Omega-3 Fish Oil Added to Statins: A Double-Blind Trial Shows Significant Benefits for Patients with Residual High Triglycerides

Table of Contents

• Key Points
• Background: Why This Research Matters
• Study Methods: How the Research Was Conducted
• Who Was in the Study?
• What Treatments Did Patients Receive?
• Key Findings: Triglyceride and Non-HDL-C Results
• Other Lipid Results: Additional Improvements
• Safety Results: Side Effects Were Comparable
• Clinical Implications: What This Means for Patients
• Study Limitations: What This Trial Could Not Prove
• Recommendations for Patients
• Frequently Asked Questions
• Source Information

Key Points

• In a randomized, double-blind trial of 200 adults in Korea, adding 4,000 mg of omega-3 fatty acids to 20 mg of atorvastatin for 8 weeks reduced triglycerides by 29.8%.
• The statin-only group's triglycerides rose 3.6% over the same period, a highly statistically significant difference between groups.
• After 8 weeks, 62.9% of the combination group reached triglycerides below 200 mg/dL, versus 22.3% of the statin-only group.
• Adverse events did not differ between groups, and LDL cholesterol changes were not significantly different, suggesting no interference with statin benefits.
• The trial was short, measured lipid levels rather than heart attacks or strokes, and enrolled mainly Korean adults with diabetes and hypertension.

Background: Why This Research Matters

For decades, doctors have focused on lowering low-density lipoprotein cholesterol (LDL-C)—commonly known as "bad" cholesterol—to prevent cardiovascular disease. Statins are the most effective and proven medications for this purpose, and they have saved countless lives by reducing heart attacks and strokes.

However, a critical problem remains: even patients who achieve excellent LDL-C control with intensive statin therapy still face a significant residual risk of cardiovascular events. In other words, getting the "bad" cholesterol to optimal levels does not eliminate the risk entirely. This has led researchers to look beyond LDL-C for additional therapeutic targets.

One such target is triglycerides (TG)—a type of fat found in the blood that the body uses for energy. Elevated triglyceride levels, a condition called hypertriglyceridemia, have recently emerged as a reliable and modifiable cardiovascular risk factor. This is especially relevant in Korea, where the prevalence of hypertriglyceridemia is actually greater than that of hypercholesterolemia (high cholesterol).

Recent scientific evidence supports an independent association between triglyceride level and cardiovascular disease, even after adjusting for conventional risk factors and high-density lipoprotein cholesterol (HDL-C, the "good" cholesterol). One study cited in the paper found that elevated triglyceride levels over a 5-year period increased the incidence of coronary heart disease (CHD), regardless of baseline triglyceride level. In another study involving hospitalized patients with acute coronary syndrome (a sudden reduction of blood flow to the heart), those with triglyceride levels above 150 mg/dL and LDL-C levels below 70 mg/dL exhibited a 15% higher coronary heart disease event rate than those with low triglycerides and high LDL-C.

Particularly in patients with type 2 diabetes mellitus, two large trials demonstrated that combining statins with triglyceride-lowering medications reduced cardiovascular events in a subgroup of subjects with marked hypertriglyceridemia and low HDL-C levels. For this reason, recent guidelines have emphasized the importance of non-HDL-C (non-high-density lipoprotein cholesterol) as a secondary treatment target for preventing cardiovascular disease in patients with mixed dyslipidemia (abnormal levels of multiple blood fats) who have already achieved their LDL-C target.

Among the various options for controlling hypertriglyceridemia, omega-3 fatty acids (OM3-FAs)—commonly known as fish oil—have shown impressive results. Previous research demonstrated that OM3-FAs induced a greater reduction of triglycerides and were associated with few adverse effects when added to statins. This phase III study was designed to rigorously test whether adding OM3-FAs to atorvastatin could improve outcomes in patients who still had high triglycerides despite statin treatment.

