Wednesday, August 01, 2018

Is Fish Oil worthless? Thoughts on Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease

By Cliff Harvey PhD (c)

A recent Cochrane Database review by Abdelhamid et al, (1) has received a lot of media and mainstream attention.
This review included 79 randomised controlled trials (RCTs)—29 with a low risk of bias according to the researchers—and most of the studies focussed on trials including omega-3 supplements (as compared to omega-3 intake from foods) either fish oil (containing the long-chain omega-3 fats DHA and EPA), or vegetable derived alpha-linolenic acid.
The researchers concluded that “Moderate- and high-quality evidence suggests that increasing EPA and DHA has little or no effect on mortality or cardiovascular health”.

Not surprisingly, this has led many in the media and mainstream to conclude that fish oil supplementation is ‘worthless’. However, it must be remembered that this review was strictly in relation to cardiovascular disease. Therefore, the utility of fish oil for the quality of life outcomes or the adjunctive treatment or prevention of other illnesses has not been addressed by this latest study. There might also be nuances within this review that should be further addressed. Overall, because it is the most recent review (at the time of writing), and with the general agreement that Cochrane reviews are the ‘gold standard’ for reviews, perhaps it is timely to re-evaluate the role of fish oil in the prevention of cardiovascular events and mortality. It should be noted though that differing methodologies and biases (often implicit) of researchers can yield differing results, especially with respect to inclusion and exclusion criteria used, and interpretation of significance should also be approached with some caution.

Overall, the review showed no effect on all-cause mortality (RR 0.98, 95% CI 0.93 to 1.03) from fish oil supplementation. However, consistent with the existing reviews, it did show a significant effect improving important cardiometabolic health markers such as triglycerides ( (Mean Difference (MD) −0.24 mmol/L, 95% CI −0.31 to −0.16, I2 = 48%) and high-density lipoprotein cholesterol (HDL-c) (MD 0.02 mmol/L, 95% CI 0.00 to 0.04, P = 0.03, I2 = 48%).

Figure 1. Funnel plot of comparison: 1 High vs low LCn3 omega-3 fats (primary outcomes), outcome: 1.1 All-cause mortality (overall) – LCn3. Abdelhamid AS, Brown TJ, Brainard JS, Biswas P, Thorpe GC, Moore HJ, et al.

There are many well-designed trials which show a range of other benefits from fish oil supplementation and to review these would be beyond the scope of the present article (a search of the academic literature shows around 220,000 results from a search for “fish oil supplementation”).
There are also many systematic reviews which show benefit from randomised trials, for health conditions and markers of cardiometabolic health. In fact, the study by Abdelhamid and colleagues contrasts with earlier reviews that suggested benefits for cardiovascular health and mortality by Wang et al, (2) (and which also showed significant effects on all-cause mortality) and by Leon et al, (3) which showed a significant reduction in deaths from cardiac causes but no significant effect on all-cause mortality.
A trend towards improved mortality outcomes in the critically ill has also been shown ( relative risk [RR], 0.71; 95% confidence interval [CI], 0.49–1.04), (4) along with reduced infectious complications  in patients receiving fish oil (relative risk 0.49, 95% confidence interval 0.26–0.93, P = 0.03). (5) Significant reductions in infection in the critically ill have also been shown in a review of intravenous fish oil formulas. (6)
A 2000 review on the effects of fish oil in diabetes showed a clinically meaningful and statistically significant improvement on triglyceride (TG) levels (-0.56 mmol/l [95% CI -0.71 to -0.41]) over a mean time-frame of 12-weeks, from fish oil supplementation. (7) Reductions in TG (− 0.34 mmol/L, [95% CI: − 0.41 to − 0.27]), have also been demonstrated in a review by  Eslick and colleagues. (8) In a review of 13 RCTs Compared with the control group, serum TG and total cholesterol levels in the fish oil group were reduced by 0.23 mmol/L (95% CI, −0.31 to −0.14, p <0.01) and 0.12 mmol/L (95% CI, −0.23 to −0.01, p =0.03), respectively. HDL-c levels were increased by 0.20 mmol/L (95% CI, 0.01 to 0.40, p <0.01). (9) These are significant findings as, out of all the commonly measured markers for cardiovascular risk, triglycerides have the strongest association with cardiovascular disease. (10-12) Reductions in relative risk for both cardiovascular disease and all-cause mortality are seen at < 1.02 mmol/L TG,(12) and so, reductions of ~ 0.5 mmol/L are highly clinically significant.

