose of SGLT2i ± metformin and with HbA1c 7.0-9.5% were randomized 2:1 to add either liraglutide 1.8 mg/day or placebo. Exclusion criteria included a history of diabetic ketoacidosis (DKA) while being treated with SGLT2i and/or estimated glomerular filtration rate <60 mL/min/1.73 m2. The primary endpoint was change in HbA1c from baseline at 26 weeks; also assessed after 26 weeks were change in body weight, the proportion of patients achieving HbA1c <7%, and safety. All were analyzed regardless of premature trial product discontinuation or initiation of glucoselowering rescue medication. Overall, 412 patients were screened, 303 were randomized and 280 (92.4%) completed treatment (92.1% with liraglutide, 93.0% with placebo). Baseline characteristics were balanced between treatment groups: mean HbA1c 8.0%, mean body weight 91.1 kg, mean duration of diabetes 9.9 years. At week 26, the mean change in HbA1c from baseline with liraglutide was 0.98% (n=203) vs 0.30% with placebo (n=100) (estimated treatment difference [ETD]: 0.68%, 95% confidence interval [CI]: 0.89, 0.48; p<0.001). The mean change in body weight from baseline with liraglutide was -2.81 kg vs 1.99 kg with placebo (ETD: 0.82 kg; 95% CI: -1.73, 0.09, p=0.077). In the liraglutide group, 51.8% of patients achieved HbA1c <7.0% vs 23.2% in the placebo group (odds ratio: 5.1, 95% CI: 2.67, 9.87; p<0.001). A higher proportion of patients in the liraglutide group reported ≥1 treatment-emergent adverse event (AE) than in the placebo group (66.3% vs 47.0%). Nausea was the most frequent AE, occurring in 26.2% of the liraglutide group and 6.0% of the placebo group, and it generally had early onset in the initial 4 weeks and was transient. Similar incidences of hypoglycemic episodes were reported in both groups (8.9% with liraglutide vs 8.0% with placebo); none were severe. The proportion of patients reporting serious AEs was low in both groups (liraglutide 2.5% vs placebo 1.0%). No fatalities occurred in either group and there were no reports of acute renal failure, DKA, diabetic foot ulcers or amputations with liraglutide in combination with SGLT-2i. In patients with T2D, the addition of liraglutide to SGLT2i therapy (± metformin) provided superior glycemic control vs placebo, and had a safety profile consistent with the known safety profile of both drug classes. The LIRA-ADD2SGLT2i is registered with ClinicalTrials.gov NCT02964247.

Project description:BackgroundLiraglutide is an antidiabetic agent with cardioprotective effect. The purpose of this study is to test efficacy of liraglutide to improve diabetic cardiomyopathy in patients with diabetes mellitus type 2 (DM2) without cardiovascular disease.MethodsPatients with DM2 were randomly assigned to receive liraglutide 1.8 mg/day or placebo in this double-blind trial of 26 weeks. Primary outcome measures were LV diastolic function (early (E) and late (A) transmitral peak flow rate, E/A ratio, early deceleration peak (Edec), early peak mitral annular septal tissue velocity (Ea) and estimated LV filling pressure (E/Ea), and systolic function (stroke volume, ejection fraction, cardiac output, cardiac index and peak ejection rate) assessed with CMR. Intention-to-treat analysis of between-group differences was performed using ANCOVA. Mean estimated treatment differences (95% confidence intervals) are reported.Results23 patients were randomized to liraglutide and 26 to placebo. As compared with placebo, liraglutide significantly reduced E (- 56 mL/s (- 91 to - 21)), E/A ratio (- 0.17 (- 0.27 to - 0.06)), Edec (- 0.9 mL/s2 * 10-3 (- 1.3 to - 0.2)) and E/Ea (- 1.8 (- 3.0 to - 0.6)), without affecting A (3 mL/s (- 35 to 41)) and Ea (0.4 cm/s (- 0.9 to 1.4)). Liraglutide reduced stroke volume (- 9 mL (- 16 to - 2)) and ejection fraction (- 3% (- 6 to - 0.1)), but did not change cardiac output (- 0.4 L/min (- 0.9 to 0.2)), cardiac index (- 0.1 L/min/m2 (- 0.4 to 0.1)) and peak ejection rate (- 46 mL/s (- 95 to 3)).ConclusionsLiraglutide reduced early LV diastolic filling and LV filling pressure, thereby unloading the left ventricle. LV systolic function reduced and remained within normal range. Future studies are needed to investigate if liraglutide-induced left ventricular unloading slows progression of diabetic cardiomyopathy into symptomatic stages. Trial registration ClinicalTrials.gov: NCT01761318.

Project description:IntroductionG protein-coupled receptor 119 (GPR119) is a promising target for the treatment of type 2 diabetes mellitus (T2DM), as both insulin and glucagon-like peptide-1 secretion can be promoted with a single drug. We compared the efficacy and safety of the GPR119 agonist DS-8500a with placebo and sitagliptin 50 mg in Japanese patients with T2DM.MethodsThis randomized, double-blind, parallel-group comparison study was conducted in Japan (trial registration NCT02628392, JapicCTI-153068). Eligible patients aged ≥ 20 years with T2DM and hemoglobin A1c (HbA1c) ≥ 7.0% and < 10.0% were randomized to receive placebo, DS-8500a (25, 50, or 75 mg), or sitagliptin 50 mg once daily for 12 weeks. The primary efficacy endpoint was change in HbA1c from baseline to week 12. Secondary endpoints included change in fasting plasma glucose (FPG), glucose AUC0-3h during a meal tolerance test, 2-hour postprandial glucose (2hr-PPG), and changes in lipid parameters (total, low-density lipoprotein (LDL-) and high-density lipoprotein (HDL-) cholesterol, and triglycerides) at week 12. Safety endpoints included adverse events, hypoglycemia, and clinical/laboratory variables.ResultsDS-8500a demonstrated dose-dependent HbA1c lowering compared with placebo at week 12: change from baseline - 0.23% (p = 0.0173), - 0.37% (p = 0.0001), and - 0.44% (p < 0.0001) in the 25-mg, 50-mg, and 75-mg groups, respectively. At 50- and 75-mg doses, DS-8500a significantly lowered FPG, glucose AUC0-3h, and 2hr-PPG compared with placebo. The glucose-lowering effect was maintained up to 12 weeks. DS-8500a did not lower any of the above parameters to a greater extent than sitagliptin. Compared with placebo and sitagliptin, DS-8500a 50 and 75 mg significantly reduced total cholesterol, LDL-cholesterol, and triglycerides, and significantly increased HDL-cholesterol. All DS-8500a doses were well tolerated. Two cases of clinically relevant drug-related hypoglycemia occurred in the DS-8500a 50-mg group.ConclusionDS-8500a was well tolerated and demonstrated significant glucose-lowering effects and favorable changes in lipid profiles up to 12 weeks in Japanese patients with T2DM.FundingDaiichi Sankyo Co. Ltd.

Dataset Information

Biliary effects of liraglutide and sitagliptin, a 12-week randomized placebo-controlled trial in type 2 diabetes patients.

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Biliary effects of liraglutide and sitagliptin, a 12-week randomized placebo-controlled trial in type 2 diabetes patients.

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