Study Methods: How the Research Was Conducted

This was a randomized, double-blind, placebo-controlled, parallel-group, phase III multicenter study. Let's break down what each of these terms means:

• Randomized: Patients were assigned to treatment groups by chance, like flipping a coin, to ensure fair comparison.
• Double-blind: Neither the patients nor the doctors knew who was receiving the active treatment versus the placebo. This prevents bias.
• Placebo-controlled: One group received a dummy pill (placebo) so researchers could compare the real effect of the medication.
• Parallel-group: Each group received one treatment throughout the study; no crossover.
• Phase III: A late-stage clinical trial that tests efficacy and safety in a larger group of patients.

The study was conducted at 36 centers throughout Korea between May 4, 2016 and May 16, 2017. Adult subjects aged 20 to 79 years with high cardiovascular disease risk, according to the Korean dyslipidemia guideline, were screened at their first visit.

The trial consisted of two main phases: a 4-week run-in period and an 8-week treatment period. During the run-in period, all patients received open-label (unblinded) atorvastatin 20 mg/day to establish a stable baseline. Patients who were already taking 20 mg/day of atorvastatin for at least 4 weeks could skip the run-in period and proceed directly to the second screening.

To be eligible for the study, participants had to meet specific criteria at their initial screening:

1. For those not taking statins for the last 4 weeks: fasting triglyceride levels ≥300 mg/dL with LDL-C levels between 100 and 160 mg/dL.
2. For those already taking statins for the last 4 weeks: fasting triglyceride levels ≥200 mg/dL and <500 mg/dL with LDL-C levels <110 mg/dL.
3. Non-smoking during the study period.

At the second screening (after the run-in period or directly for those already on atorvastatin), subjects needed to meet all of the following criteria:

1. Residual hypertriglyceridemia with fasting triglyceride levels ≥200 mg/dL and <500 mg/dL, with LDL-C levels <110 mg/dL.
2. Decreased LDL-C during the run-in period compared to the first screening (for those not previously taking statins).
3. An adherence rate of at least 80% for statin use during the run-in period.

All participants received dietary counseling for dyslipidemia based on the Korean dyslipidemia guideline during their screening visits. The researchers applied a comprehensive list of exclusion criteria to ensure patient safety, including:

• History of unstable angina, acute myocardial infarction (heart attack), coronary artery revascularization, or transient ischemic attack or stroke within 3 months prior to screening.
• History of surgery for aortic aneurysm within 6 months prior to screening.
• Unexplained muscle pain (myalgia) or a diagnosis of myalgia or rhabdomyolysis (a severe muscle breakdown condition) at screening.
• History of pancreatitis (inflammation of the pancreas) prior to screening.
• Significant comorbid medical illness in cardiovascular, hepatobiliary (liver/bile), neuropsychiatric, or endocrine systems.
• Positive HIV test result.
• History of malignant tumor within 2 years, except for completely resolved basal cell or squamous cell carcinoma.
• Use of prohibited concomitant medications.
• Sex hormone replacement or oral contraceptive use within 2 months prior to screening.
• Uncontrolled hypertension (systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg).
• Serum creatinine levels ≥2 times the upper limit of normal.
• Liver enzyme (ALT and/or AST) levels ≥3 times the upper limit of normal.
• Creatine phosphokinase levels five times the upper limit of normal.
• Certain genetic disorders, including galactose intolerance, Lapp lactase deficiency, or galactose malabsorption.
• Allergy or hypersensitivity to study medications.
• Drug or alcohol abuse within 2 years prior to screening.
• Pregnancy, breast-feeding, or plans to become pregnant during the trial.

Who Was in the Study?

A total of 558 subjects were screened for the study. Of these, 268 subjects entered the run-in period, and 215 subjects were randomly assigned to one of the two treatment groups: 105 subjects to the ATOMEGA group and 110 subjects to the atorvastatin group.

From the randomized population, 8 subjects in the ATOMEGA group and 7 subjects in the atorvastatin group were excluded from the safety analysis due to violation of eligibility criteria or incomplete measurement of triglycerides or non-HDL-C levels. This left 200 subjects (97 in the ATOMEGA group and 103 in the atorvastatin group) in the full analysis set for evaluating efficacy.

