Hypercholesterolemia, Dyslipidemia
Conditions
Keywords
Hypercholesterolemia, Dyslipidemia, simvastatin, Zocor
Brief summary
The purpose of this study was to provide human lipidomics standards with simvastatin treatment that were to be used for comparison with similar preclinical studies.
Interventions
DRUGSimvastatin
40 mg once daily for 2 weeks
DRUGPlacebo
Placebo, matching the simvastatin (40 mg) tablet as a single oral daily dose for 2 weeks
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
30 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Participant is a Caucasian (including Hispanic) male * Participant has a maximum waist size of 40 inches * Participant does not currently use any lipid-altering medications * Participant is in good health other than the diagnosis of dyslipidemia
Exclusion criteria
* Participant has had stomach ulcers within the last 3 months * Participant has had a heart attack in the last 6 months or has angina * Participant has chronic heart failure * Participant has a history of stroke, seizures, or major neurological disorder * Participant has a history of cancer * Participant has a gastrointestinal condition that affects bowel movements * Participant has type 1 or 2 diabetes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Arachidonic Acid Level After 2 Weeks of Treatment | 2 weeks | Arachidonic acid level (20:4n6) in the cholesterol ester lipid class. The mean reported was an adjusted mean, which was obtained from running a 2-period crossover model that had fixed treatment and period terms and a random participant term. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | 2 weeks | Change in fasting blood cholesterol ester, lysophosphatidylcholine, phosphatidylcholine, phosphatidylethanolamine, and triacylglycerol levels compared to placebo. The mean reported was an adjusted mean. |
| Serum Proprotein Convertase Subtilisin-like/Kexin Type 9 (PCSK9) Level | 2 weeks | Two days of standardized, pre-packaged meals were provided prior to the 10-hour fast required before blood collection. To assess how consumption of a meal would affect levels of plasma PCSK9, following each of the fasting blood draws, participants were asked to consume a high fat meal (heavy whipping cream + vanilla ice cream in a 1:4 ratio \[dose = 162 g/m\^2\]) within 20 minutes. For the duration of the test, participants were to remain seated or recumbent until blood samples were drawn 4 h after meal completion. The mean reported was an adjusted mean (defined in first outcome measure). |
| Blood Linoleic Acid Levels | 2 weeks | Change in blood linoleic acid levels for Cholesterol Ester compared to placebo. |
| Change in Fasting Delta 5 Desaturase Enzyme Activity Compared to Placebo | 2 weeks | Change in fasting delta 5 desaturase enzyme activity compared to placebo. Delta 5 desaturase enzyme activity is defined as the ratios of C20:4n-6 to C20:3n-6 and C20:5n-3 to C20:4n-3. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants All enrolled participants | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Administrative (scheduling conflict) | 1 | 1 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 31 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 30 | 2 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 |
Outcome results
Primary
Arachidonic Acid Level After 2 Weeks of Treatment
Arachidonic acid level (20:4n6) in the cholesterol ester lipid class. The mean reported was an adjusted mean, which was obtained from running a 2-period crossover model that had fixed treatment and period terms and a random participant term.
Time frame: 2 weeks
Population: Only participants with complete arachidonic acid data were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin 40 mg | Arachidonic Acid Level After 2 Weeks of Treatment | 259.1 nmol | Standard Deviation 89.1 |
| Placebo | Arachidonic Acid Level After 2 Weeks of Treatment | 269.6 nmol | Standard Deviation 85.2 |
p-value: 0.455Mixed Models Analysis
Secondary
Blood Linoleic Acid Levels
Change in blood linoleic acid levels for Cholesterol Ester compared to placebo.
Time frame: 2 weeks
Population: Only participants with complete blood linoleic acid data were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin 40 mg | Blood Linoleic Acid Levels | 1184.7 nmol | Standard Deviation 393.4 |
| Placebo | Blood Linoleic Acid Levels | 1504.7 nmol | Standard Deviation 327.8 |
Secondary
Change in Fasting Delta 5 Desaturase Enzyme Activity Compared to Placebo
Change in fasting delta 5 desaturase enzyme activity compared to placebo. Delta 5 desaturase enzyme activity is defined as the ratios of C20:4n-6 to C20:3n-6 and C20:5n-3 to C20:4n-3.
