Abstract
Aim: Information regarding the effects of omega-3 fatty acid on hypertriglyceridemic patients in Chinese is still limited. This study aimed to investigate the efficacy and safety of Omacor®, a prescription ethyl-ester omega-3 fatty acid for the treatment of hypertriglyceridemia, administered at doses of 2 g/day and 4 g/day to Taiwanese hypertriglyceridemic patients.
Methods: A multicenter, randomized, double-blind, placebo-controlled, parallel study in adults with hypertriglyceridemia was conducted. After a five-week diet lead in period patients with triglycerides = 200–1000 mg/dL were randomized to receive Omacor®, a concentrated preparation of omega-3 eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) in a dose of 1 g twice daily (2 g Omacor ®), 2 g twice daily (4 g Omacor®) or placebo, for eight weeks. The primary endpoint was the percentage change in triglyceride serum levels from baseline to the end of treatment.
Results: A total of 253 Taiwanese patients were randomized, of which 65.6% (166) were men. At the end of the treatment, the percentage change in triglyceride serum levels in both the Omacor® 4 g/day (−32.1%) and 2 g/day (−29.7%) groups was larger than in the placebo group (−5.4%) (p < 0.001). The incidence of drug-related adverse events was as follows: 0.0%, 1.2%, and 0.0% in Omacor ® 4 g/day, Omacor® 2 g/day, and placebo groups, respectively. No drug-related serious adverse events were reported during the study.
Conclusions: Omacor® may be a feasible option to treat hypertriglyceridemia in Taiwanese patients.
Keywords: Hypertriglyceridemia, Omega-3 fatty acids, Omacor, Docosahexaenoic acid, Eicosapentaenoic acid, Ethnic chinese
See editorial vol. 24: 256–257
Introduction
Hypertriglyceridemia, together with low levels of high-density lipoprotein cholesterol (HDL-C), is an independent risk factor for coronary heart disease, according to the guidelines for the management of triglycerides (TG) and cardiovascular disease1, 2). High TG levels are often concomitant with insulin resistance, obesity, and acute pancreatitis, and low levels of high-density lipoprotein cholesterol (HDL-C) are present in patients with metabolic syndrome.
The standard recommendations for hypertriglyceridemic patients comprise measures to modify the root causes, such as weight loss, increased regular exercise, reduced intake of refined carbohydrates, as well as thyroid hormone replacement in patients with hypothyroidism, or alcohol cessation. At present, there are limited drugs specially indicated for the treatment of moderately elevated triglycerides; only omega-3 fatty acids, fibrates, and niacin3). The American Heart Association states that doses of fatty acids of 2–4 g/day of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) can be used under a physician's care to lower elevated triglycerides4).
Omacor® (Pronova BioPharma), a capsule formed of 90% omega-3-acid ethyl esters, is the first US Food and Drug Administration (FDA) and EU-approved omega-3-acid drug. Omacor® is prepared from fish using various patented procedures; each capsule contains 460 mg of EPA and 380 mg of DHA5). The drug's effects include lowering plasma triglyceride levels6), increasing conversion of very low-density lipoprotein cholesterol (VLDL-C) to low-density lipoprotein cholesterol (LDL-C), depressing triglyceride synthesis6), and reducing postprandial lipemia7).
Several placebo-controlled studies have reported the efficacy of omega-3 fatty acids concentrates in lowering triglyceride in patients with moderately-elevated triglycerides. In addition, it has been observed that the degree of lowering depends on the dose and on baseline triglyceride levels3). The indicated doses of prescription omega-3 fatty acids range from 2 to 4g/day, with an efficacy on reduction of triglyceride levels of a 20%–45%3). Such a reduction is also consistent with that observed when it was combined with a statin8), such as simvastatin9). Additionally, baseline TG levels may be affected by ethnicity-related factors associated with different lifestyles and the frequency of fish intake. Indeed, the Eastern diet and lifestyle differs substantially from other countries where Omacor ® is currently authorized.
Therefore, this study aimed to demonstrate the efficacy and safety of Omacor®, administered at doses of 2 g/day and 4 g/day on hypertriglyceridemic patients in Taiwanese patients.
Materials and Methods
This was a randomized, double-blind, placebo-controlled, parallel study with two active dosage levels (1:1:1), conducted at four medical centers in Taiwan. The study consisted in five clinic visits: one screening visit (leading period), one randomization visit, and two biweekly visits with one monthly visit during the double-blind/treatment period. The study was supported and coordinated by Excelsior Pharmatech Labs. The registration number in ClinicalTrial.gov is NCT01725646. This study was conducted in accordance with the Investigational New Drug (IND), Informed Consent and IRB Regulations from the Taiwan Food and Drug Administration (TFDA), and Good Clinical Practice as outlined in the International Conference on Harmonization (ICH), E6 Good Clinical Practice (GCP). The study was approved by all appropriate national regulatory authorities and ethics committees of the participating hospitals. All patients participated voluntarily in the study after signing the informed consent.
Ethics
The study was approved by National Taiwan University Hospital (NTUH) Research Ethics Committee on May 13, 2011, by Institutional Review Board of the Taichung Veterans General Hospital (TCVGH) on July 27, 2011, by Institutional Review Board, Taipei Veterans General Hospital (TPVGH) on Sep 16, 2011, and by National Cheng Kung University Hospital (NCKUH) Institutional Review Board on July 26, 2011. The first patient was recruited on July 8, 2011 in NTUH, on Aug 25, 2011 in TCVGH, on Nov 24, 2011 in TPVGH, and on Sep 29, 2011 in NCKUH, and the last patient was recruited on Feb 20, 2013 and completed the follow-up on May 24, 2013.
The study was registered in the Center of Drug Evaluation (CDE) Taiwan and assigned a registration number, 1001401529, before recruiting the first patient, according to Taiwan's regulations. It was then assigned a delayed registration number of NCT01725646 on ClinicalTrial.gov, because the sponsor did not originally plan to publish the study internationally. It was thus registered in Taiwan's CDE but not on ClinicalTrial.gov before recruiting the first patient. The authors confirm that all ongoing and related trials for this drug/intervention are registered.
