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Original Research
Evaluation of the Effects of Neptune Krill Oil
on the Clinical Course of Hyperlipidemia
Roxandra Bunea M.D.1, Khassan El Farrah M.D., M.Sc.2,
Luisa Deutsch M.D., M.Sc.2
Assistant Professor, Department of Internal Medicine, McGill University; Riverview Medical Center, Montreal, Quebec, Canada. JSS Medical Research, Montreal, Quebec, Canada.

Altern Med Rev 2004;9(4):420-428
Krill Oil Original Research
Evaluation of the Effects of
Neptune Krill Oil on the Clinical Course
of Hyperlipidemia
Ruxandra Bunea, MD; Khassan El Farrah, MD, MSc;
Luisa Deutsch, MD
Abstract
results of the present study demonstrate within
OBJECTIVE: To assess the effects of krill oil
high levels of confidence that krill oil is effective
on blood lipids, specifically total cholesterol,
for the management of hyperlipidemia by
triglycerides, low-density lipoprotein (LDL), and
significantly reducing total cholesterol, LDL,
high-density lipoprotein (HDL). METHODS: A
and triglycerides, and increasing HDL levels.
multi-center, three-month, prospective,
At lower and equal doses, krill oil was
randomized study followed by a three-month,
significantly more effective than fish oil for the
controlled follow-up of patients treated with 1
reduction of glucose, triglycerides, and LDL
g and 1.5 g krill oil daily. Patients with
hyperlipidemia able to maintain a healthy diet
(Altern Med Rev 2004;9(4):420-428)
and with blood cholesterol levels between 194
and 348 mg/dL were eligible for enrollment in
Introduction
the trial. A sample size of 120 patients (30
patients/group) was randomly assigned to one
fatty acids (PUFAs) in the body is critical for the of four groups. Group A received krill oil at a
maintenance of healthy cell membranes and hor- body mass index (BMI)-dependent daily
mone regulation. During the last few decades the dosage of 2-3 g daily. Patients in Group B were
fatty acid content of the U.S. diet has shifted so it given 1-1.5 g krill oil daily, and Group C was
now contains much higher levels of omega-6 and given fish oil containing 180 mg
less omega-3 fatty acids. When long-chain omega- eicosapentaenoic acid (EPA) and 120 mg
6 fatty acids predominate in the phospholipids of docosahexaenoic acid (DHA) per gram of oil
cell membranes, the production of pro-inflamma- at a dose of 3 g daily. Group D was given a
tory type-2 prostaglandins (PGs) and type-4 placebo containing microcrystalline cellulose.
leukotrienes (LTs) are encouraged; whereas, the The krill oil used in this study was Neptune Krill
presence of omega-3 fatty acids promotes the pro- Oil (NKO‚), provided by Neptune Technologies
duction of anti-inflammatory PGs and LTs.1,2 & Bioresources, Laval, Quebec, Canada.
OUTCOME MEASURES: Primary parameters
tested (baseline and 90-day visit) were total
blood cholesterol, triglycerides, LDL, HDL, and
Ruxandra Bunea, MD – Assistant Professor, Department ofInternal Medicine, McGill University; Riverview Medical glucose. RESULTS: Krill oil 1-3 g/day (BMI-
dependent) was found to be effective for the
Correspondence address: 1586 Ave des Pins O. #302,Montreal, Quebec, Canada H3G 1B4.
reduction of glucose, total cholesterol,
triglycerides, LDL, and HDL, compared to both
Khassan El Farrah, MD, MSc – JSS Medical Research,Montreal, Quebec, Canada.
fish oil and placebo. CONCLUSIONS: The
Luisa Deutsch, MD – JSS Medical Research, Montreal,Quebec, Canada.
Page 420 Alternative Medicine Review ◆ Volume 9, Number 4 ◆ 2004
Copyright2004 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Original Research Krill Oil
omega-3 fatty acids highly facilitates the passage acid, have been shown to initiate an inflamma- of fatty acid molecules through the intestinal wall, tory process by triggering a flux of inflammatory increasing bioavailability and ultimately improv- PGs and LTs.3,4 Omega-3 fatty acids, mainly ing the omega-3:omega-6 fatty acid ratio.18,19 eicosapentaenoic acid (EPA) and docosahexaenoicacid (DHA), compete with the omega-6 species Materials and Methods
for the enzyme prostaglandin synthetase. Omega- 3 fatty acids trigger secretion of less potent 5-se- trial was conducted comparing krill oil to high EPA ries LTs and anti-inflammatory PGs of the 3 se- and DHA (3:2 ratio) fish oil and placebo. Eligible ries (PE , PI and thromboxanes-A ).4-9 Conse- patients were 18-85 years and had at least a six- quently, supplementation with EPA and DHA pro- month diagnosis of mildly high to very high blood motes the production of less potent PGs and LTs, cholesterol (193.9-347.9 mg/dL) and triglyceride resulting in a decrease in the formation of inflam- levels (203.8-354.4 mg/dL). Patients with famil- ial hypercholesterolemia, severely high cholesterol (>349 mg/dL), pregnancy, known or suspected omega-3 fatty acids favorably modify cardiovas- allergy to fish or seafood, known alcohol or drug cular disease and associated disorders is not yet fully confirmed. Evidence suggests an increased coagulopathy or receiving anticoagulant therapy, intake of EPA and DHA results in an increase of or co-morbidity that would interfere with study EPA and DHA in tissue, cellular lipids, and circu- results were excluded from the study.
