LDL cholesterol-raising effect of low-dose docosahexaenoic acid in middle-aged men and women.

Double-blind, randomized, placebo-controlled crossover trial in healthy middle-aged men and women aged 40 to 65 years in the United Kingdom. Data from 38 participants were analyzed for the DHA treatment period; the analyzed cohort included 19 men and 19 women.

Oral docosahexaenoic acid (DHA) 0.7 g/day as triacylglycerol was given as 3 capsules per day for 3 months per treatment period. Each capsule contained 500 mg refined triacylglycerol-derived DHA from Crypthecodinium cohnii; placebo capsules contained refined olive oil and matched antioxidants.

Low-dose DHA increased LDL cholesterol and total cholesterol rather than lowering blood lipids. Compared with placebo, DHA raised LDL cholesterol by 0.23 mmol/L (95% CI 0.08, 0.38; P=0.004), total cholesterol by 0.22 mmol/L (95% CI 0.01, 0.42; P=0.04), apolipoprotein B by 0.03 (95% CI 0.002, 0.055; P=0.03), and LDL:apo B by 0.12 (95% CI 0.004, 0.24; P=0.04). The authors concluded that about 0.7 g/day DHA increases LDL cholesterol by roughly 7% in middle-aged men and women, possibly through down-regulation of hepatic LDL receptor expression. HDL cholesterol showed a treatment-order effect, and the first treatment phase showed a significant DHA effect on HDL, but this did not change the main finding of LDL elevation.

Small sample size and short 3-month treatment periods limit precision and longer-term inference. The crossover design showed a treatment-order effect for HDL, and the population was restricted to healthy middle-aged adults, which limits generalizability. Outcomes were surrogate lipid markers rather than clinical cardiovascular events.