Study Participants
Patient eligibility criteria were: 1) age between 20 and 79 years; 2) fasting serum TG level between 200 and 1000 mg/dL at screening and also at randomization; 3) having discontinued the following lipid-altering agents: rosuvastatin, bile acid sequestrants, nicotinic acid, probucol, cholesterol absorption inhibitors, gemfibrozil or fibric acid derivatives, for at least one month; 4) if a current smoker, having no plan to change smoking habits during the study; and 5) at the randomization visit, either to have discontinued 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors, or to have been on a stable dose and schedule of HMG-CoA reductase inhibitors for at least eight weeks. The main reasons for exclusion were: 1) LDL-C control levels above the Bureau of National Health Insurance (BNHI) treatment goal at screening and randomization; 2) to be taking drugs such as nonstudy related omega-3, red yeast rice, weight loss drugs, immunomodulatory therapy, rosuvastatin, bile acid sequestrants, fibrates, niacin, probucol or cholesterol absorption inhibitors; 3) high consumption of fatty fish (>two servings of 150 g of fatty fish per week during the leading period); 4) severe diseases, such as uncontrolled diabetes mellitus, thyroid dysfunction, obstructive liver disease, chronic kidney disease, nephrotic syndrome or any serious renal, pulmonary, hepatic, biliary, gastrointestinal diseases or cancer within 6 months prior to randomization; and 5) a history of alcoholism (taking at least three glasses of wine or equivalent per day) during the previous three months. After the screening visit, patients who either had hypolipidemia with total cholesterol (TC) <120 mg/dL and LDL-C <50 mg/dL at any visit or had TG >1,000 mg/dL with a 30% elevation or more compared to baseline were requested to be withdrawn from study.
Procedures
For this intervention study, eligible patients entered a five-week leading period and were counseled on low fat diets throughout the study. After this leading phase, patients needed serum triglycerides levels of 200 mg/dL or more and to meet the selection criteria to be randomized. Patients were equally stratified by their lipid-altering agents/statin (with or without) and by the baseline triglyceride level (200–499 mg/dL or 500–1,000 mg/dL) prior to being randomized. The randomization schedules were generated using a validated SAS system that automates the random assignment of treatment groups to randomized numbers and were prepared with a 1:1:1 randomization ratio in block numbers as 6. Thus, patients were randomized to receive 1 g of Omacor® twice a day (2 g Omacor®/day), 2 g of Omacor® twice a day (4 g Omacor®/day) or placebo (i.e., olive oil in identical capsules) twice a day for a total of eight weeks. The Omacor® 2 g/day arm received one bottle with Omacor® capsules and one bottle with placebo capsules; the Omacor® 4 g/day arm received two bottles with Omacor® capsules; and the placebo arm received two bottles with placebo capsules. Every study medication bottle had the same appearance. The investigator kept individual blind-breaker envelopes containing the drug assignments.
Including the leading period, the total follow up lasted for 13 weeks. After the five-week leading period, the double blind period covered two biweekly visits and one monthly visit. At each visit, a 12-hour fasting blood sample was obtained to determine the efficacy measurements: serum TG, TC, HDL-C, and LDL-C. The listed items were assessed locally. The TG, TC, HDL-C, and LDL-C were analyzed using a homogeneous enzymatic method by Bayer-Siemens AVDIA 1800 Chemistry System with the corresponding reagent kits (AVDIA® Chemistry, Siemens).
Other additional information collected included: medical history review at screening and randomization, ECG at screening and at completion, dietary compliance (patient's dietary history review), vital signs (blood pressure, pulse), safety hematology (white blood cell count, red blood cell count, platelet count, and hemoglobin), safety biochemistry test (fasting glucose, total protein, total bilirubin, aspartate aminotransferase (AST [SGOT]), alanine aminotransferase (ALT [SGPT]), alkaline phosphatase, total bilirubin, lactate dehydrogenase, γ-gamma-glutamyl transpeptidase, blood urea nitrogen, creatinine, uric acid, sodium, potassium, chloride and high-sensitivity C-reactive protein). Blood samples were analyzed locally. Adverse events were reported spontaneously by the patient or elicited by open (non-leading) questioning.
The diet control is also an important part. A registered dietitian interviewed the enrolled patients monthly to evaluate their diet compliance. The patients had to record their diet in a diary card for three days before the interview with the dietitian. The dietitian reviewed the diary card in the interview and used a questionnaire to evaluate low fat diet compliance. In addition to the low fat diet, dietitians also evaluated fish consumption.
Study Endpoints
The primary efficacy endpoint was the effect of Omacor® for lowering serum TG, measured by the percent change from baseline to week 8 of the given treatment. Secondary endpoints included the percentage change in serum TG levels from baseline to week 4 of study treatment, the percentage change from baseline to weeks 4 and 8 in non-HDL-C concentration, TC, HDL-C, and TC: HDL-C ratio. The safety endpoint included information on adverse events (AEs), vital signs, and clinical laboratory tests.
Statistical Analysis
Sample size calculation was performed using a superiority test based on the percentage change of TG levels. From a similar study with Omacor® in Japanese cohorts10), a standard deviation (SD) of approximately 30% may be expected. Similarly, in the cited study, a reduction in serum TG of 12% and 26.6% was observed for patients with plasma TG above 200 mg/dL treated with Omacor® 2 g/day and Omacor® 4 g/day at eight weeks.
With a SD of 30% and estimated 80% power, a sample size of 74 patients in each treatment group was required to detect a difference in TG reduction of 14% at the 5% significance level (two-sided). To adjust for an expected 10% drop-out or non-compliance rate, 83 patients were included in each treatment group.
The intent-to-treat (ITT) population comprised all patients who were randomized to the study treatment and who had taken at least one dose of study medication and have at least one follow-up efficacy endpoint evaluation. The primary efficacy analysis was based on the ITT population used a last observation carried forward (LOCF) method of imputation for missing response variable due to patient early termination or incomplete assessment. The primary endpoint was also analyzed in the per protocol (PP) population, which included all patients who underwent any study treatment and had no major protocol violations affecting their efficacy assessments; and in the created strata based on statin usage or hypertriglyceridemia levels.
For the analysis of TG levels, the geometric mean and 95% confidence interval (CI) were computed by taking the exponent of the mean and of the lower and upper limits of the 95% CI of the natural-log-transformed sizes. The change from baseline to the end-of-treatment in natural-log-transformed TG level was evaluated by an analysis of covariance (ANCOVA) model with terms for baseline natural-log-transformed TG value, baseline fatty fish consumption (i.e., none, ≤ 150 g or >150 g), stratification factors and treatment group. The test drug (Omacor®) was concluded to be superior to the control (placebo) on average if the null hypothesis was rejected. The test was performed separately for each dose versus placebo. The comparison between 2 g/day Omacor® and placebo could only be concluded if 4 g/day Omacor® was superior to placebo at the significant level of 0.05 (two-sided). For the secondary efficacy endpoints, hypothesis tests (all two-sided) were performed individually at the 5% significance level and there was no adjustment for multiple tests or for adjustment for multiplicity of endpoints. All data were analyzed using the SAS system.
The safety profile of Omacor® was analyzed according to adverse events reported during the study, vital signs measurements, serum chemistry and hematology results, and ECG reports. This analysis was conducted on the “Safety Population,” which included all randomized patients. The Medical Dictionary for Regulatory Activities (MedDRA, version 15.0) adverse event dictionary was used to map verbatim adverse events to preferred terms and system organ class.