Time frame: 2 weeks
Population: Only participants with complete fasting delta 5 desaturase enzyme activity data were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Simvastatin 40 mg | Change in Fasting Delta 5 Desaturase Enzyme Activity Compared to Placebo | Cholesterol ester c20:4n6 / c20:3n6 | 12.2234 ratio | Standard Deviation 3.413 |
| Simvastatin 40 mg | Change in Fasting Delta 5 Desaturase Enzyme Activity Compared to Placebo | Cholesterol Ester c20:5n3/c20:4n3 | 17.9161 ratio | Standard Deviation 7.738 |
| Placebo | Change in Fasting Delta 5 Desaturase Enzyme Activity Compared to Placebo | Cholesterol ester c20:4n6 / c20:3n6 | 11.5662 ratio | Standard Deviation 3.684 |
| Placebo | Change in Fasting Delta 5 Desaturase Enzyme Activity Compared to Placebo | Cholesterol Ester c20:5n3/c20:4n3 | 16.3024 ratio | Standard Deviation 9.465 |
Comparison: Cholesterol ester c20:4n6 / c20:3n6p-value: 0.247Mixed Models Analysis
Comparison: Cholesterol ester c20:5n3 / c20:4n3p-value: 0.151Mixed Models Analysis
Secondary
Fasting Blood Lipidomic Levels After 2 Weeks of Treatment
Change in fasting blood cholesterol ester, lysophosphatidylcholine, phosphatidylcholine, phosphatidylethanolamine, and triacylglycerol levels compared to placebo. The mean reported was an adjusted mean.
Time frame: 2 weeks
Population: Only participants with complete blood lipidomic data were included.~For cholesterol ester 22:5n6, n=26 for the simvastatin arm and n=27 for the placebo arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Simvastatin 40 mg | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Cholesterol ester lipid 22:5n6 | 1.0 nmol | Standard Deviation 0.8 |
| Simvastatin 40 mg | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Phosphatidyl-choline lipid 20:3n6 | 117.4 nmol | Standard Deviation 54.3 |
| Simvastatin 40 mg | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Cholesterol ester lipid 18:3n3 | 10.0 nmol | Standard Deviation 4.8 |
| Simvastatin 40 mg | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Phosphatidyl-choline lipid 20:4n6 | 458.0 nmol | Standard Deviation 138.4 |
| Simvastatin 40 mg | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Cholesterol ester lipid 22:6n3 | 12.7 nmol | Standard Deviation 5.1 |
| Simvastatin 40 mg | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Phosphatidyl-choline lipid 22:5n3 | 30.3 nmol | Standard Deviation 10.2 |
| Simvastatin 40 mg | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Cholesterol ester lipid 20:3n9 | 1.3 nmol | Standard Deviation 1.1 |
| Simvastatin 40 mg | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Phosphatidyl-choline lipid 22:5n6 | 11.4 nmol | Standard Deviation 6.4 |
| Simvastatin 40 mg | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Lysophosphatidyl-choline lipid 20:4n6 | 11.1 nmol | Standard Deviation 3.8 |
| Simvastatin 40 mg | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Phosphatidyl-ethanolamine lipid 18:2n6 | 21.8 nmol | Standard Deviation 9.3 |
| Simvastatin 40 mg | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Cholesterol ester lipid 20:3n6 | 20.9 nmol | Standard Deviation 10.5 |
| Simvastatin 40 mg | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Triacylglycerol 16:00 | 788.3 nmol | Standard Deviation 431.6 |
| Simvastatin 40 mg | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Phosphatidyl-choline lipid 18:2n6 | 684.8 nmol | Standard Deviation 224.9 |
| Simvastatin 40 mg | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Triacylglycerol 20:3n9 | 4.5 nmol | Standard Deviation 5.5 |
| Simvastatin 40 mg | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Cholesterol ester lipid 16:00 | 288.9 nmol | Standard Deviation 102.1 |
| Placebo | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Triacylglycerol 20:3n9 | 4.9 nmol | Standard Deviation 2.8 |
| Placebo | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Cholesterol ester lipid 16:00 | 345.1 nmol | Standard Deviation 87.3 |
| Placebo | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Cholesterol ester lipid 18:3n3 | 14.4 nmol | Standard Deviation 6.7 |