At baseline, the two groups were very well matched. Here are the key characteristics of the study participants:

• Mean age: 58.3 years (ATOMEGA group: 58.7 ± 10.1 years; atorvastatin group: 58.0 ± 11.4 years)
• Male sex: 66.0% in the ATOMEGA group vs. 63.1% in the atorvastatin group
• Body mass index (BMI): 27.3 ± 3.5 kg/m² vs. 27.0 ± 3.4 kg/m² (both groups were in the overweight/obese range)
• Prevalence of hypertension: 82.5% vs. 81.6%
• Prevalence of diabetes: 89.7% vs. 86.4% (P=0.478)
• Fasting plasma glucose: 141.1 ± 53.0 mg/dL vs. 132.3 ± 36.9 mg/dL
• Glycosylated hemoglobin (HbA1c): 7.4% ± 1.3% vs. 7.2% ± 1.2%
• 10-year coronary heart disease risk score: 10.3% ± 7.2% vs. 8.7% ± 7.1%
• Previous use of statins: 97.9% vs. 96.1%

Baseline lipid profiles were also similar between groups:

• Triglycerides: 298.5 ± 71.2 mg/dL vs. 293.0 ± 75.7 mg/dL
• Non-HDL-C: 116.1 ± 21.7 mg/dL vs. 111.6 ± 19.7 mg/dL
• Total cholesterol (TC): 153.5 ± 22.6 mg/dL vs. 151.0 ± 21.6 mg/dL
• LDL-C: 77.1 ± 20.1 mg/dL vs. 75.7 ± 18.7 mg/dL
• HDL-C: 37.4 ± 8.6 mg/dL vs. 39.4 ± 8.9 mg/dL

No significant differences in any variable were found between the two groups, confirming that randomization successfully created comparable groups—a key requirement for a reliable clinical trial.

What Treatments Did Patients Receive?

Eligible subjects were randomly assigned in a 1:1 ratio to one of two groups for 8 weeks:

ATOMEGA group: Patients received four capsules of ATOMEGA, each containing omega-3 fatty acids 1,000 mg plus atorvastatin calcium 5 mg, and one tablet of placebo (dummy) atorvastatin 20 mg. This means the total daily dose was 4,000 mg of omega-3 fatty acids plus 20 mg of atorvastatin.

Atorvastatin group: Patients received four capsules of placebo containing olive oil 1,000 mg each (to mimic the appearance and feel of the fish oil capsules) and one tablet of atorvastatin calcium 20 mg. This was the standard statin-only therapy.

The use of olive oil as a placebo is worth noting. Olive oil contains monounsaturated fats but not the active omega-3 fatty acids (EPA and DHA) found in fish oil, making it an appropriate control that maintains blinding.

Key Findings: Triglyceride and Non-HDL-C Results

The primary efficacy endpoints of the study were the percentage changes in triglyceride (TG) and non-HDL-C levels from baseline after 8 weeks of treatment. The results were striking.

Triglyceride Reduction

The ATOMEGA group achieved a dramatic reduction in triglyceride levels:

• ATOMEGA group: Triglycerides fell from 298.5 ± 71.2 mg/dL at baseline to 210.6 ± 117.1 mg/dL, a mean percent change of –29.8% (P<0.001 compared to baseline).
• Atorvastatin group: Triglycerides actually rose slightly from 293.0 ± 75.7 mg/dL to 299.3 ± 133.9 mg/dL, a mean percent change of +3.6% (P=0.593, not significant).

The difference between the two groups was highly statistically significant (P<0.001). In plain terms, this means there is less than a 0.1% probability that this difference occurred by random chance.

Non-HDL-C Reduction

Non-HDL-C (calculated as total cholesterol minus HDL-C) is a secondary target recommended by recent guidelines because it encompasses all "bad" cholesterol particles, including LDL and VLDL:

• ATOMEGA group: Non-HDL-C fell from 116.1 ± 21.7 mg/dL to 103.6 ± 28.6 mg/dL, a mean percent change of –10.1% (P<0.001).
• Atorvastatin group: Non-HDL-C increased from 111.6 ± 19.7 mg/dL to 115.8 ± 28.6 mg/dL, a mean percent change of +4.9% (P=0.095, not significant).

Again, the difference between groups was highly statistically significant (P<0.001).

Reaching Treatment Targets

Perhaps the most clinically meaningful finding was the proportion of patients who successfully reached the triglyceride treatment target of below 200 mg/dL:

• ATOMEGA group: 62.9% of patients reached the target.
• Atorvastatin group: Only 22.3% of patients reached the target.