Results
An overview of patient disposition from screening to study termination is provided in Fig. 1. This study was conducted from July 08, 2011 (first patient first visit) to May 24, 2013 (last patient last visit). A total of 498 patients were screened and 253 were randomized: 84 patients to Omacor® 4 g/day, 82 patients to Omacor® 2 g/day, and 87 patients to placebo. Of all randomized patients, 240 patients completed the study. The baseline characteristics of each group are shown in Table 1. A total of 166 (65.6%) patients were males and the mean age was 54 years old. At baseline, the mean (SD) TG levels were 375.1 (151.7) mg/dL, 363.5 (157.0) mg/dL, and 359.0 (138.8) mg/dL in Omacor® 4 g/day, Omacor® 2 g/day, and placebo groups, respectively.
Fig. 1.
Flowchart of Subject Disposition in Trial
Table 1. Baseline characteristics of participants by treatment groups.
| Characteristics | Omacor® 4 g/day | Omacor® 2 g/day | Placebo |
|---|---|---|---|
| N = 84 | N = 82 | N = 87 | |
| Male | 55 (65.5%) | 47 (57.3%) | 64 (73.6%) |
| Age (years) | 53.7 (11.0) | 54.7 (9.2) | 54.4 (10.7) |
| Body Mass Index (kg/m2) | 26.63(3.73) | 26.61(4.19) | 26.66(3.86) |
| With Statin Treatment | 29 (34.5%) | 29 (35.4%) | 31 (35.6%) |
| Triglycerides level | |||
| ≥ 200 and <500 mg/dL | 70 (83.3%) | 70 (85.4%) | 73 (83.9%) |
| ≥ 500 and ≤ 1,000 mg/dL | 14 (16.7%) | 12 (14.6%) | 14 (16.1%) |
| Any Cardiovascular Disease | 4 (4.8%) | 3 (3.7%) | 4 (4.6%) |
| Cerebral Vascular Disease | 1 (1.2%) | 1 (1.2%) | 1 (1.1%) |
| Coronary Artery Disease | 3 (3.6%) | 2 (2.4%) | 4 (4.6%) |
| Hypertension | 55 (65.5%) | 51 (62.2%) | 50 (57.5%) |
| Diabetes mellitus | 21 (25.0%) | 19 (23.2%) | 17 (19.5%) |
| Smoking habit | 14 (16.7%) | 13 (15.9%) | 22 (25.3%) |
Data was presented as mean (SD) if continuous variables and n (%) if binary variables
Compliance
Median (interquartile range, IQR) compliance during the double-blind treatment phase was 96.6% (50.0%–117.0%), 97.1% (70.7%–110.2%) and 95.8% (59.3%–123.6%) in the Omacor® 4 g/day, Omacor® 2 g/day and placebo groups, respectively (Supplementary Table 1). About 85%–95% of patients in each treatment groups achieved a good compliance with treatment percentage above 85%. The low fat diet compliance is shown in Supplementary Table 2. From baseline to the end of the study, at least about 80% of patients achieved low fat diet compliance in each treatment group, without statistically significant differences between treatment with Omacor ® 4 g/day and Omacor® 2 g/day groups during the study follow-up. Regarding weekly fish consumption, the proportion of patients who consumed none or less than 150 g of fish per week reached at least 90% from the leading period to the end of eight weeks of treatment (Supplementary Table 3).
Supplementary Table 1. Summary of study drug compliance.
| Omcor 4 g/day | Omacor 2 g/day | Placebo | Group difference |
||||
|---|---|---|---|---|---|---|---|
| Omacor 4 g/day vs Placebo |
Omacor 2 g/day vs Placebo |
Omacor 4 g/day vs Omacor 2 g/day |
Omacor vs Placebo |
||||
| N | 82 | 82 | 87 | ||||
| Mean (SD), % | 94.9 (10.6) | 96.0 (6.4) | 93.5 (10.3) | ||||
| Median, % | 96.6 | 97.1 | 95.8 | ||||
| (Min, Max), % | (50.0, 117.0) | (70.7, 110.2) | (59.3, 123.6) | ||||
| Mean, % | 1.40 | 2.56 | −1.16 | 1.98 | |||
| 95% CI, % | −1.43 ∼ 4.22 | −0.26 ∼ 5.38 | −4.03 ∼ 1.70 | −0.46 ∼ 4.41 | |||
| p-value (a) | 0.3314 | 0.0755 | 0.4246 | ||||
| p-value (b) | 0.3051 | 0.0891 | 0.5039 | 0.1108 | |||
p-value(a): t-test for intergroup comparison
p-value(b): Rank transformation ANOVA for intergroup comparison
Supplementary Table 2. Summary of low fat diet compliance.
| Omacor 4 g/day |
Omacor 2 g/day |
Placebo |
p-value (Overall) | ||||
|---|---|---|---|---|---|---|---|
| N | % | N | % | N | % | ||
| Baseline | 0.262 | ||||||
| Compliance | 62 | 75.6% | 69 | 84.1% | 74 | 85.1% | |
| Not Compliance | 20 | 24.4% | 13 | 15.9% | 13 | 14.9% | |
| p-value (Group Comparison) | 0.242 (4 g vs 2 g) | 1.000 (2 g vs Placebo) | 0.174 (4 g vs Placebo) | ||||
| First Month | 1.000 | ||||||
| Compliance | 64 | 79.0% | 63 | 77.8% | 67 | 78.8% | |
| Not Compliance | 17 | 21.0% | 18 | 22.2% | 18 | 21.2% | |
| p-value (Group Comparison) | 1.000 (4 g vs 2 g) | 1.000 (2 g vs Placebo) | 1.000 (4 g vs Placebo) | ||||
| Second Month | 0.129 | ||||||
| Compliance | 64 | 81.0% | 75 | 91.5% | 69 | 83.1% | |
| Not Compliance | 15 | 19.0% | 7 | 8.5% | 14 | 16.9% | |
| p-value (Group Comparison) | 0.067 (4 g vs 2 g) | 0.160 (2 g vs Placebo) | 0.838 (4 g vs Placebo) | ||||
p-value: Fisher's exact test
Supplementary Table 3. Summary of fish consumption.
