Clinical trial NCT02765399: The Effect of Liraglutide Treatment on Postprandial Chylomicron and VLDL Kinetics, Liver Fat and de Novo Lipogenesis
Official title: The Effect of Liraglutide Treatment on Postprandial Chylomicron and VLDL Kinetics, Liver Fat and de Novo Lipogenesis - a Single-center Randomized Controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Type 2 Diabetes
Lead sponsor: Helsinki University Central Hospital
Sponsor class: OTHER
Collaborators: name: Göteborg University
First posted: 2016-05-06
Enrollment: 23
Sex: ALL
Minimum age (years): 30
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study aims to evaluate the mechanisms underlying the effect of incretin therapy on lipoprotein metabolism in subjects with type 2 diabetes and to study the effect of liraglutide on hepatic de novo lipogenesis.

Detailed description: The well recognized dyslipidemia in people with type 2 diabetes consists of high fasting and non-fasting plasma triglycerides (TG), low high-density lipoprotein (HDL) -cholesterol and preponderance of small dense low-density lipoprotein (LDL) particles nominated as the atherogenic lipid triad. Humans are mostly in a postprandial rather than fasting state and therefore non-fasting TG values reflect more accurately the continuous exposure of arterial wall to triglyceride rich lipoproteins (TRLs) and more importantly, to substantial cholesterol load that these particles deliver.

Postprandial lipemia is highly prevalent even in type 2 diabetes patients with normal fasting TG concentrations. Intestinal overproduction of chylomicrons (CMs) and the structural protein apolipoprotein (apo)-B48 has been identified as an integral feature of postprandial lipemia in type 2 diabetes and insulin resistance. It is clinically important to elucidate the mechanism for delayed postprandial lipemia and the interactions between dysglycemia and dyslipidemia in type 2 diabetes patients.

Eligibility criteria: Inclusion Criteria:

* Subjects with type 2 diabetes treated with a lifestyle or metformin (any dose)
* waist circumference \> 88 cm in women and \> 92 cm in men
* BMI 27-40 kg/m2
* triglycerides between 1.0 - 4.0 mmol/L
* LDL \< 4.5 mmol/l

Exclusion Criteria:

* Type 1 diabetes
* Apo E2/2 phenotype
* ALT/AST \> 3x ULN
* GFR \< 60 ml/min, clinically significant TSH outside normal range
* Lipid-lowering drugs other than statins within 6 months
* Current treatment with pioglitazone, insulin, sulphonylureas, gliptins, glinides, SGLT-2 inhibitors or thiazide diuretics (at a dose of \> 25 mg / day)
* Blood pressure \> 160 mmHg systolic and/or \> 105 diastolic
* History of pancreatitis or stomach / other major bleeding, thyroid neoplasia, persistent hypothyroidism or persistent hyperthyroidism
* Any medical condition that puts the patient in the risk of dehydration
* Concurrent medical condition that may interfere with the interpretation of efficacy and safety data during the study.
* Females of childbearing potential who are not using adequate contraceptive methods
* Subjects who have experienced side-effects previously from GLP-1 agonists
* Non-compliance or withdrawal of consent
* Any information or clinical event described in liraglutide SPC that is a contraindication for the use of liraglutide

Primary outcomes:
measure: Change in Liver Fat Content
timeFrame: Baseline and after 16 weeks
measure: Plasma Triglyceride (TG) Area Under Curve (AUC)
timeFrame: Baseline and after 16 weeks
measure: Body Weight
timeFrame: Baseline and after 16 weeks
measure: Change in HbA1c Level
timeFrame: Baseline and after 16 weeks
measure: Change in fP-glucose Level
timeFrame: Baseline and after 16 weeks
measure: Change in Insulin Level
timeFrame: Baseline and after16 weeks
measure: Change in Matsuda Index
timeFrame: Baseline and after 16 weeks
measure: Change in VAT Area
timeFrame: Baseline and after 16 weeks
measure: Change in SAT Area
timeFrame: Baseline and after 16 weeks
measure: Change in ApoCIII Level
timeFrame: Baseline and after 16 weeks
Secondary outcomes:
measure: Change in Hepatic de Novo Lipogenesis
timeFrame: Baseline and after 16 weeks
measure: Change in Systolic RR
timeFrame: Baseline and after 16 weeks
measure: Mean Total Production of apoB48
timeFrame: Baseline and after 16 weeks
measure: Mean Production Rate of apoB48 in CM
timeFrame: Baseline and after 16 weeks
measure: Mean apoB48 FTR to VLDL1 Particles
timeFrame: Baseline and after 16 weeks
measure: Mean TG Fractional Catabolic Rates in CM
timeFrame: Baseline and after 16 weeks
measure: Mean CM FDC of apoB48
timeFrame: Baseline and after 16 weeks
measure: Change in Direct CM-apoB48 Clearance
timeFrame: Baseline and after 16 weeks
measure: Mean CM-apoB48 Transfer Rates to VLDL1
timeFrame: Baseline and after 16 weeks
measure: Mean VLDL1-TG Production Rates
timeFrame: Baseline and after16 weeks
measure: Mean Fractional Catabolic Rate of VLDL2-apoB100
timeFrame: Baseline and after 16 weeks
Other outcomes:
Locations:
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
Study officials:
affiliation: Senior Endocrinologist
name: Niina Matikainen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zech LA, Grundy SM, Steinberg D, Berman M. Kinetic model for production and metabolism of very low density lipoprotein triglycerides. Evidence for a slow production pathway and results for normolipidemic subjects. J Clin Invest. 1979 Jun;63(6):1262-73. doi: 10.1172/JCI109421.
citation: Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999 Sep;22(9):1462-70. doi: 10.2337/diacare.22.9.1462.
citation: Kernan WN, Inzucchi SE, Viscoli CM, Brass LM, Bravata DM, Shulman GI, McVeety JC, Horwitz RI. Pioglitazone improves insulin sensitivity among nondiabetic patients with a recent transient ischemic attack or ischemic stroke. Stroke. 2003 Jun;34(6):1431-6. doi: 10.1161/01.STR.0000071108.00234.0E. Epub 2003 May 1.
citation: Matikainen N, Soderlund S, Bjornson E, Pietilainen K, Hakkarainen A, Lundbom N, Taskinen MR, Boren J. Liraglutide treatment improves postprandial lipid metabolism and cardiometabolic risk factors in humans with adequately controlled type 2 diabetes: A single-centre randomized controlled study. Diabetes Obes Metab. 2019 Jan;21(1):84-94. doi: 10.1111/dom.13487. Epub 2018 Sep 4.
citation: Taskinen MR, Bjornson E, Matikainen N, Soderlund S, Pietilainen KH, Ainola M, Hakkarainen A, Lundbom N, Fuchs J, Thorsell A, Andersson L, Adiels M, Packard CJ, Boren J. Effects of liraglutide on the metabolism of triglyceride-rich lipoproteins in type 2 diabetes. Diabetes Obes Metab. 2021 May;23(5):1191-1201. doi: 10.1111/dom.14328. Epub 2021 Mar 5.
citation: Bjornson E, Packard CJ, Adiels M, Andersson L, Matikainen N, Soderlund S, Kahri J, Sihlbom C, Thorsell A, Zhou H, Taskinen MR, Boren J. Investigation of human apoB48 metabolism using a new, integrated non-steady-state model of apoB48 and apoB100 kinetics. J Intern Med. 2019 May;285(5):562-577. doi: 10.1111/joim.12877. Epub 2019 Mar 12.