| Placebo | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Cholesterol ester lipid 20:3n6 | 23.5 nmol | Standard Deviation 10.2 |
| Placebo | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Cholesterol ester lipid 20:3n9 | 1.2 nmol | Standard Deviation 0.9 |
| Placebo | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Cholesterol ester lipid 22:5n6 | 1.1 nmol | Standard Deviation 0.4 |
| Placebo | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Cholesterol ester lipid 22:6n3 | 14.8 nmol | Standard Deviation 6.8 |
| Placebo | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Lysophosphatidyl-choline lipid 20:4n6 | 10.3 nmol | Standard Deviation 2.7 |
| Placebo | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Phosphatidyl-choline lipid 18:2n6 | 824.9 nmol | Standard Deviation 196.2 |
| Placebo | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Phosphatidyl-choline lipid 20:3n6 | 127.1 nmol | Standard Deviation 58.8 |
| Placebo | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Phosphatidyl-choline lipid 20:4n6 | 443.2 nmol | Standard Deviation 98.1 |
| Placebo | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Phosphatidyl-choline lipid 22:5n3 | 34.3 nmol | Standard Deviation 12.8 |
| Placebo | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Phosphatidyl-choline lipid 22:5n6 | 12.1 nmol | Standard Deviation 4.1 |
| Placebo | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Phosphatidyl-ethanolamine lipid 18:2n6 | 32.1 nmol | Standard Deviation 15.5 |
| Placebo | Fasting Blood Lipidomic Levels After 2 Weeks of Treatment | Triacylglycerol 16:00 | 1005.1 nmol | Standard Deviation 662.2 |
Comparison: Cholesterol Ester 16:00p-value: 0.014Mixed Models Analysis
Comparison: Cholesterol Ester 18:3n3p-value: <0.001Mixed Models Analysis
Comparison: Cholesterol Ester 20:3n6p-value: 0.217Mixed Models Analysis
Comparison: Cholesterol Ester 20:3n9p-value: 0.666Mixed Models Analysis
Comparison: Cholesterol Ester 22:5n6p-value: 0.776Mixed Models Analysis
Comparison: Cholesterol Ester 22:6n3p-value: 0.018Mixed Models Analysis
Comparison: Lysophosphatidylcholine 20:4n6p-value: 0.152Mixed Models Analysis
Comparison: Phosphatidylcholine 18:2n6p-value: 0.007Mixed Models Analysis
Comparison: Phosphatidylcholine 20:3n6p-value: 0.325Mixed Models Analysis
Comparison: Phosphatidylcholine 20:4n6p-value: 0.419Mixed Models Analysis
Comparison: Phosphatidylcholine 22:5n3p-value: 0.07Mixed Models Analysis
Comparison: Phosphatidylcholine 22:5n6p-value: 0.769Mixed Models Analysis
Comparison: Phosphatidylethanolamine 18:2n6p-value: <0.001Mixed Models Analysis
Comparison: Triacylglycerol 16:00p-value: 0.016Mixed Models Analysis
Comparison: Triacylglycerol 20:3n9p-value: 0.833Mixed Models Analysis
Secondary
Serum Proprotein Convertase Subtilisin-like/Kexin Type 9 (PCSK9) Level
Two days of standardized, pre-packaged meals were provided prior to the 10-hour fast required before blood collection. To assess how consumption of a meal would affect levels of plasma PCSK9, following each of the fasting blood draws, participants were asked to consume a high fat meal (heavy whipping cream + vanilla ice cream in a 1:4 ratio \[dose = 162 g/m\^2\]) within 20 minutes. For the duration of the test, participants were to remain seated or recumbent until blood samples were drawn 4 h after meal completion. The mean reported was an adjusted mean (defined in first outcome measure).
Time frame: 2 weeks
Population: Only participants with complete PCSK9 data were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Simvastatin 40 mg | Serum Proprotein Convertase Subtilisin-like/Kexin Type 9 (PCSK9) Level | Fed | 6.06 nmol | Standard Deviation 2.34 |
| Simvastatin 40 mg | Serum Proprotein Convertase Subtilisin-like/Kexin Type 9 (PCSK9) Level | Fasted | 6.47 nmol | Standard Deviation 2.11 |
| Placebo | Serum Proprotein Convertase Subtilisin-like/Kexin Type 9 (PCSK9) Level | Fed | 4.69 nmol | Standard Deviation 1.66 |
| Placebo | Serum Proprotein Convertase Subtilisin-like/Kexin Type 9 (PCSK9) Level | Fasted | 5.51 nmol | Standard Deviation 1.91 |
Comparison: Fastedp-value: 0.027Mixed Models Analysis
Comparison: Fedp-value: <0.001Mixed Models Analysis