| Omacor 4 g/day |
Omacor 2 g/day |
Placebo |
p-value (overall) |
||||
|---|---|---|---|---|---|---|---|
| N | % | N | % | N | % | ||
| Baseline | 0.4452 | ||||||
| None per week | 27 | 32.9% | 36 | 43.9% | 28 | 32.2% | |
| ≤ 150g per week | 50 | 61.0% | 40 | 48.8% | 54 | 62.1% | |
| >150g per week | 5 | 6.1% | 6 | 7.3% | 5 | 5.7% | |
| p-value (Group comparison) | 0.299 (4 g vs 2 g) | 0.211 (2 g vs Placebo) | 1.000 (4 g vs Placebo) | ||||
| First Month | 0.070 | ||||||
| None per week | 40 | 79.0% | 34 | 42.0% | 26 | 30.6% | |
| ≤ 150g per week | 36 | 21.0% | 45 | 55.6% | 52 | 61.2% | |
| >150g per week | 5 | 2 | 2.5% | 7 | 8.2% | ||
| p-value (Group comparison) | 0.263 (4 g vs 2 g) | 0.125 (2 g vs Placebo) | 0.051 (4 g vs Placebo) | ||||
| Second Month | 0.695 | ||||||
| None per week | 30 | 38.0% | 35 | 42.7% | 27 | 32.5% | |
| ≤ 150g per week | 47 | 59.5% | 44 | 53.7% | 52 | 62.7% | |
| >150g per week | 2 | 2.5% | 3 | 3.7% | 4 | 4.8% | |
| p-value (Group comparison) | 0.695 (4 g vs 2 g) | 0.378 (2 g vs Placebo) | 0.631 (4 g vs Placebo) | ||||
p-value: Fisher's exact test
Efficacy Analysis
Statistically significant reductions in TG levels were observed between Omacor® arms and placebo as early as week 2 and up to the end of the study (Fig. 2). At week 8, the percent of change in both Omacor® 4 g/day (−32.1%) and 2 g/day (−29.7%) groups was significantly larger than in the placebo group (−5.4%), Omacor® 4 g/day vs. placebo, p < 0.0001; Omacor® 2 g/day vs. placebo, p < 0.0001. When the PP population was analyzed at week 8, the percent of change was −32.4%, −31.1%, and −10.0% in Omacor® 4 g/day, Omacor® 2 g/day and placebo groups, respectively, with statistically significant differences between groups (Omacor® 4 g/day vs placebo, p = 0.0001; Omacor® 2 g/day vs placebo, p = 0.0002). Similar results were obtained at week 4, with percent changes of −27.8%, −28.7%, and −6.8% in Omacor® 4 g/day, Omacor® 2 g/day and placebo groups, respectively, with statistical differences between groups (Omacor® 4 g/day vs placebo, p < 0.0001; Omacor® 2 g/day vs placebo, p <0.0001).
Fig. 2.
Time-course of percent change in triglyceride levels (ITT population)
In addition to triglycerides, only LDL-C levels reached statistical significance when Omacor® and placebo groups were compared (Table 2). With regard to LDL-C levels, significant changes from baseline were reported at week 4 with Omacor® 2 g/day (7.2%, p = 0.0036) and Omacor® 4 g/day (6.3%, p = 0.0096) and sustained until the end of the study (9.9%, p = 0.0136 and 7.2%, p = 0.0010, respectively). Additionally, the mean LDL-C levels remained within normal ranges in all patients among the three groups during the whole study duration.
Table 2. Treatment effects after lipid-lowering therapy from baseline to end of study.
| Omacor® 4 g | Omacor® 2 g | Placebo | p-value# | |||||
|---|---|---|---|---|---|---|---|---|
| (n = 82) |
(n = 82) |
(n = 87) |
||||||
| Geometric Mean | 95%CI | Geometric Mean | 95%CI | Geometric Mean | 95%CI | Omacor 4 g/daya |
Omacor 2 g/dayb |
|
| Total cholesterol | ||||||||
| Baseline, mg/dL | 184.0 | 177.5–190.8 | 186.9 | 179.9–194.0 | 185.7 | 178.9–192.8 | 0.732 | 0.812 |
| Week 2, mg/dL | 176.9 | 169.4–184.7 | 184.2 | 176.7–192.0 | 184.1 | 177.1–191.2 | 0.035 | 0.747 |
| Change from baseline, % | −3.9% | −6.0–−1.8% | −1.4% | −4.0–1.3% | −0.9% | −3.0–1.3% | ||
| Week 4, mg/dL | 180.0 | 172.3–188.1 | 179.9 | 172.0–188.2 | 182.0 | 173.8–190.5 | 0.997 | 0.309 |
| Change from baseline, % | −1.8% | −4.3–0.8% | −3.7% | −6.7–−0.7% | −1.9% | −4.5–0.7% | ||
| Week 8, mg/dL | 178.3 | 170.3–186.7 | 181.3 | 173.2–189.7 | 186.8 | 178.9–195.1 | 0.068 | 0.092 |
| Change from baseline, | −3.1% | −5.9–−0.3% | −3.0% | −6.1–0.3% | 0.6% | −2.2–3.5% | ||
| Triglycerides | ||||||||
| Baseline, mg/dL | 351.2 | 325.2–379.3 | 338.6 | 313.0–366.4 | 336.9 | 312.8–362.9 | 0.442 | 0.923 |
| Week 2, mg/dL | 243.2 | 219.5–269.5 | 262.8 | 238.8–289.1 | 311.3 | 282.8–342.6 | <.001 | 0.003 |
| Change from baseline, % | −30.7% | −36.2–−24.8% | −22.4% | −28.9–−15.3% | −7.6% | −14.4–−0.2% | ||
| Week 4, mg/dL | 251.9 | 229.7–276.2 | 241.6 | 221.2–263.9 | 311.9 | 282.1–344.8 | <.001 | <.001 |
| Change from baseline, % | −27.8% | −33.7–−21.4% | −28.7% | −34.4–−22.4% | −6.8% | −14.1–1.1% | ||
| Week 8, mg/dL | 238.5 | 216.1–263.1 | 238.2 | 218.8–259.4 | 318.7 | 283.6–358.2 | <.001 | <.001 |
| Change from baseline, % | −32.1% | −38.0–−25.6% | −29.7% | −35.4. −23.4% | −5.4% | −14.8–5.1% | ||
| HDL-C | ||||||||
| Baseline, mg/dL | 37.1 | 35.8–38.5 | 39.3 | 37.7–40.9 | 37.4 | 35.9–39.1 | 0.757 | 0.094 |
| Week 2, mg/dL | 38.0 | 36.6–39.4 | 39.8 | 38.3–41.4 | 37.9 | 36.4–39.5 | 0.617 | 0.348 |
| Change from baseline, % | 2.3% | −0.5–5.2% | 1.5% | −1.6–4.6% | 1.2% | −1.2–3.6% | ||
| Week 4, mg/dL | 37.9 | 36.5–39.4 | 39.4 | 37.6–41.3 | 37.8 | 36.3–39.4 | 0.662 | 0.587 |
| Change from baseline, % | 1.9% | −1.9–5.9% | 0.4% | −2.6–3.6% | 0.8% | −1.9–3.5% | ||
| Week 8, mg/dL | 38.0 | 36.4–39.7 | 39.9 | 38.1–41.8 | 38.6 | 37.0–40.3 | 0.690 | 0.967 |
| Change from baseline, % | 2.4% | −1.3–6.4% | 1.6% | −1.5–4.8% | 3.2% | 0.1–6.3% | ||
| Non-HDL-C | ||||||||