latory lipids.14 In parallel, they result in a simulta-neous reduction of omega-6 fatty acids in the body.14 This fatty acid shift is predominantly marked in cell membrane-bound phospholipids ▲ Group A: Krill oil (2-3 g once daily) and results in alteration of the physicochemical Body Mass Index (BMI) < 30 – 2 g/day properties of cell membranes. This favorably modifies cellular functions, including cell signal-ing, gene expression, biosynthetic processes, and ▲ Group B: Krill oil (1-1.5 g once daily) of EPA and DHA to significantly reduce circulat- ing levels of blood triglyceride and very low-den-sity lipoprotein (VLDL), which have been asso- ▲ Group C: Fish oil (3:2) containing 180 mg ciated with increased risk of cardiovascular dis- Krill oil is extracted from Antarctic krill, Euphausia superba, a zooplankton crustacean rich in phospholipids carrying long-chain omega-3PUFAs, mainly EPA and DHA. Krill oil also con- tains various potent antioxidants, including vita- lowering medications at the usual daily dose and mins A and E, astaxanthin, and a novel flavonoid asked to report any change in dosage. Natural similar to 6,8-di-c-glucosylluteolin, but with two health products were discontinued for a two-week or more glucose molecules and one aglycone.
washout period prior to study initiation and there- after for the study duration. Patients were asked file of phospholipids naturally rich in omega-3 to record concomitant medications taken daily.
fatty acids and diverse antioxidants significantlydifferent from the usual profile of fish oils. Theassociation between phospholipids and long-chain Alternative Medicine Review ◆ Volume 9, Number 4 ◆ 2004 Page 421
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Table 1. Results of Krill Oil (1.0 g/day) on Lipids
Statistical
Rationale
and Analysis
1.0 g Krill Oil
Time (d)/mg/dL
Total Cholesterol
Triglycerides
group differencesr e f l e c t i n gchanges over time Table 2. Results of Krill Oil (1.5 g/day) on Lipids
for the same pa-tient were as-sessed for statisti- 1.5 g Krill Oil
Time (d)/mg/dL
Total Cholesterol
Triglycerides
dred-twenty patients with a mean age of 51 years blood glucose, cholesterol, triglycerides, low-den- (standard deviation 9.46) and ranging between 25 sity lipoprotein (LDL), and high-density lipopro- and 75 years were enrolled in the trial. BMI, a tein (HDL). Fasting blood lipids and glucose were tool indicating weight status in adults, was calcu- analyzed at baseline as well as 30 and 90 days lated according to the metric formula ([weight in after study initiation for all groups, and at 180 days kilograms/(height in centimeters) x (height in cen- timeters)] x 10,000).20,21 Of the 120 patients en-rolled, 30 (25%) had moderate-to-severe obesity,with a BMI higher than 30. Sixty-four (53%) sub-jects were overweight, and 26 (22%) were nor-mal weight, with a BMI between 25 and 30 andlower than 25, respectively. Women had a higher Page 422 Alternative Medicine Review ◆ Volume 9, Number 4 ◆ 2004
Copyright2004 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Original Research Krill Oil
Table 3. Results of Krill Oil (2.0 g/day) on Lipids
(28.2±5.1) com-pared to men(25.4±3.9) (p<0.001).
2 g Krill Oil
Time (d)/mg/dL
Total Cholesterol
Triglycerides
11 received 3 gdaily. In Group B,23 patients weretreated with adaily dose of 1 gkrill oil and 7 with Table 4. Results of Krill Oil (3.0 g/day) on Lipids
1.5 g. All patientsin Group B con-tinued for an addi- 3 g Krill Oil
Time (d)/mg/dL
nance dose of 500mg krill oil daily.
