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

• Sponsor: Marja-Riitta Taskinen (Other)
• Overall Status: Completed
• CT.gov ID: NCT02948777
• Collaborator: Göteborg University (Other)
• Enrollment: 14
• Location: 1
• Arm: 1
• Duration (Months): 20
• Patients Per Site Per Month: 0.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: Evolocumab	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Effects of PCSK9 Inhibition by Evolocumab on Postprandial Lipid Metabolism in Type 2 Diabetes
• Study Start Date: Oct 1, 2016
• Actual Primary Completion Date: Jun 1, 2018
• Actual Study Completion Date: Jun 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Evolocumab Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks	Drug: Evolocumab; Other Names: Repatha

Outcome Measures

Primary Outcome Measures

1. Mean ApoB Concentration Before and After Evolocumab [Baseline and after 12 weeks]

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

2. Mean TRL-C Concentration Before and After Evolocumab [Baseline and after 12 weeks]

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

3. Mean Total Production of ApoB48 Before and After Evolocumab [Baseline and after 12 weeks]

   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.

4. Mean LDL FCR of ApoB100 Before and After Evolocumab [Baseline and after 12 weeks]

   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.

5. LDL Pool Size of ApoB100 Before and After Evolocumab [Baseline and after 12 weeks]

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

Secondary Outcome Measures

1. Mean LDL-C Concentration Before and After Evolocumab [Baseline and after 12 weeks]

   Change in LDL-cholesterol concentration in plasma LDL fraction isolated by ultracentrifugation.

2. Mean ApoB48 Concentration Before and After Evolocumab [Baseline and after 12 weeks]

   Change in apolipoprotein B48 levels in total plasma measured by enzyme-linked immunosorbent assay.

3. Mean CM TG-iAUC Before and After Evolocumab [0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks]

   Change in chylomicron triglyceride incremental area under curve in plasma samples taken at particular time points after the meal. Area under the curve (AUC) was normalized so that 100% corresponds to the AUC before treatment; subsequently the percentage after treatment is in reference to this value. AUC values were calculated using the trapezoidal rule.

4. Mean ApoB48 AUC Before and After Evolocumab [0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks]

   Change in apolipoprotein B48 area under curve in plasma samples taken at particular time points after the meal. Area under the curve (AUC) was normalized so that 100% corresponds to the AUC before treatment; subsequently the percentage after treatment is in reference to this value. AUC values were calculated using the trapezoidal rule.

5. Mean VLDL1 ApoB100 Production Before and After Evolocumab [Baseline and after 12 weeks]

   Change in VLDL1 ApoB100 production rates measured from isolated VLDL from plasma samples using density ultracentrifugation and the enrichment of tracer was measured in isolated fractions following using mathematical 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.

6. Mean VLDL2 ApoB100 Production Before and After Evolocumab [Baseline and after 12 weeks]

   Change in VLDL2 apoB100 production rates measured from isolated VLDL2 from plasma samples by using density ultracentrifugation and the enrichment of tracer was measured in isolated fractions following using mathematical 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.

7. IDL Pool Size of ApoB100 Before and After Evolocumab [Baseline and after 12 weeks]

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

8. Mean IDL to LDL Transfer of ApoB100 Before and After Evolocumab [Baseline and after 12 weeks]

   Change in ApoB100 intermediate-density lipoprotein to low-density lipoprotein transfer in isolated samples from plasma by ultracentrifugation and measured using 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.

9. Mean VAT Before and After Evolocumab [Baseline and after 12 weeks]

   Change in visceral fat volume measured by magnetic resonance imaging

10. Mean Liver Fat Before and After Evolocumab [Baseline and after 12 weeks]

    Change in liver fat content measured by magnetic resonance imaging.

11. Mean SAT Before and After Evolocumab [Baseline and after 12 weeks]

    Change in subcutaneous fat volume measured by magnetic resonance imaging

12. Mean VLDL1 Triglyceride Production Before and After Evolocumab [Baseline and after 12 weeks]

    Change in VLDL1 triglyceride production measured from isolated VLDL1 from plasma samples by using density gradient ultracentrifugation. 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.

13. Mean VLDL1 FCR of triglycerideBefore and After Evolocumab [Baseline and after 12 weeks]

    Change in VLDL1 fractional catabolic rate of triglyceride measured in isolated VLDL1 from plasma samples by using density ultracentrifugation and 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.

14. Mean VLDL2 Triglyceride Total Production Before and After Evolocumab [Baseline and after 12 weeks]

    Change in VLDL2 triglyceride total production measured in isolated VLDL2 from plasma samples by using density ultracentrifugation and 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.

15. Mean VLDL2 FCR of Triglyceride Before and After Evolocumab [Baseline and after 12 weeks]

    Change in VLDL2 fractional catabolic rate of triglyceride measured in isolated VLDL2 from plasma samples by using density ultracentrifugation and 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.

16. Mean Postprandial CM of ApoB48 Before and After Evolocumab [Baseline and after 12 weeks]

    Change in Postprandial chylomicron of ApoB48 measured from plasma samples by liquid chromatography-mass spectrometry with multicompartmental modeling assay. 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.

17. Mean CM-apoB48 FCR of ApoB48 Metabolism Before and After Evolocumab [Baseline and after 12 weeks]

    Change in chylomicron-apoB48 fractional catabolic rate of ApoB48 in isolated chylomicrons from plasma samples measured by multicompartmental modeling assay. 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.

18. Mean CM-TG Production of ApoB48 Before and After Evolocumab [Baseline and after 12 weeks]

    Change in chylomicron-triglycerides production of ApoB48 in isolated chylomicrons from plasma samples measured by multicompartmental modeling assay. 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.

19. Mean CM TG-AUC Before and After Evolocumab [0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks]

    Change in chylomicron triglyceride area under curve in plasma at a particular time points after the meal. Area under the curve (AUC) was normalized so that 100% corresponds to the AUC before treatment; subsequently the percentage after treatment is in reference to this value. AUC values were calculated using the trapezoidal rule.

20. Mean ApoB48 iAUC Before and After Evolocumab [0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks]

    Change in apolipoprotein B48 incremental area under curve in plasma at a particular time points after the meal. Area under the curve (AUC) was normalized so that 100% corresponds to the AUC before treatment; subsequently the percentage after treatment is in reference to this value. AUC values were calculated using the trapezoidal rule.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 77 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Helsinki University Hospital, Biomedicum 2U	Helsinki		Finland

Sponsors and Collaborators

• Marja-Riitta Taskinen
• Göteborg University

Investigators

• Principal Investigator: 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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 27, 2016

More Information

Publications

None provided.

• Responsible Party: Marja-Riitta Taskinen, Professor, emerita, Clinical Research Institute HUCH Ltd
• ClinicalTrials.gov Identifier: NCT02948777
• Other Study ID Numbers: EVOLKIN
• First Posted: Oct 28, 2016
• Last Update Posted: Nov 3, 2021
• Last Verified: Oct 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Marja-Riitta Taskinen, Professor, emerita, Clinical Research Institute HUCH Ltd: apolipoprotein, CVD, chylomicrons, evolocumab, kinetics
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Evolocumab

Study Results

Participant Flow

Recruitment Details	After an initial telephone interview of 195 subjects, 77 were invited for a screening visit. Of these, 63 subjects were excluded because of failure to meet inclusion criteria.

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Period Title: Overall Study
STARTED	14
COMPLETED	13
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Overall Participants	14
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	7 50%
>=65 years	7 50%
Sex: Female, Male (Count of Participants)
Female	8 57.1%
Male	6 42.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	14 100%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Mean ApoB Concentration Before and After Evolocumab
Description	Change in apolipoprotein B concentration in total plasma measured by using turbidimetric immunoassay.
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	75.9 (14.5)
Week 12	35.3 (10.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Primary Outcome

Title	Mean TRL-C Concentration Before and After Evolocumab
Description	Change in TRL-cholesterol concentration in plasma samples measured by using automated direct assay (Denka Seiken, Tokyo, Japan)
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	33.4 (10.9)
Week 12	17.8 (6.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Primary Outcome

Title	Mean Total Production of ApoB48 Before and After Evolocumab
Description	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.
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	570 (60)
Week 12	580 (75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.31
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Primary Outcome

Title	Mean LDL FCR of ApoB100 Before and After Evolocumab
Description	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.
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	0.32 (0.15)
Week 12	0.78 (0.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Primary Outcome

Title	LDL Pool Size of ApoB100 Before and After Evolocumab
Description	Change in low-density lipoprotein pool size of ApoB100 in LDL fraction prepared from plasma samples using density ultracentrifugation.
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks Evolocumab
Measure Participants	13
Baseline	1500 (470)
Week 12	460 (270)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Mean LDL-C Concentration Before and After Evolocumab
Description	Change in LDL-cholesterol concentration in plasma LDL fraction isolated by ultracentrifugation.
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	1500 (470)
Week 12	460 (270)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