| Baseline, mg/dL | 146.1 | 139.9–152.5 | 146.6 | 140.1–153.4 | 147.4 | 141.3–153.8 | 0.765 | 0.858 |
| Week 2, mg/dL | 137.9 | 131.0–145.3 | 143.4 | 136.6–150.7 | 145.3 | 139.0–151.9 | 0.018 | 0.609 |
| Change from baseline, % | −5.6% | −8.3–−2.8% | −2.2% | −5.4–1.2% | −1.4% | −4.0–1.2% | ||
| Week 4, mg/dL | 141.4 | 134.3–148.8 | 139.5 | 132.4–147.0 | 143.3 | 136.0–151.0 | 0.891 | 0.257 |
| Change from baseline, % | −2,7% | −5.7–−0.4% | −4.9% | −8.3–−1.3% | −2.6% | −5.7–0.5% | ||
| Week 8, mg/dL | 139.1 | 131.7–146.9 | 140.4 | 133.2–148.0 | 147.2 | 140.0–154.7 | 0.059 | 0.101 |
| Change from baseline, % | −4.8% | −8.0–−1.4% | −4.2% | −8.1–−0.2% | −0.1% | −3.6–3.4% | ||
| LDL-C | ||||||||
| Baseline, mg/dL | 80.4 | 75.3–85.9 | 80.8 | 75.2–86.8 | 83.4 | 77.6–89.7 | 0.457 | 0.524 |
| Week 2, mg/dL | 87.4 | 81.7–93.6 | 89.0 | 82.6–96.0 | 83.2 | 76.6–90.4 | 0.010 | 0.001 |
| Change from baseline, % | 8.7% | 4.1–13.6% | 10.1% | 4.9–15.7% | −0.3% | −4.8–4.4% | ||
| Week 4, mg/dL | 85.5 | 78.8–92.7 | 86.6 | 79.3–94.6 | 81.0 | 74.3–88.3 | 0.010 | 0.004 |
| Change from baseline, % | 6.3% | 0.9–12.1% | 7.2% | 1.0–13.6% | −3.6% | −8.0–0.9% | ||
| Week 8, mg/dL | 86.2 | 79.7–93.2 | 88.8 | 81.5–96.9 | 80.5 | 73.5–88.2 | 0.014 | 0.001 |
| Change from baseline, % | 7.2% | 1.0–13.7% | 9.9% | 3.9–16.3% | −3.5% | −8.9–2.2% | ||
Abbreviations: HDL-C and LDL-C, High-density and Low-density lipoprotein cholesterol
p-value: Omacor 4 g/daya indicates the differences between Omacor 4 g/day and placebo after treatment
Omacor 2 g/dayb indicates the differences between Omacor 2 g/day and placebo after treatment
In the subgroup analysis of the primary endpoint, when the stratification was for statin or no lipid-altering medication use, the percentage change in TG levels was larger in the group that did not receive lipid-altering agents (Table 3). Similarly, the severe hypertriglyceridemia group experienced a larger change in TG levels than the group with moderate hypertriglyceridemia, although it was not statistically significant owing to the small patient numbers in the severe hypertriglyceridemia stratum (Table 4).
Table 3. Subgroup analyses by usage of statins and triglyceride-lowering effects at end of study (ITT population).
| Subgroups | Treatment Group | N | Baseline TG level (Geometric Mean with 95% CI), mg/dL |
Percent Change from Baseline (Intra p-value) |
Omacor® vs Placebo (Group Difference) |
p-value | |
|---|---|---|---|---|---|---|---|
| Statis usage | Stable statins | Omacor® 4 g | 28 | 339.8 (292.8–394.5) |
−28.7% (<.001) | −29.7% (−43.4–−12.5%) |
0.002 |
| Omacor® 2 g | 29 | 309.1 (273.9–348.9) |
−27.5% (<.001) | −31.3% (−44.7–−14.6%) |
<.001 | ||
| Placebo | 31 | 325.0 (281.1–375.7) |
4.3% (0.678) | −− | −− | ||
| No lipid-altering Agent | Omacor® 4 g | 54 | 357.3 (326.2–391.4) |
−33.8% (<.001) | −25.0% (−36.0–−12.0%) |
<.001 | |
| Omacor® 2 g | 53 | 356.0 (321.3–394.4) |
−30.8% (<.001) | −22.0% (−33.5–−8.4%) |
0.003 | ||
| Placebo | 56 | 343.7 (315.2–374.6) |
−10.4% (0.072) | −− | −− | ||
| Baseline TG level | Moderate hypertrigly ceridemia | Omacor® 4 g | 68 | 311.3 (294.3–329.3) |
−28.4% (<.001) | −25.3% (−34.5–−14.9%) |
<.001 |
| Omacor® 2 g | 70 | 302.3 (286.2–319.4) |
−25.2% (<.001) | −22.7% (−32.1–−12.0%) |
<.001 | ||
| Placebo | 73 | 301.3 (284.4–319.2) |
−3.0% (0.588) | −− | −− | ||
| Severe hypertrigly ceridemia | Omacor® 4 g | 14 | 631.4 (562.6–708.6) |
−47.7% (0.001) | −35.6% (−57.9–−1.5%) |
0.043 | |
| Omacor® 2 g | 12 | 656.4 (565.9–761.4) |
−50.7% (<.001) | −38.3% (−60.9–−2.6%) |
0.039 | ||
| Placebo | 14 | 603.0 (546.7–665.1) |
−16.8% (0.231) | −− | −− | ||
p-value: Paired t-test for intragroup comparison; t-test per ANCOVA model for intergroup comparison.
Table 4. Comparison of triglyceride levels change between the subgroup of severe and moderate hypertriglyceridemia after treatment.
| Subgroup | 200 mg/dL ≤ TG <500 mg/dL |
TG ≥ 500 mg/dL |
p-value | ||
|---|---|---|---|---|---|
| n | Change | n | Change | ||
| Omacor® 4 g | 68 | −28.4% | 14 | −47.7% | 0.6095 |
| Omacor® 2 g | 70 | −25.2% | 12 | −50.7% | 0.6654 |
Safety Analysis
The incidence of drug-related AEs was 0.0%, 1.2% (one case of nausea), and 0.0% in Omacor® 4 g/day, Omacor® 2 g/day, and placebo groups, respectively. Only one patient (1.2%) treated with Omacor® 4 g/day group had an AE with conjunctival hemorrhage, which was unlikely related to the study drug. The incidence of serious AEs in Omacor® 2 g/day group was 1.2% (one case of coronary artery disease), and in placebo group was 1.1% (one case of sick sinus syndrome), both of them were unlikely related to the study drug. The incidence of AEs that led to the study drug discontinuation was 1.2% in the Omacor® 4 g/day group and 2.3% in placebo group. There was only one patient treated with Omacor 4 g/day, who had an AE of mild myalgia, and then recovered without further treatment during the study, and the investigator thought it unlikely related to the study drug. The serum creatinine level also did not show significant elevation during the study in the three study groups (Supplementary Table 4). No drug-related severe AEs were observed during the study.
