Trial Outcomes & Findings for Effects of PCSK9 Inhibition by Evolocumab on Postprandial Lipid Metabolism in Type 2 Diabetes (NCT NCT02948777)

NCT ID: NCT02948777

Last Updated: 2021-11-03

Results Overview

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

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 14 participants
• Primary outcome timeframe: Baseline and after 12 weeks
• Results posted on: 2021-11-03

Participant Flow

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.

Participant milestones

Measure	Evolocumab Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Overall Study STARTED	14
Overall Study COMPLETED	13
Overall Study NOT COMPLETED	1

Reasons for withdrawal

Measure	Evolocumab Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Overall Study worsening of asthma symptoms resulting in oral prednisolone use.	1

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Evolocumab n=14 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	7 Participants n=5 Participants
Age, Categorical >=65 years	7 Participants n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants
Sex: Female, Male Male	6 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	14 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and after 12 weeks

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

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean ApoB Concentration Before and After Evolocumab Baseline	75.9 mg/dL Standard Deviation 14.5
Mean ApoB Concentration Before and After Evolocumab Week 12	35.3 mg/dL Standard Deviation 10.9

PRIMARY outcome

Timeframe: Baseline and after 12 weeks

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

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean TRL-C Concentration Before and After Evolocumab Baseline	33.4 mg/dL Standard Deviation 10.9
Mean TRL-C Concentration Before and After Evolocumab Week 12	17.8 mg/dL Standard Deviation 6.5

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean Total Production of ApoB48 Before and After Evolocumab Baseline	570 mg/d Standard Deviation 60
Mean Total Production of ApoB48 Before and After Evolocumab Week 12	580 mg/d Standard Deviation 75

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean LDL FCR of ApoB100 Before and After Evolocumab Baseline	0.32 pools/d Standard Deviation 0.15
Mean LDL FCR of ApoB100 Before and After Evolocumab Week 12	0.78 pools/d Standard Deviation 0.34

PRIMARY outcome

Timeframe: Baseline and after 12 weeks

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

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
LDL Pool Size of ApoB100 Before and After Evolocumab Week 12	460 mg Standard Deviation 270
LDL Pool Size of ApoB100 Before and After Evolocumab Baseline	1500 mg Standard Deviation 470

SECONDARY outcome

Timeframe: Baseline and after 12 weeks

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

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean LDL-C Concentration Before and After Evolocumab Baseline	1500 mg Standard Deviation 470
Mean LDL-C Concentration Before and After Evolocumab Week 12	460 mg Standard Deviation 270

SECONDARY outcome

Timeframe: Baseline and after 12 weeks

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

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean ApoB48 Concentration Before and After Evolocumab Baseline	6.1 mg/L Standard Deviation 3.8
Mean ApoB48 Concentration Before and After Evolocumab Week 12	5.3 mg/L Standard Deviation 3.3

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean CM TG-iAUC Before and After Evolocumab Baseline	6.8 (mmol/l)*h Standard Deviation 3.6
Mean CM TG-iAUC Before and After Evolocumab Week 12	5.8 (mmol/l)*h Standard Deviation 4.4

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean ApoB48 AUC Before and After Evolocumab Baseline	66.8 (mg/l)*h Standard Deviation 31.2
Mean ApoB48 AUC Before and After Evolocumab Week 12	57.4 (mg/l)*h Standard Deviation 26.5

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean VLDL1 ApoB100 Production Before and After Evolocumab Baseline	790 mg/d Standard Deviation 230
Mean VLDL1 ApoB100 Production Before and After Evolocumab Week 12	750 mg/d Standard Deviation 230

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean VLDL2 ApoB100 Production Before and After Evolocumab Baseline	270 mg/d Standard Deviation 91
Mean VLDL2 ApoB100 Production Before and After Evolocumab Week 12	230 mg/d Standard Deviation 96

SECONDARY outcome

Timeframe: Baseline and after 12 weeks

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

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
IDL Pool Size of ApoB100 Before and After Evolocumab Baseline	190 mg Standard Deviation 50
IDL Pool Size of ApoB100 Before and After Evolocumab Week 12	130 mg Standard Deviation 49

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean IDL to LDL Transfer of ApoB100 Before and After Evolocumab Baseline	450 mg/d Standard Deviation 190
Mean IDL to LDL Transfer of ApoB100 Before and After Evolocumab Week 12	310 mg/d Standard Deviation 140

SECONDARY outcome

Timeframe: Baseline and after 12 weeks

Change in visceral fat volume measured by magnetic resonance imaging

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean VAT Before and After Evolocumab Baseline	2420 cm3 Standard Deviation 960
Mean VAT Before and After Evolocumab Week 12	2450 cm3 Standard Deviation 1100

SECONDARY outcome

Timeframe: Baseline and after 12 weeks

Change in liver fat content measured by magnetic resonance imaging.