Total Cholesterol
Triglycerides
lyceride levels,comorbidity, andc o n c o m i t a n tmedication at baseline showed no significant dif- baseline of 247 mg/dL and 251 mg/dL to 203 mg/ ferences among the four groups (p=0.102-0.850).
dL (p=0.000) and 206 mg/dL (p=0.000), corre- After 12 weeks of treatment, patients re- spondingly (Tables 3 and 4). In comparison, people ceiving 1 or 1.5 g krill oil daily had a 13.4-per- receiving 3 g fish oil had a mean reduction in to- cent and 13.7-percent decrease in mean total cho- tal cholesterol of 5.9 percent, from a baseline 231 lesterol, from 236 mg/dL and 231 mg/dL to 204 mg/dL to 218 mg/dL (p=0.000) (Table 5). Those mg/dL (p=0.000) and 199 mg/dL (p=0.000), re- enrolled in the placebo group showed a 9.1-per- spectively (Tables 1 and 2). The group of patients cent increase in mean total cholesterol, from 222 treated with 2 or 3 g krill oil showed a significant mg/dL to 242 mg/dL (p=0.000) (Table 6).
respective reduction in mean total cholesterol of18.1 and 18 percent. Levels were reduced from a Alternative Medicine Review ◆ Volume 9, Number 4 ◆ 2004 Page 423
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Table 5. Results of Fish Oil (3.0 g/day) on Lipids
blood levels de-creased from 122mg/dL at baseline 3 g Fish Oil
Time (d)/mg/dL
Total Cholesterol
Triglycerides
significantly in-creased in all pa-tients receiving Table 6. Results of Placebo on Lipids
krill oil (p=0.000)or fish oil(p=0.002). HDL Time (d)/mg/dL
Total Cholesterol
Triglycerides
mg/dL (55% in-crease) at krill oil2 g/day; and from64.2 mg/dL to 102.5 mg/dL (59% increase) at a daily krill oil observed in all groups. Krill oil at a daily dose of dose of 3 g. Fish oil taken at 3 g/day increased 1 g, 1.5 g, 2 g, or 3 g achieved significant reduc- HDL from 56.6 mg/dL to 59.03 mg/dL (4.2% in- tions of LDL of 32, 36, 37, and 39 percent, re- crease). No significant decrease of HDL (p=0.850) spectively (p=0.000). Baseline levels were de- was observed within the placebo group, with lev- creased in the krill oil 1-g/day group from 168 els of HDL remaining almost stable, 56.8 mg/dL mg/dL to 114 mg/dL, in the 1.5-g/day group from 165 mg/dL to 106 mg/dL, and in the 2- and 3-g/ day groups from 183 mg/dL and 173 mg/dL to triglycerides by a non-significant 11 percent, from 114 mg/dL and 105 mg/dL, respectively. The labo- 120.5 mg/dL to 107.2 mg/dL (p=0.114). A daily ratory results of patients treated daily with 3 g fish dose of 1.5 g krill oil resulted in a non-significant oil did not achieve a significant reduction in LDL Page 424 Alternative Medicine Review ◆ Volume 9, Number 4 ◆ 2004
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Table 7. Effect of a Lower Maintenance Dose of Krill Oil on Lipids
reduction oft r i g l y c e r i d e s ,from 122.7 mg/dL 0.5 g Krill Oil
Time (d)/mg/dL
Total Cholesterol
Triglycerides
percent (p=0.0228)– decreasing frombaseline levels of160.4 mg/dL and 0.5 g krill oil daily (Table 7). These patients main- 152.8 mg/dL to 116.1 mg/dL and 112.3 mg/dL, tained a mean total cholesterol level of 192.5 mg/ respectively. Fish oil at 3 g/day did not achieve a dL, a reduction of 19 percent (p=0.000) from significant reduction of triglycerides (3.2%), baseline. LDL was further reduced from baseline decreasing from 140.9 mg/dL to 136.4 mg/dL by 44 percent, a reduction from 233 mg/dL to (p=0.239). Interestingly patients in the placebo 107.5 mg/dL (p=0.000). A moderate decrease in group experienced a 9.8-percent decrease in HDL was seen, from 36 percent increase at 90 days to 33 percent after 180 days of treatment, which was still a significant increase from baseline percent, from 105 mg/dL to 98 mg/dL (p=0.025), (p=0.000). Triglycerides were slightly decreased in patients receiving 1 g and 1.5 g krill oil daily, further to a reduction of 25 percent from baseline and 5.6 percent, from 92 mg/dL to 88 mg/dL (p=0.000), compared to the 12-percent reduction (p=0.011), in those receiving 2 g and 3 g krill oil observed after 90 days of treatment. Blood glu- daily. A daily dose of 3 g fish oil reduced blood cose decreased by 6.6 percent from baseline glucose by 3.3 percent, from 90 mg/dL to 87 mg/ (p=0.20), versus the 6.3-percent decrease at 90 dL (p=0.275). Placebo treatment resulted in a non- significant blood glucose increase of 0.1 percent,from 92 mg/dL to 93 mg/dL (p=0.750).
Discussion
Arteriosclerosis is the generic term for a 1 g and 1.5 g krill oil daily was significantly more number of diseases in which arterial walls become effective than 3 g fish oil in reducing glucose and thickened and lose elasticity, with atherosclerosis LDL, whereas 2 g and 3 g krill oil demonstrated a being considered the most important. With its ef- significantly greater reduction of glucose, triglyc- fects on the brain, heart, kidneys, and other vital erides, and LDL compared to 3 g fish oil. Both organs and extremities, and despite medical ad- fish oil and krill oil performed significantly better vancements, atherosclerotic heart disease and than placebo for the regulation of glucose, trig- stroke combined remain the number one cause of lycerides, total cholesterol, and HDL.
morbidity and mortality in the United States, As mentioned previously, patients receiv- ing 1 g and 1.5 g daily krill oil continued for an-other 12 weeks with a lower maintenance dose of Alternative Medicine Review ◆ Volume 9, Number 4 ◆ 2004 Page 425
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In the United States, cardiovascular dis- ease has a mortality rate of 39.9 percent for males multiple active ingredients with synergistic bio- and 43.7 percent for females, a 15-21 percent dif- activity. The exact mechanism of action for krill ference from malignant disease, which ranks sec- oil’s lipid-lowering effects is not yet entirely clear.
ond.22 It is estimated that 59.7 million Americans However, krill oil’s unique biomolecular profile have one or more forms of cardiovascular dis- of omega-3 (EPA/DHA) fatty acids already incor- ease.22 Of the population with self-reported heart porated into phospholipids has exhibited a lipid- disease, 56-64 percent report restricted activity, lowering effect on the level of the small intestine, 23-37 percent require one or more disability days which distinguishes krill oil from other known per week, and 28-34 percent are unemployed be- lipid-lowering principals.18,19 Werner et al demon- cause of disability or illness.22 The primary lesion strated essential fatty acids in the form of phos- of atherosclerosis is the fatty streak, which even- pholipids were superior to essential fatty acids as tually evolves into a fibrous plaque. Numerous triglycerides in significantly decreasing the satu- randomized trials have proven that lowering se- rated fatty acid ratios of liver triglycerides and rum cholesterol slows or reverses progression of phospholipids (each p < 0.05), while significantly coronary artery disease (CAD) and reduces coro- increasing the phospholipid concentrations of the LDL oxidation is believed to increase ath- 3-9 g fish oil is currently recommended to reduce erosclerosis through high serum LDL levels in- the risk of cardiovascular diseases.22,23 Neverthe- ducing LDL particles to migrate into subendothe- less, epidemiological studies evaluating the effects lial space. The process by which LDL particles of fish oil on coronary heart disease are contra- are oxidized begins with lipid peroxidation, fol- dictory, ranging from reverse associations to vir- lowed by fragmentation to short-chain aldehydes.
tually no effect to a beneficial effect.30-33 One is- At the same time, lecithin is converted to lyso- sue in the efficacy of EPA/DHA may be the lecithin, a selective chemotactic agent for mono- bioavailability of these fatty acids.
cytes, which become macrophages that ingest oxi- A recent study demonstrated in vivo PUFA dized LDL. The new macrophage becomes en- bioavailability depends on several factors, such gorged with oxidized LDL cholesteryl esters and as the type of lipids in which they are esterified, becomes a foam cell. Groups of foam cells form a their physical state; i.e., lipid solution or colloidal fatty streak, the earliest indication of atheroscle- particle systems, and the presence of co-ingested lipids.18 In vivo PUFA absorption was evaluated The unique molecular composition of krill by fatty acid analysis of thoracic lymph of duct- oil, with its abundance of phospholipids and anti- cannulated rats after intragastric feeding of dietary oxidants, may explain the significant effect of krill fats.19 Evidence demonstrates oral essential fatty oil for blood lipid regulation. In comparison to acid supplementation in the form of phospholip- fish oil, krill oil significantly lowered blood lip- ids is more effective than triglycerides in increas- ing concentrations of long-chain PUFAs in liver and brain.18,19 DHA is better absorbed when de- disease is tempered by the presence of methyl- livered by liposomes than by fish oil (relative lym- mercury in many fish.33 In fact, the U.S. Food and phatic absorption equal to 91 percent and 65 per- Drug Administration has advised pregnant women cent after liposome and fish oil administration, and women who may become pregnant not to eat respectively). The best bioavailability of DHA swordfish, king mackerel, tilefish, shark, or fish delivered by liposomes is revealed by an increase from locally contaminated areas.36 Therefore, it may be prudent to obtain these essential fatty ac- triacylglycerols and phospholipids, compared to ids via supplementation. Krill oil, and most fish oil concentrates, are molecularly distilled to re-move heavy metals.
Page 426 Alternative Medicine Review ◆ Volume 9, Number 4 ◆ 2004
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Conclusion
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