Supplementary Table 4. Changes of serum creatinine level during the study period by treatment groups.
| Creatinine level (mg/dL) | Omacor® 4 g/day (n = 84) |
Omacor® 2 g/day (n = 82) |
Placebo (n = 87) |
p-value |
||||
|---|---|---|---|---|---|---|---|---|
| Mean (SD) | Min–Max | Mean (SD) | Min–Max | Mean (SD) | Min–Max | Omacor 4 g/day |
Omacor 2 g/day |
|
| Baseline | 0.88 (0.24) | 0.42–2.18 | 0.86 (0.24) | 0.47–1.72 | 0.87 (0.25) | 0.46–1.71 | 0.811 | 0.630 |
| Week 2 | 0.87 (0.24) | 0.43–2.31 | 0.86 (0.25) | 0.43–1.81 | 0.88 (0.25) | 0.49–1.88 | 0.380 | 0.396 |
| Change from baseline | −0.01 | −0.04–0.02 | −0.01 | −0.03–0.01 | 0.00 | −0.02–0.02 | ||
| (95%CI) | (95%CI) | (95%CI) | ||||||
| Week 4 | 0.87 (0.24) | 0.51–2.22 | 0.87 (0.27) | 0.43–1.87 | 0.87 (0.26) | 0.45–1.87 | 0.571 | 0.407 |
| Change from baseline | −0.01 | −0.04–0.02 | 0.01 | −0.01–0.03 | −0.00 | −0.02–0.02 | ||
| (95%CI) | (95%CI) | (95%CI) | ||||||
| Week 8 | 0.86 (0.20) | 0.48–1.47 | 0.88 (0.27) | 0.42–1.94 | 0.88 (0.24) | 0.48–1.70 | 0.735 | 0.252 |
| Change from baseline | 0.00 | −0.03–0.03 | 0.03 | 0.00–0.06 | 0.01 | −0.02–0.03 | ||
| (95%CI) | (95%CI) | (95%CI) | ||||||
| End of Study | 0.89 (0.25) | 0.48–2.22 | 0.89 (0.28) | 0.42–1.94 | 0.88 (0.24) | 0.48–1.70 | 0.918 | 0.960 |
| Change from baseline | 0.00 | −0.03–0.03 | 0.03 | 0.00–0.06 | 0.01 | −0.02–0.03 | ||
| (95%CI) | (95%CI) | (95%CI) | ||||||
Discussion
The goal of the present study was to demonstrate the efficacy and safety of the doses of Omacor® 2 g/day and 4 g/day in the Taiwanese population. Based on the results obtained, the primary hypothesis was confirmed; significant improvements in triglyceride levels in both Omacor® arms versus placebo were achieved. Furthermore, it was confirmed in both the ITT and the PP population, which demonstrates the robustness of the outcome. These improvements are in agreement with the previous clinical evidence10). In fact, a review by Skulas et al.3) indicated an average triglyceride reduction for patients at the higher end of moderate hypertriglyceridemia of approximately 30% for Omacor® in studies with treatment duration between eight weeks and six months. Additionally, two randomized, double-blind, placebo-controlled studies assessing the effect of Omacor® 4 g/day reported a reduction of −38.9% after six weeks of treatment11) and −45% in TG levels after 16 weeks of treatment12), in patients with TG levels within the range of 500–2,000 mg/dL.
A reference study performed in the United States, the COMBOS trial7), which used a dose of 4 g/day in combination with simvastatin for eight weeks versus placebo, reported a median of percent change of −29.5% in the Omacor®+simvastatin arm and −6.3% in the placebo simvastatin arm. Another reference study performed in UK13) reported a mean of percent change of −22.4%. More specific to the Asian area is a Japanese phase III study10), similar to ours in both the population of patients and doses used which reported lower TG reduction in comparison with our study (−10.8% in the Omacor® 2 g group and −22.9% in the Omacor® 4 g group). A comparison among Taiwan, Japan, and UK studies at dose 4 g was showed in Supplementary Table 5.
Supplementary Table 5. Comparisons of lipid-lowering effects among the trials in Taiwan, Japan, and UK at the dose of 4 g/day.
