Health

4. The Critical Importance of Dosage There is mounting evidence that higher doses of Ω-3 interventions appear more likely to demonstrate CVD and other clinical benefits. Deficiencies of many nutrients can lead to debilitating and life-threatening chronic disease, which can be corrected with repletion of the deficient nutrient. Supplementation, on the other hand, does not have as profound an effect in people who are nutrient replete. For example, administration of thiamin in wet Beri-Beri can be curative and life-saving [24], whereas supplementation in patients with normal thiamin levels would not be so dramatic. Likewise, studies such as VITAL have shown the most CVD benefit in patients with the lowest baseline levels of Ω-3 [16], who may represent the ideal population for this therapy. High-dose Ω-3 appeared to be beneficial in multiple studies, in addition to the results produced by REDUCE-IT. OMEGA-REMODEL found that 4 g/day Ω-3 (EPA + DHA) for 6 months after acute MI demonstrated a reduction in adverse left ventricular remodeling, non-infarct myocardial fibrosis and serum biomarkers of systemic inflammation beyond the current guideline-based standard of care [25]. Further, the finding that Ω-3 EPA + DHA levels >1.5 g/day are typically required for a clinically meaningful change in TG levels further explains the inconsistent results in trials using lower doses (e.g., 1 g/day) [18]. Goodfellow et al. [26]. Administered Ω-3 of EPA + DHA at 4 g/day and measured endothelial function at baseline and after 4 months of therapy, finding a significant improvement in arterial flow-mediated dilation along with significant TG reduction whereas placebo led to no change in either parameter. Heart transplant patients who received 4 g/day Ω-3 versus placebo as prophylaxis against cyclosporine-induced hypertension demonstrated a systolic blood pressure reduction of 2 +/− 4 mm Hg in the Ω-3 group versus an increase in 17 +/− 4 mm Hg in the placebo group, with a diastolic increase of 10 +/− 3 mm Hg and 21 +/− 2 mm Hg in the treatment and placebo groups, respectively, following 6 months of treatment [27]. The authors concluded that Ω-3 supplementation at 4 g/day (EPA + DHA) was effective for prophylaxis against cyclosporine induced hypertension, which occurs in a high proportion of patients following heart transplantation [28]. In summary, the populations of Japan and Italy in the JELIS and GISSI-P trials, respectively, who demonstrated significant CVD benefits with lower-dose (1–2 g/day) Ω-3 EPA + DHA may have demonstrated such due to a “threshold level” which reaches the therapeutic window of Ω-3. This can explain why higher doses (e.g., 4 g/day) may be required to demonstrate CV benefit, particularly in studies of American populations with lower baseline Ω-3 levels. Figure 3 demonstrates a hypothetical Ω-3 threshold effect with supplement doses of 1 g/day and 4 g/day of EPA + DHA. While GISSI-P originally showed CVD protective effects with an Ω-3 formulation of EPA + DHA, REDUCE-IT and JELIS showed quite dramatic effects using EPA alone. However, a recent large meta-analysis found no statistical difference between the total EPA or combined EPA + DHA dosage on the effects on MACE [21].