Effects of PCSK9 Inhibition by Evolocumab on Postprandial Lipid Metabolism in Type 2 Diabetes

NCT02948777 | Completed Phase 4 Results FDA Drug

• 1 other identifier: EVOLKIN
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

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.

Conditions

Type 2 Diabetes Mellitus

Keywords

apolipoprotein, CVD, chylomicrons, evolocumab, kinetics

Outcome Measures

Primary Outcomes (5)

• Mean ApoB Concentration Before and After Evolocumab

  Change in apolipoprotein B concentration in total plasma measured by using turbidimetric immunoassay.

  Baseline and after 12 weeks

• Mean TRL-C Concentration Before and After Evolocumab

  Change in TRL-cholesterol concentration in plasma samples measured by using automated direct assay (Denka Seiken, Tokyo, Japan)

  Baseline and after 12 weeks

• Mean Total Production of ApoB48 Before and After Evolocumab

  Change in ApoB48 total production in plasma measured by using multicompartmental modeling. The power of mathematical modelling to describe the metabolic pathways of lipid and lipoprotein metabolism was demonstrated by Zech L et al (J Clin Invest 1979;63:1262-1273) and have been widely used over 30yrs. So far few studies have focused on the modelling of apo B48 and apo B100 after a meal that is more physiological than the fasting state (Björnson E et al. JIM 2019;285:562-577). Production rates for apo B48, apo B100 and triglycerides in chylomicrons, VLDL1 and VLDL2 were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90, 120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. Analysis of tracer/ tracee curves of stable isotopes was used to derived the estimates of kinetic parameters using a new mathematical modeling per day. These figures per day are used to report the data from this study.

  Baseline and after 12 weeks

• Mean LDL FCR of ApoB100 Before and After Evolocumab

  Change in low-density lipoprotein fractional catabolic rate of ApoB100 in LDL from plasma samples measured by multicompartmental modeling. Production rates were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90, 120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. More detailed description see Outcome measure 3.

  Baseline and after 12 weeks

• LDL Pool Size of ApoB100 Before and After Evolocumab

  Change in low-density lipoprotein pool size of ApoB100 in LDL fraction prepared from plasma samples using density ultracentrifugation.

  Baseline and after 12 weeks

Secondary Outcomes (20)

• Mean LDL-C Concentration Before and After Evolocumab

  Baseline and after 12 weeks

• Mean ApoB48 Concentration Before and After Evolocumab

  Baseline and after 12 weeks

• Mean CM TG-iAUC Before and After Evolocumab

  0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks

• Mean ApoB48 AUC Before and After Evolocumab

  0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks

• Mean VLDL1 ApoB100 Production Before and After Evolocumab

  Baseline and after 12 weeks

Study Arms (1)

Evolocumab

EXPERIMENTAL

Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks

Drug: Evolocumab

Interventions

Evolocumab DRUG

Also known as: Repatha

Evolocumab

Eligibility Criteria

• Age: 18 Years - 77 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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%.

You may not qualify if:

• 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

Sponsors & Collaborators

• Marja-Riitta Taskinen: lead
• Göteborg University: collaborator

Study Sites (1)

Helsinki University Hospital, Biomedicum 2U

Helsinki, Finland

Location

Related Publications (5)

• 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.

  PMID: 33356392 RESULT

• 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.

  PMID: 31917184 RESULT

• 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.

  PMID: 221537 RESULT

• 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.

  PMID: 30779243 RESULT

• Taskinen MR, Matikainen N, Bjornson E, Soderlund S, Inkeri J, Hakkarainen A, Parviainen H, Sihlbom C, Thorsell A, Andersson L, Adiels M, Packard CJ, Boren J. Contribution of intestinal triglyceride-rich lipoproteins to residual atherosclerotic cardiovascular disease risk in individuals with type 2 diabetes on statin therapy. Diabetologia. 2023 Dec;66(12):2307-2319. doi: 10.1007/s00125-023-06008-0. Epub 2023 Sep 29.

  PMID: 37775612 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Cardiovascular Diseases

Interventions

evolocumab

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Results Point of Contact

• Title: Prof. Marja-Riitta Taskinen
• Organization: Helsinki University and Helsinki University Hospital

marja-riitta.taskinen@helsinki.fi

+358-9-47171990

Study Officials

• Marja-Riitta Taskinen, Prof., PI

  Clinical Research institute Huch, Ltd and University of Helsinki

  PRINCIPAL INVESTIGATOR

• Jan Boren, Prof., co-PI

  University of Gothenburg and Sahlgrenska University Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor, emerita

Study Record Dates

• First Submitted: October 27, 2016
• First Posted: October 28, 2016
• Study Start: October 1, 2016
• Primary Completion: June 1, 2018
• Study Completion: June 1, 2018
• Last Updated: November 3, 2021
• Results First Posted: October 11, 2021

Record last verified: 2021-10

Locations

FI (1)