7. Secondary Outcome

Title	Mean ApoB48 Concentration Before and After Evolocumab
Description	Change in apolipoprotein B48 levels in total plasma measured by enzyme-linked immunosorbent assay.
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	6.1 (3.8)
Week 12	5.3 (3.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.27
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

8. Secondary Outcome

Title	Mean CM TG-iAUC Before and After Evolocumab
Description	Change in chylomicron triglyceride incremental area under curve in plasma samples taken at particular time points after the meal. Area under the curve (AUC) was normalized so that 100% corresponds to the AUC before treatment; subsequently the percentage after treatment is in reference to this value. AUC values were calculated using the trapezoidal rule.
Time Frame	0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	6.8 (3.6)
Week 12	5.8 (4.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.22
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

9. Secondary Outcome

Title	Mean ApoB48 AUC Before and After Evolocumab
Description	Change in apolipoprotein B48 area under curve in plasma samples taken at particular time points after the meal. Area under the curve (AUC) was normalized so that 100% corresponds to the AUC before treatment; subsequently the percentage after treatment is in reference to this value. AUC values were calculated using the trapezoidal rule.
Time Frame	0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	66.8 (31.2)
Week 12	57.4 (26.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.31
	Comments
	Method	Kruskal-Wallis
	Comments

10. Secondary Outcome

Title	Mean VLDL1 ApoB100 Production Before and After Evolocumab
Description	Change in VLDL1 ApoB100 production rates measured from isolated VLDL from plasma samples using density ultracentrifugation and the enrichment of tracer was measured in isolated fractions following using mathematical 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.
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	790 (230)
Week 12	750 (230)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.61
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

11. Secondary Outcome

Title	Mean VLDL2 ApoB100 Production Before and After Evolocumab
Description	Change in VLDL2 apoB100 production rates measured from isolated VLDL2 from plasma samples by using density ultracentrifugation and the enrichment of tracer was measured in isolated fractions following using mathematical 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.
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	270 (91)
Week 12	230 (96)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

12. Secondary Outcome

Title	IDL Pool Size of ApoB100 Before and After Evolocumab
Description	Change in intermediate-density lipoprotein pool size of ApoB100 in IDL fraction prepared from plasma samples using density ultracentrifugation.
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	190 (50)
Week 12	130 (49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

13. Secondary Outcome

Title	Mean IDL to LDL Transfer of ApoB100 Before and After Evolocumab
Description	Change in ApoB100 intermediate-density lipoprotein to low-density lipoprotein transfer in isolated samples from plasma by ultracentrifugation and measured using 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.
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	450 (190)
Week 12	310 (140)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.027
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

14. Secondary Outcome

Title	Mean VAT Before and After Evolocumab
Description	Change in visceral fat volume measured by magnetic resonance imaging
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	2420 (960)
Week 12	2450 (1100)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.84
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

15. Secondary Outcome

Title	Mean Liver Fat Before and After Evolocumab
Description	Change in liver fat content measured by magnetic resonance imaging.
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	6.6 (6.6)
Week 12	6.3 (7.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.59
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

16. Secondary Outcome

Title	Mean SAT Before and After Evolocumab
Description	Change in subcutaneous fat volume measured by magnetic resonance imaging
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	3900 (1700)
Week 12	4110 (1600)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.81
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

17. Secondary Outcome

Title	Mean VLDL1 Triglyceride Production Before and After Evolocumab
Description	Change in VLDL1 triglyceride production measured from isolated VLDL1 from plasma samples by using density gradient ultracentrifugation. 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.
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	34 (18)
Week 12	33 (13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.91
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

18. Secondary Outcome

Title	Mean VLDL1 FCR of triglycerideBefore and After Evolocumab
Description	Change in VLDL1 fractional catabolic rate of triglyceride measured in isolated VLDL1 from plasma samples by using density ultracentrifugation and 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.
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	38 (27)
Week 12	37 (23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	1
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

19. Secondary Outcome

Title	Mean VLDL2 Triglyceride Total Production Before and After Evolocumab
Description	Change in VLDL2 triglyceride total production measured in isolated VLDL2 from plasma samples by using density ultracentrifugation and 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.
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	8.8 (3.8)
Week 12	8.5 (2.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.68
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