| Taiwan |
Japan |
UK |
||||
|---|---|---|---|---|---|---|
| Geometric Mean | 95%CI | Mean (SD) | 95%CI | Mean (SD) | Min–Max | |
| Triglycerides | ||||||
| Baseline, mg/dL | 351.2 | 325.2–379.3 | 277.5 (97.3) | — | 284.3 (92.1) | 177.1–554.5 |
| Week 2, mg/dL | 243.2 | 219.5–269.5 | — | — | — | — |
| Change from baseline, % | −30.7% | −36.2–−24.8% | — | — | — | — |
| Week 4, mg/dL | 251.9 | 229.7–276.2 | 200 (87.9) | — | 222.3 (93.0) | 103.6–524.4 |
| Change from baseline, % | −27.8% | −33.7–−21.4% | −26.9% | −29.8–−24.1% | −21.8% | — |
| Week 8, mg/dL | 238.5 | 216.1–263.1 | 212.5 (107.4) | — | 217.0 (83.3) | 92.1–430.5 |
| Change from baseline, % | −32.1% | −38.0–−25.6% | −22.5% | −26.6–−18.4% | −23.7% | — |
| Week 10, mg/dL | — | — | 205.9 (99.3) | — | — | — |
| Change from baseline, % | — | — | −23.4% | −27.8–−19.0% | — | — |
| Week 12, mg/dL | — | — | 208.8 (86.0) | — | 220.5 (98.3) | 68.2–544.7 |
| Change from baseline, % | — | — | −22.9% | −26.0–−19.7% | −22.4% | — |
| Total cholesterol | ||||||
| Baseline, mg/dL | 184.0 | 177.5–190.8 | 212.0 (30.2) | — | 288.5 (43.7) | 205.0–380.9 |
| Week 2, mg/dL | 176.9 | 169.4–184.7 | — | — | — | — |
| Change from baseline, % | −3.9% | −6.0–−1.8% | — | — | — | — |
| Week 4, mg/dL | 180.0 | 172.3–188.1 | 206.2 (32.5) | — | 287.7 (50.3) | 193.4–406.0 |
| Change from baseline, % | −1.8% | −4.3–0.8% | −2.7% | −4.0–−1.5% | −0.3% | — |
| Week 8, mg/dL | 178.3 | 170.3–186.7 | 206.1 (32.9) | — | 282.3 (60.7) | 166.3–464.0 |
| Change from baseline, % | −3.1% | −5.9–−0.3% | −2.9% | −4.2–−1.5% | −0.3% | — |
| Week 10, mg/dL | — | — | 203.5 (31.6) | — | — | — |
| Change from baseline, % | — | — | −3.9% | −5.4–−2.5% | — | — |
| Week 12, mg/dL | — | — | 203.9 (31.5) | — | 291.2 (54.9) | 177.9–444.7 |
| Change from baseline, % | — | — | −3.7% | −5.0–−2.4 | 0.9% | — |
| HDL-C | ||||||
| Baseline, mg/dL | 37.1 | 35.8–38.5 | 45.7 (10.0) | — | 41.0 (10.4) | 35.9–39.1 |
| Week 2, mg/dL | 38.0 | 36.6–39.4 | — | — | — | — |
| Change from baseline, % | 2.3% | −0.5–5.2% | — | — | — | — |
| Week 4, mg/dL | 37.9 | 36.5–39.4 | 47.6 (11.2) | — | 42.9 (12.4) | 15.5–77.3 |
| Change from baseline, % | 1.9% | −1.9–5.9% | 4.1% | 2.6–5.6% | 4.7% | — |
| Week 8, mg/dL | 38.0 | 36.4–39.7 | 47.5 (11.6) | — | 41.0 (10.8) | 19.3–69.6 |
| Change from baseline, % | 2.4% | −1.3–6.4% | 3.9% | 2.2–5.6% | 0.0% | — |
| Week 10, mg/dL | — | — | 47.4 (11.3) | — | — | — |
| Change from baseline, % | — | — | 4.2% | 2.5–5.9% | — | — |
| Week 12, mg/dL | — | — | 47.6 (11.0) | — | 42.5 (11.2) | 19.3–65.7 |
| Change from baseline, % | — | — | 4.3% | 2.8–5.8% | 3.8% | — |
| LDL-C | ||||||
| Baseline, mg/dL | 80.4 | 75.3–85.9 | 125.7 (28.5) | — | 174.0 (42.5) | 99.8–245.9 |
| Week 2, mg/dL | 87.4 | 81.7–93.6 | — | .0 | — | — |
| Change from baseline, % | 8.7% | 4.1–13.6% | — | — | — | — |
| Week 4, mg/dL | 85.5 | 78.8–92.7 | 127.9 (30.3) | — | 191.4 (51.8) | 75.8–309.4 |
| Change from baseline, % | 6.3% | 0.9–12.1% | 2.3% | 0.1–4.39% | 10.0% | — |
| Week 8, mg/dL | 86.2 | 79.7–93.2 | 125.2 (31.9) | — | 184.5 (45.6) | 83.5–304.7 |
| Change from baseline, % | 7.2% | 1.0–13.7% | −0.4% | −2.9–2.0% | 6.0% | — |
| Week 10, mg/dL | — | — | 124.2 (29.7) | — | — | — |
| Change from baseline, % | — | — | −0.9% | −3.4–1.6% | — | — |
| Week 12, mg/dL | — | — | 123.6 (29.0) | — | 183.3 (56.1) | 84.7–290.4 |
| Change from baseline, % | — | — | −1.1% | −3.35–1.2% | 5.3% | — |
Abbreviations: HDL-C and LDL-C, High-density and Low-density lipoprotein cholesterol
Surprisingly, the two doses used in our study, 4 g/day and 2 g/day, achieved a very similar percentage of TG reduction. Based on the clinical evidence, it is widely accepted that the effect of this drug is dose-dependent14, 15). In addition, the Japanese study demonstrated the expected differences between both active groups. In the investigators' opinion, one explanation could be moderation of Chinese foods with a large amount of carbohydrates may attenuate the additional dose of omega-3 fatty acids on triglyceride-lowering effects16). Besides, the low fat diet compliances for Omacor® 4 g and Omacor® 2 g groups were 81.0% and 91.5%, respectively. Although the difference was not statistically significant; however, it was close to statistical significance (p = 0.067). The trend of better compliance of maintaining low fat diet may contribute to the triglyceride-lowering effects for Omacor® 2 g group, thus attenuate the dose-dependent response of higher dose of Omacor® 4 g/day.
After treatment with Omacor® 2 g, a higher omega-3/omega-6 ratio also significantly improved insulin resistance and subsequently decreased the levels of triglycerides of study participants17, 18). Another explanation is the high percentage of overweight in our study patients, which had been demonstrated to have a higher risk of severe hypertriglyceridemia (TG ≥ 500 mg/dL) while concurrent with genetic polymorphism in apolipoprotein A5 in Chinese19). An interaction between omega-3 fatty acids supplement and genetic variants in APOA5 and/or APOE4 may modify the response to omega-3 fatty acids treatment significantly independent of dose-response pattern in these patients. Not only the insulin resistance, but also the arterial stiffness, can be improved by a higher EPA/AA ratio20).
In addition, our study demonstrated an even larger reduction in triglyceride levels in Taiwanese compared to Japanese participants. The difference in triglyceride-lowering effects between the Taiwanese and Japanese might be mediated by the difference in eating habits: more fish and seaweeds are consumed by the Japanese (rich in omega-3 fatty acids), which may attenuate the additional lipid-lowering effects of fish oil in Omacor®21).
It is worth mentioning that the significant improvement with Omacor® was achieved at week two and maintained until the end of our study. According to Rupp et al.5), when Omacor® 1 g/day is administered for 30 days, the bioavailability of the drug remains constant and optimal during the treatment period, reaching plateau levels from the tenth day. In our literature review, most studies also support such a reduction after week 413, 22–24), but no data is available for the preceding period and it therefore cannot be appropriately contextualized.
The effectiveness of Omacor® is influenced by baseline TG levels3). Indeed, in our study, patients in the severe hypertriglyceridemia stratum experienced a larger change in TG levels than those in the moderate hypertriglyceridemia stratum, although it was not statistically significant. In all cases, treatment groups versus placebo were statistically significant in both the Omacor® 4 g/day and 2 g/day arms.