This difference was highly significant (P<0.001) and demonstrates that adding omega-3 fatty acids to statin therapy nearly tripled the likelihood of achieving optimal triglyceride control.

Other Lipid Results: Additional Improvements

The researchers also measured several secondary lipid parameters to understand the full effect of the combination therapy. The ATOMEGA group showed significant improvements in multiple lipid measures compared to the atorvastatin-only group:

• Total cholesterol (TC): The ATOMEGA group experienced a –6.1% change from baseline, compared to +3.8% in the atorvastatin group (P<0.001 between groups).
• VLDL-C (very low-density lipoprotein cholesterol): The ATOMEGA group saw a –30.1% change, while the atorvastatin group had +4.9% (P<0.001). VLDL-C carries triglycerides in the blood, so this large reduction aligns with the triglyceride findings.
• Apolipoprotein A1 (Apo A1): The ATOMEGA group had a –3.2% change vs. +1.0% in the atorvastatin group (P=0.016). Apo A1 is the main protein in HDL ("good") cholesterol.
• Apolipoprotein B (Apo B): The ATOMEGA group showed –3.1% vs. +3.0% in the atorvastatin group (P=0.033). Apo B is the main protein in "bad" cholesterol particles, so a reduction is beneficial.
• HDL-C: The ATOMEGA group showed a +6.4% increase vs. +2.6% in the atorvastatin group. While the increase within the ATOMEGA group was significant (P=0.003), the difference between groups did not reach statistical significance (P=0.096).
• LDL-C: The ATOMEGA group showed –1.9% vs. +6.5% in the atorvastatin group. The difference between groups was not statistically significant (P=0.226), meaning the combination therapy did not meaningfully change LDL-C beyond statin alone.

The fact that LDL-C was not significantly different between groups is actually an expected and reassuring finding—it shows that adding omega-3 fatty acids does not interfere with the cholesterol-lowering benefits of atorvastatin, while providing additional improvements in other important lipid measures.

Safety Results: Side Effects Were Comparable

Safety is always a critical concern when adding a new medication to an existing treatment regimen. The researchers carefully monitored adverse events (AEs) throughout the study, including laboratory parameters, electrocardiograms, vital signs, and physical examinations.

The key safety finding is reassuring: the incidence of adverse events did not differ between the two groups. In other words, adding omega-3 fatty acids to atorvastatin did not increase the risk of side effects compared to atorvastatin alone.

This finding is consistent with the well-established safety profile of omega-3 fatty acids. Previous studies have shown that OM3-FAs are associated with few adverse effects when added to statins, making them an attractive option for patients with residual hypertriglyceridemia.

Clinical Implications: What This Means for Patients

The results of this clinical trial have important implications for the management of patients with residual hypertriglyceridemia who are already being treated with statins. Here's what the findings mean in practical terms:

First, the study confirms that statin monotherapy is often insufficient for controlling triglycerides. In the atorvastatin-only group, triglycerides actually increased slightly over 8 weeks. Many patients with high cardiovascular risk—especially those with diabetes—continue to have elevated triglycerides despite optimal statin therapy, leaving them with residual cardiovascular risk.

Second, the combination of omega-3 fatty acids and atorvastatin provides meaningful improvements within just 8 weeks. The near-30% reduction in triglycerides and the 10% reduction in non-HDL-C represent clinically valuable improvements in a patient population that has already achieved their primary LDL-C goal. Importantly, the significant reduction in non-HDL-C addresses the guideline-recommended secondary target for preventing cardiovascular events.

Third, the high rate of achieving the triglyceride target (<200 mg/dL) is especially notable. In the ATOMEGA group, 62.9% of patients reached this goal compared to only 22.3% in the atorvastatin group. For patients at high cardiovascular risk, reaching this target could potentially translate into fewer future cardiovascular events, although this study was not designed to measure long-term cardiovascular outcomes.

Fourth, the safety profile is favorable. The fact that adverse events were comparable between the two groups suggests that this combination can be added to clinical practice without concerns about additional side effects. This is particularly important for patients with diabetes, who made up the vast majority of the study population (approximately 87–90%) and who often face polypharmacy (taking multiple medications).