There is also a significant effect of fish oil supplementation on blood pressure in hypertensive patients (> 140/85), of 2.56 mmHg and 1.47 mmHg (systolic and diastolic pressure respectively). (13) This is a similar reduction as observed for drastic reductions in sodium, which, while often recommended, can have deleterious effects for other causes of mortality, especially in those with pre-existing heart disease, in which mortality can actually be worsened with sodium reduction. (14) Thus, fish oil might be a safer approach to reducing blood pressure than the current recommendation to reduce salt intake.
Reviews also suggest a significant, positive role for fish oil supplementation at doses > 1000 mg for improved heart rate variability (15) (a marker of lifestyle or fatigue induced systemic stress) and improved cardiac function and reduced markers of inflammation in heart failure patients. (16, 17)
Although a meta-analysis of 17 studies with 672 participants showed no overall effect on insulin sensitivity, it did show a highly significant improvement in insulin sensitivity in those suffering at least one symptom of metabolic disorder (Standard Mean Difference [SMD] 0.53, 95% CI 0.17 to 0.88, p < 0.001). (18) There is a rising incidence of metabolic disorder and insulin resistance, with high rates of undiagnosed metabolic disorder, and supplementation with fish oil, based on these results, is prudent.
Fish oil was found to reduce the risk of relapse in Crohn’s Disease (RR 0.77; 95% CI 0.61 to 0.98). Although there is some debate as to whether this is a clinically meaningful result, I posit that it is actually quite a strong effect, notwithstanding that there needs to be more homogeneous research of a higher quality overall for the use of fish oil in CD. (19)
Maternal or childhood fish oil use might also reduce the risk of asthma (RR 0.71; 95% CI 0.52 to 0.96). (20) While the maternal use of fish oil supplements improves birth weight and reduces the risk of early preterm delivery. (21)
In haemodialysis patients, there was a reduction in cardiovascular events (RR 0.41; 95% CI 0.26-0.66) in the fish oil group vs placebo. Fish oil also significantly decreased the Beck Depression Inventory (BDI) score (weighted mean difference [WMD] −11.91; 95% CI −15.88 to −7.95), and the important inflammatory marker, C-reactive protein (CRP), and triglycerides (TG) [(SMD) (95 %CI)] were −0.56 (−0.89 to −0.23); −0.36 (−0.63 to −0.09), and −0.41 (−0.68 to −0.14), respectively]. (22)

The latest review by Abdelhamid and colleagues’ casts doubt upon the earlier studies and reviews showing improved cardiac and all-cause mortality in association with increased fish oil intake. However, there may still be a small effect trend towards improved outcomes and there is a significant effect demonstrated on markers of cardiometabolic health, in particular, TG and HDL-c. Other reviews show, in contrast to the latest Cochrane review, improved mortality outcomes associated with fish oil supplementation, and similar improvements in TG and HDL-c. So, overall, we might consider there to be a positive effect on cardiometabolic health.
Improvements in mood, blood lipids in diabetes, reductions in blood pressure, improvements in insulin sensitivity in metabolic disorder, possible benefits for Crohn’s Disease, other inflammatory disorders, and improved pregnancy outcomes, along with discernible improvements in various outcomes for the critically unwell, all suggest a multitude of benefits for health overall from fish oil supplementation. Effect sizes for any given outcome may be small, but when taken together, benefits from fish oil could, in fact, be very strong.

Conflict of interest
Cliff Harvey has provided consultancy services to Melrose Health, a manufacturer of food products, some of which contain fish oil.

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