Clinical trial NCT02948777: Effects of PCSK9 Inhibition by Evolocumab on Postprandial Lipid Metabolism in Type 2 Diabetes
Official title: Effects of PCSK9 Inhibition by Evolocumab on Postprandial Lipid Metabolism in Type 2 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Type 2 Diabetes Mellitus
Keywords: apolipoprotein, CVD, chylomicrons, evolocumab, kinetics
Lead sponsor: Clinical Research Institute HUCH Ltd
Sponsor class: OTHER
Collaborators: name: Göteborg University
First posted: 2016-10-28
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 77
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Postprandial lipemia is highly prevalent in type 2 diabetes subjects even with normal fasting triglyceride values. Humans are mostly in a postprandial rather than in a fasting state and therefore non-fasting triglyceride values reflect more accurately the continuous exposure of arterial wall to the substantial cholesterol load from remnant particles. Evolocumab lowers blood LDL-cholesterol. This study evaluates the effect of evolocumab on postprandial lipid metabolism in type 2 diabetes. All participants in this study receive evolocumab treatment.


Eligibility criteria: Inclusion Criteria:

* Male or female (non-fertile or using a medically approved birth control method) overweight/obese subjects with Type 2 Diabetes Mellitus treated with lifestyle counselling and a stable metformin dose for at least three months
* age 18-77 yrs.
* body mass index 25-40 kg/m2
* triglycerides between 1.5-4.5 mmol/L and low-density-lipoprotein cholesterol \>1.8 but ≤4.0 mmol/L (on Atorvastatin 20 mg/day)
* glycohemoglobin: ≤9%.
* Each patient will attend a pre-screening visit (at week -5) where eligibility criteria will be evaluated. If the patient uses another statin than atorvastatin (20 mg) at screening visit the used statin is stopped and atorvastatin 20 mg will be initiated. If the patient is not using any statin, atorvastatin 20 mg will be initiated and the lipid values will be checked after 4 weeks when all inclusion/exclusion criteria will be assessed.

Exclusion Criteria:

* Type 1 diabetes
* apolipoprotein E2/2 phenotype
* alanine transaminase / aspartate transaminase \> 3× upper limit of normal
* creatinine kinase\>3× upper limit of normal
* glomerular filtration rate \<60 ml/min
* clinically significant thyroid-stimulating hormone outside the normal range
* body mass index \>40 kg/m2
* glycohemoglobin \> 9.0 %
* fasting triglycerides \> 4.5 mmol/l
* total cholesterol \> 7.0 mmol/l
* positive urine or serum pregnancy test
* untreated or inadequately treated hypertension defined as blood pressure \>160 mmHg systolic and/or \>105 mmHg diastolic, use of thiazide diuretics at a dose of ≥25 mg/day
* subject not on a stable dose of atorvastatin (20 mg/ day before randomization)
* lipid-lowering drugs other than statins within 3 months
* any other diabetes medication except diet + metformin
* history/diagnosis of diabetes nephropathy / retinopathy
* current smoking
* weekly alcohol use over 24 doses for men and 16 for women
* history of myocardial infarction, acute coronary syndrome or coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) within the last 6 mos.
* planned revascularization (eg coronary artery bypass grafting, percutaneous coronary intervention, carotid or peripheral revascularization procedures) within 3 months of screening
* New York Heart Association class III/IV congestive heart failure persisting despite treatment
* history of hemorrhagic stroke
* hypersensitivity to (evolocumab or) any of the excipients found in the drug product
* use of estrogen therapy
* current use of antithrombotic or anticoagulant therapy
* known bleeding tendency that would be an contraindication to heparin test
* history of cancer within the past 5 years (except for adequately treated basal cell skin cancer, squamous cell skin cancer or in situ cervical cancer)
* women of childbearing potential not protected by effective birth control method and/or not willing to be tested for pregnancy
* patient considered by the investigator or any sub-investigator as inappropriate for this study for any reason

Primary outcomes:
measure: Mean ApoB Concentration Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: Mean TRL-C Concentration Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: Mean Total Production of ApoB48 Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: Mean LDL FCR of ApoB100 Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: LDL Pool Size of ApoB100 Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
Secondary outcomes:
measure: Mean LDL-C Concentration Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: Mean ApoB48 Concentration Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: Mean CM TG-iAUC Before and After Evolocumab
timeFrame: 0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks
measure: Mean ApoB48 AUC Before and After Evolocumab
timeFrame: 0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks
measure: Mean VLDL1 ApoB100 Production Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: Mean VLDL2 ApoB100 Production Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: IDL Pool Size of ApoB100 Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: Mean IDL to LDL Transfer of ApoB100 Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: Mean VAT Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: Mean Liver Fat Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: Mean SAT Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: Mean VLDL1 Triglyceride Production Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: Mean VLDL1 FCR of triglycerideBefore and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: Mean VLDL2 Triglyceride Total Production Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: Mean VLDL2 FCR of Triglyceride Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: Mean Postprandial CM of ApoB48 Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: Mean CM-apoB48 FCR of ApoB48 Metabolism Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: Mean CM-TG Production of ApoB48 Before and After Evolocumab
timeFrame: Baseline and after 12 weeks
measure: Mean CM TG-AUC Before and After Evolocumab
timeFrame: 0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks
measure: Mean ApoB48 iAUC Before and After Evolocumab
timeFrame: 0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks
Other outcomes:
Locations:
city: Helsinki
country: Finland
facility: Helsinki University Hospital, Biomedicum 2U
Study officials:
affiliation: Clinical Research institute Huch, Ltd and University of Helsinki
name: Marja-Riitta Taskinen, Prof., PI
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Gothenburg and Sahlgrenska University Hospital
name: Jan Boren, Prof., co-PI
role: PRINCIPAL_INVESTIGATOR
References:
citation: Taskinen MR, Bjornson E, Kahri J, Soderlund S, Matikainen N, Porthan K, Ainola M, Hakkarainen A, Lundbom N, Fermanelli V, Fuchs J, Thorsell A, Kronenberg F, Andersson L, Adiels M, Packard CJ, Boren J. Effects of Evolocumab on the Postprandial Kinetics of Apo (Apolipoprotein) B100- and B48-Containing Lipoproteins in Subjects With Type 2 Diabetes. Arterioscler Thromb Vasc Biol. 2021 Feb;41(2):962-975. doi: 10.1161/ATVBAHA.120.315446. Epub 2020 Dec 24.
citation: Taskinen MR, Bjornson E, Andersson L, Kahri J, Porthan K, Matikainen N, Soderlund S, Pietilainen K, Hakkarainen A, Lundbom N, Nilsson R, Stahlman M, Adiels M, Parini P, Packard C, Boren J. Impact of proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab on the postprandial responses of triglyceride-rich lipoproteins in type II diabetic subjects. J Clin Lipidol. 2020 Jan-Feb;14(1):77-87. doi: 10.1016/j.jacl.2019.12.003. Epub 2019 Dec 12.
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: 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.