20. Secondary Outcome

Title	Mean VLDL2 FCR of Triglyceride Before and After Evolocumab
Description	Change in VLDL2 fractional catabolic rate of triglyceride measured in isolated VLDL2 from plasma samples by using density ultracentrifugation and 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.
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	10 (6.3)
Week 12	15 (8.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

21. Secondary Outcome

Title	Mean Postprandial CM of ApoB48 Before and After Evolocumab
Description	Change in Postprandial chylomicron of ApoB48 measured from plasma samples by liquid chromatography-mass spectrometry with multicompartmental modeling assay. 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.
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	240 (50)
Week 12	230 (43)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.91
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

22. Secondary Outcome

Title	Mean CM-apoB48 FCR of ApoB48 Metabolism Before and After Evolocumab
Description	Change in chylomicron-apoB48 fractional catabolic rate of ApoB48 in isolated chylomicrons from plasma samples measured by multicompartmental modeling assay. 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.
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	37 (24)
Week 12	46 (32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.27
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

23. Secondary Outcome

Title	Mean CM-TG Production of ApoB48 Before and After Evolocumab
Description	Change in chylomicron-triglycerides production of ApoB48 in isolated chylomicrons from plasma samples measured by multicompartmental modeling assay. 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.
Time Frame	Baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	66.5 (0)
Week 12	66.5 (0)

24. Secondary Outcome

Title	Mean CM TG-AUC Before and After Evolocumab
Description	Change in chylomicron triglyceride area under curve in plasma at a particular time points after the meal. Area under the curve (AUC) was normalized so that 100% corresponds to the AUC before treatment; subsequently the percentage after treatment is in reference to this value. AUC values were calculated using the trapezoidal rule.
Time Frame	0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	9.5 (4.9)
Week 12	8.9 (5.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.84
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

25. Secondary Outcome

Title	Mean ApoB48 iAUC Before and After Evolocumab
Description	Change in apolipoprotein B48 incremental area under curve in plasma at a particular time points after the meal. Area under the curve (AUC) was normalized so that 100% corresponds to the AUC before treatment; subsequently the percentage after treatment is in reference to this value. AUC values were calculated using the trapezoidal rule.
Time Frame	0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Measure Participants	13
Baseline	18.4 (25.5)
Week 12	13.9 (17.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evolocumab
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.89
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	During 3 months of Evolocumab therapy
Arm/Group Title	Evolocumab
Arm/Group Description	Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks Evolocumab: Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
All Cause Mortality
	Evolocumab
	Affected / at Risk (%)	# Events
Total	0/13 (0%)
Serious Adverse Events
	Evolocumab
	Affected / at Risk (%)	# Events
Total	3/13 (23.1%)
Blood and lymphatic system disorders
Blood glucose elevation	1/13 (7.7%)
Iron deficiency anemia	1/13 (7.7%)
General disorders
Non-cardiac chest pain	1/13 (7.7%)
Other (Not Including Serious) Adverse Events
	Evolocumab
	Affected / at Risk (%)	# Events
Total	13/13 (100%)
Blood and lymphatic system disorders
Anemia	1/13 (7.7%)
Hypertension	3/13 (23.1%)
Eosinophilia	1/13 (7.7%)
Thrombocytosis	1/13 (7.7%)
Macrocytosis	1/13 (7.7%)
Hematuria	1/13 (7.7%)
Microcytosis	1/13 (7.7%)
Cardiac disorders
Bradycardia	1/13 (7.7%)
Tachycardia	1/13 (7.7%)
Gastrointestinal disorders
Gastroenteritis	1/13 (7.7%)
Abdominal pain	2/13 (15.4%)
Infections and infestations
Bronchitis	1/13 (7.7%)
Herpes simplex labialis	1/13 (7.7%)
Musculoskeletal and connective tissue disorders
Postural vertigo	1/13 (7.7%)
Back pain	1/13 (7.7%)
Nervous system disorders
Headache	2/13 (15.4%)
Dizziness	1/13 (7.7%)
Tinnitus	1/13 (7.7%)
Renal and urinary disorders
Pyuria	1/13 (7.7%)
Urinary tract infection	2/13 (15.4%)
Respiratory, thoracic and mediastinal disorders
Respiratory infection	9/13 (69.2%)
Skin and subcutaneous tissue disorders
Fungal nail disease	1/13 (7.7%)
Skin eruption	2/13 (15.4%)
Edema	1/13 (7.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.