It is also worth noting that the study population had a very high prevalence of diabetes and hypertension, along with a mean 10-year coronary heart disease risk score of approximately 9.9%. These are patients who need aggressive management of all cardiovascular risk factors, and the addition of omega-3 fatty acids to their statin therapy offers a well-tolerated strategy to further optimize their lipid profile.

Study Limitations: What This Trial Could Not Prove

While this study provides strong evidence for the benefits of adding omega-3 fatty acids to atorvastatin, it is important to understand its limitations:

• Short duration: The treatment period was only 8 weeks. While this is sufficient to observe changes in lipid levels, it does not provide information about long-term efficacy, durability of the effect, or long-term safety.
• Surrogate endpoints: The study measured changes in blood lipid levels (triglycerides, non-HDL-C, etc.) rather than actual cardiovascular events like heart attacks or strokes. While lowering these lipids is strongly associated with reduced cardiovascular risk, the study did not directly demonstrate that the combination reduces heart attacks or strokes.
• Specific population: The study was conducted in Korea with a specific population of high-risk patients (mainly those with diabetes and hypertension). The results may not be fully generalizable to other ethnic groups or to lower-risk populations.
• Specific statin and omega-3 formulation: The study used atorvastatin 20 mg and a specific ATOMEGA formulation of omega-3 fatty acids. Results might differ with other statins, other doses, or other omega-3 formulations.
• Limited follow-up: The study did not track whether patients maintained their improvements over time or whether there were any post-treatment changes in lipid levels.
• Olive oil placebo consideration: Although olive oil is a commonly used placebo in omega-3 trials, some research suggests that olive oil itself might have modest beneficial effects on lipids, which could slightly underestimate the true difference between treatment and control.

Recommendations for Patients

Based on the findings of this study, here are practical recommendations for patients and their healthcare providers:

1. Know your full lipid profile. Achieving your LDL-C goal does not mean your lipid management is complete. Ask your doctor about your triglyceride and non-HDL-C levels, especially if you have diabetes, are overweight, or have other cardiovascular risk factors.
2. Consider omega-3 supplements or prescription formulations. If your triglycerides remain above 200 mg/dL despite statin therapy, ask your doctor whether adding omega-3 fatty acids at a dose of 4,000 mg/day might be appropriate for you. This study shows that this combination can significantly improve your lipid profile without increasing side effects.
3. Take the full prescribed dose. The benefit demonstrated in this study was achieved with 4,000 mg of omega-3 fatty acids daily. Lower doses found in many over-the-counter fish oil supplements may not provide the same magnitude of benefit.
4. Follow lifestyle recommendations. Omega-3 fatty acids are a complement to—not a substitute for—a heart-healthy lifestyle. Continue to limit refined carbohydrates and saturated fats, exercise regularly, avoid smoking, and take all your prescribed medications as directed.
5. Talk to your doctor about diabetes management. The majority of patients in this study had type 2 diabetes. If you have diabetes and high triglycerides despite statin therapy, you are exactly the type of patient who could benefit from this combination approach.
6. Ask about the secondary target. If your LDL-C is well controlled, ask your doctor what your non-HDL-C target should be and whether your current treatment is adequately addressing it. This study showed that adding omega-3 fatty acids to atorvastatin reduced non-HDL-C by 10.1%, a meaningful step toward reducing residual cardiovascular risk.

As always, it is essential to discuss any medication changes with your healthcare provider. Omega-3 fatty acids may interact with blood thinners and other medications, and the right dose and formulation should be determined based on your individual needs and medical history.

Frequently Asked Questions

What did this trial find when omega-3 fatty acids were added to a statin?

In a randomized, double-blind trial at 36 centers in Korea, adults with high triglycerides despite statin therapy took either 4,000 mg of omega-3 fatty acids plus 20 mg of atorvastatin or atorvastatin alone for 8 weeks. Triglycerides fell 29.8% with the combination versus a 3.6% rise with the statin alone.

Who was eligible to join this trial?