On the other hand, LDL-C levels slightly increased after four to eight weeks with both doses of Omacor®, comparing with placebo, although the mean levels of LDL-C remained within the normal ranges throughout the study in all groups. In this context, Maki et al. in a post hoc analysis of the COMBOS trial25) showed that Omacor® treatment also increased the levels of LDL-C but only in patients in the lowest tertile (<80.4 mg/dL) level at the beginning of the study. In the present study, mean (SD) baseline LDL-C levels were 83.9 (24.3) mg/dL, 84.9 (25.8) mg/dL, and 88.1 (28.1) mg/dL in Omacor® 4 g/day, Omacor® 2 g/day, and placebo groups, respectively, which were close to the report of Maki et al. Another example is the TAK-085 study in Japan26), in which the mean (SD) baseline LDL-C levels were 129.0 (30.3) mg/dL, 133.2 (29.9) mg/dL, and 129.3 (33.0) mg/dL in Omacor® (TAK-085) 4 g/day, Omacor® (TAK-085) 2 g/day, and EPA-E groups, respectively, resulting in a slight increase or even decrease at the end of study (2.38 ± 20.5%, −0.42 ± 17.3%, and −1.49 ± 16.8% in Omacor® 4 g/day, Omacor® 2 g/day, and EPA-E groups, respectively). However, it seems that the increment of LDL-C level was larger in Omacor® 2 g/day than that in Omacor® 4 g/day in the present study, but this was not statistically significant (p = 0.391). Further studies are needed to clarify the mechanism.
Additionally, a subgroup analysis of the COMBOS trial focusing on lipoprotein sizes and concentrations revealed that Omacor® 4 g/day produced significant reductions in intermediate density lipoprotein cholesterol (IDL-C) (p < 0.0001 vs. baseline) and small LDL-C (p = 0.0035 vs. baseline)27). The TAK-085 study in Japan also showed a shift from small dense LDL-C to large buoyant LDL-C and increased LDL-C/Apo B ratios, as well as a decrement of Apo C-III after treatment with Omacor®28). Higher levels of IDL-C and small dense LDL-C usually presenting in hypertriglyceridemic patients are considered more harmful than other lipid particles because they can more easily penetrate the arterial wall29). Our recent study also demonstrated that small dense LDL-C particles might potentiate postchallenge hyperglycemia on the risk of arterial stiffness in middle-aged healthy adults30). The safety profile of both Omacor® arms was as expected, with a rate of adverse event reactions comparable to the 3% reported in the Summary of Product Characteristics. Indeed, no significant safety concerns arose during the course of the trial.
In the COMBOS trial, with a treatment period of eight weeks, the short treatment duration has been noted as a study limitation. However, a 24-month extension of the COMBOS study confirmed the results about efficacy and safety31). In this case, the goal of the study was to confirm the efficacy of Omacor ® and the duration was not considered a weakness for this purpose, but the authors admit that longer trials might better characterize clinical efficacy and safety. Additionally, the specificity of the population, all of which was Asian, offers valuable information regarding these patients, though it makes it difficult to extrapolate the results to other patient populations.
EPA also showed the effects on inflammatory markers, including high sensitivity CRP32). However, in the present study, there was no significant change in all of three treatment groups (Supplementary Table 6). This may have been due to the shorter period and the different remedies and doses, or different patient cohorts.
Supplementary Table 6. Summary of mean high-sensitivity CRP level before and after Omacor treatment.
| Unit: % | Group difference |
||||||
|---|---|---|---|---|---|---|---|
| Omcor 4 g/day |
Omacor 2 g/day |
Placebo | Omacor 4 g/day vs Placebo |
Omacor 2 g/day vs Placebo |
Omacor 4 g/day vs Omacor 2 g/day |
Omacor vs Placebo |
|
| Baseline | |||||||
| N | 84 | 82 | 87 | ||||
| Mean (SD) | 0.2272 (0.2820) | 0.1631 (0.1676) | 0.1652 (0.2475) | 0.0620 | −0.0020 | 0.0640 | 0.0300 |
| Median | 0.1130 | 0.1070 | 0.0810 | ||||
| (Min, Max) | (0.0120, 1.1830) | (0.0120, 0.8700) | (0.0120, 1.5390) | ||||
| 95% CI | −0.0097 ∼ 0.1336 | −0.0741 ∼ 0.0701 | −0.0087 ∼ 0.1367 | −0.0320 ∼ 0.0920 | |||
| p-value (a) | 0.0897 | 0.9556 | 0.0842 | 0.3420 | |||
| End of Study | |||||||
| N | 79 | 82 | 86 | ||||
| Mean (SD) | 0.2438 (0.4548) | 0.2182 (0.4560) | 0.1508 (0.2525) | ||||
| Median | 0.1030 | 0.0830 | 0.0520 | ||||
| (Min, Max) | (0.0120, 3.6870) | (0..0120, 3.1250) | (0.0120, 1.4410) | ||||
| Change | 0.0162 | 0.0550 | −0.0151 | 0.0617 | 0.0688 | −0.0072 | 0.0652 |
| 95% CI | −0.0873 ∼ 0.1197 | 0.0399 ∼ 0.1500 | −0.0737 ∼ 0.0435 | −0.0551 ∼ 0.1784 | −0.0462 ∼ 0.1838 | −0.1253 ∼ 0.1110 | −0.0345 ∼ 0.1649 |
| p-value (a) | 0.7562 | 0.2522 | 0.6093 | 0.2994 | 0.2397 | 0.9051 | 0.1987 |
| p-value (b) | 0.9939 | 0.5316 | 0.1599 | 0.1331 | 0.8708 | 0.1845 | 0.3298 |
p-value (a): t-test for intergroup comparison
p-value (b): Rank transformation ANOVA for intergroup comparison
In conclusion, the use of Omacor® 4 g/day or Omacor® 2 g/day in Taiwanese patients significantly reduced TG levels compared to placebo in the present study. Although extrapolation of data from clinical trials to routine clinical practice is not always straightforward, owing to the heterogeneous patient population, the presence of comorbidities, and the unstructured follow-up characteristics of daily practice, Omacor® appears a valid option for treating hypertriglyceridemia in Taiwanese patients. Furthermore, differences in diet and behavior in the Chinese population reinforce the need to conduct confirmatory studies on the efficacy of Omacor® in this specific population of patients.
Acknowledgements
We thank doctors from medical centers, including Chia-Ti Tsai, Jyh-Ming Juang, and Yi-Chih Wang from National Taiwan University Hospital, and Ting-Hsing Chao, Chih-Chan Lin, and Cheng-Han Lee from National Cheng-Kung University Hospital, who help the recruitments of patients in this study.
Funding
This work was supported by Excelsior Pharmatech Labs, Taipei, Taiwan.
Disclosures
Runar Vige is an employee of Pronova Biopharma Norge AS, Norway. José Emilio Ruiz Olivar is an employee of Ferrer group, Spain. They offered technical support to Excelsior and the study group. Excelsior has a partnership with Ferrer and Pronova. Excelsior is an exclusive agent of Ferrer in Taiwan, and was authorized by Pronova to conduct Omacor® study in Taiwan.
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