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

Type 2 Diabetes Mellitus Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02948777
• Other study ID #: EVOLKIN
• Status: Completed
• Phase: Phase 4
• Start date: October 2016
• Est. completion date: June 2018

Study information

• Verified date: October 2021
• Source: Clinical Research Institute HUCH Ltd
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 14
• Est. completion date: June 2018
• Est. primary completion date: June 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 77 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Evolocumab

Locations

Country	Name	City	State
Finland	Helsinki University Hospital, Biomedicum 2U	Helsinki

Sponsors (2)

Lead Sponsor	Collaborator
Marja-Riitta Taskinen	Göteborg University

Country where clinical trial is conducted

Finland, 

References & Publications (4)

Björnson E, Packard CJ, Adiels M, Andersson L, Matikainen N, Söderlund S, Kahri J, Sihlbom C, Thorsell A, Zhou H, Taskinen MR, Borén J. Investigation of human apoB48 metabolism using a new, integrated non-steady-state model of apoB48 and apoB100 kinetics. — View Citation

Taskinen MR, Björnson E, Andersson L, Kahri J, Porthan K, Matikainen N, Söderlund S, Pietiläinen K, Hakkarainen A, Lundbom N, Nilsson R, Ståhlman M, Adiels M, Parini P, Packard C, Borén J. Impact of proprotein convertase subtilisin/kexin type 9 inhibition — View Citation

Taskinen MR, Björnson E, Kahri J, Söderlund 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, Borén J. Effects of Evolocumab on the Postprandial Kinetics of — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	Mean LDL-C Concentration Before and After Evolocumab	Change in LDL-cholesterol concentration in plasma LDL fraction isolated by ultracentrifugation.	Baseline and after 12 weeks
Secondary	Mean ApoB48 Concentration Before and After Evolocumab	Change in apolipoprotein B48 levels in total plasma measured by enzyme-linked immunosorbent assay.	Baseline and after 12 weeks
Secondary	Mean CM TG-iAUC Before and After Evolocumab	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.	0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks
Secondary	Mean ApoB48 AUC Before and After Evolocumab	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.	0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks
Secondary	Mean VLDL1 ApoB100 Production Before and After Evolocumab	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.	Baseline and after 12 weeks
Secondary	Mean VLDL2 ApoB100 Production Before and After Evolocumab	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.	Baseline and after 12 weeks
Secondary	IDL Pool Size of ApoB100 Before and After Evolocumab	Change in intermediate-density lipoprotein pool size of ApoB100 in IDL fraction prepared from plasma samples using density ultracentrifugation.	Baseline and after 12 weeks
Secondary	Mean IDL to LDL Transfer of ApoB100 Before and After Evolocumab	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.	Baseline and after 12 weeks
Secondary	Mean VAT Before and After Evolocumab	Change in visceral fat volume measured by magnetic resonance imaging	Baseline and after 12 weeks
Secondary	Mean Liver Fat Before and After Evolocumab	Change in liver fat content measured by magnetic resonance imaging.	Baseline and after 12 weeks
Secondary	Mean SAT Before and After Evolocumab	Change in subcutaneous fat volume measured by magnetic resonance imaging	Baseline and after 12 weeks
Secondary	Mean VLDL1 Triglyceride Production Before and After Evolocumab	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.	Baseline and after 12 weeks
Secondary	Mean VLDL1 FCR of triglycerideBefore and After Evolocumab	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.	Baseline and after 12 weeks
Secondary	Mean VLDL2 Triglyceride Total Production Before and After Evolocumab	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.	Baseline and after 12 weeks
Secondary	Mean VLDL2 FCR of Triglyceride Before and After Evolocumab	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.	Baseline and after 12 weeks
Secondary	Mean Postprandial CM of ApoB48 Before and After Evolocumab	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.	Baseline and after 12 weeks
Secondary	Mean CM-apoB48 FCR of ApoB48 Metabolism Before and After Evolocumab	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.	Baseline and after 12 weeks
Secondary	Mean CM-TG Production of ApoB48 Before and After Evolocumab	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.	Baseline and after 12 weeks
Secondary	Mean CM TG-AUC Before and After Evolocumab	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.	0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks
Secondary	Mean ApoB48 iAUC Before and After Evolocumab	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.	0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks