ACST: Does Krill Oil Lower Triglycerides? CaPre’s Chances of Phase III Success.

Read the article disclaimer first.

Published: 12/7/2018. Last Updated: 12/14/2018 for clarity.

Author: Artem Cheprasov

SUMMARY

  • Acasti Pharma’s (ACST) CaPre, a krill oil designed to lower triglycerides, is undergoing phase III testing.
  • There is no solid evidence that proves krill oil lowers triglycerides in people with normal or high serum triglycerides.
  • Nonetheless, ACST’s TRILOGY trials face a good chance of success due to a beneficial study design.

BACKGROUND WISDOM

Acasti Pharma (ticker: ACST) is the company behind CaPre, a krill-oil-based medication undergoing phase III testing. If these trials prove to be successful, CaPre will be prescribed to people with elevated serum triglycerides.

In this report, we’ll start off with an independent look at the available evidence surrounding krill oil’s effects on triglycerides.

Then we’ll put the review of the independent literature into the context of ACST’s phase III TRILOGY trials; and what it all means for their chances of success.

A REVIEW OF THE LITERATURE ON KRILL OIL’S EFFECTS ON SERUM TRIGLYCERIDES

Details of the review can be expanded below for those interested.

A search of ClinicalTrials.gov and PubMed was conducted for relevant published data.

PubMed Search Terms

(krill OR euphausiacea OR euphausia OR superba) AND (hyperlipidemia OR hyperlipidemic OR hypolipidemic OR hypolipidemia OR dyslipidemia OR dyslipidemic OR lipid OR lipids OR triglyceride OR triglycerides OR triglyceridemia OR hypertriglyceridemia OR TG OR triacylglycerol OR TAG OR triacylglyceride OR triacylglycerols OR triacylglycerides)

Search Dates

Inception – November 24th, 2018.

Results

The above resulted in 250 items; which were manually examined for relevance. Any studies that provided data on changes in triglycerides in response to krill oil were included; even if the primary endpoint of the study was otherwise. Studies that only examined compounds that contained a mix of krill oil and another substance were excluded.

.

The published literature was categorized as follows with respect to the relevance to this article’s discussion:

Category I Evidence

These studies met the following criteria:

1. They were double-masked RCTs of ≥ 4 weeks duration that tested the effects of krill oil on people with normal AND/OR higher-than-normal serum triglycerides.

2. They presented results in a manner that allowed us to differentiate the effects of krill oil on people with normal vs. higher-than-normal serum triglycerides (≥ 150+ mg/dL or ≥ 1.8 mmol/L).

Category I Review Table

Category II Evidence

These were studies that met the following criteria:

1. They were double-masked RCTs of ≥ 4 weeks duration that tested the effects of krill oil on a mix of people with normal and higher serum triglycerides

2. It wasn’t possible to differentiate the effects of krill oil on participants with normal vs. higher levels of serum triglycerides.

Category III Evidence

These were clinical trials with designs that provided lower-strength evidence on the effects of krill oil on serum triglycerides. The designs of these studies met at least one of the following criteria: a lack of a control, no randomization, an open label design, single-masked, single-dose, or of < 4 weeks duration.

As many study authors and expert commentators have noted, the results of acute duration studies are less relevant for chronic conditions or situations where patients are expected to take a medication chronically. Lest someone doubts the importance of this, the discussion on the Berge 2014 study further below will prove the point conclusively.

As a result, category III evidence is disregarded in this article (the majority of which, in any case, claims krill oil doesn’t lower triglycerides).

Category IV Evidence

Observational/retrospective, in-vitro, and animal studies.

The conclusions of many of which are often ultimately irrelevant or completely misleading with respect to practical human medicine. As a result, category IV evidence is disregarded in this article.

DOES KRILL OIL LOWER TRIGLYCERIDES IN HEALTHY PEOPLE?

Apparently not.

In all six relevant category I and II studies, krill oil failed to lower serum triglycerides in a statistically significant manner.

Where data permits this is said with respect to all of the following: changes within a krill oil group compared to baseline and/or changes between krill oil and comparator.

DOES KRILL OIL LOWER TRIGLYCERIDES IN PEOPLE WITH HIGH TRIGLYCERIDES?

On the surface of things, it appears that the answer is yes, it does.

The best-designed study on the point revealed that krill oil temporarily lowered the levels of triglycerides in people with borderline high or high levels of triglycerides in a statistically significant manner; after 6 weeks of treatment and only as compared to within-group baseline levels (Berge 2014).

However, this effect completely disappeared after 12 weeks of treatment for all four treatment arms. Interestingly, higher doses of krill oil were sometimes less effective than lower doses in this study.

Furthermore, there was no statistically significant difference in the change in triglycerides between any krill oil group and placebo at either 6 or 12 weeks.

It was only when the data from all krill oil groups was pooled in a time and dose-independent fashion—for a purely exploratory, post-hoc, analysis—did the authors note that krill oil reduced triglycerides in a statistically significant manner over placebo.

The only two other, category I, studies available concluded that krill oil lowered triglycerides in people with borderline high or high levels of triglycerides after 4 or 12+ weeks of treatment.

Nonetheless, both of these studies have important unanswered questions or missing data.

In a crossover study, participants were encouraged to eat a high seafood diet; in contrast to many category I-II studies that ask subjects to minimize the intake of seafood to a minimum or none.

The study found that krill oil lowered triglycerides in a statistically significant manner as compared to baseline. But this reasonably raises the question of whether the seafood or the krill oil ultimately had more of the desired impact on the hypertriglyceridemia (Cicero 2016).

In the other study, it’s impossible to tell how well-masked the participants were to krill oil, active comparator, and placebo control; what their diets consisted of; the amount of EPA/DHA participants received in the krill oil vs. fish oil arms; and the numerical spread of critical parameters (Bunea 2004).

Consequently, higher-quality studies are needed in order to prove that krill oil lowers triglycerides in people with borderline high, high, or very high serum triglycerides.

IS KRILL OIL MORE EFFECTIVE THAN FISH OIL AT LOWERING TRIGLYCERIDES?

The evidence is inconclusive.

All of the relevant category II studies showed that neither was better than the other in any statistically significant manner.

A category I crossover study showed that esterified omega 3 PUFAs are more effective at lowering triglycerides than krill oil. The former is like Lovaza, a prescription fish oil medication designed to lower triglycerides. Nevertheless, this is the study confounded by a high-seafood diet and the fact that the fish oil arm received a far higher dose of EPA + DHA (Cicero 2016).

The only other category I study with a fish oil arm indicated the opposite: that krill oil might be more effective than fish oil at lowering triglycerides. However, this study doesn’t reveal the amount of EPA/DHA in the krill oil arm vs. the fish oil arm; making a legitimate comparison between fish oil and krill oil impossible (Bunea 2004).

Therefore, it’s hard to be sure if CaPre will be more or less effective than its prescription, fish-oil-derived, competitors.

A SYSTEMATIC REVIEW & META-ANALYSIS “PROVES” KRILL OIL LOWERS TRIGLYCERIDES

A systematic review and meta-analysis (SR/MA) concluded that krill oil lowers serum triglycerides in a statistically significant manner (Ursoniu 2017).

This would seem to somewhat negate our in-depth literature review and discussion above.

However, as it pertains to this entire article, this SR/MA’s conclusions have to be taken with a few words of reasonable caution:

1. According to the MA’s criteria, the results from articles with non-randomized designs should’ve been excluded from its analysis. However, the MA actually included the results from a non-randomized phase of a crossover trial. A phase that, unlike prior phases of the trial, was no longer double-blind.

2. The MA includes lower-quality category III studies and a concurrent paradoxical assessment of the risks of bias. Either of which should qualify the MA’s results.

E.G. The very-well masked Berge 2014 study and two—de facto—open-label studies are equally given a “Low” risk of bias with respect to blinding. This doesn’t appear to be in line with the Cochrane framework for systematic reviews the authors claimed to have used. Especially when its instructions are placed in light of expert commentary on the importance of blinding within krill oil studies.

3. Since the MA’s conclusion is based on a mix of category I-III evidence, we can’t delineate krill oil’s effects on patients with normal vs. high triglycerides.

4. The MA doesn’t include three category I and II studies published after the authors’ search for evidence concluded in March 2016.

This includes one trial that showed krill oil lowered triglycerides in a statistically significant manner over baseline (the trial confounded by the seafood diet); and two trials that showed no such benefit.

In sum: this systematic review and meta-analysis provided, at best, low-strength evidence with respect to the true effect of krill oil on high serum triglycerides.

WHY CAPRE’S TRILOGY TRIALS HAVE A GOOD CHANCE OF SUCCESS

Despite the fact that there is a paucity of solid evidence to back up krill oil’s beneficial effects on triglycerides on its own, CaPre’s Phase III TRILOGY trials actually stand a good chance of success.

CaPre provides 310 mg of EPA + DHA per gram.

When EPA/DHA is taken under certain scenarios, it’s more likely to exert a stronger triglyceride-lowering effect. Luckily, ACST’s TRILOGY trials include these favorable conditions:

1. The inclusion of participants solely with very high baseline triglycerides; a feature no category I or II study had.

• Some evidence suggests that the higher the person’s baseline triglycerides, the more effective EPA + DHA generally prove to be over placebo.

2. The encouragement of a healthy diet, high in seafood.

• Unlike many category I and II trials, there is no indication Acasti Pharma tried to restrict a person’s intake of healthy seafood, which may work in favor of the TRILOGY trials. Again, compared to placebo, the treatment arm will thus take in an even higher amount of beneficial EPA/DHA.

3. Study volunteers are allowed to take lipid lowering medications; statins in this case.

• When EPA/DHA is taken in concert with statins, there may very well be a synergistic effect on triglycerides over placebo or statins alone.

4. In Acasti’s phase III trials, the daily dose of EPA + DHA from krill oil is far higher than any other available krill oil research.

• There’s a noted dose-dependent effect of omega-3 fatty acids on serum triglycerides. So it’s one thing to test krill oil in general, it’s completely different when testing pharmacological doses thereof as with fish oil prescription meds.

Given the available historical data surrounding everything we’ve gone over so far, a simple probability model can be constructed to try and “predict” the chances of ACST’s phase III success.

The probability distribution of this model is shown below. The 90% highest posterior density interval (HPDI) has a range of approximately 0.4-0.8.

CaPre Phase III Probabilty Distribution

In other words, given this model’s limitations, it appears quite unlikely that the chances of success are anything less than 40% nor are they likely to be higher than 80% and are most likely closer to about 62% (relatively speaking).

SOME POTENTIAL RED FLAGS

These favorable circumstances need to be put into the context of Acasti’s own evidence that should give everyone some pause about being overly convinced that CaPre will be a definitive success.

For instance, it appears that the highest dose found in the phase II (and thus ongoing phase III) trials is less effective than the lower doses when given to patients using statins.

Keeping different phase II study designs in mind, this nonetheless seems really strange given our prior discussion on omega-3s, their dose-dependent effects, and their synergism with statins. Perhaps, as ACST put it, the odd results might have to do with a low sample size.

However, the general notion that higher doses of krill oil might be less effective than lower doses isn’t new and is supported by an excellent category I study.

So another take on these paradoxical effects is that they’re not some sort of random accident but rather confirmations of one another about an unexplained difference between how krill oil and fish oil act on serum triglycerides.

What do you think? Comment below!

This article’s author did not receive, nor was promised, any form of compensation for researching, writing, or publishing this article. While researching for, writing, and publishing this article: the author did not own any shares of any security mentioned herein or any competitor’s security. Prior to and during publication: the author had no other financial or scientific stake in any seafood-related supplement.

The following were used as sources of information for this report:

1. Acasti Pharma’s Phase I-II Presentations

2. Barter P, Ginsberg HN. Effectiveness of combined statin plus omega-3 fatty acid therapy for mixed dyslipidemia. Am J Cardiol. 2008;102(8):1040-5.

3. Berge K, Musa-veloso K, Harwood M, Hoem N, Burri L. Krill oil supplementation lowers serum triglycerides without increasing low-density lipoprotein cholesterol in adults with borderline high or high triglyceride levels. Nutr Res. 2014;34(2):126-33.

4. Berge K, Piscitelli F, Hoem N, et al. Chronic treatment with krill powder reduces plasma triglyceride and anandamide levels in mildly obese men. Lipids Health Dis. 2013;12:78.

5. Berge RK, Ramsvik MS, Bohov P, et al. Krill oil reduces plasma triacylglycerol level and improves related lipoprotein particle concentration, fatty acid composition and redox status in healthy young adults – a pilot study. Lipids Health Dis. 2015;14:163.

6. Bunea R, El farrah K, Deutsch L. Evaluation of the effects of Neptune Krill Oil on the clinical course of hyperlipidemia. Altern Med Rev. 2004;9(4):420-8.

7. Cicero AF, Rosticci M, Morbini M, et al. Lipid-lowering and anti-inflammatory effects of omega 3 ethyl esters and krill oil: a randomized, cross-over, clinical trial. Arch Med Sci. 2016;12(3):507-12.

8. Da boit M, Mastalurova I, Brazaite G, Mcgovern N, Thompson K, Gray SR. The Effect of Krill Oil Supplementation on Exercise Performance and Markers of Immune Function. PLoS ONE. 2015;10(9):e0139174.

9. Derosa G, Maffioli P. Nutraceuticals for the treatment of metabolic diseases: evidence from clinical practice. Expert Rev Endocrinol Metab. 2015;10(3):297-304.

10. Epanova NDA Documentation

11. Ito MK. A Comparative Overview of Prescription Omega-3 Fatty Acid Products. P T. 2015;40(12):826-57.

12. Köhler A, Sarkkinen E, Tapola N, Niskanen T, Bruheim I. Bioavailability of fatty acids from krill oil, krill meal and fish oil in healthy subjects–a randomized, single-dose, cross-over trial. Lipids Health Dis. 2015;14:19.

13. Konagai C, Yanagimoto K, Hayamizu K, Han L, Tsuji T, Koga Y. Effects of krill oil containing n-3 polyunsaturated fatty acids in phospholipid form on human brain function: a randomized controlled trial in healthy elderly volunteers. Clin Interv Aging. 2013;8:1247-57.

14. Kwantes JM, Grundmann O. A brief review of krill oil history, research, and the commercial market. J Diet Suppl. 2015;12(1):23-35.

15. Laidlaw M, Cockerline CA, Rowe WJ. A randomized clinical trial to determine the efficacy of manufacturers’ recommended doses of omega-3 fatty acids from different sources in facilitating cardiovascular disease risk reduction. Lipids Health Dis. 2014;13:99.

16. Lobraico JM, Dilello LC, Butler AD, Cordisco ME, Petrini JR, Ahmadi R. Effects of krill oil on endothelial function and other cardiovascular risk factors in participants with type 2 diabetes, a randomized controlled trial. BMJ Open Diabetes Res Care. 2015;3(1):e000107.

17. Lovaza NDA Documentation

18. Maki KC, Reeves MS, Farmer M, et al. Krill oil supplementation increases plasma concentrations of eicosapentaenoic and docosahexaenoic acids in overweight and obese men and women. Nutr Res. 2009;29(9):609-15.

19. Omtryg NDA Documentation

20. Ramprasath VR, Eyal I, Zchut S, Jones PJ. Enhanced increase of omega-3 index in healthy individuals with response to 4-week n-3 fatty acid supplementation from krill oil versus fish oil. Lipids Health Dis. 2013;12:178.

21. Ramprasath VR, Eyal I, Zchut S, Shafat I, Jones PJ. Supplementation of krill oil with high phospholipid content increases sum of EPA and DHA in erythrocytes compared with low phospholipid krill oil. Lipids Health Dis. 2015;14:142.

22. Rundblad A, Holven KB, Bruheim I, Myhrstad MC, Ulven SM. Effects of krill oil and lean and fatty fish on cardiovascular risk markers: a randomised controlled trial. J Nutr Sci. 2018;7:e3.

23. Salem N, Kuratko CN. A reexamination of krill oil bioavailability studies. Lipids Health Dis. 2014;13:137.

24. Sung HH, Sinclair AJ, Lewandowski PA, Su XQ. Postprandial long-chain n-3 polyunsaturated fatty acid response to krill oil and fish oil consumption in healthy women: a randomised controlled, single-dose, crossover study. Asia Pac J Clin Nutr. 2018;27(1):148-157.

25. Suzuki Y, Fukushima M, Sakuraba K, Sawaki K, Sekigawa K. Krill Oil Improves Mild Knee Joint Pain: A Randomized Control Trial. PLoS ONE. 2016;11(10):e0162769.

26. Trepanowski JF, Kabir MM, Alleman RJ, Bloomer RJ. A 21-day Daniel fast with or without krill oil supplementation improves anthropometric parameters and the cardiometabolic profile in men and women. Nutr Metab (Lond). 2012;9(1):82.

27. Ulven SM, Holven KB. Comparison of bioavailability of krill oil versus fish oil and health effect. Vasc Health Risk Manag. 2015;11:511-24.

28. Ulven SM, Kirkhus B, Lamglait A, et al. Metabolic effects of krill oil are essentially similar to those of fish oil but at lower dose of EPA and DHA, in healthy volunteers. Lipids. 2011;46(1):37-46.

29. Ursoniu S, Sahebkar A, Serban MC, et al. Lipid-modifying effects of krill oil in humans: systematic review and meta-analysis of randomized controlled trials. Nutr Rev. 2017;75(5):361-373.

30. Van der wurff IS, Von schacky C, Berge K, Kirschner PA, De groot RH. A protocol for a randomised controlled trial investigating the effect of increasing Omega-3 index with krill oil supplementation on learning, cognition, behaviour and visual processing in typically developing adolescents. BMJ Open. 2016;6(7):e011790.

31. Vascepa NDA Documentation

32. Weintraub H. Update on marine omega-3 fatty acids: management of dyslipidemia and current omega-3 treatment options. Atherosclerosis. 2013;230(2):381-9.

33. Yurko-mauro K, Kralovec J, Bailey-hall E, Smeberg V, Stark JG, Salem N. Similar eicosapentaenoic acid and docosahexaenoic acid plasma levels achieved with fish oil or krill oil in a randomized double-blind four-week bioavailability study. Lipids Health Dis. 2015;14:99.

34. Zhang R, Zhang Z, Zhang H, Decker EA, Mcclements DJ. Influence of lipid type on gastrointestinal fate of oil-in-water emulsions: In vitro digestion study. Food Res Int. 2015;75:71-78.

This article’s comment section is intended for the generation of (counter)-arguments based on reasoning or evidence, helpful reminders, or novel thoughts. Questions based on any of the aforementioned are encouraged. Sources are always appreciated.

Please understand that in order to sustain a more substantive, intelligent, and insightful discourse for all: comments containing foul language or ad hominem-like attacks against any entity will not be admitted.

2018-12-14T11:40:33+00:00

Leave A Comment