Adults aged 20 to 79 at high cardiovascular risk were screened. Those not on statins needed fasting triglycerides of at least 300 mg/dL and LDL cholesterol between 100 and 160 mg/dL. Those already on statins needed fasting triglycerides of at least 200 mg/dL. After a run-in, participants needed residual triglycerides of at least 200 mg/dL.

What does a 29.8% triglyceride reduction mean for a patient?

In this trial, average triglycerides in the combination group fell from about 298.5 mg/dL to about 210.6 mg/dL over 8 weeks, a 29.8% drop. The statin-only group rose 3.6%. The difference between groups was highly statistically significant, meaning it was very unlikely to be due to chance.

How many patients reached the triglyceride target below 200 mg/dL?

After 8 weeks, 62.9% of patients taking omega-3 fatty acids plus atorvastatin reached the triglyceride target of below 200 mg/dL, compared with only 22.3% of those taking atorvastatin alone. This difference was highly statistically significant. Reaching this target may help reduce future cardiovascular risk, though this trial did not measure heart attacks or strokes.

Were there more side effects when omega-3 fatty acids were added?

No. In this 8-week trial, the incidence of adverse events did not differ between the group taking omega-3 fatty acids plus atorvastatin and the group taking atorvastatin alone. Researchers monitored laboratory parameters, electrocardiograms, vital signs, and physical examinations. This is consistent with the known safety profile of omega-3 fatty acids when added to statins.

Did adding omega-3 fatty acids interfere with the statin's cholesterol-lowering effect?

No. LDL cholesterol changes did not differ significantly between groups (about –1.9% with the combination versus +6.5% with atorvastatin alone). This was expected and reassuring: adding omega-3 fatty acids did not reduce atorvastatin's cholesterol-lowering benefit, while other lipid measures such as non-HDL cholesterol improved.

What are the limitations of this trial that patients should know?

The trial lasted only 8 weeks and measured blood lipid levels, not heart attacks or strokes. It enrolled mainly Korean adults with high rates of diabetes and hypertension, used one specific statin dose and omega-3 formulation, and did not track long-term outcomes. Results may not apply to other groups, doses, or formulations.

My triglycerides are still high on a statin — when should I get a second opinion about adding omega-3 fish oil?

When triglycerides remain at or above 200 mg/dL despite statin therapy, that is residual hypertriglyceridemia, and a second opinion can help clarify whether adding omega-3 fatty acids at 4,000 mg daily is appropriate. In an 8-week trial, that combination lowered triglycerides by 29.8% and non-HDL-C by 10.1%, with 62.9% of patients reaching the target below 200 mg/dL and no increase in side effects. A second opinion can also review your full lipid profile, diabetes management, and medication interactions before any change. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original Article: "Efficacy and Safety of Omega-3 Fatty Acids in Patients Treated with Statins for Residual Hypertriglyceridemia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial"

Authors: Ji Eun Jun, In-Kyung Jeong, Jae Myung Yu, Sung Rae Kim, In Kye Lee, Kyung-Ah Han, Sung Hee Choi, Soo-Kyung Kim, Hyeong Kyu Park, Ji-Oh Mok, Yong-ho Lee, Hyuk-Sang Kwon, So Hun Kim, Ho-Cheol Kang, Sang Ah Lee, Chang Beom Lee, Kyung Mook Choi, Sung-Ho Her, Won Yong Shin, Mi-Seung Shin, Hyo-Suk Ahn, Seung Ho Kang, Jin-Man Cho, Sang-Ho Jo, Tae-Joon Cha, Seok Yeon Kim, Kyung Heon Won, Dong-Bin Kim, Jae Hyuk Lee, Moon-Kyu Lee

Publication: Diabetes & Metabolism Journal, 2020; Volume 44, pages 78–90. DOI: https://doi.org/10.4093/dmj.2018.0265

Trial Registration: ClinicalTrials.gov (NCT03482180)

Funding and Ethics: The study protocol was approved by the Institutional Review Board or ethics committee at each participating center. All patients provided written informed consent. The study was conducted in accordance with the ethical standards of the relevant institutional and/or national research committees and with the 1964 Helsinki Declaration and its later amendments.

This patient-friendly article is based on peer-reviewed research. The original article is an open-access publication distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.