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean Liver Fat Before and After Evolocumab Baseline	6.6 fat % Standard Deviation 6.6
Mean Liver Fat Before and After Evolocumab Week 12	6.3 fat % Standard Deviation 7.2

SECONDARY outcome

Timeframe: Baseline and after 12 weeks

Change in subcutaneous fat volume measured by magnetic resonance imaging

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean SAT Before and After Evolocumab Baseline	3900 cm3 Standard Deviation 1700
Mean SAT Before and After Evolocumab Week 12	4110 cm3 Standard Deviation 1600

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean VLDL1 Triglyceride Production Before and After Evolocumab Baseline	34 g/d Standard Deviation 18
Mean VLDL1 Triglyceride Production Before and After Evolocumab Week 12	33 g/d Standard Deviation 13

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean VLDL1 FCR of triglycerideBefore and After Evolocumab Baseline	38 pools/d Standard Deviation 27
Mean VLDL1 FCR of triglycerideBefore and After Evolocumab Week 12	37 pools/d Standard Deviation 23

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean VLDL2 Triglyceride Total Production Before and After Evolocumab Baseline	8.8 g/d Standard Deviation 3.8
Mean VLDL2 Triglyceride Total Production Before and After Evolocumab Week 12	8.5 g/d Standard Deviation 2.7

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean VLDL2 FCR of Triglyceride Before and After Evolocumab Baseline	10 pools/d Standard Deviation 6.3
Mean VLDL2 FCR of Triglyceride Before and After Evolocumab Week 12	15 pools/d Standard Deviation 8.7

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean Postprandial CM of ApoB48 Before and After Evolocumab Baseline	240 mg/d Standard Deviation 50
Mean Postprandial CM of ApoB48 Before and After Evolocumab Week 12	230 mg/d Standard Deviation 43

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean CM-apoB48 FCR of ApoB48 Metabolism Before and After Evolocumab Baseline	37 pools/d Standard Deviation 24
Mean CM-apoB48 FCR of ApoB48 Metabolism Before and After Evolocumab Week 12	46 pools/d Standard Deviation 32

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean CM-TG Production of ApoB48 Before and After Evolocumab Baseline	66.5 g/d Standard Deviation 0
Mean CM-TG Production of ApoB48 Before and After Evolocumab Week 12	66.5 g/d Standard Deviation 0

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean CM TG-AUC Before and After Evolocumab Baseline	9.5 (mmol/l)*h Standard Deviation 4.9
Mean CM TG-AUC Before and After Evolocumab Week 12	8.9 (mmol/l)*h Standard Deviation 5.9

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Evolocumab n=13 Participants Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Mean ApoB48 iAUC Before and After Evolocumab Baseline	18.4 (mg/l)*h Standard Deviation 25.5
Mean ApoB48 iAUC Before and After Evolocumab Week 12	13.9 (mg/l)*h Standard Deviation 17.5

Adverse Events

Evolocumab

Serious events: 3 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Measure	Evolocumab n=13 participants at risk 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
Blood and lymphatic system disorders Blood glucose elevation	7.7% 1/13 • During 3 months of Evolocumab therapy
General disorders Non-cardiac chest pain	7.7% 1/13 • During 3 months of Evolocumab therapy
Blood and lymphatic system disorders Iron deficiency anemia	7.7% 1/13 • During 3 months of Evolocumab therapy

Other adverse events

Measure	Evolocumab n=13 participants at risk 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
Musculoskeletal and connective tissue disorders Postural vertigo	7.7% 1/13 • During 3 months of Evolocumab therapy
Cardiac disorders Bradycardia	7.7% 1/13 • During 3 months of Evolocumab therapy
Respiratory, thoracic and mediastinal disorders Respiratory infection	69.2% 9/13 • During 3 months of Evolocumab therapy
Skin and subcutaneous tissue disorders Fungal nail disease	7.7% 1/13 • During 3 months of Evolocumab therapy
Blood and lymphatic system disorders Anemia	7.7% 1/13 • During 3 months of Evolocumab therapy
Nervous system disorders Headache	15.4% 2/13 • During 3 months of Evolocumab therapy
Nervous system disorders Dizziness	7.7% 1/13 • During 3 months of Evolocumab therapy
Skin and subcutaneous tissue disorders Skin eruption	15.4% 2/13 • During 3 months of Evolocumab therapy
Blood and lymphatic system disorders Hypertension	23.1% 3/13 • During 3 months of Evolocumab therapy
Infections and infestations Bronchitis	7.7% 1/13 • During 3 months of Evolocumab therapy
Infections and infestations Herpes simplex labialis	7.7% 1/13 • During 3 months of Evolocumab therapy
Nervous system disorders Tinnitus	7.7% 1/13 • During 3 months of Evolocumab therapy
Musculoskeletal and connective tissue disorders Back pain	7.7% 1/13 • During 3 months of Evolocumab therapy
Cardiac disorders Tachycardia	7.7% 1/13 • During 3 months of Evolocumab therapy
Renal and urinary disorders Pyuria	7.7% 1/13 • During 3 months of Evolocumab therapy
Skin and subcutaneous tissue disorders Edema	7.7% 1/13 • During 3 months of Evolocumab therapy
Blood and lymphatic system disorders Eosinophilia	7.7% 1/13 • During 3 months of Evolocumab therapy
Blood and lymphatic system disorders Thrombocytosis	7.7% 1/13 • During 3 months of Evolocumab therapy
Renal and urinary disorders Urinary tract infection	15.4% 2/13 • During 3 months of Evolocumab therapy
Gastrointestinal disorders Gastroenteritis	7.7% 1/13 • During 3 months of Evolocumab therapy
Gastrointestinal disorders Abdominal pain	15.4% 2/13 • During 3 months of Evolocumab therapy
Blood and lymphatic system disorders Macrocytosis	7.7% 1/13 • During 3 months of Evolocumab therapy
Blood and lymphatic system disorders Hematuria	7.7% 1/13 • During 3 months of Evolocumab therapy
Blood and lymphatic system disorders Microcytosis	7.7% 1/13 • During 3 months of Evolocumab therapy

Additional Information

Prof. Marja-Riitta Taskinen

Helsinki University and Helsinki University Hospital

Phone: +358-9-47171990

Email: marja-riitta.taskinen@helsinki.fi

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place